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Archive for August, 2013

Patients with mental illness face high mortality risk in drug trials – Healio

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Patients with mental illness face high mortality risk in drug trials Healio Khan and colleagues also found that short- and medium-term exposure to psychotropic agents, including atypical antipsychotic agents, selective serotonin reuptake inhibitors…

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Expert Perspective: Remote Ischemic Preconditioning for CABG …

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See on Scoop.it – Cardiovascular and vascular imaging

Clinical benefits were not evident at 30 days, but rIPC was associated with significantly lower rates of MI and all-cause mortality at 1 year. The rIPC group’s hazard ratio for 1-year all-cause mortality, compared with the …

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A small molecule may reduce damage in age-related heart attacks – University at Buffalo Reporter

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See on Scoop.it – Cardiovascular and vascular imaging

University at Buffalo Reporter A small molecule may reduce damage in age-related heart attacks University at Buffalo Reporter A small molecule developed at Yale University to limit damage done by ischemia – restricted blood flow – during heart…

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Study finds DNA in blood could help detect heart disease – Murfreesboro Post

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See on Scoop.it – Cardiovascular and vascular imaging

Study finds DNA in blood could help detect heart disease Murfreesboro Post DALLAS — DNA fragments in blood may someday help doctors quickly learn if a patient having chest pain could be suffering from narrowed heart arteries, according a new study…

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Following (or not) the guidelines for use of imaging in management of prostate cancer

Posted in Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Imaging-based Cancer Patient Management, Medical Device Therapies for Altzheimer’s Disease, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged guidlines, health, Imaging-based Cancer Patient Management, management of prostate cancer, Medical imaging, medicine, Personalized medicine, Prostate cancer, prostate cancer imaging, prostate cancer patients on August 29, 2013| 1 Comment »

Following (or not) the guidelines for use of imaging in management of prostate cancer.

Writer and curator: Dror Nir, PhD

Over diagnosis and over treatment is a trend of the last two decades. It leads to increase in health-care costs and human-misery.

The following headline on Medscape; Swedes Show That We Can Improve Imaging in Prostate Cancer elicited my curiosity.

I was expecting “good news” – well, not this time!

In spite the “general language” the study that the above mentioned headline refers to is not addressing the global use of imaging in prostate cancer patients’ pathway but is specific to use of radionuclide bone-scans as part of patients’ staging. The “bad-news” are that realization that the Swedish government had to invest many man-years to achieve “success” in reducing unnecessary use of such imaging in low risk patients. Moreover, the paper reveals under-use of such imaging technology for staging high risk prostate cancer patients.

Based on this paper, one could come to the conclusion that in reality, we are facing long lasting non-conformity with established guidelines related to the use of “full-body” imaging as part of the prostate cancer patients’ pathway in Europe and USA.

Here is a link to the original paper:

Prostate Cancer Imaging Trends After a Nationwide Effort to Discourage Inappropriate Prostate Cancer Imaging, Danil V. Makarov, Stacy Loeb, David Ulmert, Linda Drevin, Mats Lambe and Pär Stattin Correspondence to: Pär Stattin, MD, PhD, Department of Surgery and Perioperative Sciences, Urology and Andrology, Umeå University, SE- 901 87 Umeå, Sweden (e-mail:par.stattin@urologi.umu.se).

JNCI J Natl Cancer Inst (2013)doi: 10.1093/jnci/djt175

For convenience, here are the highlights:

Reducing inappropriate use of imaging to stage incident prostate cancer is a challenging problem highlighted recently as a Physician Quality Reporting System quality measure and by the American Society of Clinical Oncology and the American Urological Association in the Choosing Wisely campaign.

Since 2000, the National Prostate Cancer Register (NPCR) of Sweden has led an effort to decrease national rates of inappropriate prostate cancer imaging by disseminating utilization data along with the latest imaging guidelines to urologists in Sweden.

Results Thirty-six percent of men underwent imaging within 6 months of prostate cancer diagnosis. Overall, imaging use decreased over time, particularly in the low-risk category, among whom the imaging rate decreased from 45% to 3% (P < .001), but also in the high-risk category, among whom the rate decreased from 63% to 47% (P < .001). Despite substantial regional variation, all regions experienced clinically and statistically (P < .001) significant decreases in prostate cancer imaging.

These results may inform current efforts to promote guideline-concordant imaging in the United States and internationally.

In 1998, the baseline low-risk prostate cancer imaging rate in Sweden was 45%. Per the NCCN guidelines (7), none of these men should have received bone imaging unless they presented with symptoms suggestive of bone pain (8,24). In the United States, the imaging rate among men with low-risk prostate cancer has been reported to be 19% to 74% in a community cohort and 10% to 48% in a Surveillance Epidemiology and End Results (SEER)–Medicare cohort (10–13,16). It is challenging to compare these rates directly across the two countries because the NPCR aggregates all staging imaging into one variable. However, our sampling revealed that 88% of those undergoing imaging had at least a bone scan, whereas only 11% had any CTs and 10% had any MRI. This suggests that baseline rates of bone scan among low-risk men in Sweden were similar to those among their low-risk counterparts in the United States, whereas rates of axial imaging were likely much lower. During the study period, rates of prostate cancer imaging among low-risk men in Sweden decreased to 3%, substantially lower than those reported in the United States at any time.

Miller et al. describe a decline in imaging associated with a small-scale intervention administered in three urology practices located in the United States participating in a quality-improvement consortium. Our study’s contribution is to demonstrate that a similar strategy can be applied effectively at a national scale with an associated decline in inappropriate imaging rates, a finding of great interest for policy makers in the United States seeking to improve health-care quality.

In 1998, the baseline high-risk prostate cancer imaging rates in Sweden were 63%, and decreased by 43% in 2008 (rising slightly to 47% in 2009). Based on our risk category definitions and the guidelines advocated in Sweden, all of these men should have undergone an imaging evaluation (8,24). Swedish rates of prostate cancer imaging among men with high-risk disease are considerably lower than those reported from the SEER–Medicare cohort, where 70% to 75% underwent bone scan and 57% to 58% underwent CT (13,16). These already low rates of imaging among men with high-risk prostate cancer only decreased further during the NPCR’s effort to promote guideline-concordant imaging. Clearly in both countries, imaging for high-risk prostate cancer remains underused despite the general overuse of imaging and numerous guidelines encouraging its appropriate use (3–9).

Similar items I have covered on this this Open Access Online Scientific Journal:

Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA.

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Cardiac Contractility & Myocardium Performance: Therapeutic Implications for Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Posted in Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Origins of Cardiovascular Disease, Proteomics, tagged ATPase, Aviva Lev-Ari, Calcium, Cardiac dysrhythmia, Cardiac muscle, gene therapy, Heart Failure, Ischemia, Justin Pearlman, Larry H. Bernstein, Ryanodine Receptor, Stephen Williams, Vascular smooth muscle on August 28, 2013| 3 Comments »

Cardiac Contractility & Myocardial Performance: Therapeutic Implications of Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC

Author and Curator: Larry H Bernstein, MD, FCAP

and Article Curator: Aviva Lev-Ari, PhD, RN

Article VII Cardiac Contractility & Myocardium Performance Ventricular Arrhythmias and Non-ischemic Heart Failure

Image created by Adina Hazan 06/30/2021

Voice of Justin Pearlman, MD, PhD, FACC

Catechols refer to the stress hormones that control our response to fright, flight and fight, e.g., epinephrine, also known as adrenaline. Sudden elevation of catechols increases heart rate and also the strength of heart contraction (contractility). In the short term, that provides a boost that supports special demands to run faster, work harder. Like the healthcare system, it is not sustainable in high gear. Excess catechol push causes heart failure (catechol toxicity). Race horses routinely develop pulmonary edema by the end of a race – those pretreated for that with the diuretic LASIX have an L next to their entry in the race ticket. The same issues occur as a whole-body system and at the subcellular level. Catechols increase amount and speed of the release of calcium which in turn triggers heart muscle contraction. However, the failing heart has elevated levels of calcium that impair oxygen utilization. The following discussions address the linkages between catechols and calcium traffic, including both the catechol and calcium stimulation of speed and strength, and their detrimental effects over time.

This article is Part VII in a continuation to the following article series on tightly related topics of the Calcium Release Mechanism.

The Series consists of the following articles:

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD  and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/02/renal-distal-tubular-ca2-exchange-mechanism-in-health-and-disease/

Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differences/

Part V: Ca2+-Stimulated Exocytosis: The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocytosis/

Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/

Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/16/calcium-channel-blocker-calcium-as-neurotransmitter-sensor-and-calcium-release-related-contractile-dysfunction-ryanopathy/

Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/11/01/sensors-and-signaling-in-oxidative-stress/

Part XII: Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/21/genetic-polymorphisms-of-ion-channels-have-a-role-in-the-pathogenesis-of-coronary-microvascular-dysfunction-and-ischemic-heart-disease/

and

Advanced Topics in Sepsis and the Cardiovascular System at its End Stage

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-sepsis-and-the-cardiovascular-system-at-its-end-stage/

For most comprehensive Bibliography on the Ryanodine receptor calcium release channel complex and for FIGURES illustrating the phenomenon, see

Pharmacol Ther. 2009 August; 123(2): 151–177.

doi: 10.1016/j.pharmthera.2009.03.006

PMCID: PMC2704947

Ryanodine receptor-mediated arrhythmias and sudden cardiac death

Lynda M. Blayney and F. Anthony Lai

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704947/

This article has the following sections:

Introduction to Calcium Release Mechanism in Vascular Smooth Muscle and in Cardiomyocytes

Author: Justin D Pearlman, MD, PhD, FACC PENDING

I. Cellular Contractility Capacity — Actin, Cellular Dynamics and Calcium Efflux: Emergence of the Calcium Release-related Contractile Dysfunction

Author: Justin D Pearlman, MD, PhD, FACC

II. Integration and Interpretation of Research Results in Two Labs: Mark E Anderson’s and Roger Hajjar’s Lab

Author: Justin D Pearlman, MD, PhD, FACC PENDING

Mark Anderson’s Laboratory at the University of Iowa Carver College of Medicine recently summarized the critical roles of calcium in heart failure and arrhythmia in an article in Circulation Research. That laboratory elucidated critical facts, such as the controlling role of phosphorylation of ryanodine receptors among other details of the control and impact of Ca²⁺ homeostatic and structural proteins, ion channels, and enzymes. Their review focuses on the molecular mechanisms of defective Ca²⁺ cycling in heart failure and knowledge of those pathways may translate into new innovative therapies. The highly conserved Ca2+/calmodulin-dependent protein kinase II (CaMKII)plays an essential role in cardiac myocytes. Electrichemical activation of the cariac contraction cycle triggers a transient increase in the intracellular Ca2+ concentration ([Ca2+]i) which activates CaMKII activated through the binding of Ca2+-bound calmodulin (CaM). The activated CaMKII molecules phosphorylate many intracellular target proteins, including the sarcolemmal L-type Ca2+ channel, the ryanodine receptor, and the Ca2+ pump on the sarcoplasmic reticulum. Intersubunit autophosphorylation (positive feedback) promotes accumulation of the active CaMKII. Phosphorylated CaMKII maintains its catalytic activity until it is inactivated by constitutive phosphatase activity.

Roger J. Hajjar MD is the Director of the Cardiovascular Research Center, a cutting-edge translational research laboratory at Mt Sinai Medical Center. He is the Arthur & Janet C. Ross Professor of Medicine, Professor of Gene & Cell Medicine, Director of the Cardiology Fellowship Program, and Co-Director of the Transatlantic Cardiovascular Research Center, which combines Mount Sinai Cardiology Laboratories with those of the Universite de Paris – Madame Curie. He earned a bachelors of science degree in Biomedical Engineering at Johns Hopkins University and a medical degree from Harvard Medical School and the Harvard-MIT Division of Health Sciences and Technology. He completed his fellowship in cardiology at Massachusetts General Hospital in Boston, then became a staff cardiologist in the Heart Failure & Cardiac Transplantation Center, followed by Director of the Cardiovascular Laboratory of Integrative Physiology and Imaging, before moving to Mt. Sinai.

Roger J. Hajjar, MD and his team of investigators translate scientific findings into therapies for cardiovascular diseases. Dr. Hajjar’s team pioneered a potential gene therapy for heart failure, AAV1.SERCA2a, which can revive malfunctioning myocardium. His laboratory has completed Phase 1 and Phase 2 First-in-Man clinical trials of SERCA2a gene transfer in patients with advanced heart failure, and Phase 3 validation began in 2011. His laboratory also studies how to block signaling pathways in cardiac hypertrophy, aging, apoptosis, and diastolic failure.

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Anderson Publications (2006-2013)

2013
•He BJ, Anderson ME. Aldosterone and Cardiovascular Disease: the heart of the matter. Trends in Endocrinology & Metabolism 24(1):21-30, 2013. [PMID: 23040074]
•Luo M, Anderson ME, Mechanisms of altered Ca2+ handling in heart failure. Circ Res 113(6):690-708. 2013 [PMID: 23989713]
•Anderson ME. Why has it taken so long to learn what we still don’t know? Circ Res 113(7):840-2. 2013 [PMID: 24030016]
•Thomas C, Anderson ME. In memoriam: John B. Stokes, MD. Semin Nephrol. 33(3):207-8, 2013. [PMID: 23953797]
•Gyorke S, Ho HT, Anderson ME, et al. Ryanodine receptor phosphorylation by oxidized CaMKII contributes to the cardiotoxic effects of cardiac glycosides. Cardiovas Res [PMID: Accepted for publication]
•Kline J, Anderson ME, et al, βIV-spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells. Proc Natl Acad Sci. [PMID: Accepted for publication]
•Maier LS, Sag C, Anderson ME, Ionizing Radiation Regulates Cardiac Ca handling via increased ROS and activated CaMKII. Bas Res in Card [PMID: Accepted for publication]
•Chen B, Guo A, Zhang C, Chen R, Zhu Y, Hong J, Kutschke W, Zimmerman K, Weiss RM, Zingman L, Anderson ME, Wehrens XH, Song LS. Critical roles of Junctophilin-2 T-tubule and excitation-contraction coupling maturation during postnatal development. Cardiovas Res 2013 Oct 1; 100(1):54-62. [PMID: 23860812] [PMC3778961]
•Purohit A, Rokita AG, Xiaoqun G, Biyi C, Koval OM, Voigt N, Neef S, Sowa T, Gao Z, Luczak E, Stefansdottir H, Behunin AC, Li N, El-Accaoui RN, Yang B, Swaminathan PD, Weiss RM, Wehrens XH, Song LS, Dobrev D, Maier LS, Anderson ME. Oxidized CaMKII Triggers Atrial Fibrillation. Circulation 2013 Sep 12 [Epub ahead of print] [PMID: 24030498]
•Yoshida-Moriguchi T, Willer T, Anderson ME, Venzke D, Whyte T, Muntoni F, Lee H, Nelson SF, Yu L, Campbell, KP. SGK196 is a glycosylation-specific O-mannose kinase required for dystroglycan function. Science 2013 Aug 23; 341(6148): 896-9. [PMID:23929950]
•Scott JA, Klutho PJ, El Accaoui R, Nguyen E, Venema AN, Xie L, Jiang S, Dibbern M, Scroggins S, Prasad AM, Luczak ED, Davis MK, Li W, Guan X, Backs J, Schlueter AJ, Weiss RM, Miller FJ, Anderson ME, Grumbach IM. The Multifunctional Ca2+/Calmodulin-Dependent Kinase IIδ (CaMKIIδ) Regulates Arteriogenesis in a Mouse Model of Flow-Mediated Remodeling. PLoS One 2013 Aug 8; 8(8):e71550. [PMID: 23951185] [PMC3738514]
•Scholten A, Preisinger C, Corradini E, Bourgonje VJ, Hennrick ML, van Veen TA, Swaminathan PD, Joiner ML, Vos MA, Anderson ME, Heck AJ. A Phosphoproteomics Study Based on In Vivo Inhibition Reveals Sites of Calmodulin Dependent Protein Kinase II Regulation in the Heart. J Am Heart Assoc 2013 Aug 7; 2(4):e000318. [PMID: 23926118]
•Prasad AM, Nuno DW, Koval OM, Ketsawatsomkron P, Li W, Li H, Shen Y, Joiner ML, Kutschke W, Weiss RM, Sigmund CD, Anderson ME, Lamping KG, Grumbach IM. Differential Control of Calcium Homeostatis and Vascular Reactivity by Ca2+/Calmodulin-Dependent Kinase II. Hypertension 2013 Aug; 62(2):434-41.[PMID:23753415]
•Sanders PN, Koval OM, Jaffer OA, Prasad AM, Businga TR, Scott JA, Hayden PJ, Luczak ED, Dickey DD, Allamargot C, Olivier AK, Meyerholz DK, Robison AJ, Winder DG, Blackwell TS, Dworski R, Sammut D, Wagner BA, Buettner GR, Pope MR, Miller FJ, Dibbern ME, Haitchi HM, Mohler PJ, Howarth PH, Zabner J, Kline JN, Grumbach IM, Anderson ME. CaMKII is Essential for the Proasthmatic Effects of Oxidation. Sci Trans Med 2013 Jul 24; 5(195):195 ra97. [PMID: 23884469] Chosen as a “From the Cover” article in STM and with a commentary in JAMA. 310(9):894. doi: 10.1001/jama.2013.277035
•Wolf RM, Glynn P, Hashemi S, Zarei K, Mitchell CC, Anderson ME, Mohler PJ, Hund TJ. Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: A computational analysis. Am J Physiol Heart and Circ Physiol 2013 May; 304(9):H1253-66. [PMID: 23436330] [PMC3652094]
•Ather S, Wang W, Wang Q, Li N, Anderson ME, Wehrens XH. Inhibition of CaMKII Phosphorylation of RyR2 Prevents Inducible Ventricular Arrhythmias in Mice with Duchenne Muscular Dystrophy. Heart Rhythm 2013 Apr; (10)4:592-9 [PMID: 23246599] [PMC3605194]
•Yang J, Maity B, Huang J, Gao Z, Stewart A, Weiss RM, Anderson ME, Fisher RA. G- protein inactivator RGS6 mediates myocardial cell apoptosis and cardiomyopathy caused by doxorubicin. Cancer Res 2013 Mar 15; 73(6): 1662-7. [PMID: 23338613] [PMC3602152]
•Luo M, Guan X, Luczak ED, Di L, Kutschke W, Gao Z, Yang J, Glynn P , Sossalla S, Swaminathan PD, Weiss RM, Yang B, Rokita AG,5, Maier LS, Efimov I, Hund TJ, Anderson ME. Diabetes increases mortality after myocardial infarction by oxidizing CaMKII. J Clin Invest 2013 Mar 1; 123(3):1262-74. [PMID: 23426181] [ PMC3673230]
•Sierra A, Zhu Z, Sapay N, Sharotri V, Kline CF, Luczak ED, Subbotina E, Sivaprasadarao A, Snyder PM, Mohler PJ, Anderson ME, Vivaudou M, Zingman LV, Hodgson-Zingman DM. Regulation of cardiac ATP-sensitive potassium channel surface expression by calcium/calmodulin-dependent protein kinase II. J Biol Chem 2013 Jan 18; 288(3):1568-81. [PMID: 23223335] [PMC3548467]
•Gao Z, Rasmussen TP, Li Y , Kutschke W , Koval OM, Wu Y, Wu Y, Hall DD, Joiner ML, Wu XQ, Swaminathan PD, Purohit A, Zimmerman KA, Weiss RM, Philipson K , Song LS, Hund TJ, Anderson ME. Genetic inhibition of Na+-Ca2+ exchanger current disables fight or flight sinoatrial node activity without affecting resting heart rate. Circ Res 2013 Jan 18;112(2):309-17. [PMID: 23192947][Epub: e157-e179] [PMC3562595]
•Degrande ST, Little S, Nixon DJ, Wright P, Snyder J, Dun W, Murphy N, Kilic A, Higgins R, Binkley PF, Boyden PA, Carnes CA, Anderson ME, Hund TJ, Mohler PJ. Molecular mechanisms underlying cardiac protein phosphatase 2A regulation in heart. J Biol Chem 2013 Jan 11; 288(2):1032-46. [PMID: 23204520] [PMC3542989]
•He BJ, Anderson ME. Aldosterone and Cardiovascular Disease: the heart of the matter. Trends in Endocrinology & Metabolism 24(1):21-30, 2013. [PMID: 23040074]
• Luo M, Anderson ME, Mechanisms of altered Ca2+ handling in heart failure. Circ Res 113(6):690-708. 2013 [PMID: 23989713]
•Anderson ME. Why has it taken so long to learn what we still don’t know? Circ Res 113(7):840-2. 2013 [PMID: 24030016]
• Thomas C, Anderson ME. In memoriam: John B. Stokes, MD. Semin Nephrol. 33(3):207-8, 2013. [PMID: 23953797]

2012
•Wang Y and Anderson ME. Chapter 22: Intracellular Signaling Pathways in Cardiac Remodeling. Muscle: Fundamental Biology and Mechanisms of Disease. J. Hill and E. Olson (Eds), Elsevier, pp 299-308, 2012.
• Ather S, Wang W, Wang Q, Li N, Anderson ME, Wehrens XH. Inhibition of CaMKII Phosphorylation of RyR2 Prevents Inducible Ventricular Arrhythmiasin Mice with Duchenne Muscular Dystrophy. Heart Rhythm. 2012 Dec 11. doi:pii: S1547-5271(12)01450-6. 10.1016/j.hrthm.2012.12.016. PubMed PMID: 23246599.
• Sierra A, Zhu Z, Sapay N, Sharotri V, Kline CF, Luczak ED, Subbotina E, Sivaprasadarao A, Snyder PM, Mohler PJ, Anderson ME, Vivaudou M, Zingman LV, Hodgson-Zingman DM. Regulation of cardiac ATP-sensitive potassium channel surface expression by calcium/calmodulin-dependent protein kinase II. J Biol Chem. 2012 Dec 6. [Epub ahead of print] PubMed PMID: 23223335.
• Degrande S, Nixon D, Koval O, Curran JW, Wright P, Wang Q, Kashef F, Chiang D, Li N, Wehrens XH, Anderson ME, Hund TJ, Mohler PJ. CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome. Heart Rhythm. 2012 Dec;9(12):2034-41. doi: 10.1016/j.hrthm.2012.08.026. Epub 2012 Aug 28. PubMed PMID: 23059182.
• Degrande ST, Little S, Nixon DJ, Wright P, Snyder J, Dun W, Murphy N, Kilic A, Higgins R, Binkley PF, Boyden PA, Carnes CA, Anderson ME, Hund TJ, Mohler PJ. Molecular mechanisms underlying cardiac protein phosphatase 2A regulation in heart. J Biol Chem. 2012 Nov 30. [Epub ahead of print] PubMed PMID: 23204520.
• Gao Z, Rasmussen TP, Li Y, Kutschke W, Koval OM, Wu Y, Wu Y, Hall DD, Joiner ML, Wu X, Dominic Swaminathan P, Purohit A, Zimmerman KA, Weiss RM, Philipson K, Song LS, Hund TJ, Anderson ME. Genetic Inhibition of Na+-Ca2+ Exchanger Current Disables Fight or Flight Sinoatrial Node Activity Without Affecting Resting Heart Rate. Circ Res. 2012 Nov 27. PubMed PMID: 23192947
• Joiner ML, Koval OM, Li J, He BJ, Allamargot C, Gao Z, Luczak ED, Hall DD, Fink BD, Chen B, Yang J, Moore SA, Scholz TD, Strack S, Mohler PJ, Sivitz WI, Song LS, Anderson ME. CaMKII determines mitochondrial stress responses in heart. Nature. 2012 Nov 8;491(7423):269-73. doi: 10.1038/nature11444. Epub 2012 Oct 10. PubMed PMID: 23051746; PubMed Central PMCID: PMC3471377.
• Rokita AG, Anderson ME. New therapeutic targets in cardiology: arrhythmias and Ca2+/calmodulin-dependent kinase II (CaMKII). Circulation. 2012 Oct 23;126(17):2125-39. doi: 10.1161/CIRCULATIONAHA.112.124990. Review. PubMed PMID: 23091085; PubMed Central PMCID: PMC3532717.
• Koval OM, Snyder JS, Wolf RM, Pavlovicz RE, Glynn P, Curran J, Leymaster ND, Dun W, Wright PJ, Cardona N, Qian L, Mitchell CC, Boyden PA, Binkley PF, Li C, Anderson ME, Mohler PJ, Hund TJ. Ca2+/calmodulin-dependent protein kinase II-based regulation of voltage-gated Na+ channel in cardiac disease. Circulation. 2012 Oct 23;126(17):2084-94. doi: 10.1161/CIRCULATIONAHA.112.105320. Epub 2012Sep 24. PubMed PMID: 23008441.
• Wagner S, Rokita AG, Anderson ME, Maier LS. Redox Regulation of Sodium and Calcium Handling. Antioxid Redox Signal. 2012 Oct 3. [Epub ahead of print] PubMed PMID: 22900788.
• Wu Y, Luczak ED, Lee EJ, Hidalgo C, Yang J, Gao Z, Li J, Wehrens XH, Granzier H, Anderson ME. CaMKII effects on inotropic but not lusitropic force frequency responses require phospholamban. J Mol Cell Cardiol. 2012 Sep;53(3):429-36. doi: 10.1016/j.yjmcc.2012.06.019. Epub 2012 Jul 11. PubMed PMID: 22796260.
• Majumdar S, Anderson ME, Xu CR, Yakovleva TV, Gu LC, Malefyt TR, Siahaan TJ. Methotrexate (MTX)-cIBR conjugate for targeting MTX to leukocytes: conjugate stability and in vivo efficacy in suppressing rheumatoid arthritis. J Pharm Sci. 2012 Sep;101(9):3275-91. doi: 10.1002/jps.23164. Epub 2012 Apr 26. PubMed PMID: 22539217.
• Kashef F, Li J, Wright P, Snyder J, Suliman F, Kilic A, Higgins RS, Anderson ME, Binkley PF, Hund TJ, Mohler PJ. Ankyrin-B protein in heart failure: identification of a new component of metazoan cardioprotection. J Biol Chem. 2012 Aug 31;287(36):30268-81. doi: 10.1074/jbc.M112.368415. Epub 2012 Jul 9. PubMed PMID: 22778271; PubMed Central PMCID: PMC3436279.
• Chen B, Guo A, Gao Z, Wei S, Xie YP, Chen SR, Anderson ME, Song LS. In situ confocal imaging in intact heart reveals stress-induced Ca(2+) release variability in a murine catecholaminergic polymorphic ventricular tachycardia model of type 2 ryanodine receptor(R4496C+/-) mutation. Circ Arrhythm Electrophysiol. 2012 Aug 1;5(4):841-9. doi: 10.1161/CIRCEP.111.969733. Epub 2012 Jun 21. PubMed PMID: 22722659; PubMed Central PMCID: PMC3421047.
• Swaminathan PD, Purohit A, Hund TJ, Anderson ME. Calmodulin-dependent protein kinase II: linking heart failure and arrhythmias. Circ Res. 2012 Jun 8;110(12):1661-77. doi: 10.1161/CIRCRESAHA.111.243956. Review. PubMed PMID: 22679140.
• Chen B, Li Y, Jiang S, Xie YP, Guo A, Kutschke W, Zimmerman K, Weiss RM, Miller FJ, Anderson ME, Song LS. β-Adrenergic receptor antagonists ameliorate myocyte T-tubule remodeling following myocardial infarction. FASEB J. 2012 Jun;26(6):2531-7. doi: 10.1096/fj.11-199505. Epub 2012 Feb 28. PubMed PMID: 22375019; PubMed Central PMCID: PMC3360148.
• Scott JA, Xie L, Li H, Li W, He JB, Sanders PN, Carter AB, Backs J, Anderson ME, Grumbach IM. The multifunctional Ca2+/calmodulin-dependent kinase II regulates vascular smooth muscle migration through matrix metalloproteinase 9. Am J Physiol Heart Circ Physiol. 2012 May 15;302(10):H1953-64. doi: 10.1152/ajpheart.00978.2011. Epub 2012 Mar 16. PubMed PMID: 22427508; PubMed Central PMCID: PMC3362103.
• Gudmundsson H, Curran J, Kashef F, Snyder JS, Smith SA, Vargas-Pinto P, Bonilla IM, Weiss RM, Anderson ME, Binkley P, Felder RB, Carnes CA, Band H, Hund TJ, Mohler PJ. Differential regulation of EHD3 in human and mammalian heart failure. J Mol Cell Cardiol. 2012 May;52(5):1183-90. doi: 10.1016/j.yjmcc.2012.02.008. Epub 2012 Mar 3. PubMed PMID: 22406195; PubMed Central PMCID: PMC3360944.
• Singh MV, Swaminathan PD, Luczak ED, Kutschke W, Weiss RM, Anderson ME. MyD88 mediated inflammatory signaling leads to CaMKII oxidation, cardiac hypertrophy and death after myocardial infarction. J Mol Cell Cardiol. 2012 May;52(5):1135-44. doi: 10.1016/j.yjmcc.2012.01.021. Epub 2012 Feb 3. PubMed PMID: 22326848; PubMed Central PMCID: PMC3327770.
• Qian H, Matt L, Zhang M, Nguyen M, Patriarchi T, Koval OM, Anderson ME, He K, Lee HK, Hell JW. β2-Adrenergic receptor supports prolonged theta tetanus-induced LTP. J Neurophysiol. 2012 May;107(10):2703-12. doi: 10.1152/jn.00374.2011. Epub 2012 Feb 15. PubMed PMID: 22338020; PubMed Central PMCID: PMC3362273.

2011
• Xie YP, Chen B, Sanders P, Guo A, Li Y, Zimmerman K, Wang LC, Weiss RM, Grumbach IM, Anderson ME, Song LS. Sildenafil Prevents and Reverses Transverse-Tubule Remodeling and Ca2+ Handling Dysfunction in Right Ventricle Failure Induced by Pulmonary Artery Hypertension. Hypertension. 2011 Dec 27.[Epub ahead of print] PubMed PMID: 22203744.
•He BJ, Joiner ML, Singh MV, Luczak ED, Swaminathan PD, Koval OM, Kutschke W, Allamargot C, Yang J, Guan X, Zimmerman K, Grumbach IM, Weiss RM, Spitz DR, Sigmund CD, Blankesteijn WM, Heymans S, Mohler PJ, Anderson ME. Oxidation of CaMKII determines the cardiotoxic effects of aldosterone. Nat Med. 2011 Nov 13;17(12):1610-8. doi: 10.1038/nm.2506. PubMed PMID: 22081025.
• Zhu Z, Burnett CM, Maksymov G, Stepniak E, Sierra A, Subbotina E, Anderson ME, Coetzee WA, Hodgson-Zingman DM, Zingman LV. Reduction in number of sarcolemmal KATP channels slows cardiac action potential duration shortening under hypoxia. Biochem Biophys Res Commun. 2011 Dec 2;415(4):637-41. Epub 2011 Nov 3. PubMed PMID: 22079630; PubMed Central PMCID: PMC3230708.
•Albert CM, Chen PS, Anderson ME, Cain ME, Fishman GI, Narayan SM, Olgin JE, Spooner PM, Stevenson WG, Van Wagoner DR, Packer DL; Heart Rhythm Society Research Task Force. Full report from the first annual Heart Rhythm Society Research Forum: a vision for our research future, “dream, discover, develop, deliver”. Heart Rhythm. 2011 Dec;8(12):e1-12. Epub 2011 Nov 7. PubMed PMID: 22079558.
•Cunha SR, Hund TJ, Hashemi S, Voigt N, Li N, Wright P, Koval O, Li J, Gudmundsson H, Gumina RJ, Karck M, Schott JJ, Probst V, Le Marec H, Anderson ME, Dobrev D, Wehrens XH, Mohler PJ. Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation. Circulation. 2011 Sep 13;124(11):1212-22. Epub 2011 Aug 22. PubMed PMID: 21859974; PubMed Central PMCID: PMC3211046.
•Sag CM, Köhler AC, Anderson ME, Backs J, Maier LS. CaMKII-dependent SR Ca leak contributes to doxorubicin-induced impaired Ca handling in isolated cardiac myocytes. J Mol Cell Cardiol. 2011 Nov;51(5):749-59. Epub 2011 Jul 26. PubMed PMID: 21819992; PubMed Central PMCID: PMC3226826.
•Swaminathan PD, Purohit A, Soni S, Voigt N, Singh MV, Glukhov AV, Gao Z, He BJ, Luczak ED, Joiner ML, Kutschke W, Yang J, Donahue JK, Weiss RM, Grumbach IM, Ogawa M, Chen PS, Efimov I, Dobrev D, Mohler PJ, Hund TJ, Anderson ME. Oxidized CaMKII causes cardiac sinus node dysfunction in mice. J Clin Invest. 2011 Aug 1;121(8):3277-88. doi: 10.1172/JCI57833. Epub 2011 Jul 25. PubMed PMID: 21785215; PubMed Central PMCID: PMC3223923.
•Erickson JR, He BJ, Grumbach IM, Anderson ME. CaMKII in the cardiovascular system: sensing redox states. Physiol Rev. 2011 Jul;91(3):889-915. Review. PubMed PMID: 21742790.
•Anderson ME. Pathways for CaMKII activation in disease. Heart Rhythm. 2011 Sep;8(9):1501-3. Epub 2011 May 3. PubMed PMID: 21699838; PubMed Central PMCID: PMC3163819.
•Swaminathan PD, Anderson ME. CaMKII inhibition: breaking the cycle of electrical storm? Circulation. 2011 May 24;123(20):2183-6. Epub 2011 May 9. PubMed PMID: 21555705.
•Schulman H, Anderson ME. Ca/Calmodulin-dependent Protein Kinase II in Heart Failure. Drug Discov Today Dis Mech. 2010 Summer;7(2):e117-e122. PubMed PMID: 21503275; PubMed Central PMCID: PMC3077766.
•Zingman LV, Zhu Z, Sierra A, Stepniak E, Burnett CM, Maksymov G, Anderson ME, Coetzee WA, Hodgson-Zingman DM. Exercise-induced expression of cardiacATP-sensitive potassium channels promotes action potential shortening and energy conservation. J Mol Cell Cardiol. 2011 Jul;51(1):72-81. Epub 2011 Mar 23. PubMed PMID: 21439969; PubMed Central PMCID: PMC3103621.
•Gao Z, Singh MV, Hall DD, Koval OM, Luczak ED, Joiner ML, Chen B, Wu Y, Chaudhary AK, Martins JB, Hund TJ, Mohler PJ, Song LS, Anderson ME. Catecholamine-independent heart rate increases require Ca2+/calmodulin-dependent protein kinase II. Circ Arrhythm Electrophysiol. 2011 Jun 1;4(3):379-87. Epub 2011 Mar 15. PubMed PMID: 21406683; PubMed Central PMCID: PMC3116039.
•Singh MV, Anderson ME. Is CaMKII a link between inflammation and hypertrophy in heart? J Mol Med (Berl). 2011 Jun;89(6):537-43. Epub 2011 Jan 29. Review. PubMed PMID: 21279501.
•Anderson ME, Brown JH, Bers DM. CaMKII in myocardial hypertrophy and heart failure. J Mol Cell Cardiol. 2011 Oct;51(4):468-73. Epub 2011 Jan 27. Review. PubMed PMID: 21276796; PubMed Central PMCID: PMC3158288.
•Wagner S, Ruff HM, Weber SL, Bellmann S, Sowa T, Schulte T, Anderson ME, Grandi E, Bers DM, Backs J, Belardinelli L, Maier LS. Reactive oxygen species-activated Ca/calmodulin kinase IIδ is required for late I(Na) augmentation leading to cellular Na and Ca overload. Circ Res. 2011 Mar 4;108(5):555-65. Epub 2011 Jan 20. PubMed PMID: 21252154; PubMed Central PMCID:PMC3065330.

2010
•Hund TJ, Koval OM, Li J, Wright PJ, Qian L, Snyder JS, Gudmundsson H, Kline CF, Davidson NP, Cardona N, Rasband MN, Anderson ME, Mohler PJ. A β(IV)-spectrin/CaMKII signaling complex is essential for membrane excitability in mice. J Clin Invest. 2010 Oct 1;120(10):3508-19
•Yang J, Huang J, Maity B, Gao Z, Lõrca R, Gudmundsson H, Li J, Stewart A, Swaminathan PD, Ibeawuchi SR, Shepherd A, Chen CK, Kutschke W, Mohler PJ, Mohapatra DP, Anderson ME, Fisher RA. RGS6, a Modulator of Parasympathetic Activation in Heart. Circ Res. 2010 Sep 23. [Epub ahead of print]
•Li J, Kline CF, Hund TJ, Anderson ME, Mohler PJ. Ankyrin-B regulates Kir6.2 membrane expression and function in heart J Biol Chem. 2010 Sep 10;285(37):28723-30.
•Wei S, Guo A, Chen B, Kutschke W, Xie YP, Zimmerman K, Weiss RM, Anderson ME, Cheng H, Song LS. T-tubule remodeling during transition from hypertrophy to heart failure. Circ Res. 2010 Aug 20;107(4):520-31.
•Glukhov AV, Fedorov VV, Anderson ME, Mohler PJ, Efimov IR. Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice.Am J Physiol Heart Circ Physiol. 2010 Aug;299(2):H482-91.
•Gudmundsson H, Hund TJ, Wright PJ, Kline CF, Snyder JS, Qian L, Koval OM, Cunha SR, George M, Rainey MA, Kashef FE, Dun W, Boyden PA, Anderson ME, Band H, Mohler PJ. EH domain proteins regulate cardiac membrane protein targeting. Circ Res. 2010 Jul 9;107(1):84-95.
•Gao Z, Chen B, Joiner ML, Wu Y, Guan X, Koval OM, Chaudhary AK, Cunha SR, Mohler PJ, Martins JB, Song LS, Anderson ME .I(f) and SR Ca(2+) release both contribute to pacemaker activity in canine sinoatrial node cells. J Mol Cell Cardiol. 2010 Jul;49(1):33-40.
•Witczak CA, Jessen N, Warro DM, Toyoda T, Fujii N, Anderson ME, Hirshman MF, Goodyear LJ. CaMKII regulates contraction- but not insulin-induced glucose uptake in mouse skeletal muscle. Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1150-60.
•Koval OM, Guan X, Wu Y, Joiner ML, Gao Z, Chen B, Grumbach IM, Luczak ED, Colbran RJ, Song LS, Hund TJ, Mohler PJ, Anderson ME. CaV1.2 beta-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations. Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):4996-5000.
•Li H, Li W, Gupta AK, Mohler PJ, Anderson ME, Grumbach IM. Calmodulin kinase II is required for angiotensin II-mediated vascular smooth muscle hypertrophy. Am J Physiol Heart Circ Physiol. 2010 Feb;298(2):H688-98.

2009
• Singh, M.V., Kapoun, A., Higgins, L., Kutschke, W., Thurman, J.M., Singh, M., Yang, J., Guan, X., Lowe, J., Weiss, R.M., Zimmerman, K., Zhang, R., Yull, F.E., Blackwell, T.S., Mohler, P.J., Anderson, M.E. Ca2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart. J. Clin. Invest. 119(4):986-996, 2009. (Commentary in Nat Med 15:375, 2009)
• Wu Y, Gao Z, Chen B, Koval O, Singh M, Guan X, Hund T, Kutschke WJ, Sarma S, Grumbach I, Wehrens X, Mohler P, Song L, Anderson M.E. Calmodulin kinase II is required for fight or flight sinoatrial node physiology. Proc. Natl. Acad. Sci. 106:5972-5977, 2009. (Commentary in Sci Signaling, 2:ec130, 2009)
• Chelu M, Sarma S, Sood S, Wang S, Oort V, Jeroen R, Skapura D, Li N, Santonastasi M, Mueller F, Schotten U, Anderson ME, Valderrabano M, Dobrev D, Wehrens XHT. Calmodulin kinase II mediated sarcoplasmic reticulum calcium leak promotes atrial fibrillation. J. Clin. Invest. 119(7): 1940-1951, 2009.
• Timmins J, Ozcan L, Seimon TA, Li G, Malagelada C, Backs J, Backs T, Bassel-Duby R, Olson EN, Anderson ME, and Tabas I. Calcium/calmodulin-dependent protein kinase II links endoplasmic reticulum stress with Fas and mitochondrial apoptosis pathways.J. Clin. Invest. 119(10):2925-2941, 2009.
• Chen B, Wu Y, Mohler PJ, Anderson ME, Song L-S. Local control of Ca2+-induced Ca2+ release in mouse sinoatrial node cells. J. Mol. Cell. Cardiol. 47(5):706-715, 2009.
• Kline CF, Kurata HT, Hund TJ, Cunha SR, Koval OM, Wright PJ, Christensen M, Anderson ME, Nichols CG, Mohler PJ. Dual Role of K ATP channel C-terminal motif in membrane targeting and metabolic regulation. Proc. Natl. Acad. Sci. 106 (39):16669-74, 2009.
• Christensen MD, Dun W, Boyden PA, Anderson ME, Mohler PJ, and Hund TJ. Oxidized calmodulin kinase II regulates conduction following myocardial infarction: A computational analysis. PLoS Comput Biol. 2009. (Accepted).

2008
•Erickson JR, Anderson ME. CaMKII and its role in cardiac arrhythmia. JCardiovasc Electrophysiol. 2008 Dec;19(12):1332-6. Epub 2008 Sep 17. PubMed PMID:18803570.
•Thiel WH, Chen B, Hund TJ, Koval OM, Purohit A, Song LS, Mohler PJ, Anderson ME. Proarrhythmic defects in Timothy syndrome require calmodulin kinase II. Circulation. 2008 Nov 25;118(22):2225-34. Epub 2008 Nov 10. PubMed PMID:19001023.
•Le Scouarnec S, Bhasin N, Vieyres C, Hund TJ, Cunha SR, Koval O, Marionneau C, Chen B, Wu Y, Demolombe S, Song LS, Le Marec H, Probst V, Schott JJ, Anderson ME, Mohler PJ. Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proc Natl Acad Sci U S A. 2008 Oct7;105(40):15617-22. Epub 2008 Oct 1. PubMed PMID: 18832177; PubMed Central PMCID: PMC2563133.
•Couchonnal LF, Anderson ME. The role of calmodulin kinase II in myocardial physiology and disease. Physiology (Bethesda). 2008 Jun;23:151-9. Review. PubMed PMID: 18556468.
•Erickson JR, Joiner ML, Guan X, Kutschke W, Yang J, Oddis CV, Bartlett RK, Lowe JS, O’Donnell SE, Aykin-Burns N, Zimmerman MC, Zimmerman K, Ham AJ, Weiss RM, Spitz DR, Shea MA, Colbran RJ, Mohler PJ, Anderson ME. A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell. 2008 May 2;133(3):462-74. PubMed PMID: 18455987; PubMed Central PMCID: PMC2435269.
•Werdich AA, Lima EA, Dzhura I, Singh MV, Li J, Anderson ME, Baudenbacher FJ. Differential effects of phospholamban and Ca2+/calmodulin-dependent kinase II on [Ca2+]i transients in cardiac myocytes at physiological stimulation frequencies. Am J Physiol Heart Circ Physiol. 2008 May;294(5):H2352-62. Epub 2008 Mar 21. PubMed PMID: 18359893.
•Mohler PJ, Anderson ME. New insights into genetic causes of sinus node disease and atrial fibrillation. J Cardiovasc Electrophysiol. 2008 May;19(5):516-8. Epub 2008 Feb 21. PubMed PMID: 18298510.
•Grueter CE, Abiria SA, Wu Y, Anderson ME, Colbran RJ. Differential regulated interactions of calcium/calmodulin-dependent protein kinase II with isoforms of voltage-gated calcium channel beta subunits. Biochemistry. 2008 Feb12;47(6):1760-7. Epub 2008 Jan 19.
PubMed PMID: 18205403; PubMed Central PMCID: PMC2814322.
•Khoo MS, Grueter CE, Eren M, Yang J, Zhang R, Bass MA, Lwin ST, Mendes LA, Vaughan DE, Colbran RJ, Anderson ME. Calmodulin kinase II inhibition disrupts cardiomyopathic effects of enhanced green fluorescent protein. J Mol Cell Cardiol. 2008 Feb;44(2):405-10.
Epub 2007 Nov 28. PubMed PMID: 18048055; PubMed Central PMCID: PMC2695824.
•Lowe JS, Palygin O, Bhasin N, Hund TJ, Boyden PA, Shibata E, Anderson ME, Mohler PJ. Voltage-gated Nav channel targeting in the heart requires an ankyrin-G dependent cellular pathway. J Cell Biol. 2008 Jan 14;180(1):173-86. Epub 2008 Jan7. PubMed PMID: 18180363; PubMed Central PMCID: PMC2213608.

2007
•Khoo MS, Grueter CE, Eren M, Yang J, Zhang R, Bass MA, Lwin ST, Mendes LA, Vaughan DE, Colbran RJ, Anderson ME. Calmodulin kinase II inhibition disrupts cardiomyopathic effects of enhanced green fluorescent protein. J Mol Cell Cardiol. 2008 Feb;44(2):405-10.
Epub 2007 Nov 28. PubMed PMID: 18048055; PubMed Central PMCID: PMC2695824.
•Li J, Marionneau C, Koval O, Zingman L, Mohler PJ, Nerbonne JM, Anderson ME. Calmodulin kinase II inhibition enhances ischemic preconditioning by augmenting ATP-sensitive K+ current. Channels (Austin). 2007 Sep-Oct;1(5):387-94. Epub 2007 Dec 17. PubMed PMID: 18690039.
•Werdich AA, Baudenbacher F, Dzhura I, Jeyakumar LH, Kannankeril PJ, Fleischer S, LeGrone A, Milatovic D, Aschner M, Strauss AW, Anderson ME, Exil VJ. Polymorphic ventricular tachycardia and abnormal Ca2+ handling in very-long-chain acyl-CoA dehydrogenase null mice. Am J Physiol Heart Circ Physiol. 2007
May;292(5):H2202-11. Epub 2007 Jan 5. PubMed PMID: 17209005. Anderson ME, Mohler PJ. MicroRNA may have macro effect on sudden death. Nat Med. 2007 Apr;13(4):410-1. PubMed PMID: 17415373.
•Anderson ME. Multiple downstream proarrhythmic targets for calmodulin kinase II: moving beyond an ion channel-centric focus. Cardiovasc Res. 2007 Mar 1;73(4):657-66. Epub 2006 Dec 12. Review. PubMed PMID: 17254559.
•Grimm M, El-Armouche A, Zhang R, Anderson ME, Eschenhagen T. Reduced contractile response to alpha1-adrenergic stimulation in atria from mice with chronic cardiac calmodulin kinase II inhibition. J Mol Cell Cardiol. 2007 Mar;42(3):643-52. Epub 2006 Dec 28. PubMed PMID: 17292391.
•Grueter CE, Colbran RJ, Anderson ME. CaMKII, an emerging molecular driver for calcium homeostasis, arrhythmias, and cardiac dysfunction. J Mol Med. 2007 Jan;85(1):5-14. Epub 2006 Nov 21. Review. PubMed PMID: 17119905.

2006
• Wu Y, Shintani A, Greuter C, Zhang R, Yang J, Kranias EG, Colbran RJ, Anderson ME. Calmodulin kinase II determines dynamic Ca2+ responses in heart. J Mol Cell Cardiol 2006; 40:213-23.
• Yang Y, Zhu WZ, Joiner M-L, Zhang R, Oddis CV, Hou Y, Yang J, Price EE jr, Gleaves L, Erin M, Ni G, Vaughn DE, Xiao R-P, Anderson ME. Calmodulin kinase inhibition protects against myocardial apoptosis in vivo. Am J Physiol 2006; 291:H3065-H3075.
•Kannankeril PJ, Mitchell BM, Goonasekera SA, Chelu MG, Zhang W, Sood S, Kearney DL, Danila CI, De Biasi M, Pautler RG, Roden DM, Taffet GE, Dirksen RT, Anderson ME, Hamilton SL. Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and mild cardiomyopathy. Proc Natl Acad Sci 2006; 103:12179-12184.
• Khoo MSC, Zhang R, Ni G, Greuter C, Yang Y, Zhang W, Mendes L, Olson EN, Colbran RJ, Anderson ME. Death, cardiac dysfunction and arrhythmias due to up-regulation of calmodulin kinase II in calcineurin-induced cardiomyopathy. Circulation 2006; 114:1352-1359. Published with an accompanying editorial.
• Grueter CE, Abiria SA, Dzhura I, Wu Y, Hamm A-J, Mohler PJ, Anderson ME, Colbran RJ. Molecular basis for facilitation of native Ca2+ channels by CaMKII. Mol Cell 2006; 23:641-650. Selected as a recommended citation by the Faculty of 1000 Biology.
• Li J, Shah V, Hell J, Nerbonne JM, Anderson ME. Calmodulin kinase II inhibition shortens action potential duration by up-regulation of K+ currents. Circ Res 2006; 99:1092-1099. PMID: 17038644. Published with an accompanying editorial.
•Anderson ME, Higgins, LS, Schulman H. Disease mechanisms and emerging therapies: Protein kinases and their inhibitors in myocardial disease. Nature Clin Prac 2006; 3:437-445.

III. Therapeutic Implications of Pharmacological Agents for Cardiac Contractility Dysfunction: “The Fire From Within The Biggest Ca²⁺ Channel Erupts and Dribbles” by Anderson, ME

Author: Justin D Pearlman, MD, PhD, FACC PENDING –

Therapeutic Implications of these physiological research discoveries

JDP: RECOMMEND SPLIT TO TWO: a. contractility b. arrhythmia

IV. Selective Research Contributions on Calcium Release-related Contractile Dysfunction

Curator: Aviva Lev-Ari, PhD, RN

Summary

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

Author: Larry H Bernstein, MD, FCAP

PENDING

V. Bibliography on Calcium Release Mechanisms in Vascular Smooth Muscle, in Cardiomyocytes and the Role in Heart Failure

Curator: Aviva Lev-Ari, PhD, RN

Anderson ME, General Hospital Iowa City and University of Iowa
Wilson S. Colucci, MD, Heart Failure Lab at BMC
William Gregory Stevenson, M.D. Heart Failure Lab at BWH

Introduction to Calcium Release Mechanism in Vascular Smooth Muscle and in Cardiomyocytes

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

I. Cellular Contractility Capacity — Actin, Cellular Dynamics and Calcium Efflux: Emergence of the Calcium Release-related Contractile Dysfunction

Author: Justin D Pearlman, MD, PhD, FACC

The pumping action of the heart is mediated by repeated cycles of the release and re-uptake of calcium stored within cardiac myocytes. Similar to skeletal muscle function, the protein complex of actinomycin creates mechanical motion when calcium interacts with the threads of the protein strand tropomyosin which are wound around an actin protein filament with the third protein troponin strung out like beads along the string. Calcium (Ca++) released from the storage space (sarcoplasmic reticulum) combines with troponin to actuate a shift in the tropomyosin threads, exposing myosin binding sites to adenosinetriphosphate (ATP, the energy source), which, in turn, consume the high-energy bond of ATP and concommitantly break and make cross-bridges resulting in shifted position (filament sliding, contraction). The spiral layers of these filaments within the heart result in a reduction of chamber size. Normally the two atrial chambers contract first, to boost the load of blood in the ventricles, then the ventricles contract, relying on one-way valves to impose a forward direction to the blood ejected from the heart.

http://encyclopedia.lubopitko-bg.com/The_Role_of_Actin_and_Myosin.html

Calcium and Myosin in Muscle Contraction

There is barely enough ATP around to complete a single heart beat, so ATP is replenished from a higher energy storage form, phosphocreatine (PCr, aka creatinephosphate), which in turn in reconstituted during the relaxation phase of the heart (low pressure) when oxygenated blood, glucose, and fatty acids are delivered to local mitochondria to restock energy stores. Thus the contraction cycle, unlike a continual pump, provides low pressure respite after each high pressure contraction, which facilitates delivery of oxygenated nutrient blood to the heart muscle to replenish its energy for the action. When switching to a mechanical total heart replacement, it is not necessary to preserve the pulsatile pattern, which primarily serves to facilitate energizing the biologic pump.

The volume of blood ejected by the left ventricle from a single heart beat is called the stroke volume (SV). The amount of blood in the left ventricle just before the heart beat is called the end-diastolic volume (EDV), and just after, the end-systolic volume (ESV), so SV=EDV-ESV. The portion of the filled left ventricle that gets pumped forward through the aortic valve by a single heart beat is called the ejection fraction (EF). Thus EF = SV/EDV, expressed as a percentage. The cardiac output (CO) in liters/minute is simply the product of stroke volume and heart rate (HR): CO = SV x HR.

Heart failure has three clinical forms: high output failure, systolic failure and diastolic heart failure. With high output failure (elevated SV x HR), the demands of the body are elevated beyond the normal capacity of the heart to supply cardiac output. With systolic failure (low EF) the pumping action of the heart is insufficient to meet the needs of fresh blood delivery to the various organs of the body (including in particular the heart, brain, liver, and kidneys). Note that the heart does not draw any significant nutrients or oxygen from the blood in its chambers – rather, it is first in line after the oxygenated blood is pumped out through the aortic valve to tax 10% of the cardiac output via the coronary arteries. In diastolic failure, the LV resists filling (stiff LV) so the back pressure to the lungs is elevated, resulting in pulmonary congestion. Many textbooks incorrectly describe diastolic heart failure as heart failure with a normal EF; however, that would imply that diastolic heart failure (stiff LV) can be “cured” by a myocardial infarction (heart attack) so that the EF drops. Contrary to that mistaken description, the addition of reduced EF to a patient with diastolic heart failure results in combined systolic and diastolic heart failure. Inadequate delivery of blood from low EF has been called “forward failure” and pulmonary congestion from a stiff LV “backward failure” but those terms are not synonymous with systolic and diastolic failure, as low EF also contributes to congestive heart failure, and stiff LV can impede adequate filling, so each has components for forward and backward failure.

One can plot a curve relating stroke volume to the end diastolic volume, called the “Frank-Starling curve” whereby an increase in EDV is generally accommodated by an increase in SV. That adaptive feature is achieved by a stimulation of calcium-mediated increase in contractility (speed and strength of contraction) . In heart failure, the usual amounts of calcium stores are not adequate to meet the demands. Consequently, remodeling occurs, which includes reversion towards a fetal phenotype in which the sarcoplasmic reticulum stores and releases a greater amount of calcium. While this does result in some augmentation of contractility, it occurs at a cost. The higher levels of calcium can interfere with mitochondrial function and reduce the energy efficiency of oxygen replenishment of phosphocreatine and ATP. In research by the author of this section (JDP), the timing of oxygen uptake and utilization is adversely affected by this remodeling, as demonstrated by oxygen uptake sensitive dynamic cardiac MRI.

Thus strategies to genetically re-engineer cardiac function by modifying calcium uptake and release to elevate contractility at a given workload have potentially harmful consequences in terms of lowering the energy efficiency of the heart. If the blood supply of the heart is good (non-ischemic heart failure), one can expect opportunities for benefit. However, if the blood supply to the heart is limited (ischemic heart failure), such changes may be detrimental. Furthermore, the impediments to mitochondrial function may contribute to other adverse effects of remodeling, including in particular activation of fibrosis (adverse remodeling promoting worsened diastolic failure).

II. Integration and Interpretation of Research Results in Two Labs: Mark E Anderson’s and Roger Hajjar’s Lab

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

III. Therapeutic Implications of Pharmacological Agents for Cardiac Contractility Dysfunction: “The Fire From Within The Biggest Ca²⁺ Channel Erupts and Dribbles” by Anderson, ME

Treatment Selection

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

Positive inotropic agents

Positive inotropic agents increase myocardial contractility, and are used to support cardiac function in conditions such as decompensated congestive heart failure, cardiogenic shock, septic shock, myocardial infarction,cardiomyopathy, etc. Examples of positive inotropic agents include:

Berberine
Calcium
Calcium sensitisers
- Levosimendan
Cardiac myosin activators
- Omecamtiv
Catecholamines
- Dopamine
- Dobutamine
- Dopexamine
- Epinephrine (adrenaline)
- Isoprenaline (isoproterenol)
- Norepinephrine (noradrenaline)
Digoxin
Digitalis
Eicosanoids
- Prostaglandins^[1]
Phosphodiesterase inhibitors
Glucagon
Insulin

Negative inotropic agents

Negative inotropic agents decrease myocardial contractility, and are used to decrease cardiac workload in conditions such as angina. While negative inotropism may precipitate or exacerbate heart failure, certain beta blockers (e.g. carvedilol, bisoprolol and metoprolol) have been believed to reduce morbidity and mortality in congestive heart failure. Quite recently, however, the effectiveness of beta blockers has come under renewed critical scientific scrutiny.

Class IA antiarrhythmics such as

Class IC antiarrhythmics such as

Flecainide

and

Pressors

Therapeutic Implications

1. Arrhythmias

2. Heart Failure

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

Therapeutic Implications

Author: Larry H Bernstein, MD, FCAP

The above list of inotropic agents consists of agents developed to increase the contractile force of the heart and have had a long history of use. Even though they have been proved valid, they are not part of the specific advances that we are seeing that justifies a cardiology specialty in cardiac electrophysiology, the disorders, and the treatments. The developments we now witness were unknown and perhaps unexpected a quarter of a century ago. The methods required to understand the myocardiocyte were not yet developed. Our understanding is now based on a refined knowledge of the Ca(2+) release mechanism between the sarcomere and the myocyte cytoplasm, the Ca(2+) transport, the ion pores, the role of RyR2 and the phosphorylation of the Ca(2+) release mechanism. This and more will lead to far better therapeutic advances in the next few years based on earlier detection of changes preceding heart failure, and the possibility of treatments for potential life-threatening arrhythmias will be averted.

IV. Selective Research Contributions on Calcium Release-related Contractile Dysfunction

Curator: Aviva Lev-Ari, PhD, RN

Heart Fail Monit. 2001;1(4):122-5.

Ischemic versus non-ischemic heart failure: should the etiology be determined?

Follath F.

Source

Department of Medicine, University Hospital Zurich, Switzerland.

Abstract

In epidemiological surveys and in large-scale therapeutic trials, the prognosis of patients with ischemic heart failure is worse than in patients with a non-ischemic etiology. Even heart transplant candidates may respond better to intensified therapy if they have non-ischemic heart failure. The term ‘non-ischemic heart failure’ includes various subgroups such as hypertensive heart disease, myocarditis, alcoholic cardiomyopathy and cardiac dysfunction due to rapid atrial fibrillation. Some of these causes are reversible. The therapeutic effect of essential drugs such as angiotensin-converting enzyme inhibitors, beta-blockers and diuretics does not, in general, significantly differ between ischemic and non-ischemic heart failure. However, in some trials, response to certain drugs (digoxin, tumor necrosis factor-alpha, inhibition with pentoxifylline, growth hormone and amiodarone) was found to be better in non-ischemic patients. Patients with ischemic heart failure and non-contracting ischemic viable myocardium may, on the other hand, considerably improve following revascularization. In view of prognostic and possible therapeutic differences, the etiology of heart failure should be determined routinely in all patients. http://www.ncbi.nlm.nih.gov/pubmed/12634896

Upregulation of β₃-Adrenoceptors and Altered Contractile Response to Inotropic Amines in Human Failing Myocardium

+Author Affiliations

From the Department of Medicine, Unit of Pharmacology and Therapeutics, University of Louvain Medical School (S.M., O.F., J.-L.B.), Brussels, Belgium; INSERM U533, Physiopathologie et Pharmacologie Cellulaires et Moléculaires (J.-N.T., C.G.) and Faculté des Sciences et Techniques (C.G.), Nantes, France; and Department of Pathology, Brigham and Women’s Hospital, and Physiology Program, Harvard School of Public Health (L.K.), Boston, Mass.

Correspondence to Jean-Luc Balligand, Department of Medicine, Unit of Pharmacology and Therapeutics, FATH 5349, University of Louvain Medical School, 53 avenue Mounier, B1200 Brussels, Belgium, e-mail Balligand@mint.ucl.ac.be; or Chantal Gauthier, INSERM U533, Physiopathologie et Pharmacologie Cellulaires et Moléculaires, 44093 Nantes, France,

Abstract

Background—Contrary to β₁– and β₂-adrenoceptors, β₃-adrenoceptors mediate a negative inotropic effect in human ventricular muscle. To assess their functional role in heart failure, our purpose was to compare the expression and contractile effect of β₃-adrenoceptors in nonfailing and failing human hearts.

Methods and Results—We analyzed left ventricular samples from 29 failing (16 ischemic and 13 dilated cardiomyopathic) hearts (ejection fraction 18.6±2%) and 25 nonfailing (including 12 innervated) explanted hearts (ejection fraction 64.2±3%). β₃-Adrenoceptor proteins were identified by immunohistochemistry in ventricular cardiomyocytes from nonfailing and failing hearts. Contrary to β₁-adrenoceptor mRNA, Western blot analysis of β₃-adrenoceptor proteins showed a 2- to 3-fold increase in failing compared with nonfailing hearts. A similar increase was observed for Gα_i-2 proteins that couple β₃-adrenoceptors to their negative inotropic effect. Contractile tension was measured in electrically stimulated myocardial samples ex vivo. In failing hearts, the positive inotropic effect of the nonspecific amine isoprenaline was reduced by 75% compared with that observed in nonfailing hearts. By contrast, the negative inotropic effect of β₃-preferential agonists was only mildly reduced.

Conclusions—Opposite changes occur in β₁– and β₃-adrenoceptor abundance in the failing left ventricle, with an imbalance between their inotropic influences that may underlie the functional degradation of the human failing heart.

Key Words:

http://circ.ahajournals.org/content/103/12/1649.short

Increased beta-receptor density and improved hemodynamic response to catecholamine stimulation during long-term metoprolol therapy in heart failure from dilated cardiomyopathy.

+Author Affiliations

Cardiology Division, Stanford University School of Medicine, CA.

Abstract

Severe heart failure is associated with a reduction in myocardial beta-adrenergic receptor density and an impaired contractile response to catecholamine stimulation. Metoprolol was administered during a 6-month period to 14 patients with dilated cardiomyopathy to examine its effects on these abnormalities. The mean daily dose of metoprolol for the group was 105 mg (range, 75-150 mg). Myocardial beta-receptor density, resting hemodynamic output, and peak left ventricular dP/dt response to dobutamine infusions were compared in 9, 14, and 7 patients, respectively, before and after 6 months of metoprolol therapy while the patients were on therapy. The second hemodynamic study was performed 1-2 hours after the morning dose of metoprolol had been given. Myocardial beta-receptor density increased from 39 +/- 7 to 80 +/- 12 fmol/mg (p less than 0.05). Resting hemodynamic output showed a rise in stroke work index from 27 +/- 4 to 43 +/- 3 g/m/m2, p less than 0.05, and ejection fraction rose from 0.26 +/- 0.03 to 0.39 +/- 0.03 after 6 months of metoprolol therapy, p less than 0.05. Before metoprolol therapy, dobutamine caused a 21 +/- 4% increase in peak positive left ventricular dP/dt; during metoprolol therapy, the same dobutamine infusion rate increased peak positive dP/dt by 74 +/- 18% (p less than 0.05). Thus, long-term metoprolol therapy is associated with an increase in myocardial beta-receptor density, significant improvement in resting hemodynamic output, and improved contractile response to catecholamine stimulation. These changes indicate a restoration of beta-adrenergic sensitivity associated with metoprolol therapy, possibly related to the observed up-regulation of beta-adrenergic receptors.

http://circ.ahajournals.org/content/79/3/483.short

Ryanopathy: causes and manifestations of RyR2 dysfunction in heart failure

Belevych AE, Radwański PB, Carnes CA, Györke S. College of Medicine, The Ohio State University, Columbus, OH. Cardiovasc Res. 2013; 98(2):240-7. doi: 10.1093/cvr/cvt024. Epub 2013 Feb 12. PMID: 23408344 PMCID: PMC3633158 [Available on 2014/5/1] The cardiac ryanodine receptor (RyR2), a Ca(2+) release channel on the membrane of the sarcoplasmic reticulum (SR), plays a key role in determining the strength of the heartbeat by supplying Ca(2+) required for contractile activation. Abnormal RyR2 function is recognized as an important part of the pathophysiology of heart failure (HF). While in the normal heart, the balance between the cytosolic and intra-SR Ca(2+) regulation of RyR2 function maintains the contraction-relaxation cycle, in HF, this behaviour is compromised by excessive post-translational modifications of the RyR2. Such modification of the Ca(2+) release channel impairs the ability of the RyR2 to properly deactivate leading to a spectrum of Ca(2+)-dependent pathologies that include cardiac systolic and diastolic dysfunction, arrhythmias, and structural remodeling. In this article, we present an overview of recent advances in our understanding of the underlying causes and pathological consequences of abnormal RyR2 function in the failing heart. We also discuss the implications of these findings for HF therapy.

Circ Res. 2005 Dec 9;97(12):1314-22. Epub 2005 Nov 3.

Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure.

Ai X, Curran JW, Shannon TR, Bers DM, Pogwizd SM.

Source

Department of Medicine, University of Illinois at Chicago, IL 60612, USA.

Abstract

Abnormal release of Ca from sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RyR2) may contribute to contractile dysfunction and arrhythmogenesis in heart failure (HF). We previously demonstrated decreased Ca transient amplitude and SR Ca load associated with increased Na/Ca exchanger expression and enhanced diastolic SR Ca leak in an arrhythmogenic rabbit model of nonischemic HF. Here we assessed expression and phosphorylation status of key Ca handling proteins and measured SR Ca leak in control and HF rabbit myocytes. With HF, expression of RyR2 and FK-506 binding protein 12.6 (FKBP12.6) were reduced, whereas inositol trisphosphate receptor (type 2) and Ca/calmodulin-dependent protein kinase II (CaMKII) expression were increased 50% to 100%. The RyR2 complex included more CaMKII (which was more activated) but less calmodulin, FKBP12.6, and phosphatases 1 and 2A. The RyR2 was more highly phosphorylated by both protein kinase A (PKA) and CaMKII. Total phospholamban phosphorylation was unaltered, although it was reduced at the PKA site and increased at the CaMKII site. SR Ca leak in intact HF myocytes (which is higher than in control) was reduced by inhibition of CaMKII but was unaltered by PKA inhibition. CaMKII inhibition also increased SR Ca content in HF myocytes. Our results suggest that CaMKII-dependent phosphorylation of RyR2 is involved in enhanced SR diastolic Ca leak and reduced SR Ca load in HF, and may thus contribute to arrhythmias and contractile dysfunction in HF.

Editorial Comment on the above article abstract made by Anderson, ME

The fire from within: the biggest Ca2+ channel erupts and dribbles. [Circ Res. 2005 Dec 9;97(12):1213-5.]

http://www.ncbi.nlm.nih.gov/pubmed/16269653

The Fire From Within – The Biggest Ca²⁺ Channel Erupts and Dribbles

Mark E. Anderson

+Author Affiliations

From the University of Iowa, Carver College of Medicine, Iowa City.

Correspondence to Mark E. Anderson, MD, PhD, University of Iowa, Carver College ofMedicine, 200 Hawkins Drive, Room E 315 GH, Iowa City, IA 53342-1081. E-mail mark-e-anderson@uiowa.edu

Key Words:

See related article, pages 1314–1322

CaMKII Is a Pluripotent Signaling Molecule in Heart

The multifunctional Ca²⁺ and calmodulin (CaM)-dependent protein kinase II (CaMKII) is a serine threonine kinase that is abundant in heart where it phosphorylates Ca²⁺_ihomeostatic proteins. It seems likely that CaMKII plays an important role in cardiac physiology because these target proteins significantly overlap with the more extensively studied serine threonine kinase, protein kinase A (PKA), which is a key arbiter of catecholamine responses in heart. However, the physiological functions of CaMKII remain poorly understood, whereas the potential role of CaMKII in signaling myocardial dysfunction and arrhythmias has become an area of intense focus. CaMKII activity and expression are upregulated in failing human hearts and in many animal models of structural heart disease.¹ CaMKII inhibitory drugs can prevent cardiac arrhythmias^2,3 and suppress afterdepolarizations⁴ that are a probable proximate focal cause of arrhythmias in heart failure. CaMKII inhibition in mice reduces left ventricular dilation and prevents disordered intracellular Ca²⁺ (Ca²⁺_i) homeostasis after myocardial infarction.⁵ CaMKII overexpression in mouse heart causes severe cardiac hypertrophy, dysfunction, and sudden death that is heralded by increased SR Ca²⁺ leak⁶; these findings go a long way to making a case for CaMKII as a causative signal in heart disease and arrhythmias but do not identify critical molecular targets or test the potential role of CaMKII in a large non-rodent animal model. The work by Ai et al in this issue of Circulation Research makes an important contribution by demonstrating CaMKII upregulation causes increased Ca²⁺ leak from ryanodine receptor (RyR) Ca²⁺ release channels in a clinically-relevant model of structural heart disease.⁷

Ryanodine Receptors Are Central

Ca²⁺_i release controls cardiac contraction, and most of the Ca²⁺_i for contraction is released from the intracellular sarcoplasmic reticulum (SR) through ryanodine receptors (RyR). RyRs are huge proteins (565 kDa) that assemble with a fourfold symmetry to form a functional Ca²⁺ release channel. Approximately 90% of the RyR is not directly required to form the pore but instead protrudes into the cytoplasm where it binds numerous proteins, including PKA, CaMKII, CaM, and FK12.6 (calstabin). Cardiac contraction is initiated when Ca²⁺ current (I_Ca), through sarcolemmal L-type Ca²⁺ channels (LTCC), triggers RyR opening by a Ca²⁺-induced Ca²⁺ release (CICR) mechanism. LTCCs “face off” with RyRs across a highly ordered cytoplasmic cleft that delineates a kind of Ca²⁺furnace during each CICR-initiated heart beat (Figure). CICR has an obvious need to function reliably, so it is astounding to consider how this feed forward process is intrinsically unstable. The increased instability of CICR in heart failure is directly relevant to arrhythmias initiated by afterdepolarizations. RyRs partly rely on a collaboration of Ca²⁺-sensing proteins in the SR lumen to grade their opening probability and the amount of SR Ca²⁺ release to a given I_Ca stimulus. Thus the SR Ca²⁺ content is an important parameter for setting the inotropic state, and heart failure is generally a condition of reduced SR Ca²⁺ content and diminished myocardial contraction.

View larger version: http://www.ncbi.nlm.nih.gov/pubmed/16269653

Ca²⁺-induced Ca²⁺ release (CICR) in health and disease. Each heart beat is initiated by cell membrane depolarization that opens Ca²⁺channels. The Ca²⁺ current (I_Ca) induces ryanodine receptor (RyR) opening that allows release of myofilament activating Ca²⁺ for contraction. In healthy CICR, RyRs close during diastole while Ca²⁺ is removed from the cytoplasm by uptake into the sarcoplasmic reticulum (SR). In heart failure the SR has reduced Ca²⁺ content so that the amount of Ca²⁺ released to the myofilaments is smaller than in health. RyR hyperphosphorylation by CaMKII promotes repetitive RyR openings leading to a Ca²⁺ leak in diastole. This leak contributes to the reduction in SR Ca²⁺ content and can engage the electrogenic Na⁺-Ca²⁺ exchanger to trigger afterdepolarizations and arrhythmias.

Kinases Facilitate Communication Between LTCCs and RyRs

LTCCs and RyRs form the protein machinery for initiating contraction in cardiac and skeletal muscle, but in cardiac muscle communication between these proteins occurs without a requirement for physical contact. PKA is preassociated with LTCCs and RyRs, and PKA-dependent phosphorylation increases LTCC⁸ and RyR⁹opening. The resultant increase in Ca²⁺_i is an important reason for the positive inotropic response to cathecholamines. The multifunctional Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is activated by increased Ca²⁺_I, and so catecholamine stimulation activates CaMKII in addition to PKA.⁵ In contrast to PKA, which is tightly linked to inotropy, CaMKII inhibition does not cause a reduction in fractional shortening during acute catecholamine stimulation in mice.⁵ Prolonged catecholamine exposure does reduce contractile function by uncertain mechanisms that require CaMKII.¹⁰ CaMKII colocalizes with LTCCs¹¹ and RyRs,¹² and CaMKII can also increase LTCC¹³ and RyR¹² opening probability in cardiac myocytes. The ultrastructural environment of LTCCs and RyRs is well-suited for a Ca²⁺_i-responsive kinase to serve as a coordinating signal between LTCCs and RyRs during CICR. The recently identified role of CaMKII in heart failure suggests the possibility that excessive CaMKII activity could cause or contribute to CICR defects present in heart failure

Heart Failure Is a Disease of Disordered Ca²⁺_i Homeostasis

The key clinical phenotypes of contractile dysfunction and electrical instability in heart failure involve problems with Ca²⁺_i homeostasis. Broad changes in Ca²⁺_I-handling proteins can occur in various heart failure models, but in general heart failure is marked by a reduction in the capacity for SR Ca²⁺ uptake, enhanced activity of the sarcolemmal Na⁺-Ca²⁺ exchanger, and reduction in CICR-coordinated SR Ca²⁺ release. On the other hand, the opening probability of individual LTCCs is increased in human heart failure,¹⁴suggesting that posttranslational modifications may also be mechanistically important for understanding these Ca²⁺_i disturbances at Ca²⁺ homeostatic proteins.

Is Heart Failure a Disease of Enzymatic Over-Activity?

Heart failure is marked by hyper-adrenergic tone, and beta adrenergic receptor antagonist drugs (beta blockers) are a mainstay of therapy for reducing mortality in heart failure patients. The Marks group pioneered the concept that RyRs are hyperphosphorylated by PKA in patients with heart failure and showed that successful therapies, ranging from beta blockers to left ventricular assist devices, reduce RyR phosphorylation in step with improved mechanical function. They have developed a large body of evidence in patients and in animal models that PKA phosphorylation of Ser2809 on cardiac RyRs destabilizes binding of FK12.6 to RyRs and promotes increased RyR opening that causes an insidious Ca²⁺ leak. This leak is potentially problematic because it can reduce SR Ca²⁺ content (to depress inotropy), engage pathological Ca²⁺-dependent transcriptional programs (to promote myocyte hypertrophy), and activate arrhythmia-initiating afterdepolarizations (to cause sudden death). Indeed, RyR hyperphosphorylation can produce arrhythmias as well as mechanical dysfunction, whereas a drug that prevents FK12.6 dissociation from RyR also reduces or prevents arrhythmias.¹⁵ Taken together these findings make a strong case that RyR hyperphosphorylation (a result of net excess kinase activity) is a central event in heart failure and sudden death.

Not all findings point to hyperphosphorylation of RyR by PKA and subsequent FK12.6 dissociation as critical determinants of heart failure¹⁶ and arrhythmias.¹⁷ For example, studies in isolated and permeabilized ventricular myocytes failed to show an increase in RyR openings, called sparks, which are monitored by photoemission of a Ca²⁺-sensitive fluorescent dye.¹⁸ FKBP12.6 dissociation is not universally reported to follow RyR phosphorylation by PKA.¹⁹ Furthermore, FKBP12.6 binding to RyR is not affected during catecholamine stimulation that results in arrhythmias in a mouse model of catecholamine-induced ventricular tachycardia,^20,21 a genetic disorder of hypersensitive RyR Ca²⁺release. These findings challenge the PKA hypothesis and make room, conceptually, to consider the role of additional signals for modulating RyR activity in heart disease.

Both PKA and CaMKII may phosphorylate Ser2809, but recently CaMKII was found to exclusively phosphorylate Ser2815 and this phosphorylation caused increased RyR opening.¹² However, the PKA and CaMKII responses may be mechanistically distinct because CaMKII evoked increased RyR opening in the absence of FK12.6 dissociation. These findings together with the fact that CaMKII activity is recruited under conditions of increased PKA activity suggest that CaMKII might also be important in regulating RyRs in heart failure.

The article by Ai et al shows that expression of a CaMKII splice variant that is resident in cytoplasm (CaMKIIδc) was increased, and there was enhanced phosphorylation of the recently identified CaMKII site (Ser2815) on RyR. Both Ser2815 and the PKA site (Ser2809) were hyperphosphorylated in failing hearts, but phosphorylation of the CaMKII site was greater than the PKA site. Because both Ser2809 and Ser2815 can increase RyR openings, it seemed likely that PKA and CaMKII would work together to increase Ca²⁺leak. Surprisingly, CaMKII inhibition but not PKA inhibition suppressed the leak. These experiments were performed with meticulous attention to matching SR Ca²⁺ load, a technically difficult accomplishment that is not performed by most groups evaluating SR Ca²⁺ release. Thus, differences in the SR intraluminal Ca²⁺ could not account for these findings. Although these experiments were carefully controlled, one potential limitation is that the experiments relied exclusively on CaMKII and PKA inhibitor drugs that are notorious for nonspecific actions at ion channel proteins. They also showed that the ratio of inositol tris phosphate receptors (IP₃R) to RyRs was increased in failing left ventricular myocytes. IP₃R are important for regulating Ca²⁺_i in many cells types, including atrial myocytes, but their role in ventricle remains uncertain. The finding that the IP₃R are increased at the expense of RyR suggests that Ca²⁺_i release sites are fundamentally reordered in heart failure but leaves the impact of this change untested. IP₃R are also a target for CaMKII, so interesting questions remain about the potential role for this channel and CaMKII in heart failure, at least in this model.

What We Learned and What We Need to Know

CaMKII activity seems to be part and parcel of the adrenergic signaling seen in structural heart disease. This work shows us that CaMKII can contribute directly to increased SR Ca²⁺ leak in a clinically relevant model of heart failure that is marked by arrhythmias and sudden death.²² Acute experiments with CaMKII inhibitory drugs strongly suggest that SR Ca²⁺ leak is principally linked to CaMKII rather than PKA activity. Excessive SR Ca²⁺ release can activate inward (forward mode) Na⁺-Ca²⁺ exchanger current to cause delayed afterdepolarizations and arrhythmias and CaMKII inhibition can prevent these inward Na⁺-Ca²⁺ exchanger currents.²³ An important next step toward translating these findings will be to evaluate the effects of chronic CaMKII inhibition in this model to see whether it reverses cardiac dysfunction, arrhythmias, and whether chronic CaMKII inhibitor therapy can stop the RyR leak to refill the SR. It will be necessary to have improved pharmacological agents with fewer nonspecific effects to convincingly perform these experiments. These future experiments will tell us whether CaMKII inhibition is a potentially viable therapy for structural heart disease and arrhythmias in a non-genetic non-mouse model. We need to know whether CaMKII inhibition is really a highly-specific form of beta blockade that can preserve inotropic responses to catecholamines while preventing the adverse consequences of catecholamines in heart failure.⁵

Acknowledgments

This work was supported in part by grants from the National Institutes of Health (HL070250, HL62494, and HL046681). Dr Anderson is an Established Investigator of the American Heart Association.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association

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Xiao B, Sutherland C, Walsh MP, Chen SR. Protein kinase A phosphorylation at serine-2808 of the cardiac Ca²⁺-release channel (ryanodine receptor) does not dissociate 12.6-kDa FK506-binding protein (FKBP12.6). Circ Res. 2004; 94: 487–495.

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Cerrone M, Colombi B, Santoro M, di Barletta MR, Scelsi M, Villani L, Napolitano C, Priori SG. Bidirectional ventricular tachycardia and fibrillation elicited in a knock-in mouse model carrier of a mutation in the cardiac ryanodine receptor. Circ Res. 2005;96: e77–e82.

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George CH, Higgs GV, Lai FA. Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes. Circ Res. 2003; 93: 531–540.

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Pogwizd SM, Schlotthauer K, Li L, Yuan W, Bers DM. Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ Res.2001; 88: 1159–1167.

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Wu Y, Roden DM, Anderson ME. Calmodulin kinase inhibition prevents development of the arrhythmogenic transient inward current. Circ Res. 1999; 84:906–912.

Abstract/FREE Full Text

SOURCE

http://circres.ahajournals.org/content/97/12/1213.full?sid=f767fc5d-5a89-4681-babf-814e3d969b2f

http://circres.ahajournals.org/content/97/12/1213.full?sid=f767fc5d-5a89-4681-babf-814e3d969b2f#ref-list-1

Other tightly related articles by Prof. Anderson, ME

http://www.atgcchecker.com/pubmed/16339492

Summary

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

Author: Larry H Bernstein, MD, FCAP

PENDING

V. Bibliography on Calcium Release Mechanisms in Vascular Smooth Muscle, in Cardiomyocytes and the Role in Heart Failure

Curator: Aviva Lev-Ari, PhD, RN

Anderson ME, General Hospital Iowa City and University of Iowa
Wilson S. Colucci, MD, Heart Failure Lab at BMC
William Gregory Stevenson, M.D. Heart Failure Lab at BWH

Anderson ME, General Hospital Iowa City and University of Iowa

Latest 20 Publications by Prof. Anderson ME on Heart Failure, Calcium and Calmodulin-dependent protein kinase II: linking heart failure and arrhythmias.

Mark E. Anderson, MD, PhD

Clinical Profile Head, Department of Internal Medicine Director, Cardiovascular Research Center Professor of Internal Medicine – Cardiovascular Medicine Professor of Molecular Physiology and Biophysics

Contact Information

Primary Office: SE308 GH General Hospital Iowa City, IA 52242 Lab: 2270C CBRB Iowa City, IA 52242 Email: mark-e-anderson@uiowa.edu Web: Dr. Anderson’s Laboratory Web: Transatlantic CaMKII Alliance website (Fondation Leducq)

Dr. Anderson is clinically trained as a cardiac electrophysiologist. His research is focused on cellular signaling and ionic mechanisms that cause heart failure and sudden cardiac death. The multifunctional Ca2+/calmodulin dependent protein kinase II (CaMKII) is upregulated in heart disease and arrhythmias. Work in the Anderson laboratory implicates CaMKII as a signal that drives myocardial hypertrophy, apoptosis, mechanical dysfunction and electrical instability. The laboratory work ranges from molecular structure activity analysis of CaMKII to systems physiology using genetically modified mice to dissect cellular mechanisms of CaMKII signaling in heart. http://www.medicine.uiowa.edu/dept_primary_apr.aspx?appointment=Internal%20Medicine&id=andersonmar

Results: 1 to 20 of 419

1. Calmodulin kinase II inhibition shortens action potential duration by upregulation of K+ currents.

Li J, Marionneau C, Zhang R, Shah V, Hell JW, Nerbonne JM, Anderson ME. Circ Res. 2006 Nov 10;99(10):1092-9. Epub 2006 Oct 12.

PMID:

17038644 [PubMed – indexed for MEDLINE] Free Article

Related citations

Select item 186900392.

Calmodulin kinase II inhibition enhances ischemic preconditioning by augmenting ATP-sensitive K+ current.

Li J, Marionneau C, Koval O, Zingman L, Mohler PJ, Nerbonne JM, Anderson ME. Channels (Austin). 2007 Sep-Oct;1(5):387-94. Epub 2007 Dec 17.

PMID:

18690039 [PubMed – indexed for MEDLINE] Free Article

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Select item 122088073.

Calmodulin kinase II and arrhythmias in a mouse model of cardiac hypertrophy.

Wu Y, Temple J, Zhang R, Dzhura I, Zhang W, Trimble R, Roden DM, Passier R, Olson EN, Colbran RJ, Anderson ME. Circulation. 2002 Sep 3;106(10):1288-93.

PMID:

12208807 [PubMed – indexed for MEDLINE] Free Article

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Select item 164135754.

Suppression of dynamic Ca(2+) transient responses to pacing in ventricular myocytes from mice with genetic calmodulin kinase II inhibition.

Wu Y, Shintani A, Grueter C, Zhang R, Hou Y, Yang J, Kranias EG, Colbran RJ, Anderson ME. J Mol Cell Cardiol. 2006 Feb;40(2):213-23. Epub 2006 Jan 18.

PMID:

16413575 [PubMed – indexed for MEDLINE]

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Select item 159222735.

Calmodulin kinase II activity is required for normal atrioventricular nodal conduction.

Khoo MS, Kannankeril PJ, Li J, Zhang R, Kupershmidt S, Zhang W, Atkinson JB, Colbran RJ, Roden DM, Anderson ME. Heart Rhythm. 2005 Jun;2(6):634-40.

PMID:

15922273 [PubMed – indexed for MEDLINE]

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Select item 169829376.

Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy.

Khoo MS, Li J, Singh MV, Yang Y, Kannankeril P, Wu Y, Grueter CE, Guan X, Oddis CV, Zhang R, Mendes L, Ni G, Madu EC, Yang J, Bass M, Gomez RJ, Wadzinski BE, Olson EN, Colbran RJ, Anderson ME. Circulation. 2006 Sep 26;114(13):1352-9. Epub 2006 Sep 18.

PMID:

16982937 [PubMed – indexed for MEDLINE] Free Article

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Select item 208646737.

RGS6, a modulator of parasympathetic activation in heart.

Yang J, Huang J, Maity B, Gao Z, Lorca RA, Gudmundsson H, Li J, Stewart A, Swaminathan PD, Ibeawuchi SR, Shepherd A, Chen CK, Kutschke W, Mohler PJ, Mohapatra DP, Anderson ME, Fisher RA. Circ Res. 2010 Nov 26;107(11):1345-9. doi: 10.1161/CIRCRESAHA.110.224220. Epub 2010 Sep 23.

PMID:

20864673 [PubMed – indexed for MEDLINE] Free PMC Article

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Select item 180480558.

Calmodulin kinase II inhibition disrupts cardiomyopathic effects of enhanced green fluorescent protein.

Khoo MS, Grueter CE, Eren M, Yang J, Zhang R, Bass MA, Lwin ST, Mendes LA, Vaughan DE, Colbran RJ, Anderson ME. J Mol Cell Cardiol. 2008 Feb;44(2):405-10. Epub 2007 Nov 28.

PMID:

18048055 [PubMed – indexed for MEDLINE] Free PMC Article

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Select item 192739099.

Ca2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart.

Singh MV, Kapoun A, Higgins L, Kutschke W, Thurman JM, Zhang R, Singh M, Yang J, Guan X, Lowe JS, Weiss RM, Zimmermann K, Yull FE, Blackwell TS, Mohler PJ, Anderson ME. J Clin Invest. 2009 Apr;119(4):986-96. doi: 10.1172/JCI35814. Epub 2009 Mar 9.

PMID:

19273909 [PubMed – indexed for MEDLINE] Free PMC Article

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Select item 2279626010.

CaMKII effects on inotropic but not lusitropic force frequency responses require phospholamban.

Wu Y, Luczak ED, Lee EJ, Hidalgo C, Yang J, Gao Z, Li J, Wehrens XH, Granzier H, Anderson ME. J Mol Cell Cardiol. 2012 Sep;53(3):429-36. doi: 10.1016/j.yjmcc.2012.06.019. Epub 2012 Jul 11.

PMID:

22796260 [PubMed – indexed for MEDLINE]

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Select item 1280798611.

C terminus L-type Ca2+ channel calmodulin-binding domains are ‘auto-agonist’ ligands in rabbit ventricular myocytes.

Dzhura I, Wu Y, Zhang R, Colbran RJ, Hamilton SL, Anderson ME. J Physiol. 2003 Aug 1;550(Pt 3):731-8. Epub 2003 Jun 13.

PMID:

12807986 [PubMed – indexed for MEDLINE] Free PMC Article

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Select item 2061038012.

Ankyrin-B regulates Kir6.2 membrane expression and function in heart.

Li J, Kline CF, Hund TJ, Anderson ME, Mohler PJ. J Biol Chem. 2010 Sep 10;285(37):28723-30. doi: 10.1074/jbc.M110.147868. Epub 2010 Jul 7.

PMID:

20610380 [PubMed – indexed for MEDLINE] Free PMC Article

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Select item 2087700913.

A β(IV)-spectrin/CaMKII signaling complex is essential for membrane excitability in mice.

Hund TJ, Koval OM, Li J, Wright PJ, Qian L, Snyder JS, Gudmundsson H, Kline CF, Davidson NP, Cardona N, Rasband MN, Anderson ME, Mohler PJ. J Clin Invest. 2010 Oct;120(10):3508-19. doi: 10.1172/JCI43621. Epub 2010 Sep 27.

PMID:

20877009 [PubMed – indexed for MEDLINE] Free PMC Article

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Select item 1686169714.

Calmodulin kinase II inhibition protects against myocardial cell apoptosis in vivo.

Yang Y, Zhu WZ, Joiner ML, Zhang R, Oddis CV, Hou Y, Yang J, Price EE, Gleaves L, Eren M, Ni G, Vaughan DE, Xiao RP, Anderson ME. Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H3065-75. Epub 2006 Jul 21.

PMID:

16861697 [PubMed – indexed for MEDLINE] Free Article

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Select item 2305174615.

CaMKII determines mitochondrial stress responses in heart.

Joiner ML, Koval OM, Li J, He BJ, Allamargot C, Gao Z, Luczak ED, Hall DD, Fink BD, Chen B, Yang J, Moore SA, Scholz TD, Strack S, Mohler PJ, Sivitz WI, Song LS, Anderson ME. Nature. 2012 Nov 8;491(7423):269-73. doi: 10.1038/nature11444. Epub 2012 Oct 10.

PMID:

23051746 [PubMed – indexed for MEDLINE] Free PMC Article

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Select item 2267914016.

Calmodulin-dependent protein kinase II: linking heart failure and arrhythmias.

Swaminathan PD, Purohit A, Hund TJ, Anderson ME. Circ Res. 2012 Jun 8;110(12):1661-77. doi: 10.1161/CIRCRESAHA.111.243956. Review.

PMID:

22679140 [PubMed – indexed for MEDLINE] Free Article

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Select item 1729239117.

Reduced contractile response to alpha1-adrenergic stimulation in atria from mice with chronic cardiac calmodulin kinase II inhibition.

Grimm M, El-Armouche A, Zhang R, Anderson ME, Eschenhagen T. J Mol Cell Cardiol. 2007 Mar;42(3):643-52. Epub 2006 Dec 28.

PMID:

17292391 [PubMed – indexed for MEDLINE]

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Select item 1579358218.

Calmodulin kinase II inhibition protects against structural heart disease.

Zhang R, Khoo MS, Wu Y, Yang Y, Grueter CE, Ni G, Price EE Jr, Thiel W, Guatimosim S, Song LS, Madu EC, Shah AN, Vishnivetskaya TA, Atkinson JB, Gurevich VV, Salama G, Lederer WJ, Colbran RJ, Anderson ME. Nat Med. 2005 Apr;11(4):409-17. Epub 2005 Mar 27.

PMID:

15793582 [PubMed – indexed for MEDLINE]

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Select item 1835989319.

Differential effects of phospholamban and Ca2+/calmodulin-dependent kinase II on [Ca2+]i transients in cardiac myocytes at physiological stimulation frequencies.

Werdich AA, Lima EA, Dzhura I, Singh MV, Li J, Anderson ME, Baudenbacher FJ. Am J Physiol Heart Circ Physiol. 2008 May;294(5):H2352-62. doi: 10.1152/ajpheart.01398.2006. Epub 2008 Mar 21.

PMID:

18359893 [PubMed – indexed for MEDLINE] Free Article

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Select item 2233802020.

β2-Adrenergic receptor supports prolonged theta tetanus-induced LTP.

Qian H, Matt L, Zhang M, Nguyen M, Patriarchi T, Koval OM, Anderson ME, He K, Lee HK, Hell JW. J Neurophysiol. 2012 May;107(10):2703-12. doi: 10.1152/jn.00374.2011. Epub 2012 Feb 15.

Publications by Prof. Wilson S. Colucci, MD on Heart Failure

Wilson S. Colucci, MD

Title	Professor
Institution	Boston University School of Medicine
Department	Medicine
Division	Cardiovascular Medicine

Address	75 E. Newton St Boston, MA 02118
Telephone	(617) 638-8706

Title	Chief – Section of Medicine, Cardiovascular Medicine
Institution	Boston University School of Medicine
Department	Medicine
Division	Cardiovascular Medicine

1.	Qin F, Siwik DA, Lancel S, Zhang J, Kuster GM, Luptak I, Wang L, Tong X, Kang YJ, Cohen RA, Colucci WS. Hydrogen Peroxide-Mediated SERCA Cysteine 674 Oxidation Contributes to Impaired Cardiac Myocyte Relaxation in Senescent Mouse Heart. J Am Heart Assoc. 2013; 2(4):e000184.
	View in: PubMed

2.	Gopal DM, Kommineni M, Ayalon N, Koelbl C, Ayalon R, Biolo A, Dember LM, Downing J, Siwik DA, Liang CS, Colucci WS. Relationship of plasma galectin-3 to renal function in patients with heart failure: effects of clinical status, pathophysiology of heart failure, and presence or absence of heart failure. J Am Heart Assoc. 2012 Oct; 1(5):e000760.
	View in: PubMed

3.	Calamaras TD, Lee C, Lan F, Ido Y, Siwik DA, Colucci WS. Post-translational Modification of Serine/Threonine Kinase LKB1 via Adduction of the Reactive Lipid Species 4-Hydroxy-trans-2-nonenal (HNE) at Lysine Residue 97 Directly Inhibits Kinase Activity. J Biol Chem. 2012 Dec 7; 287(50):42400-6.
	View in: PubMed

4.	Kivikko M, Nieminen MS, Pollesello P, Pohjanjousi P, Colucci WS, Teerlink JR, Mebazaa A. The clinical effects of levosimendan are not attenuated by sulfonylureas. Scand Cardiovasc J. 2012 Dec; 46(6):330-8.
	View in: PubMed

5.	Kumar V, Calamaras TD, Haeussler DJ, Colucci W, Cohen RA, McComb ME, Pimental DR, Bachschmid MM. Cardiovascular Redox and Ox Stress Proteomics. Antioxid Redox Signal. 2012 May 18.
	View in: PubMed

6.	Qin F, Siwik DA, Luptak I, Hou X, Wang L, Higuchi A, Weisbrod RM, Ouchi N, Tu VH, Calamaras TD, Miller EJ, Verbeuren TJ, Walsh K, Cohen RA, Colucci WS. The polyphenols resveratrol and s17834 prevent the structural and functional sequelae of diet-induced metabolic heart disease in mice. Circulation. 2012 Apr 10; 125(14):1757-64.
	View in: PubMed

7.	Mazzini M, Tadros T, Siwik D, Joseph L, Bristow M, Qin F, Cohen R, Monahan K, Klein M, Colucci W. Primary carnitine deficiency and sudden death: in vivo evidence of myocardial lipid peroxidation and sulfonylation of sarcoendoplasmic reticulum calcium ATPase 2. Cardiology. 2011; 120(1):52-8.
	View in: PubMed

8.	Schulze PC, Biolo A, Gopal D, Shahzad K, Balog J, Fish M, Siwik D, Colucci WS. Dynamics in insulin resistance and plasma levels of adipokines in patients with acute decompensated and chronic stable heart failure. J Card Fail. 2011 Dec; 17(12):1004-11.
	View in: PubMed

9.	Liesa M, Luptak I, Qin F, Hyde BB, Sahin E, Siwik DA, Zhu Z, Pimentel DR, Xu XJ, Ruderman NB, Huffman KD, Doctrow SR, Richey L, Colucci WS, Shirihai OS. Mitochondrial transporter ATP binding cassette mitochondrial erythroid is a novel gene required for cardiac recovery after ischemia/reperfusion. Circulation. 2011 Aug 16; 124(7):806-13.
	View in: PubMed

10.	Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, Yaroshinsky A, Zsebo KM, Dittrich H, Hajjar RJ. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation. 2011 Jul 19; 124(3):304-13.
	View in: PubMed

11.	Papanicolaou KN, Khairallah RJ, Ngoh GA, Chikando A, Luptak I, O’Shea KM, Riley DD, Lugus JJ, Colucci WS, Lederer WJ, Stanley WC, Walsh K. Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol Cell Biol. 2011 Mar; 31(6):1309-28.
	View in: PubMed

12.	Kivikko M, Sundberg S, Karlsson MO, Pohjanjousi P, Colucci WS. Acetylation status does not affect levosimendan’s hemodynamic effects in heart failure patients. Scand Cardiovasc J. 2011 Apr; 45(2):86-90.
	View in: PubMed

13.	Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011 Jan 6; 364(1):11-21.
	View in: PubMed

14.	Velagaleti RS, Gona P, Sundström J, Larson MG, Siwik D, Colucci WS, Benjamin EJ, Vasan RS. Relations of biomarkers of extracellular matrix remodeling to incident cardiovascular events and mortality. Arterioscler Thromb Vasc Biol. 2010 Nov; 30(11):2283-8.
	View in: PubMed

15.	Lancel S, Qin F, Lennon SL, Zhang J, Tong X, Mazzini MJ, Kang YJ, Siwik DA, Cohen RA, Colucci WS. Oxidative posttranslational modifications mediate decreased SERCA activity and myocyte dysfunction in Galphaq-overexpressing mice. Circ Res. 2010 Jul 23; 107(2):228-32.
	View in: PubMed

16.	Jeong MY, Walker JS, Brown RD, Moore RL, Vinson CS, Colucci WS, Long CS. AFos inhibits phenylephrine-mediated contractile dysfunction by altering phospholamban phosphorylation. Am J Physiol Heart Circ Physiol. 2010 Jun; 298(6):H1719-26.
	View in: PubMed

17.	Kuster GM, Lancel S, Zhang J, Communal C, Trucillo MP, Lim CC, Pfister O, Weinberg EO, Cohen RA, Liao R, Siwik DA, Colucci WS. Redox-mediated reciprocal regulation of SERCA and Na+-Ca2+ exchanger contributes to sarcoplasmic reticulum Ca2+ depletion in cardiac myocytes. Free Radic Biol Med. 2010 May 1; 48(9):1182-7.
	View in: PubMed

18.	Qin F, Lennon-Edwards S, Lancel S, Biolo A, Siwik DA, Pimentel DR, Dorn GW, Kang YJ, Colucci WS. Cardiac-specific overexpression of catalase identifies hydrogen peroxide-dependent and -independent phases of myocardial remodeling and prevents the progression to overt heart failure in G(alpha)q-overexpressing transgenic mice. Circ Heart Fail. 2010 Mar; 3(2):306-13.
	View in: PubMed

19.	Biolo A, Fisch M, Balog J, Chao T, Schulze PC, Ooi H, Siwik D, Colucci WS. Episodes of acute heart failure syndrome are associated with increased levels of troponin and extracellular matrix markers. Circ Heart Fail. 2010 Jan; 3(1):44-50.
	View in: PubMed

20.	Lazar HL, Bao Y, Siwik D, Frame J, Mateo CS, Colucci WS. Nesiritide enhances myocardial protection during the revascularization of acutely ischemic myocardium. J Card Surg. 2009 Sep-Oct; 24(5):600-5.
	View in: PubMed

21.	Lancel S, Zhang J, Evangelista A, Trucillo MP, Tong X, Siwik DA, Cohen RA, Colucci WS. Nitroxyl activates SERCA in cardiac myocytes via glutathiolation of cysteine 674. Circ Res. 2009 Mar 27; 104(6):720-3.
	View in: PubMed

22.	Dhingra R, Pencina MJ, Schrader P, Wang TJ, Levy D, Pencina K, Siwik DA, Colucci WS, Benjamin EJ, Vasan RS. Relations of matrix remodeling biomarkers to blood pressure progression and incidence of hypertension in the community. Circulation. 2009 Mar 3; 119(8):1101-7.
	View in: PubMed

23.	Biolo A, Greferath R, Siwik DA, Qin F, Valsky E, Fylaktakidou KC, Pothukanuri S, Duarte CD, Schwarz RP, Lehn JM, Nicolau C, Colucci WS. Enhanced exercise capacity in mice with severe heart failure treated with an allosteric effector of hemoglobin, myo-inositol trispyrophosphate. Proc Natl Acad Sci U S A. 2009 Feb 10; 106(6):1926-9.
	View in: PubMed

24.	Brooks WW, Conrad CH, Robinson KG, Colucci WS, Bing OH. L-arginine fails to prevent ventricular remodeling and heart failure in the spontaneously hypertensive rat. Am J Hypertens. 2009 Feb; 22(2):228-34.
	View in: PubMed

25.	Holubarsch CJ, Colucci WS, Meinertz T, Gaus W, Tendera M. The efficacy and safety of Crataegus extract WS 1442 in patients with heart failure: the SPICE trial. Eur J Heart Fail. 2008 Dec; 10(12):1255-63.
	View in: PubMed

26.	Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation. 2008 Aug 19; 118(8):863-71.
	View in: PubMed

27.	Hare JM, Mangal B, Brown J, Fisher C, Freudenberger R, Colucci WS, Mann DL, Liu P, Givertz MM, Schwarz RP. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study. J Am Coll Cardiol. 2008 Jun 17; 51(24):2301-9.
	View in: PubMed

28.	Torre-Amione G, Anker SD, Bourge RC, Colucci WS, Greenberg BH, Hildebrandt P, Keren A, Motro M, Moyé LA, Otterstad JE, Pratt CM, Ponikowski P, Rouleau JL, Sestier F, Winkelmann BR, Young JB. Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): a placebo-controlled randomised trial. Lancet. 2008 Jan 19; 371(9608):228-36.
	View in: PubMed

29.	Fonarow GC, Lukas MA, Robertson M, Colucci WS, Dargie HJ. Effects of carvedilol early after myocardial infarction: analysis of the first 30 days in Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN). Am Heart J. 2007 Oct; 154(4):637-44.
	View in: PubMed

30.	Wang TJ, Larson MG, Benjamin EJ, Siwik DA, Safa R, Guo CY, Corey D, Sundstrom J, Sawyer DB, Colucci WS, Vasan RS. Clinical and echocardiographic correlates of plasma procollagen type III amino-terminal peptide levels in the community. Am Heart J. 2007 Aug; 154(2):291-7.
	View in: PubMed

31.	Colucci WS, Kolias TJ, Adams KF, Armstrong WF, Ghali JK, Gottlieb SS, Greenberg B, Klibaner MI, Kukin ML, Sugg JE. Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction: the REversal of VEntricular Remodeling with Toprol-XL (REVERT) trial. Circulation. 2007 Jul 3; 116(1):49-56.
	View in: PubMed

32.	Torre-Amione G, Bourge RC, Colucci WS, Greenberg B, Pratt C, Rouleau JL, Sestier F, Moyé LA, Geddes JA, Nemet AJ, Young JB. A study to assess the effects of a broad-spectrum immune modulatory therapy on mortality and morbidity in patients with chronic heart failure: the ACCLAIM trial rationale and design. Can J Cardiol. 2007 Apr; 23(5):369-76.
	View in: PubMed

33.	Shibata R, Izumiya Y, Sato K, Papanicolaou K, Kihara S, Colucci WS, Sam F, Ouchi N, Walsh K. Adiponectin protects against the development of systolic dysfunction following myocardial infarction. J Mol Cell Cardiol. 2007 Jun; 42(6):1065-74.
	View in: PubMed

34.	Givertz MM, Andreou C, Conrad CH, Colucci WS. Direct myocardial effects of levosimendan in humans with left ventricular dysfunction: alteration of force-frequency and relaxation-frequency relationships. Circulation. 2007 Mar 13; 115(10):1218-24.
	View in: PubMed

35.	Louhelainen M, Vahtola E, Kaheinen P, Leskinen H, Merasto S, Kytö V, Finckenberg P, Colucci WS, Levijoki J, Pollesello P, Haikala H, Mervaala EM. Effects of levosimendan on cardiac remodeling and cardiomyocyte apoptosis in hypertensive Dahl/Rapp rats. Br J Pharmacol. 2007 Apr; 150(7):851-61.
	View in: PubMed

36.	Kuster GM, Siwik DA, Pimentel DR, Colucci WS. Role of reversible, thioredoxin-sensitive oxidative protein modifications in cardiac myocytes. Antioxid Redox Signal. 2006 Nov-Dec; 8(11-12):2153-9.
	View in: PubMed

37.	Arnlöv J, Evans JC, Benjamin EJ, Larson MG, Levy D, Sutherland P, Siwik DA, Wang TJ, Colucci WS, Vasan RS. Clinical and echocardiographic correlates of plasma osteopontin in the community: the Framingham Heart Study. Heart. 2006 Oct; 92(10):1514-5.
	View in: PubMed

38.	Pimentel DR, Adachi T, Ido Y, Heibeck T, Jiang B, Lee Y, Melendez JA, Cohen RA, Colucci WS. Strain-stimulated hypertrophy in cardiac myocytes is mediated by reactive oxygen species-dependent Ras S-glutathiolation. J Mol Cell Cardiol. 2006 Oct; 41(4):613-22.
	View in: PubMed

39.	Gheorghiade M, van Veldhuisen DJ, Colucci WS. Contemporary use of digoxin in the management of cardiovascular disorders. Circulation. 2006 May 30; 113(21):2556-64.
	View in: PubMed

40.	De Luca L, Colucci WS, Nieminen MS, Massie BM, Gheorghiade M. Evidence-based use of levosimendan in different clinical settings. Eur Heart J. 2006 Aug; 27(16):1908-20.
	View in: PubMed

41.	Cohn JN, Colucci W. Cardiovascular effects of aldosterone and post-acute myocardial infarction pathophysiology. Am J Cardiol. 2006 May 22; 97(10A):4F-12F.
	View in: PubMed

42.	Izumiya Y, Shiojima I, Sato K, Sawyer DB, Colucci WS, Walsh K. Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload. Hypertension. 2006 May; 47(5):887-93.
	View in: PubMed

43.	Kotlyar E, Vita JA, Winter MR, Awtry EH, Siwik DA, Keaney JF, Sawyer DB, Cupples LA, Colucci WS, Sam F. The relationship between aldosterone, oxidative stress, and inflammation in chronic, stable human heart failure. J Card Fail. 2006 Mar; 12(2):122-7.
	View in: PubMed

44.	Ahmed A, Rich MW, Love TE, Lloyd-Jones DM, Aban IB, Colucci WS, Adams KF, Gheorghiade M. Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial. Eur Heart J. 2006 Jan; 27(2):178-86.
	View in: PubMed

45.	Bianchi P, Kunduzova O, Masini E, Cambon C, Bani D, Raimondi L, Seguelas MH, Nistri S, Colucci W, Leducq N, Parini A. Oxidative stress by monoamine oxidase mediates receptor-independent cardiomyocyte apoptosis by serotonin and postischemic myocardial injury. Circulation. 2005 Nov 22; 112(21):3297-305.
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46.	Maytin M, Colucci WS. Cardioprotection: a new paradigm in the management of acute heart failure syndromes. Am J Cardiol. 2005 Sep 19; 96(6A):26G-31G.
	View in: PubMed

47.	Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci WS, Walsh K. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest. 2005 Aug; 115(8):2108-18.
	View in: PubMed

48.	Sam F, Kerstetter DL, Pimental DR, Mulukutla S, Tabaee A, Bristow MR, Colucci WS, Sawyer DB. Increased reactive oxygen species production and functional alterations in antioxidant enzymes in human failing myocardium. J Card Fail. 2005 Aug; 11(6):473-80.
	View in: PubMed

49.	Rude MK, Duhaney TA, Kuster GM, Judge S, Heo J, Colucci WS, Siwik DA, Sam F. Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. Hypertension. 2005 Sep; 46(3):555-61.
	View in: PubMed

50.	Pfister O, Mouquet F, Jain M, Summer R, Helmes M, Fine A, Colucci WS, Liao R. CD31- but Not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res. 2005 Jul 8; 97(1):52-61.
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51.	Communal C, Colucci WS. The control of cardiomyocyte apoptosis via the beta-adrenergic signaling pathways. Arch Mal Coeur Vaiss. 2005 Mar; 98(3):236-41.
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52.	Kuster GM, Pimentel DR, Adachi T, Ido Y, Brenner DA, Cohen RA, Liao R, Siwik DA, Colucci WS. Alpha-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes is mediated via thioredoxin-1-sensitive oxidative modification of thiols on Ras. Circulation. 2005 Mar 8; 111(9):1192-8.
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53.	McMurray J, Køber L, Robertson M, Dargie H, Colucci W, Lopez-Sendon J, Remme W, Sharpe DN, Ford I. Antiarrhythmic effect of carvedilol after acute myocardial infarction: results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial. J Am Coll Cardiol. 2005 Feb 15; 45(4):525-30.
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54.	Bianchi P, Pimentel DR, Murphy MP, Colucci WS, Parini A. A new hypertrophic mechanism of serotonin in cardiac myocytes: receptor-independent ROS generation. FASEB J. 2005 Apr; 19(6):641-3.
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55.	Kuster GM, Kotlyar E, Rude MK, Siwik DA, Liao R, Colucci WS, Sam F. Mineralocorticoid receptor inhibition ameliorates the transition to myocardial failure and decreases oxidative stress and inflammation in mice with chronic pressure overload. Circulation. 2005 Feb 1; 111(4):420-7.
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56.	Taniyama Y, Ito M, Sato K, Kuester C, Veit K, Tremp G, Liao R, Colucci WS, Ivashchenko Y, Walsh K, Shiojima I. Akt3 overexpression in the heart results in progression from adaptive to maladaptive hypertrophy. J Mol Cell Cardiol. 2005 Feb; 38(2):375-85.
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57.	Colucci WS (Editor): Atlas of Heart Failure – Cardiac Function and Dysfunction, Fourth Edition, Braunwald E (Series Editor). Current Medicine. 2005.

58.	Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, Kumada M, Sato K, Schiekofer S, Ohashi K, Funahashi T, Colucci WS, Walsh K. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med. 2004 Dec; 10(12):1384-9.
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59.	Freudenberger RS, Schwarz RP, Brown J, Moore A, Mann D, Givertz MM, Colucci WS, Hare JM. Rationale, design and organisation of an efficacy and safety study of oxypurinol added to standard therapy in patients with NYHA class III – IV congestive heart failure. Expert Opin Investig Drugs. 2004 Nov; 13(11):1509-16.
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60.	Trueblood NA, Inscore PR, Brenner D, Lugassy D, Apstein CS, Sawyer DB, Colucci WS. Biphasic temporal pattern in exercise capacity after myocardial infarction in the rat: relationship to left ventricular remodeling. Am J Physiol Heart Circ Physiol. 2005 Jan; 288(1):H244-9.
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61.	Sundström J, Evans JC, Benjamin EJ, Levy D, Larson MG, Sawyer DB, Siwik DA, Colucci WS, Wilson PW, Vasan RS. Relations of plasma total TIMP-1 levels to cardiovascular risk factors and echocardiographic measures: the Framingham heart study. Eur Heart J. 2004 Sep; 25(17):1509-16.
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62.	Ito M, Adachi T, Pimentel DR, Ido Y, Colucci WS. Statins inhibit beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes via a Rac1-dependent mechanism. Circulation. 2004 Jul 27; 110(4):412-8.
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63.	Gheorghiade M, Adams KF, Colucci WS. Digoxin in the management of cardiovascular disorders. Circulation. 2004 Jun 22; 109(24):2959-64.
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64.	Sundström J, Evans JC, Benjamin EJ, Levy D, Larson MG, Sawyer DB, Siwik DA, Colucci WS, Sutherland P, Wilson PW, Vasan RS. Relations of plasma matrix metalloproteinase-9 to clinical cardiovascular risk factors and echocardiographic left ventricular measures: the Framingham Heart Study. Circulation. 2004 Jun 15; 109(23):2850-6.
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65.	Colucci WS. Landmark study: the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction Study (CAPRICORN). Am J Cardiol. 2004 May 6; 93(9A):13B-6B.
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66.	Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, Djian J, Drexler H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, van Veldhuisen DJ, Waldenstrom A, Warren M, Westheim A, Zannad F, Fleming T. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004 Apr 6; 109(13):1594-602.
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67.	Vasan RS, Evans JC, Benjamin EJ, Levy D, Larson MG, Sundstrom J, Murabito JM, Sam F, Colucci WS, Wilson PW. Relations of serum aldosterone to cardiac structure: gender-related differences in the Framingham Heart Study. Hypertension. 2004 May; 43(5):957-62.
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68.	Maytin M, Siwik DA, Ito M, Xiao L, Sawyer DB, Liao R, Colucci WS. Pressure overload-induced myocardial hypertrophy in mice does not require gp91phox. Circulation. 2004 Mar 9; 109(9):1168-71.
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69.	Sam F, Xie Z, Ooi H, Kerstetter DL, Colucci WS, Singh M, Singh K. Mice lacking osteopontin exhibit increased left ventricular dilation and reduced fibrosis after aldosterone infusion. Am J Hypertens. 2004 Feb; 17(2):188-93.
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70.	Giles TD, Chatterjee K, Cohn JN, Colucci WS, Feldman AM, Ferrans VJ, Roberts R. Definition, classification, and staging of the adult cardiomyopathies: a proposal for revision. J Card Fail. 2004 Feb; 10(1):6-8.
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71.	Siwik DA, Colucci WS. Regulation of matrix metalloproteinases by cytokines and reactive oxygen/nitrogen species in the myocardium. Heart Fail Rev. 2004 Jan; 9(1):43-51.
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72.	Sawyer DB, Colucci WS. Oxidative stress in heart failure; (Chapter 12). In: Mann DL (ed) Heart Failure: A Companion to Braunwald’s Heart Disease. Saunders. 2004; 181-92.

73.	Maytin M, Sawyer DB and Colucci WS. Role of reactive oxygen species in the regulation of cardiac myocyte phenotype. In: Pathophysiology of Cardiovascular Disease. Dhalla NS, Rupp H, Angel A and Pierce GN (eds). 51-7:Kluwer Academic Publishers . 2004.

74.	Kuramochi Y, Lim CC, Guo X, Colucci WS, Liao R, Sawyer DB. Myocyte contractile activity modulates norepinephrine cytotoxicity and survival effects of neuregulin-1beta. Am J Physiol Cell Physiol. 2004 Feb; 286(2):C222-9.
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75.	Torre-Amione G, Young JB, Colucci WS, Lewis BS, Pratt C, Cotter G, Stangl K, Elkayam U, Teerlink JR, Frey A, Rainisio M, Kobrin I. Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol. 2003 Jul 2; 42(1):140-7.
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76.	Kwon SH, Pimentel DR, Remondino A, Sawyer DB, Colucci WS. H(2)O(2) regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathways. J Mol Cell Cardiol. 2003 Jun; 35(6):615-21.
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77.	Communal C, Singh M, Menon B, Xie Z, Colucci WS, Singh K. beta1 integrins expression in adult rat ventricular myocytes and its role in the regulation of beta-adrenergic receptor-stimulated apoptosis. J Cell Biochem. 2003 May 15; 89(2):381-8.
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78.	Gheorghiade M, Colucci WS, Swedberg K. Beta-blockers in chronic heart failure. Circulation. 2003 Apr 1; 107(12):1570-5.
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79.	Remondino A, Kwon SH, Communal C, Pimentel DR, Sawyer DB, Singh K, Colucci WS. Beta-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway. Circ Res. 2003 Feb 7; 92(2):136-8.
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80.	Kivikko M, Lehtonen L, Colucci WS. Sustained hemodynamic effects of intravenous levosimendan. Circulation. 2003 Jan 7; 107(1):81-6.
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81.	Sam F, Sawyer DB and Colucci WS. Myocardial nitric oxide in cardiac remodeling. In: Inflammation and Cardiac Diseases. Feuerstein GZ, Libby P and Mann DL (eds). Birkhäuser. 2003; 155-170.

82.	Siwik DA, Pimentel DR, Xiao L, Singh K, Sawyer DB, and Colucci WS. Adrenergic and mechanical regulation of oxidative stress in the myocardium. In: Kukin ML, Fuster V (eds). Oxidative Stress and Cardiac Failure. Armonk, NY:Futura Publishing Co., Inc.. 2003; 153-171.

83.	Ooi H, Colucci WS, Givertz MM. Endothelin mediates increased pulmonary vascular tone in patients with heart failure: demonstration by direct intrapulmonary infusion of sitaxsentan. Circulation. 2002 Sep 24; 106(13):1618-21.
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84.	Hare JM, Nguyen GC, Massaro AF, Drazen JM, Stevenson LW, Colucci WS, Fang JC, Johnson W, Givertz MM, Lucas C. Exhaled nitric oxide: a marker of pulmonary hemodynamics in heart failure. J Am Coll Cardiol. 2002 Sep 18; 40(6):1114-9.
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85.	Maytin M, Colucci WS. Molecular and cellular mechanisms of myocardial remodeling. J Nucl Cardiol. 2002 May-Jun; 9(3):319-27.
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86.	Xiao L, Pimentel DR, Wang J, Singh K, Colucci WS, Sawyer DB. Role of reactive oxygen species and NAD(P)H oxidase in alpha(1)-adrenoceptor signaling in adult rat cardiac myocytes. Am J Physiol Cell Physiol. 2002 Apr; 282(4):C926-34.
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87.	Sawyer DB, Siwik DA, Xiao L, Pimentel DR, Singh K, Colucci WS. Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol. 2002 Apr; 34(4):379-88.
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88.	Communal C, Colucci WS, Remondino A, Sawyer DB, Port JD, Wichman SE, Bristow MR, Singh K. Reciprocal modulation of mitogen-activated protein kinases and mitogen-activated protein kinase phosphatase 1 and 2 in failing human myocardium. J Card Fail. 2002 Apr; 8(2):86-92.
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89.	Cuffe MS, Califf RM, Adams KF, Benza R, Bourge R, Colucci WS, Massie BM, O’Connor CM, Pina I, Quigg R, Silver MA, Gheorghiade M. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002 Mar 27; 287(12):1541-7.
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90.	Leier CV, Silver MA, Rich MW, Eichhorn EJ, Fowler MB, Giles TD, Johnstone DE, Le Jemtel TH, Lachmann JS, Levine TB, Armstrong PW, Dec WG, Jessup M, Howlett J, Hershberger RE, Cohn JN, Adams KF, Colucci WS, Warner-Stevenson L, Hosenpud JD, Bristow MR, Pina I, Baughman KL, Binkley PF, Ventura HO, Francis GS, White M, Miller LW, Berry B, Missov E. Nuggets, pearls, and vignettes of master heart failure clinicians. Part 4–treatment. Congest Heart Fail. 2002 Mar-Apr; 8(2):98-124.
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91.	Colucci WS (Section Editor, “Heart Failure”): In: Cardiovascular Therapeutics, Antman E (Editor-in-Chief) Philadelphia: Saunders, 2002. . Colucci WS (Section Editor, “Heart Failure”). In: Cardiovascular Therapeutics, Antman E (Editor-in-Chief). Saunders. 2002.

92.	Sawyer DB, Colucci WS. Molecular and cellular events in myocardial hypertrophy and failure. In: “Heart Failure: Cardiac Function and Dysfunction”, Colucci WS (ed): In: Atlas of Heart Diseases, Third Edition, Braunwald E (Editor-in-Chief). Philadelphia:Current Medicine. 2002.

93.	Givertz MM, Colucci WS. Beta-Blockers. In: “Heart Failure: Cardiac Function and Dysfunction”, Colucci WS (ed): In: Atlas of Heart Diseases, Third Edition, Braunwald E (Editor-in-Chief). Philadelphia:Current Medicine. 2002.

94.	Givertz MM, Colucci WS. Treatment of heart failure: New approaches. In: “Heart Failure: Cardiac Function and Dysfunction”, Colucci WS (ed): In: Atlas of Heart Diseases, Third Edition, Braunwald E (Editor-in-Chief). Philadelphia:Current Medicine. 2002.

95.	Colucci WS (Editor): Atlas of Heart Failure – Cardiac Function and Dysfunction, Third Edition, Braunwald E (Series Editor). Philadelphia:Current Medicine. 2002.

96.	Singh K, Xiao L, Remondino A, Sawyer DB, Colucci WS. Adrenergic regulation of cardiac myocyte apoptosis. J Cell Physiol. 2001 Dec; 189(3):257-65.
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97.	Pimentel DR, Amin JK, Xiao L, Miller T, Viereck J, Oliver-Krasinski J, Baliga R, Wang J, Siwik DA, Singh K, Pagano P, Colucci WS, Sawyer DB. Reactive oxygen species mediate amplitude-dependent hypertrophic and apoptotic responses to mechanical stretch in cardiac myocytes. Circ Res. 2001 Aug 31; 89(5):453-60.
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98.	Sam F, Sawyer DB, Xie Z, Chang DL, Ngoy S, Brenner DA, Siwik DA, Singh K, Apstein CS, Colucci WS. Mice lacking inducible nitric oxide synthase have improved left ventricular contractile function and reduced apoptotic cell death late after myocardial infarction. Circ Res. 2001 Aug 17; 89(4):351-6.
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99.	Xie Z, Pimental DR, Lohan S, Vasertriger A, Pligavko C, Colucci WS, Singh K. Regulation of angiotensin II-stimulated osteopontin expression in cardiac microvascular endothelial cells: role of p42/44 mitogen-activated protein kinase and reactive oxygen species. J Cell Physiol. 2001 Jul; 188(1):132-8.
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100.	Loh E, Elkayam U, Cody R, Bristow M, Jaski B, Colucci WS. A randomized multicenter study comparing the efficacy and safety of intravenous milrinone and intravenous nitroglycerin in patients with advanced heart failure. J Card Fail. 2001 Jun; 7(2):114-21.
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101.	Trueblood NA, Xie Z, Communal C, Sam F, Ngoy S, Liaw L, Jenkins AW, Wang J, Sawyer DB, Bing OH, Apstein CS, Colucci WS, Singh K. Exaggerated left ventricular dilation and reduced collagen deposition after myocardial infarction in mice lacking osteopontin. Circ Res. 2001 May 25; 88(10):1080-7.
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102.	Givertz MM, Slawsky MT, Moraes DL, McIntyre KM, Colucci WS. Noninvasive determination of pulmonary artery wedge pressure in patients with chronic heart failure. Am J Cardiol. 2001 May 15; 87(10):1213-5; A7.
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103.	Yancy CW, Fowler MB, Colucci WS, Gilbert EM, Bristow MR, Cohn JN, Lukas MA, Young ST, Packer M. Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure. N Engl J Med. 2001 May 3; 344(18):1358-65.
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104.	Fowler MB, Vera-Llonch M, Oster G, Bristow MR, Cohn JN, Colucci WS, Gilbert EM, Lukas MA, Lacey MJ, Richner R, Young ST, Packer M. Influence of carvedilol on hospitalizations in heart failure: incidence, resource utilization and costs. U.S. Carvedilol Heart Failure Study Group. J Am Coll Cardiol. 2001 May; 37(6):1692-9.
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105.	Jain M, DerSimonian H, Brenner DA, Ngoy S, Teller P, Edge AS, Zawadzka A, Wetzel K, Sawyer DB, Colucci WS, Apstein CS, Liao R. Cell therapy attenuates deleterious ventricular remodeling and improves cardiac performance after myocardial infarction. Circulation. 2001 Apr 10; 103(14):1920-7.
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106.	Xiao L, Pimental DR, Amin JK, Singh K, Sawyer DB, Colucci WS. MEK1/2-ERK1/2 mediates alpha1-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes. J Mol Cell Cardiol. 2001 Apr; 33(4):779-87.
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107.	Podesser BK, Siwik DA, Eberli FR, Sam F, Ngoy S, Lambert J, Ngo K, Apstein CS, Colucci WS. ET(A)-receptor blockade prevents matrix metalloproteinase activation late postmyocardial infarction in the rat. Am J Physiol Heart Circ Physiol. 2001 Mar; 280(3):H984-91.
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108.	Colucci WS. Nesiritide for the treatment of decompensated heart failure. J Card Fail. 2001 Mar; 7(1):92-100.
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109.	Givertz MM, Sawyer DB, Colucci WS. Antioxidants and myocardial contractility: illuminating the “Dark Side” of beta-adrenergic receptor activation? Circulation. 2001 Feb 13; 103(6):782-3.
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110.	Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol. 2001 Jan; 280(1):C53-60.
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111.	Amin JK, Xiao L, Pimental DR, Pagano PJ, Singh K, Sawyer DB, Colucci WS. Reactive oxygen species mediate alpha-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes. J Mol Cell Cardiol. 2001 Jan; 33(1):131-9.
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112.	Ooi H and Colucci WS. Pharmacological Treatment of Heart Failure; (Chapter 34). In: Hardman JG, Limbird LE and Gilman AG (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th Edition, McGraw Hill. McGraw Hill. 2001; 901-932.

113.	Colucci WS and Braunwald E. Pathophysiology of Heart Failure, (Chapter 16). In: Braunwald E (ed): Heart Disease. 6th Edition. Philadelphia:WB Saunders Co. 2001; 503-533.

114.	Colucci WS and Schoen FJ. Primary Tumors of the Heart; (Chapter 49). In: Braunwald E. (ed): Heart Disease. 6th Edition. Philadelphia:WB Saunders Co. 2001; 1807-22.

115.	Ooi H and Colucci WS. Congestive Heart Failure. In: Rakel & Bope: Conn’s Current Therapy. Philadelphia:WB Saunders Co. 2001; pp. 310-14.

116.	Colucci WS. Heart Failure. In: Essential Atlas of Heart Diseases, Second Edition, Braunwald E (Editor–in-Chief). Philadelphia:Current Medicine. 2001.

117.	Holubarsch CJ, Colucci WS, Meinertz T, Gaus W, Tendera M. Survival and prognosis: investigation of Crataegus extract WS 1442 in congestive heart failure (SPICE)–rationale, study design and study protocol. Eur J Heart Fail. 2000 Dec; 2(4):431-7.
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118.	Lim CC, Apstein CS, Colucci WS, Liao R. Impaired cell shortening and relengthening with increased pacing frequency are intrinsic to the senescent mouse cardiomyocyte. J Mol Cell Cardiol. 2000 Nov; 32(11):2075-82.
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119.	Nagata K, Communal C, Lim CC, Jain M, Suter TM, Eberli FR, Satoh N, Colucci WS, Apstein CS, Liao R. Altered beta-adrenergic signal transduction in nonfailing hypertrophied myocytes from Dahl salt-sensitive rats. Am J Physiol Heart Circ Physiol. 2000 Nov; 279(5):H2502-8.
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120.	Slawsky MT, Colucci WS, Gottlieb SS, Greenberg BH, Haeusslein E, Hare J, Hutchins S, Leier CV, LeJemtel TH, Loh E, Nicklas J, Ogilby D, Singh BN, Smith W. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators. Circulation. 2000 Oct 31; 102(18):2222-7.
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121.	Satoh N, Suter TM, Liao R, Colucci WS. Chronic alpha-adrenergic receptor stimulation modulates the contractile phenotype of cardiac myocytes in vitro. Circulation. 2000 Oct 31; 102(18):2249-54.
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122.	Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation. 2000 Oct 3; 102(14):1718-23.
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123.	Singh K, Communal C, Colucci WS. Inhibition of protein phosphatase 1 induces apoptosis in neonatal rat cardiac myocytes: role of adrenergic receptor stimulation. Basic Res Cardiol. 2000 Oct; 95(5):389-96.
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124.	Colucci WS, Elkayam U, Horton DP, Abraham WT, Bourge RC, Johnson AD, Wagoner LE, Givertz MM, Liang CS, Neibaur M, Haught WH, LeJemtel TH. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. N Engl J Med. 2000 Jul 27; 343(4):246-53.
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125.	Sam F, Sawyer DB, Chang DL, Eberli FR, Ngoy S, Jain M, Amin J, Apstein CS, Colucci WS. Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart. Am J Physiol Heart Circ Physiol. 2000 Jul; 279(1):H422-8.
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126.	Givertz MM, Colucci WS, LeJemtel TH, Gottlieb SS, Hare JM, Slawsky MT, Leier CV, Loh E, Nicklas JM, Lewis BE. Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation. 2000 Jun 27; 101(25):2922-7.
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127.	Siwik DA, Chang DL, Colucci WS. Interleukin-1beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circ Res. 2000 Jun 23; 86(12):1259-65.
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128.	Communal C, Colucci WS, Singh K. p38 mitogen-activated protein kinase pathway protects adult rat ventricular myocytes against beta -adrenergic receptor-stimulated apoptosis. Evidence for Gi-dependent activation. J Biol Chem. 2000 Jun 23; 275(25):19395-400.
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129.	Brooks WW, Bing OH, Boluyt MO, Malhotra A, Morgan JP, Satoh N, Colucci WS, Conrad CH. Altered inotropic responsiveness and gene expression of hypertrophied myocardium with captopril. Hypertension. 2000 Jun; 35(6):1203-9.
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130.	Sanders GP, Mendes LA, Colucci WS, Givertz MM. Noninvasive methods for detecting elevated left-sided cardiac filling pressure. J Card Fail. 2000 Jun; 6(2):157-64.
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131.	Colucci WS, Sawyer DB, Singh K, Communal C. Adrenergic overload and apoptosis in heart failure: implications for therapy. J Card Fail. 2000 Jun; 6(2 Suppl 1):1-7.
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132.	Bisognano JD, Weinberger HD, Bohlmeyer TJ, Pende A, Raynolds MV, Sastravaha A, Roden R, Asano K, Blaxall BC, Wu SC, Communal C, Singh K, Colucci W, Bristow MR, Port DJ. Myocardial-directed overexpression of the human beta(1)-adrenergic receptor in transgenic mice. J Mol Cell Cardiol. 2000 May; 32(5):817-30.
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133.	Sawyer DB, Colucci WS. Mitochondrial oxidative stress in heart failure: “oxygen wastage” revisited. Circ Res. 2000 Feb 4; 86(2):119-20.
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134.	Singh K, Communal C, Sawyer DB, Colucci WS. Adrenergic regulation of myocardial apoptosis. Cardiovasc Res. 2000 Feb; 45(3):713-9.
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135.	Cuffe MS, Califf RM, Adams KF, Bourge RC, Colucci W, Massie B, O’Connor CM, Pina I, Quigg R, Silver M, Robinson LA, Leimberger JD, Gheorghiade M. Rationale and design of the OPTIME CHF trial: outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure. Am Heart J. 2000 Jan; 139(1 Pt 1):15-22.
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136.	Sawyer DB, Colucci, WS. Myocardial Nitric Oxide in Heart Failure. In: Loscalzo J and Vita JA, (ed): Contemporary Cardiology: Nitric Oxide and the Cardiovascular System. Totowa, NJ:Humana Press Inc. 2000; pp. 309-19.

137.	Sawyer DB, Colucci WS. Role of oxidative stress, cytokines and apoptosis in myocardial dysfunction. In: Tardiff J-C and Bourassa MG, ed. Antioxidants and Cardiovascular Disease. Dordrecht:Kluwar. 2000.

138.	Communal C, Singh K, Sawyer DB, Colucci WS. Opposing effects of beta(1)- and beta(2)-adrenergic receptors on cardiac myocyte apoptosis : role of a pertussis toxin-sensitive G protein. Circulation. 1999 Nov 30; 100(22):2210-2.
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139.	Sam F, Colucci WS. Role of endothelin-1 in myocardial failure. Proc Assoc Am Physicians. 1999 Sep-Oct; 111(5):417-22.
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140.	Siwik DA, Tzortzis JD, Pimental DR, Chang DL, Pagano PJ, Singh K, Sawyer DB, Colucci WS. Inhibition of copper-zinc superoxide dismutase induces cell growth, hypertrophic phenotype, and apoptosis in neonatal rat cardiac myocytes in vitro. Circ Res. 1999 Jul 23; 85(2):147-53.
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141.	Singh K, Sirokman G, Communal C, Robinson KG, Conrad CH, Brooks WW, Bing OH, Colucci WS. Myocardial osteopontin expression coincides with the development of heart failure. Hypertension. 1999 Feb; 33(2):663-70.
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142.	Givertz MM, Colucci WS. Treatment of heart failure: New approaches. In: “Heart Failure: Cardiac Function and Dysfunction”, Colucci WS (ed): In: Atlas of Heart Diseases, Second Edition, Braunwald E (Editor-in-Chief). Philadelphia:Current Medicine. 1999.

143.	Colucci WS (Editor): Atlas of Heart Failure – Cardiac Function and Dysfunction, Second Edition, Braunwald E (Series Editor). Philadelphia:Current Medicine. 1999.

144.	Sawyer DB, Colucci WS. Molecular and cellular events in myocardial hypertrophy and failure. In: “Heart Failure: Cardiac Function and Dysfunction”, Colucci WS (ed): In: Atlas of Heart Diseases, Second Edition, Braunwald E (Editor-in-Chief). Philadelphia:Current Medicine. 1999.

145.	Colucci WS. The effects of norepinephrine on myocardial biology: implications for the therapy of heart failure. Clin Cardiol. 1998 Dec; 21(12 Suppl 1):I20-4.
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146.	Sawyer DB, Colucci WS. Nitric oxide in the failing myocardium. Cardiol Clin. 1998 Nov; 16(4):657-64, viii.
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147.	Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation. 1998 Sep 29; 98(13):1329-34.
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148.	Sam F, Colucci WS. Endothelin-1 in heart failure: does it play a role? Cardiologia. 1998 Sep; 43(9):889-92.
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149.	Pagano PJ, Chanock SJ, Siwik DA, Colucci WS, Clark JK. Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts. Hypertension. 1998 Aug; 32(2):331-7.
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150.	Givertz MM, Colucci WS. New targets for heart-failure therapy: endothelin, inflammatory cytokines, and oxidative stress. Lancet. 1998 Aug; 352 Suppl 1:SI34-8.
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151.	Eberli FR, Sam F, Ngoy S, Apstein CS, Colucci WS. Left-ventricular structural and functional remodeling in the mouse after myocardial infarction: assessment with the isovolumetrically-contracting Langendorff heart. J Mol Cell Cardiol. 1998 Jul; 30(7):1443-7.
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152.	Lo MW, Toh J, Emmert SE, Ritter MA, Furtek CI, Lu H, Colucci WS, Uretsky BF, Rucinska E. Pharmacokinetics of intravenous and oral losartan in patients with heart failure. J Clin Pharmacol. 1998 Jun; 38(6):525-32.
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153.	Calderone A, Thaik CM, Takahashi N, Chang DL, Colucci WS. Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts. J Clin Invest. 1998 Feb 15; 101(4):812-8.
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154.	Hare JM, Givertz MM, Creager MA, Colucci WS. Increased sensitivity to nitric oxide synthase inhibition in patients with heart failure: potentiation of beta-adrenergic inotropic responsiveness. Circulation. 1998 Jan 20; 97(2):161-6.
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155.	Colucci WS. Molecular and cellular mechanisms of myocardial failure. Am J Cardiol. 1997 Dec 4; 80(11A):15L-25L.
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156.	Cohn JN, Fowler MB, Bristow MR, Colucci WS, Gilbert EM, Kinhal V, Krueger SK, Lejemtel T, Narahara KA, Packer M, Young ST, Holcslaw TL, Lukas MA. Safety and efficacy of carvedilol in severe heart failure. The U.S. Carvedilol Heart Failure Study Group. J Card Fail. 1997 Sep; 3(3):173-9.
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157.	Givertz MM, Hartley LH, Colucci WS. Long-term sequential changes in exercise capacity and chronotropic responsiveness after cardiac transplantation. Circulation. 1997 Jul 1; 96(1):232-7.
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158.	Hare JM, Shernan SK, Body SC, Graydon E, Colucci WS, Couper GS. Influence of inhaled nitric oxide on systemic flow and ventricular filling pressure in patients receiving mechanical circulatory assistance. Circulation. 1997 May 6; 95(9):2250-3.
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159.	Cohn JN, Bristow MR, Chien KR, Colucci WS, Frazier OH, Leinwand LA, Lorell BH, Moss AJ, Sonnenblick EH, Walsh RA, Mockrin SC, Reinlib L. Report of the National Heart, Lung, and Blood Institute Special Emphasis Panel on Heart Failure Research. Circulation. 1997 Feb 18; 95(4):766-70.
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160.	Colucci WS, Braunwald E. Cardiac tumors, cardiac manifestations of systemic diseases, and traumatic cardiac injury, Chapter 241. In: Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL, eds. Harrison’s Principles of Internal Medicine, 14th Edition. New York:McGraw-Hill. 1997; pp 1341-4.

161.	Colucci WS, Schoen FJ, Braunwald E. Primary tumors of the heart, Chapter 42. In: Braunwald E, ed. Heart Disease, 5th Edition. Philadelphia:WB Saunders Co. 1997; pp 1464-77.

162.	Colucci WS, Braunwald E. Pathophysiology of heart failure, Chapter 13. In: Braunwald E, ed. Heart Disease, 5th Edition. Philadelphia:WB Saunders Co. 1997; pp 394-420.

163.	Colucci WS. Heart Failure. In: Essential Atlas of Heart Diseases, First Edition, Braunwald E (Editor–in-Chief). Philadelphia:Current Medicine. 1997.

164.	Braunwald E, Colucci WS, Grossman W. Clinical aspects of heart failure, Chapter 15. In: Braunwald E, ed. Heart Disease, 5th Edition. Philadelphia:WB Saunders Co.. 1997; pp 445-70.

165.	Newton GE, Parker AB, Landzberg JS, Colucci WS, Parker JD. Muscarinic receptor modulation of basal and beta-adrenergic stimulated function of the failing human left ventricle. J Clin Invest. 1996 Dec 15; 98(12):2756-63.
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166.	Keaney JF, Hare JM, Balligand JL, Loscalzo J, Smith TW, Colucci WS. Inhibition of nitric oxide synthase augments myocardial contractile responses to beta-adrenergic stimulation. Am J Physiol. 1996 Dec; 271(6 Pt 2):H2646-52.
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167.	Faggiano P, Colucci WS. The force-frequency relation in normal and failing heart. Cardiologia. 1996 Dec; 41(12):1155-64.
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168.	Packer M, Colucci WS, Sackner-Bernstein JD, Liang CS, Goldscher DA, Freeman I, Kukin ML, Kinhal V, Udelson JE, Klapholz M, Gottlieb SS, Pearle D, Cody RJ, Gregory JJ, Kantrowitz NE, LeJemtel TH, Young ST, Lukas MA, Shusterman NH. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation. 1996 Dec 1; 94(11):2793-9.
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169.	Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN, Fowler MB, Krueger SK, Hershberger R, Uretsky BF, Bowers JA, Sackner-Bernstein JD, Young ST, Holcslaw TL, Lukas MA. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group. Circulation. 1996 Dec 1; 94(11):2800-6.
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170.	Givertz MM, Hare JM, Loh E, Gauthier DF, Colucci WS. Effect of bolus milrinone on hemodynamic variables and pulmonary vascular resistance in patients with severe left ventricular dysfunction: a rapid test for reversibility of pulmonary hypertension. J Am Coll Cardiol. 1996 Dec; 28(7):1775-80.
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171.	Colucci WS. Apoptosis in the heart. N Engl J Med. 1996 Oct 17; 335(16):1224-6.
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172.	Snider GL, Colucci WS, Sawin CT. A trial of increased access to primary care. N Engl J Med. 1996 Sep 19; 335(12):896; author reply 897-8.
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173.	Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996 May 23; 334(21):1349-55.
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174.	Colucci WS. Myocardial endothelin. Does it play a role in myocardial failure? Circulation. 1996 Mar 15; 93(6):1069-72.
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175.	Maki T, Gruver EJ, Davidoff AJ, Izzo N, Toupin D, Colucci W, Marks AR, Marsh JD. Regulation of calcium channel expression in neonatal myocytes by catecholamines. J Clin Invest. 1996 Feb 1; 97(3):656-63.
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176.	Colucci WS. Pathophysiologic and clinical considerations in the treatment of heart failure: An overview. Chapter 8. In: Cardiovascular Therapeutics, Smith TW (Editor-in-Chief). Philadelphia:WB Saunders. 1996; pp 171-175.

177.	Stevenson LW, Colucci WS. Management of patients hospitalized with heart failure, Chapter 10. In Cardiovascular Therapeutics, Smith TW (Editor-in-Chief). Philadelphia:WB Saunders. 1996; pp 199-209.

178.	Colucci WS. Principles and practice of inotropic therapy, Chapter 126. In: Messerli FH, ed. Cardiovascular Drug Therapy, 2nd Edition. Philadelphia:WB Saunders Co. 1996; pp 1146-1150.

179.	Colucci WS (Section Editor, “Heart Failure”). In: Cardiovascular Therapeutics, Smith TW (Editor-in-Chief). Philadelphia:Saunders. 1996.

180.	Calderone A, Takahashi N, Izzo NJ, Thaik CM, Colucci WS. Pressure- and volume-induced left ventricular hypertrophies are associated with distinct myocyte phenotypes and differential induction of peptide growth factor mRNAs. Circulation. 1995 Nov 1; 92(9):2385-90.
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181.	Hare JM, Loh E, Creager MA, Colucci WS. Nitric oxide inhibits the positive inotropic response to beta-adrenergic stimulation in humans with left ventricular dysfunction. Circulation. 1995 Oct 15; 92(8):2198-203.
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182.	Parker JD, Newton GE, Landzberg JS, Floras JS, Colucci WS. Functional significance of presynaptic alpha-adrenergic receptors in failing and nonfailing human left ventricle. Circulation. 1995 Oct 1; 92(7):1793-800.
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183.	Hare JM, Colucci WS. Role of nitric oxide in the regulation of myocardial function. Prog Cardiovasc Dis. 1995 Sep-Oct; 38(2):155-66.
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184.	Thaik CM, Calderone A, Takahashi N, Colucci WS. Interleukin-1 beta modulates the growth and phenotype of neonatal rat cardiac myocytes. J Clin Invest. 1995 Aug; 96(2):1093-9.
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185.	Levy AP, Levy NS, Loscalzo J, Calderone A, Takahashi N, Yeo KT, Koren G, Colucci WS, Goldberg MA. Regulation of vascular endothelial growth factor in cardiac myocytes. Circ Res. 1995 May; 76(5):758-66.
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186.	Loh E, Barnett JV, Feldman AM, Couper GS, Vatner DE, Colucci WS, Galper JB. Decreased adenylate cyclase activity and expression of Gs alpha in human myocardium after orthotopic cardiac transplantation. Circ Res. 1995 May; 76(5):852-60.
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187.	Hare JM, Keaney JF, Balligand JL, Loscalzo J, Smith TW, Colucci WS. Role of nitric oxide in parasympathetic modulation of beta-adrenergic myocardial contractility in normal dogs. J Clin Invest. 1995 Jan; 95(1):360-6.
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188.	Colucci WS (Editor): Atlas of Heart Failure – Cardiac Function and Dysfunction, First Edition, Braunwald E (Series Editor). Philadelphia:Current Medicine. 1995.

189.	Colucci WS. Treatment of stable heart failure: New approaches. In “Heart Failure: Cardiac Function and Dysfunction”, Colucci WS (ed): In: Atlas of Heart Diseases, Braunwald E (Editor-in-Chief). Philadelphia:Current Medicine. 1995.

190.	Thaik C, Colucci WS. Molecular and cellular abnormalities in hypertrophied and failing myocardium. In “Heart Failure: Cardiac Function and Dysfunction”, Colucci WS (ed): In: Atlas of Heart Diseases, Braunwald E (Editor-in-Chief). Philadelphia:Current Medicine. 1995.

191.	Colucci WS. Secondary molecular alterations in failing human myocardium. In: Molecular Interventions and Local Drug Delivery in Cardiovascular Disease, Edelman ER (ed). London:WB Saunders. 1995.

192.	Loh E, Stamler JS, Hare JM, Loscalzo J, Colucci WS. Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction. Circulation. 1994 Dec; 90(6):2780-5.
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193.	Takahashi N, Calderone A, Izzo NJ, Mäki TM, Marsh JD, Colucci WS. Hypertrophic stimuli induce transforming growth factor-beta 1 expression in rat ventricular myocytes. J Clin Invest. 1994 Oct; 94(4):1470-6.
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194.	Izzo NJ, Colucci WS. Regulation of alpha 1B-adrenergic receptor half-life: protein synthesis dependence and effect of norepinephrine. Am J Physiol. 1994 Mar; 266(3 Pt 1):C771-5.
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195.	Izzo NJ, Tulenko TN, Colucci WS. Phorbol esters and norepinephrine destabilize alpha 1B-adrenergic receptor mRNA in vascular smooth muscle cells. J Biol Chem. 1994 Jan 21; 269(3):1705-10.
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196.	Landzberg JS, Parker JD, Gauthier DF, Colucci WS. Effects of intracoronary acetylcholine and atropine on basal and dobutamine-stimulated left ventricular contractility. Circulation. 1994 Jan; 89(1):164-8.
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197.	Matoba Y, Colucci WS, Fields BN, Smith TW. The reovirus M1 gene determines the relative capacity of growth of reovirus in cultured bovine aortic endothelial cells. J Clin Invest. 1993 Dec; 92(6):2883-8.
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198.	Colucci WS, Sonnenblick EH, Adams KF, Berk M, Brozena SC, Cowley AJ, Grabicki JM, Kubo SA, LeJemtel T, Littler WA, et al. Efficacy of phosphodiesterase inhibition with milrinone in combination with converting enzyme inhibitors in patients with heart failure. The Milrinone Multicenter Trials Investigators. J Am Coll Cardiol. 1993 Oct; 22(4 Suppl A):113A-118A.
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199.	Schmidt TA, Allen PD, Colucci WS, Marsh JD, Kjeldsen K. No adaptation to digitalization as evaluated by digitalis receptor (Na,K-ATPase) quantification in explanted hearts from donors without heart disease and from digitalized recipients with end-stage heart failure. Am J Cardiol. 1993 Jan 1; 71(1):110-4.
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200.	Packer M, Narahara KA, Elkayam U, Sullivan JM, Pearle DL, Massie BM, Creager MA, and the Principal Investigators of the Reflect Study. Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. J Am Coll Cardiol. 1993; 22:65-72.

201.	Colucci WS. In situ assessment of – and -Adrenergic responses in failing human myocardium. Circulation. 1993; 87(Suppl VII):63-7.

202.	Feldman AM, Bristow MR, Parmley WW, Carson PE, Pepine CJ, Gilbert EM, Strobeck JE, Hendrix GH, Powers ER, Bain RP, White BH, for the Vesnarinone Study Group. Effects of vesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med. 1993; 329:149-55.

203.	Bialecki RA, Kulik TJ, Colucci WS. Stretching increases calcium influx and efflux in cultured pulmonary arterial smooth muscle cells. Am J Physiol. 1992 Nov; 263(5 Pt 1):L602-6.
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204.	Sen L, Bialecki RA, Smith E, Smith TW, Colucci WS. Cholesterol increases the L-type voltage-sensitive calcium channel current in arterial smooth muscle cells. Circ Res. 1992 Oct; 71(4):1008-14.
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205.	Willich SN, Tofler GH, Brezinski DA, Schafer AI, Muller JE, Michel T, Colucci WS. Platelet alpha 2 adrenoceptor characteristics during the morning increase in platelet aggregability. Eur Heart J. 1992 Apr; 13(4):550-5.
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206.	Bialecki RA, Tulenko TN, Colucci WS. Cholesterol enrichment increases basal and agonist-stimulated calcium influx in rat vascular smooth muscle cells. J Clin Invest. 1991 Dec; 88(6):1894-900.
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207.	Kulik TJ, Bialecki RA, Colucci WS, Rothman A, Glennon ET, Underwood RH. Stretch increases inositol trisphosphate and inositol tetrakisphosphate in cultured pulmonary vascular smooth muscle cells. Biochem Biophys Res Commun. 1991 Oct 31; 180(2):982-7.
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208.	Landzberg JS, Parker JD, Gauthier DF, Colucci WS. Effects of myocardial alpha 1-adrenergic receptor stimulation and blockade on contractility in humans. Circulation. 1991 Oct; 84(4):1608-14.
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209.	Parker JD, Landzberg JS, Bittl JA, Mirsky I, Colucci WS. Effects of beta-adrenergic stimulation with dobutamine on isovolumic relaxation in the normal and failing human left ventricle. Circulation. 1991 Sep; 84(3):1040-8.
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210.	Creager MA, Quigg RJ, Ren CJ, Roddy MA, Colucci WS. Limb vascular responsiveness to beta-adrenergic receptor stimulation in patients with congestive heart failure. Circulation. 1991 Jun; 83(6):1873-9.
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211.	Colucci WS. Cardiovascular effects of milrinone. Am Heart J. 1991 Jun; 121(6 Pt 2):1945-7.
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212.	Sperti G, Colucci WS. Calcium influx modulates DNA synthesis and proliferation in A7r5 vascular smooth muscle cells. Eur J Pharmacol. 1991 Apr 25; 206(4):279-84.
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213.	Sen L, Liang BT, Colucci WS, Smith TW. Enhanced alpha 1-adrenergic responsiveness in cardiomyopathic hamster cardiac myocytes. Relation to the expression of pertussis toxin-sensitive G protein and alpha 1-adrenergic receptors. Circ Res. 1990 Nov; 67(5):1182-92.
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214.	Colucci WS. In vivo studies of myocardial beta-adrenergic receptor pharmacology in patients with congestive heart failure. Circulation. 1990 Aug; 82(2 Suppl):I44-51.
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215.	Izzo NJ, Seidman CE, Collins S, Colucci WS. Alpha 1-adrenergic receptor mRNA level is regulated by norepinephrine in rabbit aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1990 Aug; 87(16):6268-71.
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216.	Arnold JM, Ribeiro JP, Colucci WS. Muscle blood flow during forearm exercise in patients with severe heart failure. Circulation. 1990 Aug; 82(2):465-72.
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217.	Creager MA, Hirsch AT, Dzau VJ, Nabel EG, Cutler SS, Colucci WS. Baroreflex regulation of regional blood flow in congestive heart failure. Am J Physiol. 1990 May; 258(5 Pt 2):H1409-14.
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218.	Treasure CB, Vita JA, Cox DA, Fish RD, Gordon JB, Mudge GH, Colucci WS, Sutton MG, Selwyn AP, Alexander RW, et al. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation. 1990 Mar; 81(3):772-9.
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219.	Ribeiro JP, White HD, Hartley LH, Colucci WS. Acute increase in exercise capacity with milrinone: lack of correlation with resting hemodynamic responses. Braz J Med Biol Res. 1990; 23(11):1069-78.
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220.	Bialecki RA, Izzo NJ, Colucci WS. Endothelin-1 increases intracellular calcium mobilization but not calcium uptake in rabbit vascular smooth muscle cells. Biochem Biophys Res Commun. 1989 Oct 16; 164(1):474-9.
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221.	Colucci WS. Myocardial and vascular actions of milrinone. Eur Heart J. 1989 Aug; 10 Suppl C:32-8.
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222.	Quigg RJ, Rocco MB, Gauthier DF, Creager MA, Hartley LH, Colucci WS. Mechanism of the attenuated peak heart rate response to exercise after orthotopic cardiac transplantation. J Am Coll Cardiol. 1989 Aug; 14(2):338-44.
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223.	Colucci WS, Ribeiro JP, Rocco MB, Quigg RJ, Creager MA, Marsh JD, Gauthier DF, Hartley LH. Impaired chronotropic response to exercise in patients with congestive heart failure. Role of postsynaptic beta-adrenergic desensitization. Circulation. 1989 Aug; 80(2):314-23.
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224.	Denniss AR, Colucci WS, Allen PD, Marsh JD. Distribution and function of human ventricular beta adrenergic receptors in congestive heart failure. J Mol Cell Cardiol. 1989 Jul; 21(7):651-60.
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225.	Denniss AR, Marsh JD, Quigg RJ, Gordon JB, Colucci WS. Beta-adrenergic receptor number and adenylate cyclase function in denervated transplanted and cardiomyopathic human hearts. Circulation. 1989 May; 79(5):1028-34.
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226.	Colucci WS. Positive inotropic/vasodilator agents. Cardiol Clin. 1989 Feb; 7(1):131-44.
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227.	Colucci WS. Observations on the intracoronary administration of milrinone and dobutamine to patients with congestive heart failure. Am J Cardiol. 1989 Jan 3; 63(2):17A-22A.
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228.	Arai Y, Saul JP, Albrecht P, Hartley LH, Lilly LS, Cohen RJ, Colucci WS. Modulation of cardiac autonomic activity during and immediately after exercise. Am J Physiol. 1989 Jan; 256(1 Pt 2):H132-41.
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229.	Colucci WS, Parker JD. Effects of beta-adrenergic agents on systolic and diastolic myocardial function in patients with and without heart failure. J Cardiovasc Pharmacol. 1989; 14 Suppl 5:S28-37.
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230.	Leatherman GF, Shook TL, Leatherman SM, Colucci WS. Use of a conductance catheter to detect increased left ventricular inotropic state by end-systolic pressure-volume analysis. Basic Res Cardiol. 1989; 84 Suppl 1:247-56.
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231.	Colucci WS, Akers M, Wise GM. Differential effects of norepinephrine and phorbol ester on alpha-1 adrenergic receptor number and surface-accessibility in DDT1 MF-2 cells. Biochem Biophys Res Commun. 1988 Oct 31; 156(2):924-30.
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232.	Colucci WS. Do positive inotropic agents adversely affect the survival of patients with chronic congestive heart failure? III. Antagonist’s viewpoint. J Am Coll Cardiol. 1988 Aug; 12(2):566-9.
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233.	Creager MA, Hirsch AT, Nabel EG, Cutler SS, Colucci WS, Dzau VJ. Responsiveness of atrial natriuretic factor to reduction in right atrial pressure in patients with chronic congestive heart failure. J Am Coll Cardiol. 1988 Jun; 11(6):1191-8.
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234.	Saul JP, Arai Y, Berger RD, Lilly LS, Colucci WS, Cohen RJ. Assessment of autonomic regulation in chronic congestive heart failure by heart rate spectral analysis. Am J Cardiol. 1988 Jun 1; 61(15):1292-9.
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235.	Lee RT, Mudge GH, Colucci WS. Coronary artery fistula after mitral valve surgery. Am Heart J. 1988 May; 115(5):1128-30.
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236.	Fish RD, Sperti G, Colucci WS, Clapham DE. Phorbol ester increases the dihydropyridine-sensitive calcium conductance in a vascular smooth muscle cell line. Circ Res. 1988 May; 62(5):1049-54.
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237.	Colucci WS, Denniss AR, Leatherman GF, Quigg RJ, Ludmer PL, Marsh JD, Gauthier DF. Intracoronary infusion of dobutamine to patients with and without severe congestive heart failure. Dose-response relationships, correlation with circulating catecholamines, and effect of phosphodiesterase inhibition. J Clin Invest. 1988 Apr; 81(4):1103-10.
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238.	Givertz MM, Colucci WS. Inotropic and vasoactive agents in the cardiac intensive care unit, Chapter 45. In: Brown DL, ed. Cardiac Intensive Care. Philadelphia:WB Saunders Co. 1988; pp. 545-54.

239.	Colucci WS, Leatherman GF, Ludmer PL, Gauthier DF. Beta-adrenergic inotropic responsiveness of patients with heart failure: studies with intracoronary dobutamine infusion. Circ Res. 1987 Oct; 61(4 Pt 2):I82-6.
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240.	Nabel EG, Colucci WS, Lilly LS, Cutler SS, Majzoub JA, St John Sutton MG, Dzau VJ, Creager MA. Relationship of cardiac chamber volume to baroreflex activity in normal humans. J Clin Endocrinol Metab. 1987 Sep; 65(3):475-81.
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241.	Ribeiro JP, Knutzen A, Rocco MB, Hartley LH, Colucci WS. Periodic breathing during exercise in severe heart failure. Reversal with milrinone or cardiac transplantation. Chest. 1987 Sep; 92(3):555-6.
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242.	Ludmer PL, Baim DS, Antman EM, Gauthier DF, Rocco MB, Friedman PL, Colucci WS. Effects of milrinone on complex ventricular arrhythmias in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1987 Jun 1; 59(15):1351-5.
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243.	Colucci WS. Usefulness of calcium antagonists for congestive heart failure. Am J Cardiol. 1987 Jan 30; 59(3):52B-58B.
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244.	Ribeiro JP, White HD, Arnold JM, Hartley LH, Colucci WS. Exercise responses before and after long-term treatment with oral milrinone in patients with severe heart failure. Am J Med. 1986 Nov; 81(5):759-64.
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245.	Arnold JM, Ludmer PL, Wright RF, Ganz P, Braunwald E, Colucci WS. Role of reflex sympathetic withdrawal in the hemodynamic response to an increased inotropic state in patients with severe heart failure. J Am Coll Cardiol. 1986 Aug; 8(2):413-8.
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246.	Baim DS, Colucci WS, Monrad ES, Smith HS, Wright RF, Lanoue A, Gauthier DF, Ransil BJ, Grossman W, Braunwald E. Survival of patients with severe congestive heart failure treated with oral milrinone. J Am Coll Cardiol. 1986 Mar; 7(3):661-70.
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247.	Colucci WS, Wright RF, Jaski BE, Fifer MA, Braunwald E. Milrinone and dobutamine in severe heart failure: differing hemodynamic effects and individual patient responsiveness. Circulation. 1986 Mar; 73(3 Pt 2):III175-83.
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248.	Colucci WS, Alexander RW. Norepinephrine-induced alteration in the coupling of alpha 1-adrenergic receptor occupancy to calcium efflux in rabbit aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1986 Mar; 83(6):1743-6.
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249.	Colucci WS, Gimbrone MA, Alexander RW. Phorbol diester modulates alpha-adrenergic receptor-coupled calcium efflux and alpha-adrenergic receptor number in cultured vascular smooth muscle cells. Circ Res. 1986 Mar; 58(3):393-8.
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250.	Colucci WS, Wright RF, Braunwald E. New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. 2. N Engl J Med. 1986 Feb 6; 314(6):349-58.
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251.	Colucci WS. Adenosine 3′,5′-cyclic-monophosphate-dependent regulation of alpha 1-adrenergic receptor number in rabbit aortic smooth muscle cells. Circ Res. 1986 Feb; 58(2):292-7.
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252.	Colucci WS, Wright RF, Braunwald E. New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. 1. N Engl J Med. 1986 Jan 30; 314(5):290-9.
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253.	Ludmer PL, Wright RF, Arnold JM, Ganz P, Braunwald E, Colucci WS. Separation of the direct myocardial and vasodilator actions of milrinone administered by an intracoronary infusion technique. Circulation. 1986 Jan; 73(1):130-7.
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254.	Powers RE, Colucci WS. An increase in putative voltage dependent calcium channel number following reserpine treatment. Biochem Biophys Res Commun. 1985 Oct 30; 132(2):844-9.
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255.	White HD, Ribeiro JP, Hartley LH, Colucci WS. Immediate effects of milrinone on metabolic and sympathetic responses to exercise in severe congestive heart failure. Am J Cardiol. 1985 Jul 1; 56(1):93-8.
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256.	Colucci WS, Brock TA, Gimbrone MA, Alexander RW. Nonlinear relationship between alpha 1-adrenergic receptor occupancy and norepinephrine-stimulated calcium flux in cultured vascular smooth muscle cells. Mol Pharmacol. 1985 May; 27(5):517-24.
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257.	Kern MJ, Horowitz JD, Ganz P, Gaspar J, Colucci WS, Lorell BH, Barry WH, Mudge GH. Attenuation of coronary vascular resistance by selective alpha 1-adrenergic blockade in patients with coronary artery disease. J Am Coll Cardiol. 1985 Apr; 5(4):840-6.
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258.	Fifer MA, Colucci WS, Lorell BH, Jaski BE, Barry WH. Inotropic, vascular and neuroendocrine effects of nifedipine in heart failure: comparison with nitroprusside. J Am Coll Cardiol. 1985 Mar; 5(3):731-7.
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259.	Colucci WS, Fifer MA, Lorell BH, Wynne J. Calcium channel blockers in congestive heart failure: theoretic considerations and clinical experience. Am J Med. 1985 Feb 22; 78(2B):9-17.
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260.	Jaski BE, Fifer MA, Wright RF, Braunwald E, Colucci WS. Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside. J Clin Invest. 1985 Feb; 75(2):643-9.
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261.	Colucci WS, Ludmer PL, Wright RF, Arnold JM, Ganz P, Braunwald E. Myocardial and vascular effects of intracoronary versus intravenous milrinone. Trans Assoc Am Physicians. 1985; 98:136-45.
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262.	Colucci WS, Brock TA, Atkinson WJ, Alexander RW, Gimbrone MA. Cultured vascular smooth muscle cells: an in vitro system for study of alpha-adrenergic receptor coupling and regulation. J Cardiovasc Pharmacol. 1985; 7 Suppl 6:S79-86.
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263.	Monrad ES, McKay RG, Baim DS, Colucci WS, Fifer MA, Heller GV, Royal HD, Grossman W. Improvement in indexes of diastolic performance in patients with congestive heart failure treated with milrinone. Circulation. 1984 Dec; 70(6):1030-7.
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264.	Colucci WS, Gimbrone MA, Alexander RW. Regulation of myocardial and vascular alpha-adrenergic receptor affinity. Effects of guanine nucleotides, cations, estrogen, and catecholamine depletion. Circ Res. 1984 Jul; 55(1):78-88.
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265.	Braunwald E, Colucci WS. Evaluating the efficacy of new inotropic agents. J Am Coll Cardiol. 1984 Jun; 3(6):1570-4.
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266.	Ganz P, Gaspar J, Colucci WS, Barry WH, Mudge GH, Alexander RW. Effects of prostacyclin on coronary hemodynamics at rest and in response to cold pressor testing in patients with angina pectoris. Am J Cardiol. 1984 Jun 1; 53(11):1500-4.
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267.	Colucci WS, Brock TA, Gimbrone MA, Alexander RW. Regulation of alpha 1-adrenergic receptor-coupled calcium flux in cultured vascular smooth muscle cells. Hypertension. 1984 Mar-Apr; 6(2 Pt 2):I19-24.
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268.	Braunwald E, Colucci WS. Vasodilator therapy of heart failure. Has the promissory note been paid? N Engl J Med. 1984 Feb 16; 310(7):459-61.
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269.	Colucci WS, Braunwald E. Adrenergic receptors: new concepts and implications for cardiovascular therapeutics. Cardiovasc Clin. 1984; 14(3):39-59.
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270.	Colucci WS, Jaski BE, Fifer MA, Wright RF, Braunwald E. Milrinone: a positive inotropic vasodilator. Trans Assoc Am Physicians. 1984; 97:124-33.
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271.	Polak JF, Holman BL, Wynne J, Colucci WS. Right ventricular ejection fraction: an indicator of increased mortality in patients with congestive heart failure associated with coronary artery disease. J Am Coll Cardiol. 1983 Aug; 2(2):217-24.
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272.	Colucci WS. New developments in alpha-adrenergic receptor pharmacology: implications for the initial treatment of hypertension. Am J Cardiol. 1983 Feb 24; 51(4):639-43.
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273.	Colucci WS, Lorell BH, Schoen FJ, Warhol MJ, Grossman W. Hypertrophic obstructive cardiomyopathy due to Fabry’s disease. N Engl J Med. 1982 Oct 7; 307(15):926-8.
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274.	Colucci WS. Alpha-adrenergic receptor blockade with prazosin. Consideration of hypertension, heart failure, and potential new applications. Ann Intern Med. 1982 Jul; 97(1):67-77.
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275.	Colucci WS, Gimbrone MA, McLaughlin MK, Halpern W, Alexander RW. Increased vascular catecholamine sensitivity and alpha-adrenergic receptor affinity in female and estrogen-treated male rats. Circ Res. 1982 Jun; 50(6):805-11.
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276.	Rude RE, Grossman W, Colucci WS, Benotti JR, Carabello BA, Wynne J, Malacoff R, Braunwald E. Problems in assessment of new pharmacologic agents for the heart failure patient. Am Heart J. 1981 Sep; 102(3 Pt 2):584-90.
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277.	Colucci WS, Alexander RW, Mudge GH, Rude RE, Holman BL, Wynne J, Grossman W, Braunwald E. Acute and chronic effects of pirbuterol on left ventricular ejection fraction and clinical status in severe congestive heart failure. Am Heart J. 1981 Sep; 102(3 Pt 2):564-8.
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278.	Colucci WS, Williams GH, Braunwald E. Clinical, hemodynamic, and neuroendocrine effects of chronic prazosin therapy for congestive heart failure. Am Heart J. 1981 Sep; 102(3 Pt 2):615-21.
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279.	Colucci WS, Alexander RW, Williams GH, Rude RE, Holman BL, Konstam MA, Wynne J, Mudge GH, Braunwald E. Decreased lymphocyte beta-adrenergic-receptor density in patients with heart failure and tolerance to the beta-adrenergic agonist pirbuterol. N Engl J Med. 1981 Jul 23; 305(4):185-90.
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280.	Colucci WS, Holman BL, Wynne J, Carabello B, Malacoff R, Grossman W, Braunwald E. Improved right ventricular function and reduced pulmonary vascular resistance during prazosin therapy of congestive heart failure. Am J Med. 1981 Jul; 71(1):75-80.
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281.	Colucci WS, Williams GH, Alexander RW, Braunwald E. Mechanisms and implications of vasodilator tolerance in the treatment of congestive heart failure. Am J Med. 1981 Jul; 71(1):89-99.
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282.	Rude RE, Turi Z, Brown EJ, Lorell BH, Colucci WS, Mudge GH, Taylor CR, Grossman W. Acute effects of oral pirbuterol on myocardial oxygen metabolism and systemic hemodynamics in chronic congestive heart failure. Circulation. 1981 Jul; 64(1):139-45.
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283.	Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation. 1981 Mar; 63(3):645-51.
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284.	Colucci WS, Gimbrone MA, Alexander RW. Regulation of the postsynaptic alpha-adrenergic receptor in rat mesenteric artery. Effects of chemical sympathectomy and epinephrine treatment. Circ Res. 1981 Jan; 48(1):104-11.
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285.	Colucci WS, Williams GH, Braunwald E. Increased plasma norepinephrine levels during prazosin therapy for severe congestive heart failure. Ann Intern Med. 1980 Sep; 93(3):452-3.
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286.	Dzau VJ, Colucci WS, Williams GH, Curfman G, Meggs L, Hollenberg NK. Sustained effectiveness of converting-enzyme inhibition in patients with severe congestive heart failure. N Engl J Med. 1980 Jun 19; 302(25):1373-9.
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287.	Colucci WS, Gimbrone MA, Alexander RW. Characterization of postsynaptic alpha-adrenergic receptors by [3H]-dihydroergocryptine binding in muscular arteries from the rat mesentery. Hypertension. 1980 Mar-Apr; 2(2):149-55.
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288.	Colucci WS, Wynne J, Holman BL, Braunwald E. Long-term therapy of heart failure with prazosin: a randomized double blind trial. Am J Cardiol. 1980 Feb; 45(2):337-44.
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289.	Poole-Wilson PA, Colucci WS, Chatterjee K, Coats AJS, Massie BM (Editors). Heart Failure. New York:Churchill Livingstone. 1977.

Publications on Heart Failure by Prof. William Gregory Stevenson, M.D.

Title	Professor of Medicine
Institution	Brigham and Women’s Hospital
Department	Medicine
Address	Brigham and Women’s Hospital Cardiovascular 75 Francis St Boston MA 02115
Phone	617/732-7535
Fax	617/732-7134

Givertz MM, Teerlink JR, Albert NM, Westlake Canary CA, Collins SP, Colvin-Adams M, Ezekowitz JA, Fang JC, Hernandez AF, Katz SD, Krishnamani R, Stough WG, Walsh MN, Butler J, Carson PE, Dimarco JP, Hershberger RE, Rogers JG, Spertus JA, Stevenson WG, Sweitzer NK, Tang WH, Starling RC. Acute decompensated heart failure: update on new and emerging evidence and directions for future research. J Card Fail. 2013 Jun; 19(6):371-89.

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Tokuda M, Kojodjojo P, Tung S, Tedrow UB, Nof E, Inada K, Koplan BA, Michaud GF, John RM, Epstein LM, Stevenson WG. Acute failure of catheter ablation for ventricular tachycardia due to structural heart disease: causes and significance. J Am Heart Assoc. 2013; 2(3):e000072.

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Ng J, Barbhaiya C, Chopra N, Reichlin T, Nof E, Tadros T, Stevenson WG, John RM. Automatic external defibrillators-friend or foe? Am J Emerg Med. 2013 Aug; 31(8):1292.e1-2.

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Steven D, Sultan A, Reddy V, Luker J, Altenburg M, Hoffmann B, Rostock T, Servatius H, Stevenson WG, Willems S, Michaud GF. Benefit of pulmonary vein isolation guided by loss of pace capture on the ablation line: results from a prospective 2-center randomized trial. J Am Coll Cardiol. 2013 Jul 2; 62(1):44-50.

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Kojodjojo P, Tokuda M, Bohnen M, Michaud GF, Koplan BA, Epstein LM, Albert CM, John RM, Stevenson WG, Tedrow UB. Electrocardiographic left ventricular scar burden predicts clinical outcomes following infarct-related ventricular tachycardia ablation. Heart Rhythm. 2013 Aug; 10(8):1119-24.

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Nof E, Stevenson WG, Epstein LM, Tedrow UB, Koplan BA. Catheter Ablation of Atrial Arrhythmias After Cardiac Transplantation: Findings at EP Study Utility of 3-D Mapping and Outcomes. J Cardiovasc Electrophysiol. 2013 May; 24(5):498-502.

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Michaud GF, Stevenson WG. Feeling a little loopy? J Cardiovasc Electrophysiol. 2013 May; 24(5):553-5.

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Epstein AE, Dimarco JP, Ellenbogen KA, Estes NA, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Tracy CM, Epstein AE, Darbar D, Dimarco JP, Dunbar SB, Estes NA, Ferguson TB, Hammill SC, Karasik PE, Link MS, Marine JE, Schoenfeld MH, Shanker AJ, Silka MJ, Stevenson LW, Stevenson WG, Varosy PD, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Creager MA, Demets D, Ettinger SM, Guyton RA, Hochman JS, Kushner FG, Ohman EM, Stevenson W, Yancy CW. 2012 ACCF/AHA/HRS Focused Update Incorporated Into the ACCF/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2013 Jan 22; 127(3):e283-352.

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Tracy CM, Epstein AE, Darbar D, Dimarco JP, Dunbar SB, Mark Estes NA, Ferguson TB, Hammill SC, Karasik PE, Link MS, Marine JE, Schoenfeld MH, Shanker AJ, Silka MJ, Stevenson LW, Stevenson WG, Varosy PD, Epstein AE, Dimarco JP, Ellenbogen KA, Mark Estes NA, Freedman RA, Gettes LS, Marc Gillinov A, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Kristin Newby L, Page RL, Schoenfeld MH, Silka MJ, Warner Stevenson L, Sweeney MO, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Creager MA, Demets D, Ettinger SM, Guyton RA, Hochman JS, Kushner FG, Ohman EM, Stevenson W, Yancy CW. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg. 2012 Dec; 144(6):e127-45.

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John RM, Tedrow UB, Koplan BA, Albert CM, Epstein LM, Sweeney MO, Miller AL, Michaud GF, Stevenson WG. Ventricular arrhythmias and sudden cardiac death. Lancet. 2012 Oct 27; 380(9852):1520-9.

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Tracy CM, Epstein AE, Darbar D, DiMarco JP, Dunbar SB, Estes NA, Ferguson TB, Hammill SC, Karasik PE, Link MS, Marine JE, Schoenfeld MH, Shanker AJ, Silka MJ, Stevenson LW, Stevenson WG, Varosy PD, Ellenbogen KA, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hayes DL, Page RL, Stevenson LW, Sweeney MO. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2012 Oct 2; 126(14):1784-800.

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Tracy CM, Epstein AE, Darbar D, Dimarco JP, Dunbar SB, Estes NA, Ferguson TB, Hammill SC, Karasik PE, Link MS, Marine JE, Schoenfeld MH, Shanker AJ, Silka MJ, Stevenson LW, Stevenson WG, Varosy PD. 2012 ACCF/AHA/HRS Focused Update of the 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Heart Rhythm. 2012 Oct; 9(10):1737-53.

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Tokuda M, Tedrow UB, Kojodjojo P, Inada K, Koplan BA, Michaud GF, John RM, Epstein LM, Stevenson WG. Catheter ablation of ventricular tachycardia in nonischemic heart disease. Circ Arrhythm Electrophysiol. 2012 Oct 1; 5(5):992-1000.

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John RM, Stevenson WG. Ventricular arrhythmias in patients with implanted cardioverter defibrillators. Trends Cardiovasc Med. 2012 Oct; 22(7):169-73.

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Waldo AL, Wilber DJ, Marchlinski FE, Stevenson WG, Aker B, Boo LM, Jackman WM. Safety of the open-irrigated ablation catheter for radiofrequency ablation: safety analysis from six clinical studies. Pacing Clin Electrophysiol. 2012 Sep; 35(9):1081-9.

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Tedrow UB, Sobieszczyk P, Stevenson WG. Transvenous ethanol ablation of ventricular tachycardia. Heart Rhythm. 2012 Oct; 9(10):1640-1.

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Stevenson WG, Tedrow UB. Ablation for ventricular tachycardia during stable sinus rhythm. Circulation. 2012 May 8; 125(18):2175-7.

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Wissner E, Stevenson WG, Kuck KH. Catheter ablation of ventricular tachycardia in ischaemic and non-ischaemic cardiomyopathy: where are we today? A clinical review. Eur Heart J. 2012 Jun; 33(12):1440-50.

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Vollmann D, Stevenson WG, Lüthje L, Sohns C, John RM, Zabel M, Michaud GF. Misleading long post-pacing interval after entrainment of typical atrial flutter from the cavotricuspid isthmus. J Am Coll Cardiol. 2012 Feb 28; 59(9):819-24.

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Stevenson WG, Hernandez AF, Carson PE, Fang JC, Katz SD, Spertus JA, Sweitzer NK, Tang WH, Albert NM, Butler J, Westlake Canary CA, Collins SP, Colvin-Adams M, Ezekowitz JA, Givertz MM, Hershberger RE, Rogers JG, Teerlink JR, Walsh MN, Stough WG, Starling RC. Indications for cardiac resynchronization therapy: 2011 update from the Heart Failure Society of America Guideline Committee. J Card Fail. 2012 Feb; 18(2):94-106.

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Inada K, Tokuda M, Roberts-Thomson KC, Steven D, Seiler J, Tedrow UB, Stevenson WG. Relation of high-pass filtered unipolar electrograms to bipolar electrograms during ventricular mapping. Pacing Clin Electrophysiol. 2012 Feb; 35(2):157-63.

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Albert CM, Chen PS, Anderson ME, Cain ME, Fishman GI, Narayan SM, Olgin JE, Spooner PM, Stevenson WG, Van Wagoner DR, Packer DL. Full report from the first annual Heart Rhythm Society Research Forum: a vision for our research future, “dream, discover, develop, deliver”. Heart Rhythm. 2011 Dec; 8(12):e1-12.

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Stevenson WG, John RM. Ventricular arrhythmias in patients with implanted defibrillators. Circulation. 2011 Oct 18; 124(16):e411-4.

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Tokuda M, Sobieszczyk P, Eisenhauer AC, Kojodjojo P, Inada K, Koplan BA, Michaud GF, John RM, Epstein LM, Sacher F, Stevenson WG, Tedrow UB. Transcoronary ethanol ablation for recurrent ventricular tachycardia after failed catheter ablation: an update. Circ Arrhythm Electrophysiol. 2011 Dec; 4(6):889-96.

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John RM, Stevenson WG. Catheter-based ablation for ventricular arrhythmias. Curr Cardiol Rep. 2011 Oct; 13(5):399-406.

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Martinek M, Stevenson WG, Inada K, Tokuda M, Tedrow UB. QRS characteristics fail to reliably identify ventricular tachycardias that require epicardial ablation in ischemic heart disease. J Cardiovasc Electrophysiol. 2012 Feb; 23(2):188-93.

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Asimaki A, Tandri H, Duffy ER, Winterfield JR, Mackey-Bojack S, Picken MM, Cooper LT, Wilber DJ, Marcus FI, Basso C, Thiene G, Tsatsopoulou A, Protonotarios N, Stevenson WG, McKenna WJ, Gautam S, Remick DG, Calkins H, Saffitz JE. Altered desmosomal proteins in granulomatous myocarditis and potential pathogenic links to arrhythmogenic right ventricular cardiomyopathy. Circ Arrhythm Electrophysiol. 2011 Oct; 4(5):743-52.

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Wijnmaalen AP, Roberts-Thomson KC, Steven D, Klautz RJ, Willems S, Schalij MJ, Stevenson WG, Zeppenfeld K. Catheter ablation of ventricular tachycardia after left ventricular reconstructive surgery for ischemic cardiomyopathy. Heart Rhythm. 2012 Jan; 9(1):10-7.

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Stevenson WG, Couper GS. A surgical option for ventricular tachycardia caused by nonischemic cardiomyopathy. Circ Arrhythm Electrophysiol. 2011 Aug; 4(4):429-31.

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Tokuda M, Kojodjojo P, Epstein LM, Koplan BA, Michaud GF, Tedrow UB, Stevenson WG, John RM. Outcomes of cardiac perforation complicating catheter ablation of ventricular arrhythmias. Circ Arrhythm Electrophysiol. 2011 Oct; 4(5):660-6.

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Kosmidou I, Inada K, Seiler J, Koplan B, Stevenson WG, Tedrow UB. Role of repeat procedures for catheter ablation of postinfarction ventricular tachycardia. Heart Rhythm. 2011 Oct; 8(10):1516-22.

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Bohnen M, Stevenson WG, Tedrow UB, Michaud GF, John RM, Epstein LM, Albert CM, Koplan BA. Incidence and predictors of major complications from contemporary catheter ablation to treat cardiac arrhythmias. Heart Rhythm. 2011 Nov; 8(11):1661-6.

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Wijnmaalen AP, Stevenson WG, Schalij MJ, Field ME, Stephenson K, Tedrow UB, Koplan BA, Putter H, Epstein LM, Zeppenfeld K. ECG identification of scar-related ventricular tachycardia with a left bundle-branch block configuration. Circ Arrhythm Electrophysiol. 2011 Aug; 4(4):486-93.

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Steven D, Roberts-Thomson KC, Inada K, Seiler J, Koplan BA, Tedrow UB, Sweeney MO, Epstein LE, Stevenson WG. Long-term follow-up in patients with presumptive Brugada syndrome treated with implanted defibrillators. J Cardiovasc Electrophysiol. 2011 Oct; 22(10):1115-9.

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Bohnen M, Shea JB, Michaud GF, John R, Stevenson WG, Epstein LM, Tedrow UB, Albert C, Koplan BA. Quality of life with atrial fibrillation: do the spouses suffer as much as the patients? Pacing Clin Electrophysiol. 2011 Jul; 34(7):804-9.

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Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Huezey JY, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS, Smith SC, Priori SG, Estes NA, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Jacobs AK, Anderson JL, Albert N, Buller CE, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Kushner FG, Ohman EM, Stevenson WG, Tarkington LG, Yancy CW. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2011 Mar 15; 123(10):e269-367.

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Wann LS, Curtis AB, Ellenbogen KA, Estes NA, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Heuzey JY, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS, Jacobs AK, Anderson JL, Albert N, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Kushner FG, Ohman EM, Stevenson WG, Yancy CW. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on Dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2011 Mar 15; 123(10):1144-50.

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Wann LS, Curtis AB, Ellenbogen KA, Estes NA, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2011 Mar 15; 57(11):1330-7.

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Wann LS, Curtis AB, Ellenbogen KA, Estes NA, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Heuzey JY, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS, Jacobs AK, Anderson JL, Albert N, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Kushner FG, Ohman EM, Stevenson WG, Yancy CW. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran). A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Heart Rhythm. 2011 Mar; 8(3):e1-8.

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Dukkipati SR, d’Avila A, Soejima K, Bala R, Inada K, Singh S, Stevenson WG, Marchlinski FE, Reddy VY. Long-term outcomes of combined epicardial and endocardial ablation of monomorphic ventricular tachycardia related to hypertrophic cardiomyopathy. Circ Arrhythm Electrophysiol. 2011 Apr; 4(2):185-94.

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Tedrow UB, Stevenson WG. Recording and interpreting unipolar electrograms to guide catheter ablation. Heart Rhythm. 2011 May; 8(5):791-6.

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Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NA, Page RL, Ezekowitz MD, Slotwiner DJ, Jackman WM, Stevenson WG, Tracy CM, Fuster V, Rydén LE, Cannom DS, Le Heuzey JY, Crijns HJ, Lowe JE, Curtis AB, Olsson SB, Ellenbogen KA, Prystowsky EN, Halperin JL, Tamargo JL, Kay GN, Wann LS, Jacobs AK, Anderson JL, Albert N, Hochman JS, Buller CE, Kushner FG, Creager MA, Ohman EM, Ettinger SM, Stevenson WG, Guyton RA, Tarkington LG, Halperin JL, Yancy CW. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011 Jan 11; 57(2):223-42.

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Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NA, Page RL, Ezekowitz MD, Slotwiner DJ, Jackman WM, Stevenson WG, Tracy CM, Fuster V, Rydén LE, Cannom DS, Le Heuzey JY, Crijns HJ, Lowe JE, Curtis AB, Olsson S, Ellenbogen KA, Prystowsky EN, Halperin JL, Tamargo JL, Kay GN, Wann LS, Jacobs AK, Anderson JL, Albert N, Hochman JS, Buller CE, Kushner FG, Creager MA, Ohman EM, Ettinger SM, Stevenson WG, Guyton RA, Tarkington LG, Halperin JL, Yancy CW. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Heart Rhythm. 2011 Jan; 8(1):157-76.

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Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NA, Page RL, Ezekowitz MD, Slotwiner DJ, Jackman WM, Stevenson WG, Tracy CM, Fuster V, Rydén LE, Cannom DS, Le Heuzey JY, Crijns HJ, Lowe JE, Curtis AB, Olsson S, Ellenbogen KA, Prystowsky EN, Halperin JL, Tamargo JL, Kay GN, Wann L, Jacobs AK, Anderson JL, Albert N, Hochman JS, Buller CE, Kushner FG, Creager MA, Ohman EM, Ettinger SM, Stevenson WG, Guyton RA, Tarkington LG, Halperin JL, Yancy CW. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011 Jan 4; 123(1):104-23.

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Stevenson WG, Asirvatham SJ. Teaching rounds in cardiac electrophysiology. Circ Arrhythm Electrophysiol. 2010 Dec; 3(6):563.

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Rosman JZ, John RM, Stevenson WG, Epstein LM, Tedrow UB, Koplan BA, Albert CM, Michaud GF. Resetting criteria during ventricular overdrive pacing successfully differentiate orthodromic reentrant tachycardia from atrioventricular nodal reentrant tachycardia despite interobserver disagreement concerning QRS fusion. Heart Rhythm. 2011 Jan; 8(1):2-7.

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Gautam S, John RM, Stevenson WG, Jain R, Epstein LM, Tedrow U, Koplan BA, McClennen S, Michaud GF. Effect of therapeutic INR on activated clotting times, heparin dosage, and bleeding risk during ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2011 Mar; 22(3):248-54.

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Inada K, Seiler J, Roberts-Thomson KC, Steven D, Rosman J, John RM, Sobieszczyk P, Stevenson WG, Tedrow UB. Substrate characterization and catheter ablation for monomorphic ventricular tachycardia in patients with apical hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol. 2011 Jan; 22(1):41-8.

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Sacher F, Roberts-Thomson K, Maury P, Tedrow U, Nault I, Steven D, Hocini M, Koplan B, Leroux L, Derval N, Seiler J, Wright MJ, Epstein L, Haissaguerre M, Jais P, Stevenson WG. Epicardial ventricular tachycardia ablation a multicenter safety study. J Am Coll Cardiol. 2010 May 25; 55(21):2366-72.

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Britton KA, Stevenson WG, Levy BD, Katz JT, Loscalzo J. Clinical problem-solving. The beat goes on. N Engl J Med. 2010 May 6; 362(18):1721-6.

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Ross JJ, Britton KA, Desai AS, Stevenson WG. Interactive medical case. The beat goes on. N Engl J Med. 2010 Apr 15; 362(15):e53.

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Tedrow UB, Stevenson WG. Arrhythmias: Catheter ablation for prevention of ventricular tachycardia. Nat Rev Cardiol. 2010 Apr; 7(4):181-2.

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Sacher F, Wright M, Tedrow UB, O’Neill MD, Jais P, Hocini M, Macdonald R, Davies DW, Kanagaratnam P, Derval N, Epstein L, Peters NS, Stevenson WG, Haissaguerre M. Wolff-Parkinson-White ablation after a prior failure: a 7-year multicentre experience. Europace. 2010 Jun; 12(6):835-41.

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Inada K, Roberts-Thomson KC, Seiler J, Steven D, Tedrow UB, Koplan BA, Stevenson WG. Mortality and safety of catheter ablation for antiarrhythmic drug-refractory ventricular tachycardia in elderly patients with coronary artery disease. Heart Rhythm. 2010 Jun; 7(6):740-4.

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Steven D, Seiler J, Roberts-Thomson KC, Inada K, Stevenson WG. Mapping of atrial tachycardias after catheter ablation for atrial fibrillation: use of bi-atrial activation patterns to facilitate recognition of origin. Heart Rhythm. 2010 May; 7(5):664-72.

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Stevenson WG, Tedrow U. Preventing ventricular tachycardia with catheter ablation. Lancet. 2010 Jan 2; 375(9708):4-6.

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Al-Khatib SM, Calkins H, Eloff BC, Packer DL, Ellenbogen KA, Hammill SC, Natale A, Page RL, Prystowsky E, Jackman WM, Stevenson WG, Waldo AL, Wilber D, Kowey P, Yaross MS, Mark DB, Reiffel J, Finkle JK, Marinac-Dabic D, Pinnow E, Sager P, Sedrakyan A, Canos D, Gross T, Berliner E, Krucoff MW. Planning the Safety of Atrial Fibrillation Ablation Registry Initiative (SAFARI) as a Collaborative Pan-Stakeholder Critical Path Registry Model: a Cardiac Safety Research Consortium “Incubator” Think Tank. Am Heart J. 2010 Jan; 159(1):17-24.

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Seiler J, Stevenson WG. Atrial fibrillation in congestive heart failure. Cardiol Rev. 2010 Jan-Feb; 18(1):38-50.

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Steven D, Roberts-Thomson KC, Seiler J, Inada K, Tedrow UB, Mitchell RN, Sobieszczyk PS, Eisenhauer AC, Couper GS, Stevenson WG. Ventricular tachycardia arising from the aortomitral continuity in structural heart disease: characteristics and therapeutic considerations for an anatomically challenging area of origin. Circ Arrhythm Electrophysiol. 2009 Dec; 2(6):660-6.

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Roberts-Thomson KC, Seiler J, Steven D, Inada K, Michaud GF, John RM, Koplan BA, Epstein LM, Stevenson WG, Tedrow UB. Percutaneous access of the epicardial space for mapping ventricular and supraventricular arrhythmias in patients with and without prior cardiac surgery. J Cardiovasc Electrophysiol. 2010 Apr; 21(4):406-11.

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Steven D, Reddy VY, Inada K, Roberts-Thomson KC, Seiler J, Stevenson WG, Michaud GF. Loss of pace capture on the ablation line: a new marker for complete radiofrequency lesions to achieve pulmonary vein isolation. Heart Rhythm. 2010 Mar; 7(3):323-30.

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Roberts-Thomson KC, Steven D, Seiler J, Inada K, Koplan BA, Tedrow UB, Epstein LM, Stevenson WG. Coronary artery injury due to catheter ablation in adults: presentations and outcomes. Circulation. 2009 Oct 13; 120(15):1465-73.

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See VY, Roberts-Thomson KC, Stevenson WG, Camp PC, Koplan BA. Atrial arrhythmias after lung transplantation: epidemiology, mechanisms at electrophysiology study, and outcomes. Circ Arrhythm Electrophysiol. 2009 Oct; 2(5):504-10.

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Stevenson WG, Saltzman JR. Gastroesophageal reflux and atrial-esophageal fistula. Heart Rhythm. 2009 Oct; 6(10):1463-4.

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Aliot EM, Stevenson WG, Almendral-Garrote JM, Bogun F, Calkins CH, Delacretaz E, Della Bella P, Hindricks G, Jaïs P, Josephson ME, Kautzner J, Kay GN, Kuck KH, Lerman BB, Marchlinski F, Reddy V, Schalij MJ, Schilling R, Soejima K, Wilber D. EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a Registered Branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA). Heart Rhythm. 2009 Jun; 6(6):886-933.

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Aliot EM, Stevenson WG, Almendral-Garrote JM, Bogun F, Calkins CH, Delacretaz E, Bella PD, Hindricks G, Jaïs P, Josephson ME, Kautzner J, Kay GN, Kuck KH, Lerman BB, Marchlinski F, Reddy V, Schalij MJ, Schilling R, Soejima K, Wilber D. EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a Registered Branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA). Europace. 2009 Jun; 11(6):771-817.

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Raymond JM, Sacher F, Winslow R, Tedrow U, Stevenson WG. Catheter ablation for scar-related ventricular tachycardias. Curr Probl Cardiol. 2009 May; 34(5):225-70.

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Lee JC, Steven D, Roberts-Thomson KC, Raymond JM, Stevenson WG, Tedrow UB. Atrial tachycardias adjacent to the phrenic nerve: recognition, potential problems, and solutions. Heart Rhythm. 2009 Aug; 6(8):1186-91.

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Steven D, Roberts-Thomson KC, Seiler J, Michaud GF, John RM, Stevenson WG. Fibrillation in the superior vena cava mimicking atrial tachycardia. Circ Arrhythm Electrophysiol. 2009 Apr; 2(2):e4-7.

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Roberts-Thomson KC, Seiler J, Steven D, Inada K, John R, Michaud G, Stevenson WG. Short AV response to atrial extrastimuli during narrow complex tachycardia: what is the mechanism? J Cardiovasc Electrophysiol. 2009 Aug; 20(8):946-8.

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Koplan BA, Stevenson WG. Ventricular tachycardia and sudden cardiac death. Mayo Clin Proc. 2009 Mar; 84(3):289-97.

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Khairy P, Stevenson WG. Catheter ablation in tetralogy of Fallot. Heart Rhythm. 2009 Jul; 6(7):1069-74.

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Stevenson WG, Tedrow UB, Koplan BA. Management of ventricular tachycardia complicating cardiac surgery. Heart Rhythm. 2009 Aug; 6(8 Suppl):S66-9.

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Lee JC, Epstein LM, Huffer LL, Stevenson WG, Koplan BA, Tedrow UB. ICD lead proarrhythmia cured by lead extraction. Heart Rhythm. 2009 May; 6(5):613-8.

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Tedrow U, Stevenson WG. Strategies for epicardial mapping and ablation of ventricular tachycardia. J Cardiovasc Electrophysiol. 2009 Jun; 20(6):710-3.

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Stevenson WG. Ventricular scars and ventricular tachycardia. Trans Am Clin Climatol Assoc. 2009; 120:403-12.

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Stevenson WG, Wilber DJ, Natale A, Jackman WM, Marchlinski FE, Talbert T, Gonzalez MD, Worley SJ, Daoud EG, Hwang C, Schuger C, Bump TE, Jazayeri M, Tomassoni GF, Kopelman HA, Soejima K, Nakagawa H. Irrigated radiofrequency catheter ablation guided by electroanatomic mapping for recurrent ventricular tachycardia after myocardial infarction: the multicenter thermocool ventricular tachycardia ablation trial. Circulation. 2008 Dec 16; 118(25):2773-82.

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Seiler J, Lee JC, Roberts-Thomson KC, Stevenson WG. Intracardiac echocardiography guided catheter ablation of incessant ventricular tachycardia from the posterior papillary muscle causing tachycardia–mediated cardiomyopathy. Heart Rhythm. 2009 Mar; 6(3):389-92.

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Eckart RE, Field ME, Hruczkowski TW, Forman DE, Dorbala S, Di Carli MF, Albert CE, Maisel WH, Epstein LM, Stevenson WG. Association of electrocardiographic morphology of exercise-induced ventricular arrhythmia with mortality. Ann Intern Med. 2008 Oct 7; 149(7):451-60, W82.

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Goldberger JJ, Cain ME, Hohnloser SH, Kadish AH, Knight BP, Lauer MS, Maron BJ, Page RL, Passman RS, Siscovick D, Stevenson WG, Zipes DP. American Heart Association/american College of Cardiology Foundation/heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death: a scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention. Heart Rhythm. 2008 Oct; 5(10):e1-21.

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Goldberger JJ, Cain ME, Hohnloser SH, Kadish AH, Knight BP, Lauer MS, Maron BJ, Page RL, Passman RS, Siscovick D, Siscovick D, Stevenson WG, Zipes DP. American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death: a scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention. Circulation. 2008 Sep 30; 118(14):1497-1518.

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Goldberger JJ, Cain ME, Hohnloser SH, Kadish AH, Knight BP, Lauer MS, Maron BJ, Page RL, Passman RS, Siscovick D, Stevenson WG, Zipes DP. American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society Scientific Statement on Noninvasive Risk Stratification Techniques for Identifying Patients at Risk for Sudden Cardiac Death. A scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention. J Am Coll Cardiol. 2008 Sep 30; 52(14):1179-99.

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Seiler J, Roberts-Thomson KC, Raymond JM, Vest J, Delacretaz E, Stevenson WG. Steam pops during irrigated radiofrequency ablation: feasibility of impedance monitoring for prevention. Heart Rhythm. 2008 Oct; 5(10):1411-6.

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Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG, Arnold JM, Buxton AE, Camm AJ, Connolly SJ, Dubuc M, Ducharme A, Guerra PG, Hohnloser SH, Lambert J, Le Heuzey JY, O’Hara G, Pedersen OD, Rouleau JL, Singh BN, Stevenson LW, Stevenson WG, Thibault B, Waldo AL. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008 Jun 19; 358(25):2667-77.

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Sacher F, Tedrow UB, Field ME, Raymond JM, Koplan BA, Epstein LM, Stevenson WG. Ventricular tachycardia ablation: evolution of patients and procedures over 8 years. Circ Arrhythm Electrophysiol. 2008 Aug; 1(3):153-61.

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Vest JA, Seiler J, Stevenson WG. Clinical use of cooled radiofrequency ablation. J Cardiovasc Electrophysiol. 2008 Jul; 19(7):769-73.

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Stevenson WG, Berul CI. Arrhythmia and Electrophysiology: the eagle can land. Circ Arrhythm Electrophysiol. 2008 Apr; 1(1):1.

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Roberts-Thomson KC, Seiler J, Raymond JM, Stevenson WG. Exercise induced tachycardia with atrioventricular dissociation: what is the mechanism? Heart Rhythm. 2009 Mar; 6(3):426-8.

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Zeppenfeld K, Stevenson WG. Ablation of ventricular tachycardia in patients with structural heart disease. Pacing Clin Electrophysiol. 2008 Mar; 31(3):358-74.

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Cooper JM, Sapp JL, Robinson D, Epstein LM, Stevenson WG. A rewarming maneuver demonstrates the contribution of blood flow to electrode cooling during internally irrigated RF ablation. J Cardiovasc Electrophysiol. 2008 Apr; 19(4):409-14.

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Zeppenfeld K, Schalij MJ, Bartelings MM, Tedrow UB, Koplan BA, Soejima K, Stevenson WG. Catheter ablation of ventricular tachycardia after repair of congenital heart disease: electroanatomic identification of the critical right ventricular isthmus. Circulation. 2007 Nov 13; 116(20):2241-52.

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Eckart RE, Hruczkowski TW, Tedrow UB, Koplan BA, Epstein LM, Stevenson WG. Sustained ventricular tachycardia associated with corrective valve surgery. Circulation. 2007 Oct 30; 116(18):2005-11.

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Sacher F, Sobieszczyk P, Tedrow U, Eisenhauer AC, Field ME, Selwyn A, Raymond JM, Koplan B, Epstein LM, Stevenson WG. Transcoronary ethanol ventricular tachycardia ablation in the modern electrophysiology era. Heart Rhythm. 2008 Jan; 5(1):62-8.

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Sacher F, Vest J, Raymond JM, Stevenson WG. Incessant donor-to-recipient atrial tachycardia after bilateral lung transplantation. Heart Rhythm. 2008 Jan; 5(1):149-51.

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Sacher F, Vest J, Raymond JM, Stevenson WG. Atrial pacing inducing narrow QRS tachycardia followed by wide complex tachycardia. J Cardiovasc Electrophysiol. 2007 Nov; 18(11):1213-5.

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Stevenson WG, Soejima K. Catheter ablation for ventricular tachycardia. Circulation. 2007 May 29; 115(21):2750-60.

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Koplan BA, Stevenson WG. Sudden arrhythmic death syndrome. Heart. 2007 May; 93(5):547-8.

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Parkash R, Stevenson WG. Atrial fibrillation and clinical events in chronic heart failure. J Am Coll Cardiol. 2007 Jan 23; 49(3):376; author reply 376-7.

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Sacher F, Jais P, Stephenson K, O’Neill MD, Hocini M, Clementy J, Stevenson WG, Haissaguerre M. Phrenic nerve injury after catheter ablation of atrial fibrillation. Indian Pacing Electrophysiol J. 2007; 7(1):1-6.

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Tedrow UB, Stevenson WG, Wood MA, Shepard RK, Hall K, Pellegrini CP, Ellenbogen KA. Activation sequence modification during cardiac resynchronization by manipulation of left ventricular epicardial pacing stimulus strength. Pacing Clin Electrophysiol. 2007 Jan; 30(1):65-9.

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Dzau VJ, Antman EM, Black HR, Hayes DL, Manson JE, Plutzky J, Popma JJ, Stevenson W. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: part I: Pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease). Circulation. 2006 Dec 19; 114(25):2850-70.

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Dzau VJ, Antman EM, Black HR, Hayes DL, Manson JE, Plutzky J, Popma JJ, Stevenson W. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: part II: Clinical trial evidence (acute coronary syndromes through renal disease) and future directions. Circulation. 2006 Dec 19; 114(25):2871-91.

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Stevenson WG, Tedrow U. Management of atrial fibrillation in patients with heart failure. Heart Rhythm. 2007 Mar; 4(3 Suppl):S28-30.

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Tedrow U, Stevenson WG. Substrate mapping and the aging atrium. Heart Rhythm. 2007 Feb; 4(2):145-6.

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Eckart RE, Hruczkowski TW, Stevenson WG, Epstein LM. Myopotentials leading to ventricular fibrillation detection after advisory defibrillator generator replacement. Pacing Clin Electrophysiol. 2006 Nov; 29(11):1273-6.

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Perloff JK, Middlekauf HR, Child JS, Stevenson WG, Miner PD, Goldberg GD. Usefulness of post-ventriculotomy signal averaged electrocardiograms in congenital heart disease. Am J Cardiol. 2006 Dec 15; 98(12):1646-51.

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Koplan BA, Epstein LM, Albert CM, Stevenson WG. Survival in octogenarians receiving implantable defibrillators. Am Heart J. 2006 Oct; 152(4):714-9.

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Veenhuyzen GD, Hruczkowski T, Dhir SK, Stevenson WG. Another way to prove the presence and participation of an accessory pathway in supraventricular tachycardia? J Cardiovasc Electrophysiol. 2006 Oct; 17(10):1147-9.

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Yan AT, Shayne AJ, Brown KA, Gupta SN, Chan CW, Luu TM, Di Carli MF, Reynolds HG, Stevenson WG, Kwong RY. Characterization of the peri-infarct zone by contrast-enhanced cardiac magnetic resonance imaging is a powerful predictor of post-myocardial infarction mortality. Circulation. 2006 Jul 4; 114(1):32-9.

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Sapp JL, Cooper JM, Zei P, Stevenson WG. Large radiofrequency ablation lesions can be created with a retractable infusion-needle catheter. J Cardiovasc Electrophysiol. 2006 Jun; 17(6):657-61.

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Field ME, Miyazaki H, Epstein LM, Stevenson WG. Narrow complex tachycardia after slow pathway ablation: continue ablating? J Cardiovasc Electrophysiol. 2006 May; 17(5):557-9.

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Tedrow UB, Kramer DB, Stevenson LW, Stevenson WG, Baughman KL, Epstein LM, Lewis EF. Relation of right ventricular peak systolic pressure to major adverse events in patients undergoing cardiac resynchronization therapy. Am J Cardiol. 2006 Jun 15; 97(12):1737-40.

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Ames A, Stevenson WG. Cardiology patient page. Catheter ablation of atrial fibrillation. Circulation. 2006 Apr 4; 113(13):e666-8.

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Koplan BA, Soejima K, Baughman K, Epstein LM, Stevenson WG. Refractory ventricular tachycardia secondary to cardiac sarcoid: electrophysiologic characteristics, mapping, and ablation. Heart Rhythm. 2006 Aug; 3(8):924-9.

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Zei PC, Stevenson WG. Epicardial catheter mapping and ablation of ventricular tachycardia. Heart Rhythm. 2006 Mar; 3(3):360-3.

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Miyazaki H, Stevenson WG, Stephenson K, Soejima K, Epstein LM. Entrainment mapping for rapid distinction of left and right atrial tachycardias. Heart Rhythm. 2006 May; 3(5):516-23.

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Parkash R, Stevenson WG, Epstein LM, Maisel WH. Predicting early mortality after implantable defibrillator implantation: a clinical risk score for optimal patient selection. Am Heart J. 2006 Feb; 151(2):397-403.

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Stevenson WG, Epstein LM. Endpoints for ablation of atrial fibrillation. Heart Rhythm. 2006 Feb; 3(2):146-7.

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Stevenson LW, Stevenson WG. Cost-effectiveness of ICDs. N Engl J Med. 2006 Jan 12; 354(2):205-7; author reply 205-7.

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Nazarian S, Maisel WH, Miles JS, Tsang S, Stevenson LW, Stevenson WG. Impact of implantable cardioverter defibrillators on survival and recurrent hospitalization in advanced heart failure. Am Heart J. 2005 Nov; 150(5):955-60.

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Intini A, Goldstein RN, Jia P, Ramanathan C, Ryu K, Giannattasio B, Gilkeson R, Stambler BS, Brugada P, Stevenson WG, Rudy Y, Waldo AL. Electrocardiographic imaging (ECGI), a novel diagnostic modality used for mapping of focal left ventricular tachycardia in a young athlete. Heart Rhythm. 2005 Nov; 2(11):1250-2.

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Parkash R, Maisel WH, Toca FM, Stevenson WG. Atrial fibrillation in heart failure: high mortality risk even if ventricular function is preserved. Am Heart J. 2005 Oct; 150(4):701-6.

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Reynolds DW, Chen PS, Deal BJ, Donahue JK, Ellenbogen KA, Epstein AE, Friedman PA, Hammill SC, Hohnloser SH, Kanter RJ, Lindsay BD, Natale A, Saffitz J, Stevenson WG. Highlights of Heart Rhythm 2005, the Annual Scientific Sessions of the Heart Rhythm Society, May 4-7, 2005, New Orleans, Louisiana. Heart Rhythm. 2005 Sep; 2(9):1025-33.

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Stevenson WG, Soejima K. Recording techniques for clinical electrophysiology. J Cardiovasc Electrophysiol. 2005 Sep; 16(9):1017-22.

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Tedrow U, Stevenson WG, Benzaquen LR. Apical left ventricular aneurysm presenting with malignant ventricular tachycardia responsive to aneurysmectomy. Heart. 2005 May; 91(5):623.

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Brunckhorst CB, Delacretaz E, Soejima K, Maisel WH, Friedman PL, Stevenson WG. Impact of changing activation sequence on bipolar electrogram amplitude for voltage mapping of left ventricular infarcts causing ventricular tachycardia. J Interv Card Electrophysiol. 2005 Mar; 12(2):137-41.

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Stevenson WG. Catheter ablation of monomorphic ventricular tachycardia. Curr Opin Cardiol. 2005 Jan; 20(1):42-7.

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Stevenson WG. To freeze or burn the epicardium? Heart Rhythm. 2005 Jan; 2(1):91-2.

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Stevenson WG, Chaitman BR, Ellenbogen KA, Epstein AE, Gross WL, Hayes DL, Strickberger SA, Sweeney MO. Clinical assessment and management of patients with implanted cardioverter-defibrillators presenting to nonelectrophysiologists. Circulation. 2004 Dec 21; 110(25):3866-9.

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Tedrow U, Maisel WH, Epstein LM, Soejima K, Stevenson WG. Feasibility of adjusting paced left ventricular activation by manipulating stimulus strength. J Am Coll Cardiol. 2004 Dec 7; 44(11):2249-52.

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Stevenson WG, Stevenson LW. Atrial fibrillation and heart failure–five more years. N Engl J Med. 2004 Dec 2; 351(23):2437-40.

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Brunckhorst CB, Delacretaz E, Soejima K, Jackman WM, Nakagawa H, Kuck KH, Ben-Haim SA, Seifert B, Stevenson WG. Ventricular mapping during atrial and right ventricular pacing: relation of electrogram parameters to ventricular tachycardia reentry circuits after myocardial infarction. J Interv Card Electrophysiol. 2004 Dec; 11(3):183-91.

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Curtis AB, Abraham WT, Chen PS, Ellenbogen KA, Epstein AE, Friedman PA, Hohnloser SH, Kanter RJ, Stevenson WG. Highlights of Heart Rhythm 2004, the Annual Scientific Sessions of the Heart Rhythm Society: May 19 to 22, 2004, in San Francisco, California. J Am Coll Cardiol. 2004 Oct 19; 44(8):1550-6.

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Stevenson WG, Cooper J, Sapp J. Optimizing RF output for cooled RF ablation. J Cardiovasc Electrophysiol. 2004 Oct; 15(10 Suppl):S24-7.

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Soejima K, Stevenson WG. Athens, athletes, and arrhythmias: the cardiologist’s dilemma. J Am Coll Cardiol. 2004 Sep 1; 44(5):1059-61.

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Cooper JM, Sapp JL, Tedrow U, Pellegrini CP, Robinson D, Epstein LM, Stevenson WG. Ablation with an internally irrigated radiofrequency catheter: learning how to avoid steam pops. Heart Rhythm. 2004 Sep; 1(3):329-33.

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Soejima K, Couper G, Cooper JM, Sapp JL, Epstein LM, Stevenson WG. Subxiphoid surgical approach for epicardial catheter-based mapping and ablation in patients with prior cardiac surgery or difficult pericardial access. Circulation. 2004 Sep 7; 110(10):1197-201.

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Brunckhorst CB, Delacretaz E, Soejima K, Maisel WH, Friedman PL, Stevenson WG. Identification of the ventricular tachycardia isthmus after infarction by pace mapping. Circulation. 2004 Aug 10; 110(6):652-9.

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Friedman PL, Dubuc M, Green MS, Jackman WM, Keane DT, Marinchak RA, Nazari J, Packer DL, Skanes A, Steinberg JS, Stevenson WG, Tchou PJ, Wilber DJ, Worley SJ. Catheter cryoablation of supraventricular tachycardia: results of the multicenter prospective “frosty” trial. Heart Rhythm. 2004 Jul; 1(2):129-38.

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Sapp JL, Soejima K, Cooper JM, Epstein LM, Stevenson WG. Ablation lesion size correlates with pacing threshold: a physiological basis for use of pacing to assess ablation lesions. Pacing Clin Electrophysiol. 2004 Jul; 27(7):933-7.

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Soejima K, Stevenson WG, Sapp JL, Selwyn AP, Couper G, Epstein LM. Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars. J Am Coll Cardiol. 2004 May 19; 43(10):1834-42.

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Tedrow U, Sweeney MO, Stevenson WG. Physiology of cardiac resynchronization. Curr Cardiol Rep. 2004 May; 6(3):189-93.

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Sapp JL, Cooper JM, Soejima K, Sorrell T, Lopera G, Satti SD, Koplan BA, Epstein LM, Edelman E, Rogers C, Stevenson WG. Deep myocardial ablation lesions can be created with a retractable needle-tipped catheter. Pacing Clin Electrophysiol. 2004 May; 27(5):594-9.

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Stevenson WG, Sweeney MO. Single site left ventricular pacing for cardiac resynchronization. Circulation. 2004 Apr 13; 109(14):1694-6.

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Koplan BA, Parkash R, Couper G, Stevenson WG. Combined epicardial-endocardial approach to ablation of inappropriate sinus tachycardia. J Cardiovasc Electrophysiol. 2004 Feb; 15(2):237-40.

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Lopera G, Stevenson WG, Soejima K, Maisel WH, Koplan B, Sapp JL, Satti SD, Epstein LM. Identification and ablation of three types of ventricular tachycardia involving the his-purkinje system in patients with heart disease. J Cardiovasc Electrophysiol. 2004 Jan; 15(1):52-8.

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Blomström-Lundqvist C, Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm AJ, Campbell WB, Haines DE, Kuck KH, Lerman BB, Miller DD, Shaeffer CW, Stevenson WG, Tomaselli GF, Antman EM, Smith SC, Alpert JS, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Hiratzka LF, Hunt SA, Jacobs AK, Russell RO, Priori SG, Blanc JJ, Budaj A, Burgos EF, Cowie M, Deckers JW, Garcia MA, Klein WW, Lekakis J, Lindahl B, Mazzotta G, Morais JC, Oto A, Smiseth O, Trappe HJ. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias–executive summary. a report of the American college of cardiology/American heart association task force on practice guidelines and the European society of cardiology committee for practice guidelines (writing committee to develop guidelines for the management of patients with supraventricular arrhythmias) developed in collaboration with NASPE-Heart Rhythm Society. J Am Coll Cardiol. 2003 Oct 15; 42(8):1493-531.

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Blomström-Lundqvist C, Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm AJ, Campbell WB, Haines DE, Kuck KH, Lerman BB, Miller DD, Shaeffer CW, Stevenson WG, Tomaselli GF, Antman EM, Smith SC, Alpert JS, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Hiratzka LF, Hunt SA, Jacobs AK, Russell RO, Priori SG, Blanc JJ, Budaj A, Burgos EF, Cowie M, Deckers JW, Garcia MA, Klein WW, Lekakis J, Lindahl B, Mazzotta G, Morais JC, Oto A, Smiseth O, Trappe HJ. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias). Circulation. 2003 Oct 14; 108(15):1871-909.

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Delacretaz E, Soejima K, Brunckhorst CB, Maisel WH, Friedman PL, Stevenson WG. Assessment of radiofrequency ablation effect from unipolar pacing threshold. Pacing Clin Electrophysiol. 2003 Oct; 26(10):1993-6.

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Soejima K, Stevenson WG. Catheter ablation of ventricular tachycardia in patients with ischemic heart disease. Curr Cardiol Rep. 2003 Sep; 5(5):364-8.

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Tung S, Soejima K, Maisel WH, Suzuki M, Epstein L, Stevenson WG. Recognition of far-field electrograms during entrainment mapping of ventricular tachycardia. J Am Coll Cardiol. 2003 Jul 2; 42(1):110-5.

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Stevenson WG, Soejima K. Inside or out? Another option for incessant ventricular tachycardia. J Am Coll Cardiol. 2003 Jun 4; 41(11):2044-5.

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Brunckhorst CB, Stevenson WG, Soejima K, Maisel WH, Delacretaz E, Friedman PL, Ben-Haim SA. Relationship of slow conduction detected by pace-mapping to ventricular tachycardia re-entry circuit sites after infarction. J Am Coll Cardiol. 2003 Mar 5; 41(5):802-9.

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Koplan BA, Stevenson WG, Epstein LM, Aranki SF, Maisel WH. Development and validation of a simple risk score to predict the need for permanent pacing after cardiac valve surgery. J Am Coll Cardiol. 2003 Mar 5; 41(5):795-801.

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Ellison KE, Stevenson WG, Sweeney MO, Epstein LM, Maisel WH. Management of arrhythmias in heart failure. Congest Heart Fail. 2003 Mar-Apr; 9(2):91-9.

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Stevenson WG, Epstein LM. Predicting sudden death risk for heart failure patients in the implantable cardioverter-defibrillator age. Circulation. 2003 Feb 4; 107(4):514-6.

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Maisel WH, Stevenson WG, Epstein LM. Changing trends in pacemaker and implantable cardioverter defibrillator generator advisories. Pacing Clin Electrophysiol. 2002 Dec; 25(12):1670-8.

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Khan HH, Maisel WH, Ho C, Suzuki M, Soejima K, Solomon S, Stevenson WG. Effect of radiofrequency catheter ablation of ventricular tachycardia on left ventricular function in patients with prior myocardial infarction. J Interv Card Electrophysiol. 2002 Dec; 7(3):243-7.

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Fenelon G, Stambler BS, Huvelle E, Brugada P, Stevenson WG. Left ventricular dysfunction is associated with prolonged average ventricular fibrillation cycle length in patients with implantable cardioverter defibrillators. J Interv Card Electrophysiol. 2002 Dec; 7(3):249-54.

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Soejima K, Stevenson WG, Maisel WH, Sapp JL, Epstein LM. Electrically unexcitable scar mapping based on pacing threshold for identification of the reentry circuit isthmus: feasibility for guiding ventricular tachycardia ablation. Circulation. 2002 Sep 24; 106(13):1678-83.

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Maisel WH, Stevenson WG. Syncope–getting to the heart of the matter. N Engl J Med. 2002 Sep 19; 347(12):931-3.

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Maisel WH, Stevenson WG, Epstein LM. Reduced atrial blood flow in patients with coronary artery disease. Coron Artery Dis. 2002 Aug; 13(5):283-90.

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Soejima K, Stevenson WG. Ventricular tachycardia associated with myocardial infarct scar: a spectrum of therapies for a single patient. Circulation. 2002 Jul 9; 106(2):176-9.

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Brunckhorst CB, Stevenson WG, Jackman WM, Kuck KH, Soejima K, Nakagawa H, Cappato R, Ben-Haim SA. Ventricular mapping during atrial and ventricular pacing. Relationship of multipotential electrograms to ventricular tachycardia reentry circuits after myocardial infarction. Eur Heart J. 2002 Jul; 23(14):1131-8.

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Friedman RA, Walsh EP, Silka MJ, Calkins H, Stevenson WG, Rhodes LA, Deal BJ, Wolff GS, Demaso DR, Hanisch D, Van Hare GF. NASPE Expert Consensus Conference: Radiofrequency catheter ablation in children with and without congenital heart disease. Report of the writing committee. North American Society of Pacing and Electrophysiology. Pacing Clin Electrophysiol. 2002 Jun; 25(6):1000-17.

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Stevenson WG, Ellison KE, Sweeney MO, Epstein LM, Maisel WH. Management of arrhythmias in heart failure. Cardiol Rev. 2002 Jan-Feb; 10(1):8-14.

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Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med. 2001 Dec 18; 135(12):1061-73.

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Sapp J, Soejima K, Couper GS, Stevenson WG. Electrophysiology and anatomic characterization of an epicardial accessory pathway. J Cardiovasc Electrophysiol. 2001 Dec; 12(12):1411-4.

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Sweeney MO, Ellison KE, Stevenson WG. Implantable cardioverter defibrillators in heart failure. Cardiol Clin. 2001 Nov; 19(4):653-67.

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Maisel WH, Stevenson WG, Tung S, Blier LE, Brunckhorst CB. Less is more: 4:2:1 block. Circulation. 2001 Sep 4; 104(10):E50.

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Delacrétaz E, Stevenson WG. Catheter ablation of ventricular tachycardia in patients with coronary heart disease. Part II: Clinical aspects, limitations, and recent developments. Pacing Clin Electrophysiol. 2001 Sep; 24(9 Pt 1):1403-11.

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Maisel WH, Sweeney MO, Stevenson WG, Ellison KE, Epstein LM. Recalls and safety alerts involving pacemakers and implantable cardioverter-defibrillator generators. JAMA. 2001 Aug 15; 286(7):793-9.

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Soejima K, Suzuki M, Maisel WH, Brunckhorst CB, Delacretaz E, Blier L, Tung S, Khan H, Stevenson WG. Catheter ablation in patients with multiple and unstable ventricular tachycardias after myocardial infarction: short ablation lines guided by reentry circuit isthmuses and sinus rhythm mapping. Circulation. 2001 Aug 7; 104(6):664-9.

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Delacretaz E, Stevenson WG. Catheter ablation of ventricular tachycardia in patients with coronary heart disease: part I: Mapping. Pacing Clin Electrophysiol. 2001 Aug; 24(8 Pt 1):1261-77.

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Delacretaz E, Ganz LI, Soejima K, Friedman PL, Walsh EP, Triedman JK, Sloss LJ, Landzberg MJ, Stevenson WG. Multi atrial maco-re-entry circuits in adults with repaired congenital heart disease: entrainment mapping combined with three-dimensional electroanatomic mapping. J Am Coll Cardiol. 2001 May; 37(6):1665-76.

View in: PubMed
Soejima K, Delacretaz E, Suzuki M, Brunckhorst CB, Maisel WH, Friedman PL, Stevenson WG. Saline-cooled versus standard radiofrequency catheter ablation for infarct-related ventricular tachycardias. Circulation. 2001 Apr 10; 103(14):1858-62.

View in: PubMed
Soejima K, Stevenson WG, Maisel WH, Delacretaz E, Brunckhorst CB, Ellison KE, Friedman PL. The N + 1 difference: a new measure for entrainment mapping. J Am Coll Cardiol. 2001 Apr; 37(5):1386-94.

View in: PubMed
Delacretaz E, Soejima K, Gottipaty VK, Brunckhorst CB, Friedman PL, Stevenson WG. Single catheter determination of local electrogram prematurity using simultaneous unipolar and bipolar recordings to replace the surface ECG as a timing reference. Pacing Clin Electrophysiol. 2001 Apr; 24(4 Pt 1):441-9.

View in: PubMed
Stevenson WG, Maisel WH. Electrocardiography artifact: what you do not know, you do not recognize. Am J Med. 2001 Apr 1; 110(5):402-3.

View in: PubMed
Stevenson WG, Soejima K. Knowing where to look. J Cardiovasc Electrophysiol. 2001 Mar; 12(3):367-8.

View in: PubMed
Stevenson WG, Stevenson LW. Prevention of sudden death in heart failure. J Cardiovasc Electrophysiol. 2001 Jan; 12(1):112-4.

View in: PubMed
Stevenson WG, Delacretaz E. Radiofrequency catheter ablation of ventricular tachycardia. Heart. 2000 Nov; 84(5):553-9.

View in: PubMed
Stevenson WG, Delacretaz E. Strategies for catheter ablation of scar-related ventricular tachycardia. Curr Cardiol Rep. 2000 Nov; 2(6):537-44.

View in: PubMed
Soejima K, Stevenson WG, Delacretaz E, Brunckhorst CB, Maisel WH, Friedman PL. Identification of left atrial origin of ectopic tachycardia during right atrial mapping: analysis of double potentials at the posteromedial right atrium. J Cardiovasc Electrophysiol. 2000 Sep; 11(9):975-80.

View in: PubMed
Weinfeld MS, Drazner MH, Stevenson WG, Stevenson LW. Early outcome of initiating amiodarone for atrial fibrillation in advanced heart failure. J Heart Lung Transplant. 2000 Jul; 19(7):638-43.

View in: PubMed
Maisel WH, Stevenson WG. Sudden death and the electrophysiological effects of angiotensin-converting enzyme inhibitors. J Card Fail. 2000 Jun; 6(2):80-2.

View in: PubMed
Ellison KE, Stevenson WG, Sweeney MO, Lefroy DC, Delacretaz E, Friedman PL. Catheter ablation for hemodynamically unstable monomorphic ventricular tachycardia. J Cardiovasc Electrophysiol. 2000 Jan; 11(1):41-4.

View in: PubMed
Delacretaz E, Stevenson WG, Ellison KE, Maisel WH, Friedman PL. Mapping and radiofrequency catheter ablation of the three types of sustained monomorphic ventricular tachycardia in nonischemic heart disease. J Cardiovasc Electrophysiol. 2000 Jan; 11(1):11-7.

View in: PubMed
Delacretaz E, Soejima K, Stevenson WG, Friedman PL. Short ventriculoatrial intervals during orthodromic atrioventricular reciprocating tachycardia: what is the mechanism? J Cardiovasc Electrophysiol. 2000 Jan; 11(1):121-4.

View in: PubMed
Soejima K, Delacretaz E, Stevenson WG, Friedman PL. DDD-pacing-induced cardiomyopathy following AV node ablation for persistent atrial tachycardia. J Interv Card Electrophysiol. 1999 Dec; 3(4):321-3.

View in: PubMed
Stevenson WG, Stevenson LW. Atrial fibrillation in heart failure. N Engl J Med. 1999 Sep 16; 341(12):910-1.

View in: PubMed
Kocovic DZ, Harada T, Friedman PL, Stevenson WG. Characteristics of electrograms recorded at reentry circuit sites and bystanders during ventricular tachycardia after myocardial infarction. J Am Coll Cardiol. 1999 Aug; 34(2):381-8.

View in: PubMed
Delacretaz E, Stevenson WG, Winters GL, Mitchell RN, Stewart S, Lynch K, Friedman PL. Ablation of ventricular tachycardia with a saline-cooled radiofrequency catheter: anatomic and histologic characteristics of the lesions in humans. J Cardiovasc Electrophysiol. 1999 Jun; 10(6):860-5.

View in: PubMed
Delacretaz E, Stevenson WG, Winters GL, Friedman PL. Radiofrequency ablation of atrial flutter. Circulation. 1999 Apr 13; 99(14):E1-2.

View in: PubMed
Friedman PL, Stevenson WG. Proarrhythmia. Am J Cardiol. 1998 Oct 16; 82(8A):50N-58N.

View in: PubMed
Ellison KE, Friedman PL, Ganz LI, Stevenson WG. Entrainment mapping and radiofrequency catheter ablation of ventricular tachycardia in right ventricular dysplasia. J Am Coll Cardiol. 1998 Sep; 32(3):724-8.

View in: PubMed
Lefroy DC, Fang JC, Stevenson LW, Hartley LH, Friedman PL, Stevenson WG. Recipient-to-donor atrioatrial conduction after orthotopic heart transplantation: surface electrocardiographic features and estimated prevalence. Am J Cardiol. 1998 Aug 15; 82(4):444-50.

View in: PubMed
Stevenson WG, Friedman PL, Kocovic D, Sager PT, Saxon LA, Pavri B. Radiofrequency catheter ablation of ventricular tachycardia after myocardial infarction. Circulation. 1998 Jul 28; 98(4):308-14.

View in: PubMed
Stevenson WG, Delacretaz E, Friedman PL, Ellison KE. Identification and ablation of macroreentrant ventricular tachycardia with the CARTO electroanatomical mapping system. Pacing Clin Electrophysiol. 1998 Jul; 21(7):1448-56.

View in: PubMed
Lefroy DC, Ellison KE, Friedman PL, Stevenson WG. Arrhythmia of the month: shortening of ventriculoatrial conduction time during radiofrequency catheter ablation of a concealed accessory pathway. J Cardiovasc Electrophysiol. 1998 Apr; 9(4):445-7.

View in: PubMed
Ganz LI, Couper GS, Friedman PL, Stevenson WG, Ellison K. Use of telemetered permanent pacemaker intracardiac electrograms to diagnose ventricular tachycardia. Am J Cardiol. 1997 Dec 1; 80(11):1511-3.

View in: PubMed
stevenson WG, Friedman PL, Ganz LI. Radiofrequency catheter ablation of ventricular tachycardia late after myocardial infarction. J Cardiovasc Electrophysiol. 1997 Nov; 8(11):1309-19.

View in: PubMed
Stevenson WG, Ellison KE, Lefroy DC, Friedman PL. Ablation therapy for cardiac arrhythmias. Am J Cardiol. 1997 Oct 23; 80(8A):56G-66G.

View in: PubMed
Ellison KE, Stevenson WG, Couper GS, Friedman PL. Ablation of ventricular tachycardia due to a postinfarct ventricular septal defect: identification and transection of a broad reentry loop. J Cardiovasc Electrophysiol. 1997 Oct; 8(10):1163-6.

View in: PubMed
Harada T, Stevenson WG, Kocovic DZ, Friedman PL. Catheter ablation of ventricular tachycardia after myocardial infarction: relation of endocardial sinus rhythm late potentials to the reentry circuit. J Am Coll Cardiol. 1997 Oct; 30(4):1015-23.

View in: PubMed
Stevenson WG, Sweeney MO. Arrhythmias and sudden death in heart failure. Jpn Circ J. 1997 Sep; 61(9):727-40.

View in: PubMed
Maisel WH, Kuntz KM, Reimold SC, Lee TH, Antman EM, Friedman PL, Stevenson WG. Risk of initiating antiarrhythmic drug therapy for atrial fibrillation in patients admitted to a university hospital. Ann Intern Med. 1997 Aug 15; 127(4):281-4.

View in: PubMed
Stevenson WG, Sweeney MO. Pharmacologic and nonpharmacologic treatment of ventricular arrhythmias in heart failure. Curr Opin Cardiol. 1997 May; 12(3):242-50.

View in: PubMed
Stevenson WG, Friedman PL, Sager PT, Saxon LA, Kocovic D, Harada T, Wiener I, Khan H. Exploring postinfarction reentrant ventricular tachycardia with entrainment mapping. J Am Coll Cardiol. 1997 May; 29(6):1180-9.

View in: PubMed
Hadjis TA, Stevenson WG, Harada T, Friedman PL, Sager P, Saxon LA. Preferential locations for critical reentry circuit sites causing ventricular tachycardia after inferior wall myocardial infarction. J Cardiovasc Electrophysiol. 1997 Apr; 8(4):363-70.

View in: PubMed
Hadjis TA, Harada T, Stevenson WG, Friedman PL. Effect of recording site on postpacing interval measurement during catheter mapping and entrainment of postinfarction ventricular tachycardia. J Cardiovasc Electrophysiol. 1997 Apr; 8(4):398-404.

View in: PubMed
Merliss AD, Seifert MJ, Collins RF, Higgins JP, Reimold SC, Lee RT, Friedman PL, Stevenson WG. Catheter ablation of idiopathic left ventricular tachycardia associated with a false tendon. Pacing Clin Electrophysiol. 1996 Dec; 19(12 Pt 1):2144-6.

View in: PubMed
Stevenson WG, Stevenson LW, Middlekauff HR, Fonarow GC, Hamilton MA, Woo MA, Saxon LA, Natterson PD, Steimle A, Walden JA, Tillisch JH. Improving survival for patients with atrial fibrillation and advanced heart failure. J Am Coll Cardiol. 1996 Nov 15; 28(6):1458-63.

View in: PubMed
Stevenson WG, Ridker PM. Should survivors of myocardial infarction with low ejection fraction be routinely referred to arrhythmia specialists? JAMA. 1996 Aug 14; 276(6):481-5.

View in: PubMed
Friedman PL, Stevenson WG, Kocovic DZ. Autonomic dysfunction after catheter ablation. J Cardiovasc Electrophysiol. 1996 May; 7(5):450-9.

View in: PubMed
Ganz LI, Stevenson WG. Catheter mapping and ablation of ventricular tachycardia. Coron Artery Dis. 1996 Jan; 7(1):29-35.

View in: PubMed
Stevenson WG, Stevenson LW, Middlekauff HR, Fonarow GC, Hamilton MA, Woo MA, Saxon LA, Natterson PD, Steimle A, Walden JA, et al. Improving survival for patients with advanced heart failure: a study of 737 consecutive patients. J Am Coll Cardiol. 1995 Nov 15; 26(6):1417-23.

View in: PubMed
Stevenson WG. Ventricular tachycardia after myocardial infarction: from arrhythmia surgery to catheter ablation. J Cardiovasc Electrophysiol. 1995 Oct; 6(10 Pt 2):942-50.

View in: PubMed
Bartlett TG, Mitchell R, Friedman PL, Stevenson WG. Histologic evolution of radiofrequency lesions in an old human myocardial infarct causing ventricular tachycardia. J Cardiovasc Electrophysiol. 1995 Aug; 6(8):625-9.

View in: PubMed
Stevenson WG, Sager PT, Natterson PD, Saxon LA, Middlekauff HR, Wiener I. Relation of pace mapping QRS configuration and conduction delay to ventricular tachycardia reentry circuits in human infarct scars. J Am Coll Cardiol. 1995 Aug; 26(2):481-8.

View in: PubMed
Stevenson WG. Mechanisms and management of arrhythmias in heart failure. Curr Opin Cardiol. 1995 May; 10(3):274-81.

View in: PubMed
Stevenson WG, Sager PT, Friedman PL. Entrainment techniques for mapping atrial and ventricular tachycardias. J Cardiovasc Electrophysiol. 1995 Mar; 6(3):201-16.

View in: PubMed
Stevenson WG. Functional approach to site-by-site catheter mapping of ventricular reentry circuits in chronic infarctions. J Electrocardiol. 1994; 27 Suppl:130-8.

View in: PubMed

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Leaving Hospital Against Medical Advice (AMA): Higher Rates of Hospital Readmission and Death

Posted in Health Law & Patient Safety, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, tagged Allan Garland, Canadian Medical Association, Canadian Medical Association Journal, University of Manitoba on August 26, 2013| Leave a Comment »

Leaving Hospital Against Medical Advice (AMA): Higher Rates of Hospital Readmission and Death

Reporter: Aviva Lev-Ari, PhD, RN

Rates of readmission and death associated with leaving hospital against medical advice: a population-based study

CMAJ August 26, 2013 First published August 26, 2013, doi:10.1503/cmaj.130029

+Author Affiliations

Department of Internal Medicine (Garland, Ramsey, Olafson, Kraut), Department of Community Health Sciences (Garland, Ramsey, Fransoo, Chateau, Kraut), Manitoba Center for Health Policy (Garland, Fransoo, Chateau, Yogendran), University of Manitoba, Winnipeg, Man.

Allan Garland, E-mail agarland@hsc.mb.ca

Abstract

Background: Leaving hospital against medical advice may have adverse consequences. Previous studies have been limited by evaluating specific types of patients, small sample sizes and incomplete determination of outcomes. We hypothesized that leaving hospital against medical advice would be associated with increases in subsequent readmission and death.

Methods: In a population-based analysis involving all adults admitted to hospital and discharged alive in Manitoba from Apr. 1, 1990, to Feb. 28, 2009, we evaluated all-cause 90-day mortality and 30-day hospital readmission. We used multivariable regression, adjusted for age, sex, socioeconomic status, year of hospital admission, patient comorbidities, hospital diagnosis, past frequency of admission to hospital, having previously left hospital against medical advice and data clustering (patients with multiple admissions). For readmission, we assessed both between-person and within-person effects of leaving hospital against medical advice.

Results: Leaving against medical advice occurred in 21 417 of 1 916 104 index hospital admissions (1.1%), and was associated with higher adjusted rates of 90-day mortality (odds ratio [OR] 2.51, 95% confidence interval [CI] 2.18-2.89), and 30-day hospital readmission (within-person OR 2.10, CI 1.99-2.21; between-person OR 3.04, CI 2.79-3.30). In our additional analyses, elevated rates of readmission and death associated with leaving against medical advice were manifest within 1 week and persisted for at least 180 days after discharge.

Interpretation: Adults who left the hospital against medical advice had higher rates of hospital readmission and death. The persistence of these effects suggests that they are not solely a result of incomplete treatment of acute illness. Interventions aimed at reducing these effects may need to include longitudinal interventions extending beyond admission to hospital.

http://www.cmaj.ca/content/early/2013/08/26/cmaj.130029

Published: Aug 26, 2013 | Updated: Aug 26, 2013

By Chris Kaiser, Cardiology Editor, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

Adults who left the hospital against medical advice had higher rates of hospital readmission and death.
Note that the increased risk persisted for at least 180 days after discharge suggesting that they are not solely a result of incomplete treatment of acute illness.

In one of the largest and most comprehensive studies of its kind, researchers found that leaving the hospital against medical advice more than doubled the risk of mortality and rehospitalization, a risk that persisted out to 6 months.

Out of nearly 2 million index hospital admissions, the 1.1% of patients who left before being officially discharged were two-and-a-half times more likely to die within 90 days (OR 2.51), according toAllan Garland, MD, co-head of the section of critical care medicine at the University of Manitoba in Winnipeg, and colleagues.

Patients who left against medical advice also had three times the rate of readmissions in the month following their departure (OR 3.04), the researchers reported online in the Canadian Medical Association Journal.

The risk of readmission appears to be strongest early on, as one-quarter of rehospitalizations occurred within 1 day of leaving against the doctor’s orders and 75% occurred within 2 weeks.

“For both hospital readmission and death, the elevated rates among patients who left against medical advice started out high and then declined, but remained significantly elevated to at least 180 days,” wrote the authors.

One of the obvious reasons for early adverse events is incomplete treatment of the index acute illness. “But because the risk persisted out to 6 months, there are likely other factors involved,” Garland told MedPage Today in an interview.

One hypothesis is that these patients as a group are less compliant with medical advice or medication orders in the outpatient setting, he said.

“Even if we identify those at risk of leaving the hospital against medical advice and perform an intervention to keep them in the hospital, we might still need to address longer-term risk factors based on potential unhealthy outpatient behaviors,” Garland said.

This is all speculative at this point, he pointed out, but noted they are planning two additional phases of the study. These will evaluate why people leave against medical advice and then quantify personal characteristics and health habits that contribute to a general failure to adhere to physician advice.

“We already know that the strongest predictor for people leaving against medical advice is having done so in the past,” Garland said. “You might call them ‘frequent flyers,’ and an intervention at the hospital probably isn’t enough. We will probably need longitudinal interventions as well that address health habits.”

In related work yet unpublished, Garland’s group identified several index diagnoses that are associated with patients leaving the hospital against advice. These include substance abuse, overdose, tuberculosis, and diabetic ketoacidosis — findings that confirm similar smaller studies.

Patients less likely to leave against medical advice included those having major surgery and those admitted with a cancer diagnosis — unique findings because these patient populations are typically excluded from such studies, Garland said.

Most of the studies examining this topic have been small, or from single hospitals, or aimed at specific types of patients. In contrast, the current study looked at 1,916,104 adult admissions and live discharges over 19 years (1990–2009) in Manitoba with more than 21,000 incidents of patients leaving against medical advice (the most for one patient was 39 times).

The mean age of patients who left prematurely was 42, and 54 for those who stayed. Men were more likely than women to leave against medical advice, as were younger patients and those with certain chronic conditions such as hypertension and diabetes.

“It’s rare that patients want to leave against medical advice, but when they do, healthcare professionals should explain the risk to them,” Garland said. “They can point to our paper — which demonstrated in a rigorous and broad way — that what they’re about to do is known to be harmful.”

A limitation of the study is the potential for misclassified discharge information. Also, the authors had no data on the severity of the acute illness, nor did they know if readmissions or deaths were for the same reason as the index admission. Finally, results may not be applicable to regions that do not have publicly funded universal health coverage.

Although those with a lower income were more likely to leave the hospital against medical advice, it was not due to the potential burden of medical bills because Canada has universal health coverage.

Garland pointed to anecdotal evidence that suggests this group of patients feels outside financial pressure to resume work as soon as possible — an area that could be addressed during an inpatient intervention.

http://www.medpagetoday.com/TheGuptaGuide/PublicHealth/41182?xid=nl_mpt_guptaguide_2013-08-26&utm_source=guptaguide&utm_medium=email&utm_content=mpt&utm_campaign=08%7C26%7C2013&userid=99985&eun=g5099207d10r&email=avivalev-ari@alum.berkeley.edu&mu_id=5099207

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Cardiovascular Genetics: Functional Characterization and Clinical Applications @ 2013 Annual Conference of American Society of Human Genetics in Boston, 10/22-26, 2013

Posted in Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Resident-cell-based, tagged American Society of Human Genetics, Atrioventricular septal defect, Brugada syndrome, Coronary artery disease, genetics, Genome-wide association study, Sonic Hedgehog on August 26, 2013| Leave a Comment »

Cardiovascular Genetics: Functional Characterization and Clinical Applications @ 2013 Annual Conference of American Society of Human Genetics in Boston, 10/22-26, 2013

Reporter: Aviva Lev- Ari, PhD, RN

Sessions and Events

The 63rd Annual Conference of American Society of Human Genetics in Boston, 10/22-26, 2013

http://www.ashg.org/cgi-bin/2013/ashg13SOE.pl

PLATFORM ABSTRACTS

http://www.ashg.org/2013meeting/pdf/46025_Platform_bookmark%20for%20Web%20Final%20from%20AGS.pdf

We express a special interest in Session 58

Friday, October 25, 2013 Boston Convention Center

2:00 PM–4:15 PM

Concurrent Platform (abstract-driven) Session E (54-62)

SESSION 58 – Cardiovascular Genetics: Functional Characterization and Clinical Applications

Room 205, Level 2, Convention Center

Moderators:	Dan E. Arking, Johns Hopkins Univ. Sch. of Med.
	Myriam Fornage, Univ. of Texas Hlth Sci. Ctr. at Houston

Human Syndromic Atrioventricular Septal Defect

367/2:00 A homozygous mutation in Smoothened, a member of the Sonic hedgehog (SHH)-GLI pathway is involved in human syndromic atrioventricular septal defect. W. S. Kerstjens-Frederikse, Y. Sribudiani, M. E. Baardman, L. M. A. Van Unen, R. Brouwer, M. van den Hout, C. Kockx, W. Van IJcken, A. J. Van Essen, P. A. Van Der Zwaag, G. J. Du Marchie Sarvaas, R. M. F. Berger, F. W. Verheijen, R. M. W. Hofstra.

A homozygous mutation in Smoothened, a member of the Sonic Hedgehog (SHH)-GLI pathway is involved in human syndromic atrioventricular septal defect.

W.S. Kerstjens-Frederikse1, Y. Sribudiani2, M.E. Baardman1, L.M.A. Van Unen2, R. Brouwer2, M. van den Hout2, C. Kockx2, W. Van IJcken2, A.J. Van Essen1, P.A. Van Der Zwaag1, G.J. Du Marchie

Sarvaas3, R.M.F. Berger3, F.W. Verheijen2, R.M.W. Hofstra2.

1) Dept Gen, Univ of Groningen, Univ Med Ctr Groningen, Netherlands;

2) Dept Gen, Erasmus Med Ctr, Rotterdam, Netherlands; 3) Dept Ped Cardiol, Univ of Groningen, Univ Med Ctr Groningen, Netherlands.

Introduction: Atrioventricular septal defect (AVSD) is a common congenital heart disease with a high impact on personal health. It is often accompanied by other congenital anomalies and in many of these syndromic AVSDs, defects in the sonic hedgehog (SHH)-GLI signalling pathway have been detected. SMO codes for the transmembrane protein smoothened (SMO), which is active in cells with a primary cilium and is located on the ciliary membrane. SMO is a key protein in the SHH-GLI signaling cascade.

Methods: Two probands, a twin boy and girl, presented with an AVSD, large fontanel, postaxial polydactyly and skin syndactyly of the second and third toes of both feet. The boy also had hypospadias. The parents were consanguineous and they had one healthy older child. Karyotyping was normal and Smith-Lemli-Opitz syndrome (SLOS) was excluded. Exome sequencing was performed and candidate variants were validated by Sanger sequencing.

Results: A novel homozygous missense mutation c.1725C>T (p.R575W) in SMO (7q32.3) was detected. Functional studies in fibroblasts of the patients showed normal expression of SMO protein but an abnormal localization of SMO, outside the cilia. Moreover we show severely reduced downstream GLI1 mRNA expression after stimulation with the SMO agonist purmorphamine. These results, together with the previously described association of SHH signalling defects with AVSD and SLOS, suggest that this SMO mutation is involved in syndromic AVSD in these patients.

Conclusion: We present the first reported smoothened mutation in humans, in two patients with an AVSD and a phenotype resembling Smith-Lemli-Opitz syndrome

Left Ventricular Noncompaction – Model in Zebrafish

368/2:15 Identification of PRDM16 as a disease gene for left ventricular non-compaction and the efficient generation of a personalized disease model in zebrafish. A.-K. Arndt, S. Schaefer, R. Siebert, S. A. Cook, H.-H. Kramer, S. Klaassen, C. A. MacRae.

Identification of PRDM16 as a disease gene for left ventricular noncompaction

and the efficient generation of a personalized disease

model in zebrafish. A.-K. Arndt1,2, S. Schaefer3, R. Siebert4, S.A. Cook5,

H.-H. Kramer2, S. Klaassen6, C.A. MacRae1.

1) Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA;

2) Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig- Holstein, Kiel, Germany,;

3) Max-Delbruck-Center for Molecular Medicine, Berlin, Germany; 4) Institute of Human Genetics, University Hospital Schleswig Holstein, Kiel, Germany;

5) National Heart Centre, Singapore;

6) Department of Pediatric Cardiology, Charité, Berlin, Germany.

Using our own data and publically available array comparative genomic hybridization data, we identified the transcription factor PRDM16(PR domain containing 16) as a causal gene for the cardiomyopathy associated with monosomy 1p36, and confirmed its role in individuals with non-syndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). In a cohort of 75 non-syndromic patients with LVNC we detected 3 sporadic mutations, including 1 truncation mutant, 1 frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported non-synonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in over 6500 controls.

PRDM16 has not previously been associated with cardiovascular disease. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in impaired cardiomyocyte proliferation with associated physiologic defects in cardiac contractility and cell-cell coupling.

Using a phenotype-driven screening approach in the fish, we have identified 5 compounds that are able to rescue the physiologic defects associated with mutant or haploinsufficient PRDM16. Notably, all of the compounds had the capacity to restore cardiomyocyte proliferation and to prevent apoptosis in the model. Wildtype zebrafish also demonstrated a significant increase in cardiomyocyte numbers after treatment with the compounds suggesting a pro-proliferative effect of the compounds. In addition, the compounds also rescued the contractile and electrical defects observed in these disease models. These findings underline the importance of personalized disease models for specific pathways, to accelerate the exploration of disease biology and the development of innovative therapeutic approaches.

Genetics of Cerebral Small Vessel Disease

369/2:30 Mutation and copy number variation of FOXC1 causes cerebral small vessel disease. C. R. French, S. Seshadri, A. L. Destefano, M. Fornage, D. J. Emery, M. Hofker, J. Fu, A. J. Waskiewicz, O. J. Lehmann.

Mutation and copy number variation of FOXC1 causes cerebral small vessel disease. C.R. French1, S. Seshadri2, A.L Destefano3, M. Fornage4, D.J. Emery5, M. Hofker6, J. Fu6, A.J. Waskiewicz7, O.J. Lehmann1, 8.

1) Ophthalmology, University of Alberta, Edmonton, AB, Canada;

2) Department of Neurology, Boston University, Boston, MA, U. S. A;

3) School of Public Health, Boston University, Boston, MA, U. S. A;

4) Institute of Molecular Medicine and School of Public Health, University of Texas Health Sciences

Center, Houston, TX, U.S.A;

5) Department of Radiology, University of Alberta, Edmonton, AB, Canada;

6) Department of Medical Genetics, University Medical Center Groningen, Groningen, The Netherlands;

7) Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada;

8) Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.

Cerebral small vessel disease (CSVD) represents a major risk factor for stroke and cognitive decline in the elderly. The ability to readily visualize its microangiopathic features by magnetic resonance imaging provides opportunities for using markers of CSVD to identify novel stroke associated pathways. Using targeted genome-wide association analysis we identified CSVD associated single nucleotide polymorphisms (SNPs) adjacent to the forkhead transcription factor FOXC1, and using eQTL analysis in two independent data sets, demonstrate that such SNP’s are associated with FOXC1 expression levels.

We further demonstrate, using magnetic resonance imaging, that patients with either FOXC1 mutation or copy number variation exhibit CSVD. These findings, present in patients as young as two years of age and observed with missense and nonsense mutations as well as FOXC1-encompassing segmental deletion and duplication, demonstrate FOXC1 dysfunction induces cerebral small vessel pathology. A causative role for FOXC1 in the development and maintenance of cerebral vasculature is supported by the cerebral hemorrhage generated by morpholino-induced suppression of FOXC1 orthologs in a zebrafish model system. Furthermore, in vivo imaging demonstrates profoundly impaired migration of neural crest cells and their subsequent association with nascent vasculature, a process required for the differentiation of perivascular mural cells. In addition, foxc1 inhibition reduces the expression of pdgfra, a gene critically required for vascular stability via its role in mural cell recruitment. Taken together, these data support a requirement for Foxc1 in stabilizing newly formed vasculature via recruitment of neural crest derived mural cells, and define a casual role for FOXC1 in cerebrovascular pathology.

Genetics & Brugada Syndrome

370/2:45 Genetic association of common variants with a rare cardiac disease, the Brugada syndrome, in a multi-centric study. C. Dina, J. Barc, Y. Mizusawa, C. A. Remme, J. B. Gourraud, F. Simonet, P. J. Schwartz, L. Crotti, P. Guicheney, A. Leenhardt, C. Antzelevitch, E. Schulze-Bahr, E. R. Behr, J. Tfelt-Hansen, S. Kaab, H. Watanabe, M. Horie, N. Makita, W. Shimizu, P. Froguel, B. Balkau, M. Gessler, D. Roden, V. M. Christoffels, H. Le Marec, A. A. Wilde, V. Probst, J. J. Schott, R. Redon, C. R. Bezzina.

Genetic association of common variants with a rare cardiac disease,

the Brugada Syndrome, in a multi-centric study. C. Dina1,2, J. Barc3, Y.

Mizusawa3, C.A. Remme3, J.B. Gourraud1,2, F. Simonet1, P.J. Schwartz4,

L. Crotti4, P. Guicheney5, A. Leenhardt6, C. Antzelevitch7, E. Schulze-Bahr8,

E.R. Behr9, J. Tfelt-Hansen10, S. Kaab11, H. Watanabe12, M. Horie13, N.

Makita14, W. Shimizu15, P. Froguel 16, B. Balkau17, M. Gessler18, D.

Roden19, V.M. Christoffels3, H. Le Marec1,2, A.A. Wilde3, V. Probst1,2, J.J.

Schott1,2, R. Redon1,2, C.R. Bezzina3.

1) Thorx Inst, INSERM UMR 1087, CNRS, Nantes, France;

2) CHU Nantes, l’institut du thorax, Nantes, France;

3) Heart Failure Research Center, Academic Medical Center, Amsterdam, Netherlands;

4) University of Pavia, Pavia, Italy;

5) InsermUMR956, UPMC, Paris, France;

6) Cardiology Unit, Hôpital Bichat, Assistance Publique- Hôpitaux de Paris, Nantes, France;

7) Department of Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY, United States;

8) Department of Cardiovascular Medicine, University Hospital, Münster, Germany;

9) Cardiovascular Sciences Research Centre, St George’s University, London, United Kingdom;

10) Laboratory of Molecular Cardiology, University of Copenhagen, Copenhagen, Denmark;

11) 1Department of Medicine I, Ludwig-Maximilians University, Munich, Germany;

12) Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;

13) Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan;

14) Department of Molecular Physiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan;

15) Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan;

16) CNRS UMR 8199, Pasteur Institute, Lille, France;

17) Inserm UMR 1018, Centre for research in Epidemiology and Population Health, Villejuif, France;

18) Theodor-Boveri-Institute, University of Wuerzburg, Wuerzburg, Germany;

19) Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, United States.

The Brugada Syndrome (BrS) is considered as a rare Mendelian disorder with autosomal dominant transmission. BrS is associated with an increased risk of sudden cardiac death and specific electrocardiographic features consisting of ST-segment elevation in the right precordial leads. Loss-of-function mutations in SCN5A, encoding the pore-forming subunit of the cardiac sodium channel (Nav1.5), are identified in ~20% of patients. However, studies in families harbouring mutations in SCN5A have demonstrated low disease penetrance and in some instances absence of the familial SCN5A mutation in some affected members. These observations suggest a more complex inheritance model. To identify common genetic factors modulating disease risk, we conducted a genome-wide association study on 312 individuals with BrS and 1115 ancestry-matched controls. Two genomic regions displayed significant association. Both associations were replicated on two independent case/control sets from Europe (598/855) and Japan (208/1016) and a third locus emerged, all three with extremely significant p-values (1.10-14 down to 1.10-68). To our knowledge, this is the first time that several common variants are associated with a rare disease, with very high effect (Osdds-ratio) ranging from 1.58 to 2.55. While two loci displaying association hits had already been shown to influence ECG parameters in the general population, the third one encompasses a transcription factor which had never been related to cardiac arrhythmia. We showed that this factor regulates Nav1.5 channel expression in hearts of homozygous knockout embryos and influence cardiac conduction velocity in adult heterozygous mice. At last, we found that the cumulative effect of the 3 loci on disease susceptibility was unexpectedly large, indicating that common genetic variation may have a strong impact on predisposition to rare disease.

Mutations, Vasculopathy with Fever and Early Onset Strokes

371/3:00 Loss-of-function mutations in CECR1, encoding adenosine deaminase 2, cause systemic vasculopathy with fever and early onset strokes. Q. Zhou, A. Zavialov, M. Boehm, J. Chae, M. Hershfield, R. Sood, S. Burgess, A. Zavialov, D. Chin, C. Toro, R. Lee, M. Quezado, A. Ombrello, D. Stone, I. Aksentijevich, D. Kastner.

Loss-of-Function Mutations in CECR1, Encoding Adenosine Deaminase

2,Cause Systemic Vasculopathy with Fever and Early Onset

Strokes. Q. Zhou1, A. Zavialov2, M. Boehm3, J. Chae1, M. Hershfield4, R.

Sood5, S. Burgess6, A. Zavialov2, D. Chin1, C. Toro7, R. Lee8, M. Quezado9,

A. Ombrello1, D. Stone1, I. Aksentijevich1, D. Kastner1.

1) Inflammatory Disease Section, NHGRI, Bethesda, USA;

2) Turku Centre for Biotechnology, University of Turku, Turku, Finland;

3) Laboratory of Cardiovascular Regenerative Medicine, NHLBI, Bethesda, USA;

4) Department of Medicine, Duke University Medical Center, Durham, USA;

5) Zebrafish Core, NHGRI, Bethesda, USA;

6) Developmental Genomics Section, NHGRI, Bethesda, USA;

7) NIH Undiagnosed Diseases Program, NIH, Bethesda, USA;

8) Translational Surgical Pathology Section, NCI, Bethesda, USA;

9) General Surgical Pathology Section, NCI, Bethesda, USA.

We recently observed 5 unrelated patients with fevers, systemic inflammation, livedo reticularis, vasculopathy, and early-onset recurrent ischemic strokes. We performed exome sequencing on affected patients and their unaffected parents. The 5 patients shared 3 missense mutations in CECR1, encoding adenosine deaminase 2 (ADA2), with the genotypes A109D/ Y453C, Y453C/G47A, G47A/H112Q, R169Q/Y453C, and R169Q/28kb genomic deletion encompassing the 5’UTR and first exon of CECR1.

All mutations are either novel or present at low frequency (<0.001) in several large databases, consistent with the recessive inheritance. The Y453C mutation was present in 2/13004 alleles in an NHLBI database. Both alleles are found in 2 affected siblings who suffered from late-onset ischemic stroke, indicating that heterozygous mutations in ADA2 might be associated with susceptibility to adult stroke. Computer modeling based on the crystal structure of the human ADA2 suggests that CECR1 mutations either disrupt protein stability or impair ADA2 enzyme activity. All patients had at least a 10-fold reduction in serum and plasma concentrations of ADA2, and reduced ADA2-specific adenosine deaminase activity. Western blots showed a decrease in protein expression in supernatants of cultured patients’ cells. ADA2 is homologous to ADA1, which is mutated in some patients with SCID.

In contrast to ADA1, ADA2 is expressed predominantly in myeloid cells and is a secreted protein, and its affinity for adenosine is much less than ADA1. Animal models suggest that ADA2 is the prototype for a family of growth factors (ADGFs).Although there is no mouse homolog of CECR1, there are 2 zebrafish homologs, Cecr1a and Cecr1b. Using morpholino technology to knock down the expression of the ADA2 homologs, we observed intracranial hemorrhages in approximately 50% of the zebrafish embryos harboring the knockdown construct, relative to 3% in controls. Immunohistochemical studies of endothelial cells from patients’ skin biopsies demonstrate a diffuse systemic vasculopathy characterized by impaired endothelial integrity, endothelial cellular activation, and a perivascular infiltrate of CD8 T-cells and CD163-positive macrophages. ADA2 is not expressed in the endothelial cells. Our data suggest that ADA2 may be necessary for vascular integrity in the developing zebrafish as an endothelial cell-extrinsic growth factor, and that the near absence of functional ADA2 in patients may lead to strokes by a similar mechanism.

Genetics of Atherosclerotic Plaque in Patients with Chronic Coronary Artery Disease

372/3:15 Genetic influence on LpPLA2 activity at baseline as evaluated in the exome chip-enriched GWAS study among ~13600 patients with chronic coronary artery disease in the STABILITY (STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY) trial. L. Warren, L. Li, D. Fraser, J. Aponte, A. Yeo, R. Davies, C. Macphee, L. Hegg, L. Tarka, C. Held, R. Stewart, L. Wallentin, H. White, M. Nelson, D. Waterworth.

Genetic influence on LpPLA2 activity at baseline as evaluated in the exome chip-enrichedGWASstudy among ~13600 patients with chronic coronary artery disease in the STABILITY (STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY) trial.

L. Warren1, L. Li1, D. Fraser1, J. Aponte1, A. Yeo2, R. Davies3, C. Macphee3, L. Hegg3,

L. Tarka3, C. Held4, R. Stewart5, L. Wallentin4, H. White5, M. Nelson1, D.

Waterworth3.

1) GlaxoSmithKline, Res Triangle Park, NC;

2) GlaxoSmithKline, Stevenage, UK;

3) GlaxoSmithKline, Upper Merion, Pennsylvania, USA;

4) Uppsala Clinical Research Center, Department of Medical Sciences, Uppsala University, Uppsala, Sweden;

5) 5Green Lane Cardiovascular Service, Auckland Cty Hospital, Auckland, New Zealand.

STABILITY is an ongoing phase III cardiovascular outcomes study that compares the effects of darapladib enteric coated (EC) tablets, 160 mg versus placebo, when added to the standard of care, on the incidence of major adverse cardiovascular events (MACE) in subjects with chronic coronary heart disease (CHD). Blood samples for determination of the LpPLA2 activity level in plasma and for extraction of DNA was obtained at randomization. To identify genetic variants that may predict response to darapladib, we genotyped ~900K common and low frequency coding variations using Illumina OmniExpress GWAS plus exome chip in advance of study completion. Among the 15828 Intent-to-Treat recruited subjects, 13674 (86%) provided informed consent for genetic analysis. Our pharmacogenetic (PGx) analysis group is comprised of subjects from 39 countries on five continents, including 10139 Whites of European heritage, 1682 Asians of East Asian or Japanese heritage, 414 Asians of Central/South Asian heritage, 268 Blacks, 1027 Hispanics and 144 others. Here we report association analysis of baseline levels of LpPLA2 to support future PGx analysis of drug response post trial completion. Among the 911375 variants genotyped, 213540 (23%) were rare (MAF < 0.5%).

Our analyses were focused on the drug target, LpPLA2 enzyme activity measured at baseline. GWAS analysis of LpPLA2 activity adjusting for age, gender and top 20 principle component scores identified 58 variants surpassing GWAS-significant threshold (5e-08).

Genome-wide stepwise regression analyses identified multiple independent associations from PLA2G7, CELSR2, APOB, KIF6, and APOE, reflecting the dependency of LpPLA2 on LDL-cholesterol levels. Most notably, several low frequency and rare coding variants in PLA2G7 were identified to be strongly associated with LpPLA2 activity. They are V279F (MAF=1.0%, P= 1.7e-108), a previously known association, and four novel associations due to I1317N (MAF=0.05%, P=4.9e-8), Q287X (MAF=0.05%, P=1.6e-7), T278M (MAF=0.02%, P=7.6e-5) and L389S (MAF=0.04%, P=4.3e-4).

All these variants had enzyme activity lowering effects and each appeared to be specific to certain ethnicity. Our comprehensive PGx analyses of baseline data has already provided great insight into common and rare coding genetic variants associated with drug target and related traits and this knowledge will be invaluable in facilitating future PGx investigation of darapladib response.

Genetics of influence IL-18 regulation in patients with Acute Coronary Syndrome

373/3:30 Genome-wide association study identifies common and rare genetic variants in caspase-1-related genes that influence IL-18 regulation in patients with acute coronary syndrome. A. Johansson, N. Eriksson, E. Hagström, C. Varenhorst, A. Åkerblom, M. Bertilsson, T. Axelsson, B. J. Barratt, R. C. Becker, A. Himmelmann, S. James, H. A. Katus, G. Steg, R. F. Storey, A. Syvänen, L. Wallentin, A. Siegbahn.

Genome-wide association study identifies common and rare genetic

variants in caspase-1-related genes that influence IL-18 regulation in

patients with Acute Coronary Syndrome. A. Johansson1, 2, N. Eriksson1,

E. Hagström1,3, C. Varenhorst1,3, A. Åkerblom1,3, M. Bertilsson1, T. Axelsson4,

B.J. Barratt5, R.C. Becker6, A. Himmelmann7, S. James1,3, H.A.

Katus8, G. Steg9, R.F. Storey10, A. Syvänen4, L. Wallentin1,3, A. Siegbahn1,11.

1) Uppsala Clinical Research Center, Uppsala University, Sweden;

2) Department of Immunoloy, Genetics and Pathology, Uppsala University, Sweden;

3) Department of Medical Sciences, Cardiology, Uppsala University, Sweden;

4) Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory, Uppsala University, Sweden;

5) AstraZeneca R&D, Alderley Park, Cheshire, UK;

6) Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA;

7) AstraZeneca Research and Development, Mölndal, Sweden;

8) Medizinishe Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany;

9) INSERM-Unité 698, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France; Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France;

10) Department of Cardiovascular Science, University of Sheffield, Sheffield, UK;

11) Department of Medical Sciences, Clinical Chemistry, Uppsala University, Sweden.

Interleukin 18 (IL-18) levels are increased in patients with acute coronary syndromes (ACS) and correlated with myocardial injury. We performed a genome-wide association study (GWAS) to identify genetic determinants of IL-18 levels in patients with ACS. In the PLATelet inhibition and patient Outcomes (PLATO) trial, enrolling a broad selection of ACS patients, baseline plasma IL-18 levels were measured in 16633 patients. Of these, 9340 were successfully genotyped using Illumina HumanOmni2.5 or HumanOmniExpressExome BeadChip and SNPs imputed using 1000 Genomes Phase I integrated variant set. Seven independent associations, in five chromosomal regions, were identified. The first region, with two independent (r2 = 0.11) association signals (rs34649619, p = 1.17*10−50 and rs360718, p = 2.03*10−12), is located within IL18. Both top SNPs are located in predicted promoter regions, and the insertion polymorphism rs34649619 (T/TA) disrupts a transcription factor binding site for FOXI1, FOXD3 and FOXA2. The second region, also represented by two independent (r2 = 0.003) association signals (rs385076, p = 6.99*10−72 and rs149451729, p = 3.79*10−16), is located in NLRC4. While rs385076 overlaps with a regulatory region, rs149451729 is a rare coding variant resulting in an amino acid substitution, predicted to be deleterious. The third region is located upstream of CARD16, CARD17, and CARD18 and one of the top SNPs (rs17103763, p = 6.19*10−9) has previously been associated with expression levels of CARD16. The two remaining chromosomal regions are located within GSFMF/MROH6 (rs2290414, p = 5.66*10−17) and RAD17 (rs17229943, p = 5.00*10−12).

While the latter genes have not been associated with IL-18 production previously, others are known to be involved in IL-18 release. NLRC4 is an inflammasome that activates the inflammatory cascade in the presence of bacterial molecules. It recruits and activates procaspase-1, which in its turn is responsible for the maturation of pro-IL-18. CARD16-18, also known as COP1, INCA and ICEBERG, encode caspase inhibitors, known to bind to and prevent procaspase-1 activation. Our results suggest that SNPs in IL18 and caspase-1-associated genes are important for IL-18 production. By combining the identified SNPs in a Mendelian randomization study, the causal effect of IL-18 on clinical endpoints could be further evaluated in a longitudinal study.

Thoracic Aortic Aneurysmal Genes

374/3:45 Prevalence and predictors of pneumothorax in patients with connective tissue disorders enrolled in the GenTAC (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry. J. P. Habashi, G. L. Oswald, K. W. Holmes, E. M. Reynolds, S. LeMaire, W. Ravekes, N. B. McDonnell, C. Maslen, R. V. Shohet, R. E. Pyeritz, R. Devereux, D. M. Milewicz, H. C. Dietz, GenTAC Registry Consortium.

Prevalence and Predictors of Pneumothorax in Patients with Connective Tissue Disorders Enrolled in the GenTAC (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry.

J.P. Habashi1, G.L. Oswald2, K.W. Holmes1,5, E.M.

Reynolds10, S. LeMaire3, W. Ravekes1, N.B. McDonnell4, C. Maslen5, R.V.

Shohet6, R.E. Pyeritz7, R. Devereux8, D.M. Milewicz9, H.C. Dietz2, GenTAC

Registry Consortium.

1) Dept Pediatric Cardiology, Johns Hopkins Univ, Baltimore, MD;

2) Dept. Medical Genetics, Johns Hopkins Univ, Baltimore, MD;

3) Baylor College of Medicine, Houston TX;

4) NIA at Harbor Hospital, Baltimore, MD;

5) Oregon Health & Science University, Portland, OR;

6) Queen’s Medical Center, Honolulu, HI;

7) The University of Pennsylvania, Philadelphia, PA; 8) Weill Cornell Medical College of Cornell University, New York NY;

9) University of Texas Medical School at Houston, Houston, TX;

10) University of Maryland, Baltimore, MD.

Spontaneous pneumothorax—described as escape of air into the pleural space surrounding the lung in the absence of traumatic injury—is a rare occurrence in the general population (0.1-0.5%), however is well recognized in Marfan syndrome (MFS)(4-5%). Associations between pneumothorax and other connective tissue disorders (CTDs) are less well recognized. We sought to examine potential associations of

pneumothorax with MFS,
vascular Ehlers-Danlos syndrome (vEDS) and other CTDs.

Phenotypic data were analyzed on all GenTAC patients with confirmed diagnoses of

MFS,
vEDS,
Loeys-Dietz syndrome (LDS),
bicuspid aortic valve with aortic enlargement (BAVe) or
familial thoracic aortic aneurysm and dissection (FTAAD)

to assess the prevalence of pneumothorax and associated features (1918 total pts).

Of 695 patients with Ghent criteria-confirmed MFS, 73 had experienced a spontaneous pneumothorax (prevalence 10.5%), higher than reported in the literature. The frequency of pneumothorax in vEDS patients (16/107, 15%) was similar to the frequency in the MFS group. The prevalences of pneumothorax in LDS (4/73, 5.5%), FTAAD (13/237, 5.5%), and BAVe (19/ 806, 2.4%) were significantly less than that for MFS and vEDS (p<0.001), yet greater than reported for the general population. In MFS patients with a pneumothorax, there was a three-fold increase in reported skeletal features of pectus carinatum, pectus excavatum, scoliosis and/or kyphosis compared to those without pneumothorax. Similarly, in vEDS, there was a four-fold increase in pectus carinatum, scoliosis and kyphosis in those patients with a pneumothorax compared to those without pneumothorax. In a subset of patients with self-reported data (n=846), smoking was not associated with increased prevalence of pneumothorax. Gender was not a predictor of pneumothorax in any of the diagnostic categories analyzed despite literature reports of increased prevalence in males. In patients enrolled in the GenTAC registry with a diagnosis of MFS, vEDS, BAVe, FTAAD or LDS, the prevalence of pneumothorax was significantly increased in all CTDs analyzed as compared to the general population. The prevalence of pneumothorax was significantly higher in patients with MFS or vEDS than in the other CTDs.

These data suggest that skeletal features may be a predictor for pneumothorax. Patients presenting with a spontaneous pneumothorax should be evaluated for several potential CTDs; such an evaluation could unmask an undiagnosed aortic aneurysm.

375/4:00 Surprising clinical lessons from targeted next-generation sequencing of thoracic aortic aneurysmal genes. B. Loeys, D. Proost, G. Vandeweyer, S. Salemink, M. Kempers, G. Oswald, H. Dietz, G. Mortier, L. Van Laer.

Surprising clinical lessons from targeted next generation sequencing of thoracic aortic aneurysmal genes. B. Loeys1,2, D. Proost1, G. Vandeweyer1, S. Salemink2, M. Kempers2, G. Oswald3, H. Dietz3, G. Mortier1, L. Van Laer1.

1) Center for Medical Genetics, University of Antwerp/ Antwerp University Hospital, Antwerp, Belgium;

2) Department of Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;

3) Mc Kusick Nathans Institute for Genetic Medicine, Johns Hopkins University Hospital, Baltimore, USA.

Thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized world, is genetically heterogeneous and at least 14 causative genes have been identified, accounting for both syndromic and non-syndromic forms. The diagnosis is not always straightforward because a considerable clinical overlap exists between patients with mutations in different genes, and mutations in the same gene cause a wide phenotypic variability. Molecular confirmation of the diagnosis is becoming increasingly important for gene-tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor-intensive. To shorten the turn-around-time, to increase mutation-uptake and to reduce the overall cost of molecular testing, we developed a TAA gene panel for next generation sequencing (NGS) of 14 TAA genes (ACTA2, COL3A1, EFEMP2, FBN1, FLNA, MYH11, MYLK, NOTCH1, SKI, SLC2A10, SMAD3, TGFB2, TGFBR1 and TGFBR2). We obtained enrichment with Haloplex technology and performed 2×150 bp paired-end runs on a Miseq sequencer in a series of 57 consecutive TAA patients, both syndromic and non-syndromic.

The sensitivity and false positive rate were previously shown to be 100% and 3%, respectively. Applying our NGS approach, we identified a causal mutation in 16 patients (28%). This uptake is really high as on average one molecular study per patient (range 0-6) was performed prior to inclusion in this study. One mutation was found in each of the 6 following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous); two mutations inNOTCH1and eight in FBN1. An additional 6 variants of unknown significance were identified: 2 in FLNA, 2 in NOTCH1, 1 in FBN1 and 1 heterozygous in EFEMP2. All variants were confirmed by Sanger sequencing.

Remarkably, from the eight FBN1 positive patients, three patients had previously been tested FBN1 negative by certified labs, indicating that the sensitivity of Sanger sequencing is not 100%. Interestingly, in two FBN1 mutation positive patients

the clinical diagnosis of Marfan syndrome was unsuspected. Similarly,
the clinical diagnosis of vascular Ehlers-Danlos syndrome (COL3A1) had not been made. Finally,
the ACTA2 mutation was identified postmortem from paraffin-embedded extracted DNA.

We conclude that our NGS approach for TAA genetic testing overcomes the intrinsic hurdles of Sanger sequencing and becomes a powerful tool in the elaboration of clinical phenotypes assigned to different genes.

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Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Human Immune System in Health and in Disease, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, Technology Transfer: Biotech and Pharmaceutical, tagged actomyosin, Aviva Lev-Ari, Calcium, Calcium-Channel Blocker, CAM, Cell Biology, Cell Motility, cofilin, contractile ring, Cornell University, Cytoskeleton, elastin peptides, gelsolin, GTPases, Heart Failure, laminin, Larry H. Bernstein, metastasis initiating cells, mitosis, Motility, myosin, osteoblasts, phosphoinositides, Phosphorylation, PIP2, PIPK, PKC, Rho effector, Smooth muscle tissue, Stephen Williams, T cells, voltage-gated L-type channels on August 26, 2013| 11 Comments »

Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Author: Larry H. Bernstein, MD

Author: Stephen Williams, PhD

and

Curator: Aviva Lev-Ari, PhD, RN

Article II Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Image generated by Adina Hazan, 06/30/2021

This article is Part II in a series of articles on Calcium and its role in Cell motility

The Series consists of the following articles:

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD  and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/02/renal-distal-tubular-ca2-exchange-mechanism-in-health-and-disease/

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

Part V: Ca2+-Stimulated Exocytosis: The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocytosis/

Aviva Lev-Ari, PhD, RN

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/16/calcium-channel-blocker-calcium-as-neurotransmitter-sensor-and-calcium-release-related-contractile-dysfunction-ryanopathy/

Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/11/01/sensors-and-signaling-in-oxidative-stress/

Part XII: Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/21/genetic-polymorphisms-of-ion-channels-have-a-role-in-the-pathogenesis-of-coronary-microvascular-dysfunction-and-ischemic-heart-disease/

This article, constitute, Part II, it is a broad, but not complete review of the emerging discoveries of the critical role of calcium signaling on cell motility and by extension, embryonic development, cancer metastasis, changes in vascular compliance at the junction between the endothelium and the underlying interstitial layer. The effect of calcium signaling on the heart in arrhtmogenesis and heart failure will be a third in this series, while the binding of calcium to troponin C in the synchronous contraction of the myocardium had been discussed by Dr. Lev-Ari in Part I.

Universal MOTIFs essential to skeletal muscle, smooth muscle, cardiac syncytial muscle, endothelium, neovascularization, atherosclerosis and hypertension, cell division, embryogenesis, and cancer metastasis. The discussion will be presented in several parts:

1. Biochemical and signaling cascades in cell motility

2. Extracellular matrix and cell-ECM adhesions

3. Actin dynamics in cell-cell adhesion

4. Effect of intracellular Ca++ action on cell motility

5. Regulation of the cytoskeleton

6. Role of thymosin in actin-sequestration

7. T-lymphocyte signaling and the actin cytoskeleton

Part 1. Biochemical and Signaling Cascades in Cell Motility

BIOCHEMISTRY AND BIOMECHANICS OF CELL MOTILITY

Song Li, Jun-Lin Guan, and Shu Chien

University of California, Berkeley, CA; Cornell University, Ithaca, NY; UCSD, La Jolla, CA

Annu. Rev. Biomed. Eng. 2005. 7:105–50 [doi:10.1146/annurev.bioeng.7.060804.100340]

Cell motility or migration is an essential cellular process for a variety of biological events. In embryonic development, cells migrate to appropriate locations for the morphogenesis of tissues and organs. Cells need to migrate to heal the wound in repairing damaged tissue. Vascular endothelial cells (ECs) migrate to form new capillaries during angiogenesis. White blood cells migrate to the sites of inflammation to kill bacteria. Cancer cell metastasis involves their migration through the blood vessel wall to invade surrounding tissues.

Variety of important roles for cell migration:

1. Embryogenesis

2. Wound healing (secondary extension)

3. Inflammatory infiltrate (chemotaxis)

4. Angiogenesis

5. Cancer metastasis

6. Arterial compliance

7. Myocardial and skeletal muscle contraction

8. Cell division

Portrait of Cell in Migration:

1. protrusion of leading edge

2. Formation of new adhesions at front

3. Cell contraction

4. Release of adhesions at rear

Microenvironmental factor:

1. Concentration gradient of chemoattractants

2. Gradient of immobilized ECM proteins

3. Gradient of matrix rigidity

4. Mechanotaxis

Extracellular signals are sensed by receptors or mechanosensors on cell surface or in cell interior to initiate migration. Actin polymerization is the key event leading to protrusion at the leading edge and new focal adhesions anchor the actin filaments and the cell to the underlying surface. This is followed by contraction of the actin filaments. The contraction of actomyosin filaments pulls the elongate body forward and at the same time the tail retracts.

Part 2. Cell-ECM Adhesions

Cytoskeleton and cell-ECM adhesions are two major molecular machineries involved in mechano-chemical signal transduction during cell migration. Although all three types of cytoskeleton (actin microfilaments, microtubules, and intermediate filaments) contribute to cell motility, actin cytoskeleton plays the central role. The polymerization of actin filaments provides the driving force for the protrusion of the leading edge as lamellipodia (sheet-like protrusions) or filopodia (spike-like protrusions), and actomyosin contraction generates the traction force at (focal adhesions) FAs and induces the retraction at the rear. It is generally accepted that actin filaments interact with the double-headed myosin to generate the force for cell motility and that actomyosin contraction/relaxation involves the modulation of myosin light chain (MLC) phosphorylation. Rho family GTPases, including Cdc42, Rac, and Rho, are the key regulators of actin polymerization, actomyosin contraction, and cell motility. Cdc42 activation induces the formation of filopodia; Rac activation induces lamellipodia; and Rho activation increases actin polymerization, stress fiber formation, and actomyosin contractility. All three types of Rho GTPases stimulate new FA formation.

Integrins are the major receptors for ECM proteins. The integrin family includes more than 20 transmembrane heterodimers composed of α and β subunits with noncovalent association. The extracellular domain of integrin binds to specific ligands, e.g., ECM proteins such as fibronectin (FN), vitronectin, collagen, and laminin. The cytoplasmic domain interacts with cytoskeletal proteins (e.g., paxillin, talin, vinculin, and actin) and signaling molecules in the focal adhesion (FA) sites. The unique structural features of integrins enable them to mediate outside-in signaling, in which extracellular stimuli induce the intracellular signaling cascade via integrin activation, and inside-out signaling, in which intracellular signals modulate integrin activation and force generation through FAs.

Part 3. Actin Dynamics in Cell-cell Adhesion

Actin filaments are linked to the focal adhesions (Fas) between cell and ECM through a protein complex that includes talin, vinculin, α-actinin, and filamin. Such a complex couples the actomyosin contractile apparatus to FAs, and plays an important role in the force transmission between ECM and the cell.

3a. Actin dynamics and cell–cell adhesion in epithelia

Valeri Vasioukhin and Elaine Fuchs

Howard Hughes Medical Institute, Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL

Current Opinion in Cell Biology 2001, 13:76–84

Recent advances in the field of intercellular adhesion highlight the importance of adherens junction association with the underlying actin cytoskeleton. In skin epithelial cells a dynamic feature of adherens junction formation involves filopodia, which physically project into the membrane of adjacent cells, catalyzing the clustering of adherens junction protein complexes at their tips. In turn, actin polymerization is stimulated at the cytoplasmic interface of these complexes. Although the mechanism remains unclear, the VASP/Mena family of proteins seems to be involved in organizing actin polymerization at these sites. In vivo, adherens junction formation appears to rely upon filopodia in processes where epithelial sheets must be physically moved closer to form stable intercellular connections, for example, in ventral closure in embryonic development or wound healing in the postnatal animal.

Located at cell–cell borders, adherens junctions are electron dense transmembrane structures that associate with the actin cytoskeleton. In their absence, the formation of other cell–cell adhesion structures is dramatically reduced. The transmembrane core of adherens junctions consists of cadherins, of which E-cadherin is the epithelial prototype. Its extracellular domain is responsible for homotypic, calcium-dependent, adhesive interactions with E-cadherins on the surface of opposing cells. Its cytoplasmic domain is important for associations with other intracellular proteins involved in the clustering of surface cadherins to form a junctional structure.

The extracellular domain of the transmembrane E-cadherin dimerizes and interacts in a calcium-dependent manner with similar molecules on neighboring cells. The intracellular juxtamembrane part of E-cadherin binds to p120ctn, an armadillo repeat protein capable of modulating E-cadherin clustering. The distal segment of E-cadherin’s cytoplasmic domain can interact with β-catenin or plakoglobin, armadillo repeat proteins which in turn bind to α-catenin. The carboxyl end of α-catenin binds directly to f-actin, and, through a direct mechanism, α-catenin can link the membrane-bound cadherin–catenin complex to the actin cytoskeleton. Additionally, α-catenin can bind to either vinculin or ZO1, and it is required for junctional localization of zyxin. Vinculin and zyxin can recruit VASP (and related family members), which in turn can associate with the actin cytoskeleton, providing the indirect mechanism to link the actin cytoskeleton to adherens junctions. ZO1 is also a member of tight junctions family, providing a means to link these junctions with adherens junctions.

Through a site near its transmembrane domain, cadherins bind directly to the catenin p120ctn, and through a more central site within the cytoplasmic domain, cadherins bind preferentially to β-catenin. Cell migration appears to be promoted by p120ctn through recruiting and activating small GTPases. β-catenin is normally involved in adherens junction formation through its ability to bind to β-catenin and link cadherins to the actin cytoskeleton. However, β-catenin leads a dual life in that it can also act as a transcriptional cofactor when stimulated by the Wnt signal transduction pathway

α-Catenin: More than just a Bridge between Adherens Junctions and the Actin Cytoskeleton

α-catenin was initially discovered as a member of the E-cadherin–catenin complex. It is related to vinculin, an actin-binding protein that is found at integrin-based focal contacts. The amino-terminal domain of α-catenin is involved in α-catenin/plakoglobin binding and is also important for dimerization. Its central segment can bind to α-actinin and to vinculin, and it partially encompasses the region of the protein necessary for cell adhesion (which is the adhesion-modulation domain; amino acids 509–643). The carboxy-terminal domain of both vinculin and α-catenin is involved in filamentous actin (f-actin) binding, and for α-catenin, this domain is also involved in binding to ZO1. VH1, VH2 and VH3 are three regions sharing homology to vinculin. The percentage amino acid identity and the numbers correspond to the amino acid residues of the α-catenin polypeptide.

α-catenin is the only catenin that can directly bind to actin filaments , and E-cadherin–catenin complexes do not associate with the actin cytoskeleton after α-catenin is removed by extraction with detergent. Cancer cell lines lacking α-catenin still express E-cadherin and β-catenin, but do not show proper cell–cell adhesion unless the wild-type gene is reintroduced into the cancer cell. This provides strong evidence that clustering of the E-cadherin–catenin complex and cell–cell adhesion requires the presence of α-catenin.

Although intercellular adhesion is dependent upon association of the E-cadherin–β-catenin protein complex with α-catenin and the actin cytoskeleton, it is unclear whether α-catenin’s role goes beyond linking the two structures. Fusion of a nonfunctional tailless E-cadherin (E C71) with α-catenin resulted in a chimeric protein able to confer cell–cell adhesion on mouse fibroblasts in vitro, and generation of additional chimeric proteins enabled delineation of the region of α-catenin that is important for cell aggregation. Not surprisingly, the essential domain of α-catenin was its carboxy-terminal domain (~amino acids 510–906), containing the actin-binding site, which encompasses residues 630–906 of this domain.

The binding of α-catenin to the actin cytoskeleton is required for cell–cell adhesion, but α-catenin appears to have additional function(s) beyond its ability to link E-cadherin–β-catenin complexes to actin filaments. The domain encompassing residues 509–643 of α-catenin has been referred to as an adhesion-modulation domain to reflect this added, and as yet unidentified, function. Besides its association with β-catenin and f-actin, α-catenin binds to a number of additional proteins, some of which are actin binding proteins themselves. Additionally, the localization of vinculin to cell–cell borders is dependent upon the presence of α-catenin. α-catenin can also bind to the MAGUK (membrane-associated guanylate kinase) family members ZO1 and ZO2. Thus, the role for α-catenin might not simply be to link E-cadherin–catenin complexes to the actin cytoskeleton but rather to organize a multiprotein complex with multiple actin-binding, bundling and polymerization activities.

The decisive requirement for α-catenin’s actin-binding domain in adherens junction formation underscores the importance of the actin cytoskeleton in intercellular adhesion. Thus, it is perhaps not surprising that the majority of f-actin in epithelial cells localizes to cell–cell junctions. When epidermal cells are incubated in vitro in culture media with calcium concentrations below 0.08 mM they are unable to form adherens junctions. However, when the calcium concentrations are raised to the levels naturally occurring in skin (1.5–1.8 mM), intercellular adhesion is initiated.

This switch in part promotes a calcium-dependent conformational change in the extracellular domain of E-cadherin that is necessary for homotypic interactions to take place. It appears that the actin cytoskeleton has a role in facilitating the process that brings opposing membranes together and stabilizing them once junction formation has been initiated. In this regard, the formation of cell–cell adhesion can be divided into two categories:

active adhesion, a process that utilizes the actin cytoskeleton to generate the force necessary to bring opposing membranes together, and
passive adhesion, a process which may not require actin if the membranes are already closely juxtaposed and stabilized by the deposition of cadherin–catenin complexes.

Upon a switch from low to high calcium, cadherin-mediated intercellular adhesion is activated. Passive adhesion: in cells whose actin cytoskeleton has been largely disrupted by cytochalasin D, cadherin–catenin complexes occur at sites where membranes of neighboring cells directly contact each other. Active adhesion: neighboring cells with functional actin cytoskeletons can draw their membranes together, forming a continuous epithelial sheet. Upon initial membrane contact, E-cadherin forms punctate aggregates or puncta along regions where opposing membranes are in contact with one another. Each of these puncta is contacted by a bundle of actin filaments that branch off from the cortical belt of actin filaments underlying the cell membrane. At later stages in the process, those segments of the circumferential actin cables that reside along the zone of cell–cell contacts disappear, and the resulting semi-circles of cortical actin align to form a seemingly single circumferential cable around the perimeter of the two cells. At the edges of the zone of cell–cell contact, plaques of E-cadherin–catenin complexes connect the cortical belt of actin to the line of adhesion. At the center of the developing zone of adhesion, E-cadherin puncta associate with small bundles of actin filaments oriented perpendicular to the zone.

Multiple E-cadherin-containing puncta that form along the developing contact rapidly associate with small bundles of actin filaments. As the contact between cells lengthens, puncta continue to develop at a constant average density, with new puncta at the edges of the contact. The segment of the circumferential actin cable that underlies the developing contact gradually ‘dissolves’, and merges into a large cable, encompassing both cells. This is made possible through cable-mediated connections to the E-cadherin plaques at the edges of the contact. As contact propagates, E-cadherin is deposited along the junction as a continuous line. The actin cytoskeleton reorganizes and is now oriented along the cell–cell contact. In primary keratinocytes, two neighboring cells send out filopodia, which, upon contact, slide along each other and project into the opposing cell’s membrane. Filopodia are rich in f-actin. Embedded tips of filopodia are stabilized by puncta, which are transmembrane clusters of adherens junction proteins.

This process draws regions of the two cell surfaces together, which are then clamped by desmosomes. Radial actin fibers reorganize at filopodia tips in a zyxin-, vinculin-, VASP-, and Mena-dependent fashion. Actin polymerization is initiated at stabilized puncta, creating the directed reverse force needed to push and merge puncta into a single line as new puncta form at the edges. The actin-based movement physically brings remaining regions of opposing membranes together and seals them into epithelial sheets. As filopodia contain actin rather than keratin intermediate filaments, they become natural zones of adherens junctions, whereas the cell surface flanking filopodia becomes fertile ground for desmosome formation, alternating adherens junctions and desmosomes.

Possible Roles of Myosin in Cell–cell Adhesion.

[a] A hypothetical ‘purse string’ model for myosin-driven epithelial sheet closure at a large circular wound site in the cornea of an adult mouse. At the edge of wound site epithelial cables of actin appear to extend from cell to cell, forming a ring around the wound circumference. Contraction of actin cables driven by myosin can lead to wound closure.

[b] Inside out ‘purse string’ model for contact propagation (compaction) in MDCK cells. During contact formation in MDCK cells, circumferential actin cables contact cadherin–catenin plaques at the edges of the contact. Contraction of actin cables driven by myosin can lead to the contact expansion.

What Regulates the Actin Dynamics that are Important for Cell–cell Adhesion?

The answer to this remains uncertain, but the small GTPases of the Rho family seem to be likely candidates, given that Rho, Rac1 and Cdc42 promote stress fiber, lamellipodia and filopodia formation, respectively.

In vivo mutagenesis studies in Drosophila reveal a role for Rac1 and Rho in dorsal closure and/or in head involution, processes that involve complex and well orchestrated rearrangements of cells. In contrast, Cdc42 appears to be involved in regulating polarized cell shape changes. In vitro, keratinocytes microinjected with dominant negative Rac1 or with C3 toxin, a specific inhibitor of Rho, are unable to form cadherin-based cell–cell contacts. Similarly, overexpression of a constitutively active form of Rac1 or Cdc42 in MDCK cells increases junctional localization of E-cadherin–catenin complexes, whereas the dominant negative forms of Rac1 and Cdc42, or C3 microinjection, have the opposite effect. The finding that Tiam1, a guanine nucleotide exchange factor for Rac1, increases E-cadherin mediated cell–cell adhesion, inhibits hepatocyte growth-factor-induced cell scattering and reverses the loss of adhesion in Ras-transformed cells is consistent with the above. Together, these findings provide compelling evidence that activation of the Rho family of small GTPases plays a key role in the actin dynamics that are necessary for adherens junction formation.

We found that E-cadherin–catenin-enriched puncta, which assemble during the first stages of epithelial sheet formation, are sites of de novo actin polymerization. This led us to postulate that actin polymerization might provide the force that is subsequently necessary to merge the double role of puncta into a single row and ultimately into an epithelial sheet. Knowledge of how actin polymerization might generate movement comes largely from studies of the mechanism by which the pathogen Listeria monocytogenes pirates actin polymerization and utilizes it for intracellular propulsion. For this endeavor, these bacteria recruit two types of cellular components, the VASP family of proteins and the Arp2/3 complex. The Arp2/3 protein complex is required for de novo nucleation of actin filament polymerization, whereas VASP appears to accelerate bacterial movement by about 10 fold.

Although most studies have revealed positive roles for VASP and its cousins in actin reorganization/ polymerization, recent experiments have shown that in certain instances these proteins act negatively in directing cell movement. A further complication is the finding that VASP family proteins can be phosphorylated, thereby inhibiting their actin nucleation and f-actin binding ability. A role for VASP may be in the actin polymerization necessary for filopodia extensions. In this regard, VASP family proteins localize to the tips of filopodia during neural growth and in calcium-stimulated keratinocytes. VASP family proteins in this process might provide directionality to the process of actin polymerization, reshaping f-actin into parallel bundles to produce and extend filopodia-like structures from branched lamellipodial networks.

The Might of Myosins

Although actin polymerization seems to be important in generating the cellular movement necessary for intercellular adhesion, this does not rule out the possibility that the myosin family of actin motor proteins may also play a role. It is known, for instance, that cells can use myosin–actin contractile forces to alter cell shape, and myosin II is a ubiquitously expressed protein involved in such diverse processes as cell spreading, cytokinesis, cell migration, generation of tension within actin stress fiber networks and retrograde flow of actin filaments at the leading edge of moving cells. Interestingly, mouse corneal cells at a wound edge assemble cables of actin filaments anchored to E-cadherin–catenin complexes. The cells surrounding the wound site display myosin-II-associated actin filaments that are aligned in a structure resembling a purse string. It has been postulated that closure of the wound may be achieved through myosin-directed contraction of the actin filaments, in a mechanism similar to that of pulling on a purse string.

Overall, through guilt by association, myosins have been implicated in cell–cell adhesion and in adherens junction formation and although the models proposed are attractive, direct experimental evidence is still lacking. BDM (2,3-butanedione monoxime), a general inhibitor of myosin function, had no obvious effect on intercellular junction formation in our keratinocyte adhesion assays (V Vasioukhin, E Fuchs, unpublished data). However, the role of myosins clearly deserves a more detailed investigation, and this awaits the development of new and improved inhibitors and activators of myosin action.

Key references:

1. Imamura Y, Itoh M, Maeno Y, Tsukita S, Nagafuchi A: Functional domains of α-catenin required for the strong state of cadherin based cell adhesion. J Cell Biol 1999, 144:1311-1322.

Three distinct functional domains for α-catenin were identified: a vinculin binding domain, a ZO-1-binding domain and an adhesion modulation domain. Both ZO1-binding (also actin binding) and adhesion modulation domains are necessary for strong adhesion.

2. Vasioukhin V, Bauer C, Yin M, Fuchs E: Directed actin polymerization is the driving force for epithelial cell–cell adhesion. Cell 2000, 100:209-219.

A dynamic filopodia-driven process of cell–cell adhesion is described in primary mouse keratinocyte cultures. Newly forming adherens junctions were identified as sites of actin polymerization and/or reorganization, involving VASP/Mena family members.

3. Raich WB, Agbunag C, Hardin J: Rapid epithelial-sheet sealing in the Caenorhabditis elegans embryo requires cadherin-dependent filopodial priming. Curr Biol 1999, 9:1139-1146.

An elegant in vivo analysis of filopodia-based cell–cell junction formation during epithelial-sheet closure in embryonic development of C. elegans.

4. Loisel TP, Boujemaa R, Pantaloni D, Carlier MF: Reconstitution of actin-based motility of Listeria and Shigella using pure proteins. Nature 1999, 401:613-616.

Using an in vitro reconstitution approach, the authors show that Arp2/3, actin, cofilin and capping proteins are required for motility of Listeria, in contrast VASP seems to act by increasing the speed of movement by about 10 fold.

3b. Role for Gelsolin in Actuating Epidermal Growth Factor Receptor-mediated Cell Motility

Philip Chen, Joanne E. Murphy-Ullrich, and Alan Wells

Department of Pathology, University of Alabama at Birmingham, AL

J Cell Biology Aug 1996; 134(3): 689-698

Phospholipase C-~/(PLC~/) is required for EGF-induced motility (Chen, P., H. Xie, M.C. Sekar, K.B. Gupta, and A. Wells. J. Cell Biol. 1994. 127:847-857); however, the molecular basis of how PLC~/modulates the actin filament network underlying cell motility remains undetermined. One connection to the actin cytoskeleton may be direct hydrolysis of PIP 2 with subsequent mobilization of membrane-associated actin modifying proteins. We used signaling restricted EGFR mutants expressed in receptor-devoid NR6 fibroblast cells to investigate whether EGFR activation of PLC causes gelsolin mobilization from the cell membrane in vivo and whether this translocation facilitates cell movement. Gelsolin anti-sense oligonucleotide (20 p,M) treatment of NR6 ceils expressing the motogenic full-length (WT) and truncated c’ 1000 EGFR decreased endogenous gelsolin by 30–60%; this resulted in preferential reduction of EGF (25 nM)-induced cell movement by >50% with little effect on the basal motility. As 14 h of EGF stimulation of cells did not increase total cell gelsolin content, we determined whether EGF induced redistribution of gelsolin from the membrane fraction. EGF treatment decreased the gelsolin mass associated with the membrane fraction in motogenic WT and c’1000 EGFR NR6 cells but not in cells expressing the fully mitogenic, but nonmotogenic c’973 EGFR. Blocking PLC activity with the pharmacologic agent U73122 (1 ~M) diminished both this mobilization of gelsolin and EGF-induced motility, suggesting that gelsolin mobilization is downstream of PLC. Concomitantly observed was reorganization of submembranous actin filaments correlating directly with PLC activation and gelsolin mobilization. In vivo expression of a peptide that is reported to compete in vitro with gelsolin in binding to PIP2 dramatically increased basal cell motility in NR6 cells expressing either motogenic (WT and c’1000) or nonmotogenic (c’973) EGFR; EGF did not further augment cell motility and gelsolin mobilization. Cells expressing this peptide demonstrated actin reorganization similar to that observed in EGF-treated control cells; the peptide-induced changes were unaffected by U73122. These data suggest that much of the EGF induced motility and cytoskeletal alterations can be reproduced by displacement of select actin-modifying proteins from a PIP2-bound state. This provides a signaling mechanism for translating cell surface receptor mediated biochemical reactions to the cell movement machinery.

3c. Actomyosin Contraction at the Cell Rear Drives Nuclear Translocation in Migrating Cortical Interneurons

Francisco J. Martini and Miguel Valdeolmillos

Instituto de Neurociencias de Alicante, Universidad Miguel Hernandez, Alacant, Spain

Journal of Neuroscience 2010 • 30(25):8660–8670

Neuronal migration is a complex process requiring the coordinated interaction of cytoskeletal components and regulated by calcium signaling among other factors. Migratory neurons are polarized cells in which the largest intracellular organelle, the nucleus, has to move repeatedly. Current views support a central role for pulling forces that drive nuclear movement. By analyzing interneurons migrating in cortical slices of mouse brains, we have found that nucleokinesis is associated with a precise pattern of actin dynamics characterized by the initial formation of a cup-like actin structure at the rear nuclear pole. Time-lapse experiments show that progressive actomyosin contraction drives the nucleus forward. Nucleokinesis concludes with the complete contraction of the cup-like structure, resulting in an actin spot at the base of the retracting trailing process. Our results demonstrate that this actin remodeling requires a threshold calcium level provided by low-frequency spontaneous fast intracellular calcium transients. Microtubule stabilization with taxol treatment prevents actin remodeling and nucleokinesis, whereas cells with a collapsed microtubule cytoskeleton induced by nocodazole treatment, display nearly normal actin dynamics and nucleokinesis. In summary, the results presented here demonstrate that actomyosin forces acting at the rear side of the nucleus drives nucleokinesis in tangentially migrating interneurons in a process that requires calcium and a dynamic cytoskeleton of microtubules.

3d. Migration of Zebrafish Primordial Germ Cells: A Role for Myosin Contraction and Cytoplasmic Flow

H Blaser, M Reichman-Fried, I Castanon, K Dumstrei, F L Marlow, et al.

Max Planck Institute, Gottingen & Dresden, Germany; Vanderbilt University, Nashville, Tenn; National Institute of Genetics, Shizuoka, Japan

Developmental Cell 2006; 11: 613–627 [DOI 10.1016/j.devcel.2006.09.023]

The molecular and cellular mechanisms governing cell motility and directed migration in response to the chemokine SDF-1 are largely unknown. Here, we demonstrate that zebrafish primordial germ cells whose migration is guided by SDF-1 generate bleb-like protrusions that are powered by cytoplasmic flow. Protrusions are formed at sites of higher levels of free calcium where activation of myosin contraction occurs. Separation of the acto-myosin cortex from the plasma membrane at these sites is followed by a flow of cytoplasm into the forming bleb. We propose that polarized activation of the receptor CXCR4 leads to a rise in free calcium that in turn activates myosin contraction in the part of the cell responding to higher levels of the ligand SDF-1. The biased formation of new protrusions in a particular region of the cell in response to SDF-1 defines the leading edge and the direction of cell migration.

Part 4. Calcium Signaling

4a. Indirect Association of Ezrin with F-Actin: Isoform Specificity and Calcium Sensitivity

Charles B. Shuster and Ira M. Herman

Tufts University Health Science Schools, Boston, MA

J Cell Biology Mar 1995; 128(5): 837-848

Muscle and nonmuscle isoactins are segregated into distinct cytoplasmic domains, but the mechanism regulating subcellular sorting is unknown (Herman, 1993a). To reveal whether isoform-specific actin-binding proteins function to coordinate these events, cell extracts derived from motile (Era) versus stationary (Es) cytoplasm were selectively and sequentially fractionated over filamentous isoactin affinity columns prior to elution with a KC1 step gradient. A polypeptide of interest, which binds specifically to/3-actin filament columns, but not to muscle actin columns has been conclusively identified as the ERM family member, ezrin. We studied ezrin-/3 interactions in vitro by passing extracts (Era) over isoactin affinity matrices in the presence of Ca2+-containing versus Ca2+-free buffers, with or without cytochalasin D. Ezrin binds and can be released from/3-actin Sepharose-4B in the presence of Mg2+/EGTA and 100 mM NaC1 (at 4°C and room temperature), but not when affinity fractionation of Em is carried out in the presence of 0.2 mM CaC12 or 2/~M cytochalasin D. N-acetyl-(leucyl)2-norleucinal and E64, two specific inhibitors of the calcium-activated protease, calpain I, protect ezrin binding to β-actin in the presence of calcium. Biochemical analysis of endothelial lysates reveals that a calpain I cleavage product of ezrin emerges when cell locomotion is stimulated in response to monolayer injury. Immunofluorescence analysis shows that anti-ezrin and anti-β-actin IgGs can be simultaneously co-localized, extending the results of isoactin affinity fractionation of Em-derived extracts and suggesting that ezrin and β-actin interact in vivo. To test the hypothesis that ezrin binds directly to β-actin, we performed three sets of studies under a wide range of physiological conditions (pH 7.0-8.5) using purified pericyte ezrin and either α- or β-actin. Results of these experiments reveal that purified ezrin does not directly bind to β-actin filaments. We mapped cellular free calcium in endothelial monolayers crawling in response to injury. Confocal imaging of fluo-3 fluorescence followed by simultaneous double antibody staining reveals a transient rise of free calcium within ezrin-/3-actin-enriched domains in the majority of motile cells bordering the wound edge. These results support the notion that calcium and calpain I modulate ezrin and β-actin interactions during forward protrusion formation.

4b. Calcium channel and glutamate receptor activities regulate actin organization in salamander retinal neurons

Massimiliano Cristofanilli and Abram Akopian

New York University School of Medicine, New York, NY

J Physiol 575.2 (2006) pp 543–554

Intracellular Ca2+ regulates a variety of neuronal functions, including neurotransmitter release, protein phosphorylation, gene expression and synaptic plasticity. In a variety of cell types, including neurons, Ca2+ is involved in actin reorganization, resulting in either actin polymerization or depolymerization. Very little, however, is known about the relationship between Ca2+ and the actin cytoskeleton organization in retinal neurons. We studied the effect of high-K+-induced depolarization on F-actin organization in salamander retina and found that Ca2+ influx through voltage-gated L-type channels causes F-actin disruption, as assessed by 53±5% (n=23, P <0.001) reduction in the intensity of staining with Alexa-Fluor488-phalloidin, a compound that permits visualization and quantification of polymerized actin. Calcium-induced F-actin depolymerization was attenuated in the presence of protein kinase C antagonists, chelerythrine or bis-indolylmaleimide hydrochloride (GF 109203X). In addition, phorbol 12-myristate 13-acetate (PMA), but not 4α-PMA, mimicked the effect of Ca2+ influx on F-actin. Activation of ionotropic AMPA and NMDA glutamate receptors also caused a reduction in F-actin. No effect on F-actin was exerted by caffeine or thapsigargin, agents that stimulate Ca2+ release from internal stores. In whole-cell recording from a slice preparation, light-evoked ‘off’ but not ‘on’ EPSCs in ‘on–off’ ganglion cells were reduced by 60±8% (n=8, P <0.01) by cytochalasin D. These data suggest that elevation of intracellular Ca2+ during excitatory synaptic activity initiates a cascade for activity-dependent actin remodelling, which in turn may serve as a feedback mechanism to attenuate excite-toxic Ca2+ accumulation induced by synaptic depolarization.

4c. Electric Field-directed Cell Shape Changes, Displacement, and Cytoskeletal Reorganization Are Calcium Dependent

Edward K. Onuma and Sek-Wen Hui
Roswell Park Memorial Institute, Buffalo, New York
J Cell Biology 1988; 106: 2067-2075

C3H/10T1/2 mouse embryo fibroblasts were stimulated by a steady electric field ranging up to 10 V/cm. Some cells elongated and aligned perpendicular to the field direction. A preferential positional shift toward the cathode was observed which was inhibited by the calcium channel blocker D-600 and the calmodulin antagonist trifluoperazine. Rhodaminephalloidin labeling of actin filaments revealed a field induced disorganization of the stress fiber pattern, which was reduced when stimulation was conducted in calcium-depleted buffer or in buffer containing calcium antagonist CoC12, calcium channel blocker D-600, or calmodulin antagonist trifluoperazine. Treatment with calcium ionophore A23187 had similar effects, except that the presence of D-600 did not reduce the stress fiber disruption. The calcium-sensitive photoprotein aequorin was used to monitor changes in intracellular-free calcium. Electric stimulation caused an increase of calcium to the micromolar range. This increase was inhibited by calcium-depleted buffer or by CoC12, and was reduced by D-600. A calcium-dependent mechanism is proposed to explain the observed field-directed cell shape changes, preferential orientation, and displacement.

4d. Local Calcium Elevation and Cell Elongation Initiate Guided Motility in Electrically Stimulated osteoblast-Like Cells

N Ozkucur, TK Monsees, S Perike, H Quynh Do, RHW Funk.
Carl Gustav Carus, TU-Dresden, Dresden, Germany; University of the Western Cape, SAfrica.
Plos ONE 2009; 4 (7): e6131

Investigation of the mechanisms of guided cell migration can contribute to our understanding of many crucial biological processes, such as development and regeneration. Endogenous and exogenous direct current electric fields (dcEF) are known to induce directional cell migration, however the initial cellular responses to electrical stimulation are poorly understood. Ion fluxes, besides regulating intracellular homeostasis, have been implicated in many biological events, including regeneration. Therefore understanding intracellular ion kinetics during EF-directed cell migration can provide useful information for development and regeneration.
We analyzed the initial events during migration of two osteogenic cell types, rat calvarial and human SaOS-2 cells, exposed to strong (10–15 V/cm) and weak (#5 V/cm) dcEFs. Cell elongation and perpendicular orientation to the EF vector occurred in a time- and voltage-dependent manner. Calvarial osteoblasts migrated to the cathode as they formed new filopodia or lamellipodia and reorganized their cytoskeleton on the cathodal side. SaOS-2 cells showed similar responses except towards the anode. Strong dcEFs triggered a rapid increase in intracellular calcium levels, whereas a steady state level of intracellular calcium was observed in weaker fields. Interestingly, we found that dcEF induced intracellular calcium elevation was initiated with a local rise on opposite sides in calvarial and SaOS-2 cells, which may explain their preferred directionality. In calcium-free conditions, dcEFs induced neither intracellular calcium elevation nor directed migration, indicating an important role for calcium ions. Blocking studies using cadmium chloride revealed that voltage-gated calcium channels (VGCCs) are involved in dcEF-induced intracellular calcium elevation. Taken together, these data form a time scale of the morphological and physiological rearrangements underlying EF-guided migration of osteoblast-like cell types and reveal a requirement for calcium in these reactions. We show for the first time here that dcEFs trigger different patterns of intracellular calcium elevation and positional shifting in osteogenic cell types that migrate in opposite directions.

4e. TRPM4 Regulates Migration of Mast Cells in Mice

T Shimizua, G Owsianik, M Freichelb, V Flockerzi, et al.
Laboratory of Ion Channel Research, KU Leuven, Leuven, Belgium; Universität des Saarlandes, Homburg, Germany; National Institute for Physiological Sciences,Okazaki, Japan
Cell Calcium 2008; xxx–xxx

We demonstrate here that the transient receptor potential melastatin subfamily channel, TRPM4, controls migration of bone marrow-derived mast cells (BMMCs), triggered by dinitrophenylated human serum albumin (DNP-HSA) or stem cell factor (SCF). Wild-type BMMCs migrate after stimulation with DNPHSA or SCF whereas both stimuli do not induce migration in BMMCs derived from TRPM4 knockout mice (trpm4−/−). Mast cell migration is a Ca2+-dependent process, and TRPM4 likely controls this process by setting the intracellular Ca2+ level upon cell stimulation. Cell migration depends on filamentous actin (F-actin) rearrangement, since pretreatment with cytochalasin B, an inhibitor of F-actin formation, prevented both DNP-HSA- and SCF-induced migration in wild-type BMMC. Immunocytochemical experiments using fluorescence-conjugated phalloidin demonstrate a reduced level of F-actin formation in DNP-HSA-stimulated BMMCs from trpm4−/− mice. Thus, our results suggest that TRPM4 is critically involved in migration of BMMCs by regulation of Ca2+-dependent actin cytoskeleton rearrangements.
4f. Nuclear and cytoplasmic free calcium level changes induced by elastin peptides in human endothelial cells
G FAURY, Y USSON, M ROBERT-NICOUD, L ROBERT, AND J VERDETTI.
Institut Albert Bonniot, Universite´ J. Fourier, Grenoble, Fr; and Universite´ Paris, Paris, Fr
PNAS: Cell Biology 1998; 95: pp. 2967–2972.

The extracellular matrix protein ‘‘elastin’’ is the major component of elastic fibers present in the arterial wall. Physiological degradation of elastic fibers, enhanced in vascular pathologies, leads to the presence of circulating elastin peptides (EP). EP have been demonstrated to influence cell migration and proliferation. EP also induce, at circulating pathophysiological concentrations (and not below), an endothelium-and NO- dependent vasorelaxation mediated by the 67-kDa subunit of the elastin-laminin receptor. Here, by using the techniques of patch-clamp, spectrofluorimetry and confocal microscopy, we demonstrate that circulating concentrations of EP activate low specificity calcium channels on human umbilical venous endothelial cells, resulting in increase in cytoplasmic and nuclear free calcium concentrations. This action is independent of phosphoinositide metabolism. Furthermore, these effects are inhibited by lactose, an antagonist of the elastin-laminin receptor, and by cytochalasin D, an actin microfilament depolymerizer. These observations suggest that EP-induced signal transduction is mediated by the elastin-laminin receptor via coupling of cytoskeletal actin microfilaments to membrane channels and to the nucleus. Because vascular remodeling and carcinogenesis are accompanied by extracellular matrix modifications involving elastin, the processes here described could play a role in the elastin-laminin receptor-mediated cellular migration, differentiation, proliferation, as in atherogenesis, and metastasis formation.

Part 5. Regulation of the Cytoskeleton

5a Regulation of the Actin Cytoskeleton by PIP2 in Cytokinesis

MR Logan and CA Mandato
McGill University, Montreal, Ca
Biol. Cell (2006) 98, 377–388 [doi:10.1042/BC20050081]

Cytokinesis is a sequential process that occurs in three phases:

assembly of the cytokinetic apparatus,
furrow progression and
fission (abscission) of the newly formed daughter cells.

The ingression of the cleavage furrow is dependent on the constriction of an equatorial actomyosin ring in many cell types. Recent studies have demonstrated that this structure is highly dynamic and undergoes active polymerization and depolymerization throughout the furrowing process. Despite much progress in the identification of contractile ring components, little is known regarding the mechanism of its assembly and structural rearrangements. PIP2 (phosphatidylinositol 4,5-bisphosphate) is a critical regulator of actin dynamics and plays an essential role in cell motility and adhesion. Recent studies have indicated that an elevation of PIP2 at the cleavage furrow is a critical event for furrow stability. We discuss the role of PIP2-mediated signaling in the structural maintenance of the contractile ring and furrow progression. In addition, we address the role of other phosphoinositides, PI(4)P (phosphatidylinositol-4-phosphate) and PIP3 (phosphatidylinositol 3,4,5-triphosphate) in these processes.

Regulation of the actin cytoskeleton by PIPKs (phosphatidylinositol phosphate kinases) and PIP2 (phosphatidylinositol 4,5-bisphosphate)

PIP2 is generated by the activity of type I (PIPKIs) or type II (PIPKII) kinase isoforms (α, β, γ) which utilize PI(4)P (phosphatidylinositol 4-phosphate) and PI(5)P (phosphatidylinositol 5-phosphate) as substrates respectively. PIPKIs are localized to the plasma membrane and are thought to account for the majority of PIP2 synthesis, whereas PIPKIIs are predominantly localized to intracellular sites. PIP2 plays a key role in re-structuring the actin cytoskeleton in several ways. In general, high levels of PIP2 are associated with actin polymerization, whereas low levels block assembly or promote actin severing activity. PIP2 facilitates actin polymerization in multiple ways such as:

(i) activating N-WASp (neuronal Wiskott–Aldrich syndrome protein)- and Arp2/3 (actin-related protein 2/3)-mediated actin branching,
(ii) binding and impairing the activity of actin-severing proteins, such as gelsolin and cofilin/ADF (actin depolymerizing factor); and
(iii) uncapping actin filaments for the addition on new actin monomers

This polymerization signal is counteracted by the generation of IP3 (inositol 1,4,5-triphosphate) and DAG (diacylglycerol), following PLC (phospholipase C)-mediated hydrolysis of PIP2. IP3-mediated activation of Ca2+/CaM (calmodulin) promotes the activation of severing proteins such as gelsolins and cofilin, which lead to solubilization of the actin network (Figure 1). In addition to influencing actin polymerization, PIP2 modulates the function of several actin cross-linking and regulatory proteins which are critical for the assembly of stress fibres, gel meshworks and membrane attachment. For example, PIP2 negatively regulates cross-linking mediated by filamin and the actin-bundling activity of α-actinin. In contrast, PIP2 induces conformational changes in vinculin, talin and ERM (ezrin/radixin/moesin) family proteins to promote anchoring of the actin cytoskeleton to the plasma membrane. PLC-mediated hydrolysis of PIP2 and the downstream activation of Ca2+/CaM and PKC (protein kinase C) also influences actin-myosin based contractility. Ca2+/CaM activates MLCK (myosin regulatory light chain kinase), leading to phosphorylation of the MLC (myosin regulatory light chain). Similarly, PKC has been shown to phosphorylate and activate MLC (Figure 1).

Figure 1 Summary of PIP2-mediated regulation of the actin cytoskeleton

Role of PIP2-mediated signaling in cell division

Prior to cell division cells undergo a global cell rounding which is a prerequisite step for the initiation of the cleavage furrow. In frog, sea urchin and newt eggs these shape changes correlate with an increase in cortical tension that precedes or occurs near the onset of the cleavage furrow. Precise mapping of the changes in cortical tension have shown that peaks of tension are propagated in waves that occur in front of and at the same time as furrow initiation. These tension waves are generated by actomyosin-based contractility and subside after the furrow has passed. Experiments in Xenopus eggs, zebrafish and Xenopus embryos indicated that site-specific Ca2+ waves were generated within the cleavage furrow that would be predicted to coincide with peaks of cortical tension. The injection of heparin, a competitive inhibitor of IP3 receptors, or Ca2+ chelators were both demonstrated to significantly delay or arrest furrowing , and a similar inhibitory effect was observed of microinjected PIP2 antibodies that caused a depletion of the intracellular pool of DAG and Ca2+ in Xenopus blastomeres. In addition, the increase in cortical contractility of Xenopus oocytes has been shown to occur via a PKC-dependent pathway. Together, these studies demonstrate a role for PIP2-mediated signaling at the early stages of cytokinesis.

Recent studies have supported that PIP2-mediated signaling also plays a critical role in ingression of the cleavage furrow, although significant differences have been shown in the localization of PIP2 and the role of PLC. Lithium and the PLC inhibitor, U73122, caused a rapid (within minutes) regression of cleavage furrows in crane fly spermatocytes, but did not block their initial formation. PIP2 may become concentrated within the cleavage furrow and could facilitate anchoring of the plasma membrane to structural components of the actomyosin ring. A PIPKI homologue, its3, and PIP2 were reported at the septum of dividing fission yeast, Schizosaccharomyces pombe. A temperature sensitive mutant of its3 exhibited disrupted actin patches, following a shift to the restrictive temperature, and also impaired cytokinesis. Although a contractile ring was still evident in these cells, abnormalities, such as an extra ring, were found. Two recent studies demonstrated an increase in PIP2-specific GFP-labeled PH domains within the cleavage furrow of mammalian cells. Both of these reports suggested de novo synthesis of PIP2 occurs within the furrow. Another study found that endogenous and over-expressed PIPKIβ, but not PIPKIγ, concentrated in the cleavage furrow of CHO (Chinese hamster ovary) cells. The expression of a kinase-dead mutant of this isoform and microinjection of PIP2-specific antibodies both caused a significant increase in the number of multinucleated cells. A multinucleated phenotype was, similarly, observed in multiple cell lines (CHO, HeLa, NIH 3T3 and 293T) transfected with high levels of PIP2-specific PH domains, synaptojanin [which dephosphorylates PIP2 to PI(4)P], or a kinase-dead mutant of PIPKIα. In addition, a small percentage of CHO and HeLa cells expressing high levels of PIP2-specific PH domains or synaptojanin showed signs of F-actin dissociation from the plasma membrane. CHO cells transfected with PIP2 PH domains, but not PH domains specific for PI(3,4)P2 (phosphatidylinositol 3,4-bisphosphate) and PIP3, also exhibited impaired furrow expansion induced by the application of hypotonic buffer. This suggests one of the primary roles of PIP2 is to promote cytoskeleton–membrane anchoring at the furrow.

Role of PI3Ks (phosphoinositide 3-kinases) and PI4Ks (phosphoinositide 4-kinases) in cytokinesis PI4Ks generate the PIPKI substrate, PI(4)P, and play a critical role in PIP2 generation. Studies in lower organisms support the requirement of PI4Ks for cytokinesis. In Saccharomyces cerevisiae two PI4Ks, STT4 and PIK1, have non-overlapping functions in Golgi-tomembrane trafficking and cell-wall integrity respectively. Both genes are also required for cell division. Conditional mutants of Pik1p exhibited a cytokinesis defect: cells arrest with large buds and fully divided nuclei. In addition, STT4 was identified as a gene implicated in reorientation of the mitotic spindle prior to cytokinesis. Spermatocytes derived from fwd mutant males had unstable furrows that failed to ingress and abnormal contractile rings with dissociated myosin II and F-actin, fwd has homology with yeast PIK1 and human PI4KIIIβ. Although PIK1 is an essential gene in yeast, the deletion of fwd was not lethal and female flies were fertile. A study in fission yeast suggests that PI4Ks may be recruited to the furrow, as reported for PIPKs. Desautels et al. (2001) identified a PI4K as a binding partner of Cdc4p, a contractile ring protein with homology to the myosin essential light chain. A Cdc4p mutant, G107S, abolished the interaction with PI4K and induced the formation of multinucleated cells with defects in septum formation. This finding suggests that, at least for fission yeast, anchoring of PI4K to the contractile ring may concentrate PI(4)P substrate within the furrow for subsequent PIP2 generation.

An increased synthesis of PIP2 by PIPKIs at the cleavage furrow is anticipated to promote both actin polymerization and structural support to the contractile ring. Structural proteins of the contractile ring regulated by PIP2 include anillin, septin and ERM proteins. The concentration of PIP2 at the cleavage furrow is postulated to be a critical molecule in the recruitment of these proteins and their integration with the actomyosin ring. Anillin exhibits actin-bundling activity and is required at the terminal stages of cytokinesis in Drosophila and human cells. The depletion of anillin in Drosophila and human cells causes cytokinesis failure, which is correlated with uncoordinated actomyosin contraction of the medial ring. Anillin also functions as a cofactor to promote the recruitment of septins to actin bundles. Mutations within the PH domain of anillin were recently demonstrated to impair septin localization to both the furrow canal and the contractile ring in Drosophila cells, blocking cellularization and furrow progression. Septins have also been shown to bind to phosphoinositides and this interaction regulates their subcellular localization. The mammalian septin, H5, bound PIP2 and PIP3 liposomes at its N-terminal basic region, which is conserved in most septin proteins. The over-expression of synaptojanin and treatment with neomycin (which depletes cellular PIP2) both caused disruption of actin stress fibres and dissociation of H5 from filamentous structures in Swiss 3T3 cells. Septins are co-localized with actin at the cleavage furrow and form ring structures that are postulated to structurally support the contractile ring.

Studies suggest that PLC-mediated hydrolysis of PIP2 and the subsequent release of intracellular Ca2+ stores is a necessary event for furrow stability and ingression. A role for Ca2+ is similarly supported by previous findings that Ca2+ waves were localized to the cleavage furrow in frog embryos, eggs and fish. PLC second messengers have also been implicated in cytokinesis. For example, CaM was localized to mitotic spindles of HeLa cells and the inhibition of its activity was reported to cause cytokinesis defects. A recent RNAi (RNA interference) screen also identified PI4Ks and PIPKs, but not PLC genes, as critical proteins for cytokinesis in Drosophila. This may indicate PLC is required for completion of furrowing, rather than its initiation.

It is hypothesized that PLC activity may promote actin filament severing through the activation of Ca2+-dependent actin-severing proteins, such as gelsolin and cofilin. Depending on the localization of PLC, this could either drive disassembly of actin filaments of the medial ring or the cortical actin network. Furthermore, the activation of PKC and CaM would activate actomyosin contraction via the phosphorylation of MLCK. At the furrow, PKC and CaM could act in concert with the Rho effectors ROCK and Citron kinase, which also phosphorylate and activate MLC.

The activation of CaM and/or PKC may also provide positive feedback for the recruitment of PIP2 effectors and regulate GTPase-mediated actin polymerization. Both PKC and CaM have been shown to promote the dissociation of MARCKS (myristoylated alanine-rich C kinase substrates) family proteins from PIP2. MARCKS are postulated to play a major regulatory role in phosphoinositide signalling by sequestering PIP2 at the membrane. Thus the activation of PKC and CaM promotes PIP2 availability for the recruitment of PH-domain-containing effector proteins. Studies in yeast and mammalian cells have supported that CaM and PKC can mediate positive feedback for PIP2 synthesis by activating PIPKs.

Signaling Crosstalk: Role of GTPases and Phosphoinositides

On the basis of the present available data, PIP2 has been shown to be a critical molecule for structural integrity of the contractile ring and furrow stability. However, the observation that furrows are initiated in cells treated with agents that either sequester PIP2 or prevent its hydrolysis suggests PIP2 does not provide the originating signal for furrow formation. Recent studies suggest that the recruitment and activation of RhoA may provide this early signal.

Figure 2 Proposed model of PIP2 and GTPase signaling at the cleavage furrow

Ect2, is recruited to the cleavage furrow via its interaction withMgcRacGAP at the central spindle. Ect2 and MgcRacGAP regulate the activities of Rho GTPases (RhoA, Cdc42 and Rac) and are functionally implicated in the assembly of the contractile ring. Active RhoA and Cdc42 are increased at the furrow, whereas Rac is suppressed (grey). Furrow-recruited GTPases (RhoA, ARF6 and Cdc42) are predicted to activate PIPKI, leading to the generation of PIP2. PI3K activity is suppressed at the furrow (grey), which may be due to MgcRacGAP-mediated inhibition of Rac and/or the activity of the PIP3 phosphatase, PTEN. Cycles of PIP2 synthesis and hydrolysis by PLC are thought to play a critical role in re-structuring the contractile ring throughout the duration of furrowing. PIP2-mediated activation of anillin, septins and ERM proteins promotes cross-linking and membrane anchoring of the contractile ring. PLC-mediated activation of PKC and CaM can facilitate the contraction of the actomyosin ring, similar to RhoA effectors, ROCK and Citron kinase. CaM may also regulate IQGAP–Cdc42 interactions, and thereby modulate actin organization. It is hypothesized that Cdc42-mediated actin polymerization via effectors, such as N-WASp (neuronalWiskott–Aldrich syndrome protein) and Arp2/3 (actin-related protein 2/3), may reduce membrane tension outside the inner region of RhoA-mediated contractility.

Protein required for cell movement identified (sciencedaily.com)
Hypoxia Modulates Fibroblastic Architecture, Adhesion and Migration: A Role for HIF-1α in Cofilin Regulation and Cytoplasmic Actin Distribution (plosone.org)
Myo1e Impairment Results in Actin Reorganization, Podocyte Dysfunction, and Proteinuria in Zebrafish and Cultured Podocytes (plosone.org)
Metabolic Pumps and Intracellular Homeostasis, Hormones and Cell Function, Intercellular Communication, Cell Motility and Contractility, Part B … of Medical Cell Biology. A Multi-Volume Work) ebook (enwoloqu.wordpress.com)
Novel molecules to target the cytoskeleton (sciencedaily.com)
Musculoskeletal System (March 4th) (mindsictportfolio.wordpress.com)
New understanding of actin filament growth in cells (medicalnewstoday.com)
Multi-disciplinary Penn research identifies protein required for cell movement (eurekalert.org)
ERK Positive Feedback Regulates a Widespread Network of Tyrosine Phosphorylation Sites across Canonical T Cell Signaling and Actin Cytoskeletal Proteins in Jurkat T Cells (plosone.org)
Coronary Circulation Combined Assessment: Optical Coherence Tomography (OCT), Near-Infrared Spectroscopy (NIRS) and Intravascular Ultrasound (IVUS) – Detection of Lipid-Rich Plaque and Prevention of ACS (pharmaceuticalintelligence.com)

Actin core bundle fimbrin (Photo credit: Wikipedia)

English: Diagram showing Actin-Myosin filaments in Smooth muscle. The actin fibers attach to the cell wall and to dense bodies in the cytoplasm. When activated the slide over the myosin bundles causing shortening of the cell walls (Photo credit: Wikipedia)

English: Figure 2: The matrix can play into other pathways inside the cell even through just its physical state. Matrix immobilization inhibits the formation of fibrillar adhesions and matrix reorganization. Likewise, players of other signaling pathways inside the cell can affect the structure of the cytoskeleton and thereby the cell’s interaction with the ECM. (Photo credit: Wikipedia)

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Coronary Circulation Combined Assessment: Optical Coherence Tomography (OCT), Near-Infrared Spectroscopy (NIRS) and Intravascular Ultrasound (IVUS) – Detection of Lipid-Rich Plaque and Prevention of Acute Coronary Syndrome (ACS)

Posted in Atherogenic Processes & Pathology, Cardiac and Cardiovascular Surgical Procedures, Frontiers in Cardiology and Cardiovascular Disorders, Medical Devices R&D and Inventions, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Origins of Cardiovascular Disease, PCI, Peripheral Arterial Disease & Peripheral Vascular Surgery, tagged Cardiology, Coronary circulation, InfraReDx, Intravascular ultrasound, IVUS, myocardial infarction, Near-Infrared Spectroscopy, NIRS, optical coherence tomography, TVC Imaging System™ on August 25, 2013| 2 Comments »

Coronary Circulation Combined Assessment: Optical Coherence Tomography (OCT), Near-Infrared Spectroscopy (NIRS) and Intravascular Ultrasound (IVUS) – Detection of Lipid-Rich Plaque and Prevention of Acute Coronary Syndrome (ACS)

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC

and

Article Curator: Aviva Lev-Ari, PhD, RN

The clinical motivations for coronary artery imaging include identifying and characterizing obstructive lesions, analyzing suitability for various feasible interventions, and assessing comparative risk with and without interventions. With improvements in non-invasive detection of fixed obstructions in the coronary arteries, it should not be surprising that half of the lesions that cause heart attacks (myocardial infarction) among those who had recent imaging consisted of unstable plaques that were less than 50% obstructive. Therefore there is growing interest not only in more reliable detection of lesions that exceed 50% obstruction, but also improved characterization of lesions that are not obstructive but may be unstable.

By way of analogy, think of impaired blood supply to the heart as a traffic jam in a roadway. The best time to check for a traffic jam is during rush hour. The corresponding clinical scenario is stress testing. There are three major roadways in the heart: left anterior, left circumflex, and right, each with branches (forks). The two left major vessels stem from a short but treacherous left main (“widow maker”). A temporary traffic jam results in symptoms of impaired delivery (angina, from hunger due to late delivery of food). Alternatively, a prolonged traffic disruption can result in suicidal tissue destruction (starvation). A fixed obstruction consists of potholes and landslides resulting in a persisting shutdown of half or more of the lanes in the highway. An unstable plaque consists of a less severe abnormality that can cause accidents (plaque rupture, local hemorrhage, sudden occlusion). A road may shutdown not only from progressive road damage, but also a truck can flip over and shutdown a relatively clean roadway.

Among patients who had recent coronary imaging prior to the onset of a heart attack, half do not have occlusive lesions. Instead of slow progressive reduction in vessel diameter leading to a critically severe flow reduction, the mechanism in the cases of no severe narrowing is attributed to unstable plaque, meaning plaque with thin fibrous caps that rupture, causing sudden thrombosis. Stress tests focus on detection of fixed obstructions and do not warn who has unstable plaque. Thus the next great frontier for coronary imaging is not just to identify flow reducing lesions, but also to identify unstable plaque even if it is not currently flow limiting. This article presents candidate imaging methods and their current capabilities.

Coronary imaging methods include:

intra-coronary ultrasound (IVUS)
optical coherence imaging (fiberoptic)
computed tomographic xray angiography (CTA)
magnetic resonance angiography (MRA)

near infra-red spectroscopic imaging (NIRS)

NIRS-IVUS Imaging To Characterize the Composition and Structure of Coronary Plaques

David Rizik, MD1 and James, A. Goldstein, MD2

1. Scottsdale Healthcare Hospital, Scottsdale, AZ

2. Department Cardiovascular Medicine, William Beaumont Hospital, Royal Oak, MI

This supplement,

http://www.invasivecardiology.com/files/Infraredx_FINALPDF.pdf

authored by highly experienced interventional cardiologists expert in the field of coronary plaque characterization, contains a detailed description of the new NIRS-IVUS combination catheter, and the clinical information obtained during its use in over 90 hospitals in over 10 countries. Case vignettes, cohort outcomes, reviews, and plans for future studies are also presented. It is our hope that this information will be useful in the near term to those seeking to improve PCI. For the longer term, we believe that the NIRS-IVUS system is an excellent candidate for evaluation as a detector of vulnerable plaque. Success in the prospective studies that are planned will make it possible to detect vulnerable plaques and thereby enhance efforts to prevent coronary events.

Imaging Methods for Detection of Intravascular Plaque – Direct, Robust and/or Validated

Cap Thickness – OCT

Expansive Remodeling – IVUS & NIRS-IVUS [Combination TVC System & TVC Insight Catheter]

Plaque Volume – IVUS & NIRS-IVUS

Calcification – Angiography, IVUS & NIRS-IVUS

Thrombus – Angioscopy & OCT

Inflammation Macrophages – Indirect by OCT

Lipid Core – IVUS & NIRS-IVUS

Requires Blood-Free FOV – Angioscopy & OCT

based on Table 1 p.5

http://www.invasivecardiology.com/files/Infraredx_FINALPDF.pdf

Comparative Intravascular Imaging for Lipid Core Plaque: VH-IVUS vs OCT vs NIRS

Eric Fuh, MD and Emmanouil S. Brilakis, MD, PhD

VA North Texas Healthcare System, Dallas, TX and Division of Cardiology, Dept of Medicine, UT Southwestern Medical Center, Dallas, TX

Conclusions

VH-IVUS, OCT, and NIRS can assist in the detection and evaluation of lipid core plaque. Comparative studies have shown important differences between modalities, but are all limited from lack of comparison with the gold standard of histology. Given the different strengths and weaknesses of each modality, combination imaging will likely provide the best results.41 Further refinement of the clinical implications of LCP detection and its impact on optimizing treatment strategy selection will stimulate advances in LCP detection imaging.

OCT and NIRS can image through calcified lesions, whereas IVUS cannot. LCPs are often accompanied by neovascularization, which can only be visualized by OCT. VH-IVUS may classify stents, which usually appear white (misclassified as “calcium”) surrounded by red (misclassified as “necrotic core”), although this does not appear to be a limitation for NIRS and OCT.54

Reference 41:

Bourantas CV, Gracia-Gracia HM, Naka KK, et al. Hybrid intravascular imaging: current applications and prospective potential in the study of coronary atherosclerosis, JACC 2013;61:1369-1378

Abstract

The miniaturization of medical devices and the progress in image processing have allowed the development of a multitude of intravascular imaging modalities that permit more meticulous examination of coronary pathology. However, these techniques have significant inherent limitations that do not allow a complete and thorough assessment of coronary anatomy. To overcome these drawbacks, fusion of different invasive and noninvasive imaging modalities has been proposed. This integration has provided models that give a more detailed understanding of coronary artery pathology and have proved useful in the study of the atherosclerotic process. In this review, the authors describe the currently available hybrid imaging approaches, discuss the technological innovations and efficient algorithms that have been developed to integrate information provided by different invasive techniques, and stress the advantages of the obtained models and their potential in the study of coronary atherosclerosis.

http://content.onlinejacc.org/article.aspx?articleid=1671094

Reference 54

Kim SW, Mintz GS, Hong YJ, et al. The virtual histology intravascular ultrasound appearance of newly placed drug-eluting stents. Am J Cardiol. 2008;102:1182-1186.

American Journal of Cardiology
Volume 102, Issue 9 , Pages 1182-1186, 1 November 2008

The Virtual Histology Intravascular Ultrasound Appearance of Newly Placed Drug-Eluting Stents

Received 17 January 2008; received in revised form 17 March 2008; accepted 17 March 2008. published online 13 June 2008.

Intravascular ultrasound (IVUS) is used before and after intervention and at follow-up to assess the quality of the acute result as well as the long-term effects of stent implantation. Virtual histology (VH) IVUS classifies tissue into fibrous and fibrofatty plaque, dense calcium, and necrotic core. Although most interventional procedures include stent implantation, VH IVUS classification of stent metal has not been validated. In this study, the VH IVUS appearance of acutely implanted stents was assessed in 27 patients (30 lesions). Most stent struts (80%) appeared white (misclassified as “calcium”) surrounded by red (misclassified as “necrotic core”); 2% appeared just white, and 17% were not detectable (compared with grayscale IVUS because of the software-imposed gray medial stripe). The rate of “white surrounded by red” was similar over the lengths of the stents; however, undetectable struts were mostly at the distal edges (31%). Quantitatively, including the struts within the regions of interest increased the amount of “calcium” from 0.23 ± 0.35 to 1.07 ± 0.66 mm² (p <0.0001) and the amount of “necrotic core” from 0.59 ± 0.65 to 1.31 ± 0.87 mm² (p <0.0001). Most important, because this appearance occurs acutely, it is an artifact, and the red appearance should not be interpreted as peristrut inflammation or necrotic core when it is seen at follow-up. In conclusion, acutely implanted stents have an appearance that can be misclassified by VH IVUS as “calcium with or without necrotic core.” It is important not to overinterpret VH IVUS studies of chronically implanted stents when this appearance is observed at follow-up. A separate classification for stent struts is necessary to avoid these misconceptions and misclassifications.

http://www.ajconline.org/article/S0002-9149(08)00567-5/abstract?refissn=1936-8798&refuid=S1936-8798%2812%2900367-6

Table 2. Comparison of three intravascular imaging modalities for the detection of coronary lipid core plaque.

Intravascular Imaging Modalities for Detecting LCP

Vol. 25, Supplement A, 2013

13A

VH-IVUS (20 MHz) OCT NIRS-IVUS (40 MHz)

Hybrid intravascular imaging No No Yes

Axial resolution, μm 200 10 100

Imaging through blood ++ – ++

Need for blood column clearance during image acquisition No Yes No

Imaging through stents No Yes Yes

Imaging through calcium No Yes Yes for NIRS – No for IVUS

Imaging neovascularization No Yes No

Detection of non-superficial LCPs Yes No No

Evaluation of LCP cap thickness + ++ *

Detection of thrombus – + *

Expansive remodeling ++ – ++

Need for manual image processing for LCP detection Yes Yes No

++ = excellent; + = good; ± = possible; – = impossible; * = potential under investigation

VH-IVUS = virtual histology intravascular ultrasound; OCT = optical coherence tomogra-phy; NIRS = near-infrared spectroscopy; LCP = lipid core plaque

The Search for Vulnerable Plaque — The Pace Quickens

Ryan D. Madder, MD1, Gregg W. Stone, MD2, David Erlinge, MD3, James E. Muller, MD4

Affiliations

1Frederik Meijer Heart & Vascular Institute, Spectrum Health, Grand Rapids, Michigan;

2New York Presbyterian Hospital, Columbia University and Car-diovascular Research Foundation, New York, New York;

3Department of Cardiology, Lund University, Lund, Sweden;

4Infraredx, Inc., Burlington, Massachusetts

Disclosure: Drs. Madder and Erlinge report no financial relationships or conflicts of interest regarding the content herein.

Dr. Stone is a consultant for Infraredx, Inc., Volcano Corp., Medtronic, and Boston Scientific, and is a member of the scientific advisory boards for Boston Scientific and Abbott Vascular.

Dr. Muller is a full-time employee of Infraredx, Inc from which he receives salary and equity.

Address for Correspondence: Email: ryan.madder@spectrumhealth.org

The search for the vulnerable plaque has been a lengthy endeavor requiring the work of multiple individuals and institutions over many years. It is disappointing that in more than 2 decades since the “vulnerable plaque” concept was formulated, over 40 million coronary events have occurred. However, it is encouraging that positive answers are now available for most of the questions related to a vulnerable plaque detection and treatment strategy. As shown in Table 1, most of the essential preconditions of a successful vulnerable plaque strategy are present. This positive information has accelerated the pace of work in this area. The pathophysiology of coronary events is well-understood; powerful imaging methods are available; and therapies, both existing and novel, may well be effective (although appropriately powered randomized trials are required to demonstrate their safety and effectiveness). The time is approaching for the conduct of prospective outcome trials to determine the value of a vulnerable plaque strategy for more effective prevention of coronary events.

Table 1. Essential Components of a Strategy to Prevent Coronary Events by the Detection and Treatment of Vulnerable Plaques


Essential Components	Evidencefrom Published Research
*Pathophysiology of Coronary Events*
• Are the causes of coronary events known?	Yes	Constantinides and others have shown that most coronary events are caused by rupture of a thin-capped LRP with subsequent formation of an occlusive thrombus.1-5
• Are LRPs focal?	Yes	Cheruvu et al demonstrated that ruptures and TCFA occupy less than 4% of the length of arteries studied at autopsy.8
• Are LRPs stable over time?	Yes	Kubo et al demonstrated that most fibroatheromas by radiofrequency IVUS remain fibroatheromas over time.39
*Detection of Suspected Vulnerable Plaque by Invasive Imaging* *(For Secondary Prevention)*
• Can invasive imaging safely detect LRP?	Yes	Waxman et al, Ino et al, and many others have demonstrated the safety of detecting LRP in patients.40
• Do cross-sectional studies show increased LRP concentrated at culprit sites?	Yes	Madder et al, Erlinge et al, Ino et al have shown LRP concentrated at the culprit site across the spectrum of ACS.14,16,41
• Do prospective studies show that suspected vulnerable plaque can be detected in advance?	Yes	PROSPECT, VIVA, PREDICTION established the principle by proving that increased plaque burden predicted events but prediction lacked specificity.23-25
• Is more specific detection of vulnerable plaque possible?	?	NIRS-IVUS and OCT may provide more specific detection of VP, but have not yet been tested in a prospective study.
*Can Vulnerable Plaques be Treated?*
• Is systemic treatment of LRPs possible with current agents?	Yes	YELLOW study showed a reduction in LRP with rosuvastatin.33
• Is focal treatment of LRPs possible with current methods?	Yes	Ruptured LRPs are routinely stented in ACS in clinical practice with good outcomes.
• Can systemic treatment be enhanced with new agents?	?	PCSK9 inhibitors, Apo A1 Milano, other agents in development may be more effective than statins, but more costly.35,36
• Can focal treatments be enhanced with new methods?	?	Bioresorbable vascular scaffolds and/or drug-coated balloons may be useful for VP.
*Primary Prevention*
• Can demographic and serum biomarkers be used as a first step in a screening strategy?	Yes	Framingham Risk Score, improved serum biomarkers, and genetic markers can identify individuals at increased risk.
• Can non-invasive imaging with CTA detect LRP and increased risk?	Yes	Motoyama et al have identified CTA markers associated with future events.26
*Cost-Effectiveness*
• Will a strategy of detection and treatment of vulnerable plaque, if proven to be successful, be cost-effective for secondary prevention?	Probably	Bosch et al demonstrated that for patients already undergoing invasive imaging, the added costs of detection and treatment of VP are likely to be less than the cost of second events, leading to a cost-saving approach that also improves health.38
• Will a strategy of detection and treatment of vulnerable plaque, if proven to be successful, be cost-effective for primary prevention?	?	Bosch et al: For primary prevention the cost of screening would be greater than for secondary prevention. Cost-effectiveness would depend upon cost, the accuracy of detection, and effectiveness of therapy.38
ACS = acute coronary syndrome; CTA = coronary computed tomographic angiography; LRP = lipid-rich plaque; TCFA = thin-capped fibroatheroma;

References

1. Constantinides P. Plaque fissures in human coronary thrombosis. J Atheroscler Res. 1966;6:1-17.

2. Friedman M, Van den Bovenkamp GJ. The pathogenesis of a coronary thrombus. Am J Pathol. 1966;48:19-44.

3. Burke AP, Farb A, Malcom GT, et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997;336:1276-1282.

4. Farb A, Tang AL, Burke AP, et al. Sudden coronary death. Frequency of active coronary lesions, inactive coronary lesions, and myocardial infarction. Circulation. 1995;92:1701-1709.

5. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20:1262-1275.

6. Waksman R, Serruys PW. Handbook of the Vulnerable Plaque. Martin Dunitz: London, England, 2004.

7. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473:317-325.

8. Cheruvu P, Finn A, Gardner C, et al. Frequency and distribution of thin-cap fibroatheroma and ruptured plaques in human coronary arteries – a pathologic study. J Am Coll Cardiol. 2007;50:940-949.

9. Hong M, Mintz GS, Lee CW, et al. Comparison of coronary plaque rupture between stable angina and acute myocardial infarction: a three-vessel intravascular ultrasound study in 235 patients. Circulation. 2004;110:928-933.

10. Fujii K, Kobayashi Y, Mintz GS, et al. Intravascular ultrasound assessment of ulcerated ruptured plaques. A comparison of culprit and non-culprit lesions of patients with acute coronary syndromes and lesions in patients without acute coronary syndromes. Circulation. 2003;108:2473-2478.

11. Ehara S, Kobayashi Y, Yoshiyama M, et al. Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction. An intravascular ultrasound study. Circulation. 2004;110:3424-3429.

12. Lee SY, Mintz GS, Kim SY, et al. Attenuated plaque detected by intravascular ultrasound: clinical, angiographic, and morphologic features and post-percutaneous coronary intervention complications in patients with acute coronary syndromes. J Am Coll Cardiol Intv. 2009;2:65-72.

13. Asakura M, Ueda Y, Yamaguchi O, et al. Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: an angioscopic study. J Am Coll Cardiol. 2001;37:1284-1288.

14. Ino Y, Kubo T, Tanaka A, et al. Difference of culprit lesion morphologies between ST-segment elevation myocardial infarction and non-ST-segment elevation acute coronary syndrome. J Am Coll Cardiol Intv. 2011;4:76-82.

15. Madder RD, Smith JL, Dixon SR, Goldstein JA. Composition of target lesions by near-infrared spectroscopy in patients with acute coronary syndrome versus stable angina. Circ Cardiovasc Interv. 2012;5:55-61.

16. Madder RD, Goldstein JA, Madden SP, et al. Detection by near-infrared spectroscopy of large lipid core plaques at culprit sites in patients with acute ST-segment elevation myocardial infarction. J Am Coll Cardiol Intv. In press, 2013.

17. Hoffmann U, Moselewski F, Nieman K, et al. Noninvasive assessment of plaque morphology and composition in culprit and stable lesions in acute coronary syndrome and stable lesions in stable angina by mulitdetector computed tomography. J Am Coll Cardiol. 2006;47:1655-1662.

18. Motoyama S, Kondo T, Sarai M, et al. Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol. 2007;50:319-326.

19. Madder RD, Chinnaiyan KM, Marandici AM, Goldstein JA. Features of disrupted plaques by coronary computed tomographic angiography: correlates with invasively proven complex lesions. Circ Cardiovasc Imaging. 2011;4:105-113.

20. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation. 1989;79;733-743.

21. Kolodgie FD, Burke AP, Farb A, et al. The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes. Curr Opin Cardiol. 2001;16:285-292.

22. Yamagishi M, Terashima M, Awano K, et al. Morphology of vulnerable coronary plaque: insights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome. J Am Coll Cardiol. 2000;35:106-111.

23. Stone GW, Maehara A, Lansky A, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364:226-235.

24. Calvert PA, Obaid DR, O’Sullivan M, et al. Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VH-IVUS in Vulnerable Atherosclerosis) study. J Am Coll Cardiol Imaging. 2011;4:894-901.

25. Stone PH, Saito S, Takahashi S, et al. Prediction of progression of coronary artery disease and clinical outcomes using vascular profiling of endothelial shear stress and arterial plaque characteristics: the PREDICTION study. Circulation. 2012;126:172-181.

26. Motoyama S, Sarai M, Harigaya H, et al. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol. 2009;54:49-57.

27. Stone GW, Maehara A, Mintz GS. The reality of vulnerable plaque detection. J Am Coll Cardiol Imaging. 2011;4:902-904.

28. Madder RD, Steinberg DH, Anderson RD. Multimodality direct coronary imaging with combined near-infrared spectroscopy and intravascular ultrasound: Initial US experience. Catheter Cardiovasc Interv. 2013;81:551-7.

29. Kume T, Akasaka T, Kawamoto T, et al. Measurement of the thickness of the fibrous cap by optical coherence tomography. Am Heart J. 2006;152:755.e1-4.

30. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080.

31. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556-1565.

32. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365:2078-2087.

33. Kini AS, Baber U, Kovacic JC, et al. Changes in plaque lipid content after short-term, intensive versus standard statin therapy: the YELLOW trial. J Am Coll Cardiol. 2013 (In press).

34. Takarada S, Imanishi T, Kubo T, et al. Effect of statin therapy on coronary fibrous-cap thickness in patients with acute coronary syndrome: assessment by optical coherence tomography study. Atherosclerosis. 2009;202:491-497.

35. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 2012;380:29-36.

36. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290:2292-2300.

37. Braunwald, E. Epilogue: What do clinicians expect from imagers? J Am Coll Cardiol. 2006;47:C101-C103.

38. Bosch JL, Beinfeld MT, Muller JE, Brady T, Gazelle GS. A cost-effectiveness analysis of a hypothetical catheter-based strategy for the detection and treatment of vulnerable coronary plaques with drug-eluting stents. J Interv Cardiol. 2005;18:339-349.

39. Kubo T, Maehara A, Mintz GS, et al. The dynamic nature of coronary artery lesion morphology assessed by serial virtual histology intravascular ultrasound tissue characterization. J Am Coll Cardiol. 2010;55:1590-1597.

40. Waxman S, Dixon SR, L’Allier P, et al. In vivo validation of a catheter-based near-infrared spectroscopy system for detection of lipid core coronary plaques: initial results and exploratory analysis of the SPECTroscopic Assessment of Coronary Lipid (SPECTACL) multicenter study. J Am Coll Cardiol Imaging. 2009;2:858-868.

41. Erlinge D, Muller JE, Puri R, et al. Validation of a near-infrared spectroscopic signature of lipid located at culprit lesions in ST-segment elevation myocardial infarction. European Atherosclerosis Society. June 2013 (abstract).

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Proposed Algorithm for Vulnerable Plaque Screening and Treatment

SOURCE

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Long-term Consequences of a Lipid Core Plaque

Christos V. Bourantas, MD, PhD1, Hector M. Garcia, MD, PhD1, Roberto Diletti, MD1, Carlos A.M. Campos, MD1, Yaojun Zhang, MD, PhD1, Scot Garg, MRCP, PhD2, Patrick W. Serruys, MD, PhD1

1Department of Interventional Cardiology, Erasmus University Medical Centre, Thoraxcenter, Rotterdam, The Netherlands and 2Department of Cardiology, East Lancashire NHS Trust, Haslingden Road, Blackburn, Lancashire, United Kingdom.

Disclosures: The authors report no financial relationships or conflicts of interest regarding the content herein.

Address for correspondence: Email: p.w.j.c.serruys@erasmusmc.nl

The advent of intravascular imaging in the 1980s allowed us to study in vivo plaque morphology and its prognostic implications.

Angioscopy and intravascular ultrasound (IVUS) were the first imaging techniques that provided information about the composition of plaque and allowed detection of its lipid component.7,8

However, the first applications of these modalities in the clinical setting not only underscored their potential value in the study of atherosclerosis but also highlighted their limitations in characterizing atheroma.9-11 Therefore an effort was made over the last few years to develop advanced techniques that would allow more reliable assessment of a plaque’s composition. Today several modalities are available for this purpose including:

the radiofrequency analysis of the IVUS backscatter signal (RF-IVUS),
near-infrared spectroscopy (NIRS),
optical coherence tomography (OCT),
magnetic resonance spectroscopy,
intravascular magnetic resonance imaging,
Raman spectroscopy,
photoacoustic imaging, and
time resolved spectroscopic imaging (Figure 1).

Some of these modalities are still in their infancy, while others have already been used in the clinical setting providing robust evidence about the prognostic implications of the differing compositions of the plaque. The aim of this review article is to present the most recent evidence about the long-term consequences of the atheroma’s phenotype.

Current Evidence from NIRS-based Clinical Studies

NIRS relies on the principle that different organic molecules absorb and scatter NIRS light to different degrees and wavelengths. Recent advances in device technology enabled the development of a catheter suitable for assessing the plaque in human coronaries that is able to emit NIR light and acquire the scattered signal. Spectral analysis of the obtained signal provides a color-coded display, called a chemogram (Figure 1C), which provides the probability that lipid core is present in the superficial plaque (studied depth approximately: 1 mm). Several studies have examined the reliability of this technique using histology as the gold standard and demonstrated a high overall accuracy in detecting lipid-rich plaques while others demonstrated its feasibility in the clinical setting.19-20

The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis (NCT01789411) – NIRS sub-study was the first prospective trial designed to evaluate the prognostic implications of an increased lipid component, as detected by NIRS, in coronary plaques. Two hundred three patients that underwent X-ray angiography, and PCI if it was indicated, had NIRS in a non-culprit coronary segment and were followed-up for 1 year. Twenty-eight patients sustained a MACE during the follow-up period; 21 of these events were non-culprit lesion related. Lipid plaque burden index appeared to be an independent predictor of MACE (hazard ratio: 4.04, 95% confidence interval: 1.33-12.29; P=0.01).

Currently, the Chemometric Observation of Lipid Rich Plaque of Interest in Native Coronary Arteries (COLOR, NCT00831116) registry is recruiting patients. This study is planning to recruit 2000 patients that will be investigated with NIRS imaging, and aims to examine the association between the presence of a necrotic core in the atheroma and subsequent coronary events. Preliminary results indicate that the absence of lipid-rich plaques is related with better outcomes (www.infraredx.com/the-color-registry).

Current Evidence From OCT-based Clinical Studies

OCT imaging with its high resolution appears able to provide detailed assessment of the superficial plaque and visualize structures that are unseen by other techniques such as the presence of micro calculations of thin-capped fibroatheroma (TCFA). However, a significant limitation of this technique is its poor penetration (1-2 mm), which does not permit through visualization of plaque burden, as well as its low capacity in differentiating lipid from calcific tissue when these are deeply embedded in the vessel wall.21

In this analysis, 53 patients who underwent PCI had OCT imaging in non-obstructive lesion sat baseline and repeat angiography at 7 months follow-up. They found that plaques with a TCFA phenotype, exhibiting vessel walldiscontinuities, macrophages, neo-vessels, and thrombi were morelikely to progress and cause significant angiographic obstructions.²²

Future Perspective in Plaque Imaging – Conclusions

Cumulative data derived from intravascular imaging studies have provided robust evidence about the prognostic implications of plaque’s composition and burden, and demonstrated a strong association between the presence of lipid-rich plaques and future cardiovascular events. Plaque pathology and quantification of lipid components is done by hybrid catheters able to acquire different intravascular imaging data.23

References on page 26A in

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1.Kragel AH, Reddy SG, Wittes JT, Roberts WC. Morphometric analysis of the composition ofatherosclerotic plaques in the four major epicardial coronary arteries in acute myocardial infarctionand in sudden coronary death. Circulation. 1989;80:1747-1756.

2.ﾭacteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J.1983;50:127-134.

3.Clark E, Graef I, Chasis H. Thrombosis of the aorta and coronary arteries. Archives of Pathology.1936;22:183-212.

4.Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death:a comprehensive morphological classification scheme for atherosclerotic lesions. ArteriosclerThromb Vasc Biol. 2000;20:1262-1275.

5.Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediatelesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council onArteriosclerosis, American Heart Association. Circulation. 1994;89:2462-2478.

6.ﾭrotic lesions and a histological classification of atherosclerosis. A report from the Committee onVascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation.1995;92:1355-1374.

7.Di Mario C, The SH, Madretsma S, et al. Detection and characterization of vascular lesionsby intravascular ultrasound: an in vitro study correlated with histology. J Am Soc Echocardiogr. 1992;5:135-146.

8.ﾭdation by histomorphologic analysis and association with stable and unstable coronary syndromes.J Am Coll Cardiol. 1996;28:1-6.

9.Hiro T, Leung CY, Russo RJ, et al. Variability in tissue characterization of atherosclerotic plaqueby intravascular ultrasound: a comparison of four intravascular ultrasound systems. Am J CardImaging. 1996;10:209-218.

10.ﾭdial infarction: ability of optical coherence tomography compared with intravascular ultrasoundand coronary angioscopy. J Am Coll Cardiol. 2007;50:933-939.

11.ﾭated with future risk of acute coronary syndrome: detection of vulnerable patients by angioscopy.J Am Coll Cardiol. 2006;47:2194-2200.

12.ﾭnary syndrome using integrated backscatter intravascular ultrasound. J Am Coll Cardiol.2006;47:734-741.

13.Amano T, Matsubara T, Uetani T, et al. Lipid-rich plaques predict non-target-lesion ischemicevents in patients undergoing percutaneous coronary intervention. Circ J. 2011;75:157-166.

14.ﾭsclerosis. N Engl J Med. 2011;364:226-235.

15.Calvert PA, Obaid DR, O’Sullivan M, et al. Association between IVUS findings and adverseﾭsclerosis) Study. JACC Cardiovasc Imaging. 2011;4:894-901.

16.Granada JF, Wallace-Bradley D, Win HK, et al. In vivo plaque characterization using intravascularultrasound-virtual histology in a porcine model of complex coronary lesions. Arterioscler ThrombVasc Biol. 2007;27:387-393.

17.Sales FJ, Falcao BA, Falcao JL, et al. Evaluation of plaque composition by intravascular ultrasound“virtual histology”: the impact of dense calcium on the measurement of necrotic tissue. ﾭvention. 2010;6:394-399.

18.ﾭtual histology intravascular ultrasound in porcine coronary artery disease. Circ Cardiovasc Imaging. 2010;3:384-391.

19.ﾭmens with a novel catheter-based near-infrared spectroscopy system. JACC Cardiovasc Imaging. 2008;1:638-648.

20.Waxman S, Dixon SR, L’Allier P, et al. In vivo validation of a catheter-based near-infrared spectrosﾭcopy system for detection of lipid core coronary plaques: initial results of the SPECTACL study.JACC Cardiovasc Imaging. 2009;2:858-868.

21.Manfrini O, Mont E, Leone O, et al. Sources of error and interpretation of plaque morphology byoptical coherence tomography. Am J Cardiol. 2006;98:156-159.

22.Uemura S, Ishigami K, Soeda T, et al. Thin-cap fibroatheroma and microchannel findings inoptical coherence tomography correlate with subsequent progression of coronary atheromatousplaques. Eur Heart J. 2012;33:78-85.

23.ﾭplications and prospective potential in the study of coronary atherosclerosis. J Am Coll Cardiol.2013;61:1369-378.

24.ﾭtroscopy and intra-vascular ultrasound catheter to identify composition and structure of coronaryplaque. EuroIntervention. 2010;5:755-756.

25.ﾭﾭgrated Biomarker and Imaging Study-3 (IBIS-3). EuroIntervention. 2012;8:235-241.

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NIRS-IVUS Imaging Identifies Lesions at High Risk of Peri-Procedural Myocardial Infarction

James A. Goldstein, MD, Simon R. Dixon, MBChB*, Gregg W. Stone, MD

From the Department of Cardiovascular Medicine, William Beaumont Hospital, Royal Oak, MI.

Address for correspondence: James A. Goldstein, MD, FACC, Department of Cardiovascular Medicine, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48073. Email: jgoldstein@beaumont.edu

Disclosures: Dr. Goldstein is a consultant for and owns equity in Infraredx, Inc. Dr. Stone is a consultant for Infraredx, Inc., Volcano Corp., Medtronic, and Boston Scientific, and is a member of the scientific advisory boards for Boston Scientific and Abbott Vascular. Dr. Dixon reports no financial relationships or conflicts

Abstract:

Percutaneous coronary intervention (PCI) is associated with distal embolization complications, including peri-procedural myocardial infarction (PPMI), including no-reflow, in 3%-15% of cases. These complications are predominantly related to distal embolization of lipid core plaque (LCP) components. Catheter-based near-infrared spectroscopy (NIRS) provides rapid, automated detection of LCPs, the magnitude of which appears associated with a high-risk of PPMI. Employing this technique may facilitate development of preventive measures such as embolic protection devices (EPDs).

J INVASIVE CARDIOL 2013;25 (Suppl A):14A-16A

Key words: Distal embolization, lipid core plaque, near-infrared spectroscopy, peri-procedural myocardial infarction

Figures 1. A 62-year-old man with stable angina underwent coronary angiography, which demonstrated a complex hazy ulcerated culprit lesion in the mid-right coronary artery (Figure 1A, solid arrow). Neither the angiogram nor an intravascular ultrasound image indicated the presence of thrombus. NIRS demonstrated a large yellow signal spanning the circumference of the culprit site (Figure 1B, white rectangle), indicating the presence of a napkin-ring LCP; a smaller LCP was evident distally (Figure 1, open arrow).

Figure 2. Balloon angioplasty was performed (Figure 2A, arrow), which led to prompt no-reflow (Figure 2B, arrow) associated with severe bradyarrhythmia and profound hypotension (Figure 2C). After brief cardiopulmonary resuscitation and pharmacological support with atropine and dopamine, physiologic rhythm and blood pressure were restored and stenting resulted in excellent angiographic outcome. However, the patient developed a peri-stenting non-transmural infarction (peak creatine kinase of 512 ng/mL) and required an additional day of hospital care in an intensive care unit. (Goldstein JA, et al. JACC Cardiovasc Imaging. 2009;2(12):1420-1424. Reproduced with permission.)

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Pharmacological Therapy of Lipid Core Plaque

Jason C. Kovacic, MD, PhD, Annpoorna Kini, MD, MRCP

From The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York.

Address for correspondence: Dr. Annapoorna Kini, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1030, New York, NY, 10029. Email: annapoorna.kini@mountsinai.org

Disclosures: Dr. Kovacic is supported by National Institutes of Health Grant K08HL111330 and has received research support from AstraZeneca. Dr. Kini acknowledges honoraria from Medscape and has received research grant support from InfraReDx.

A new group of terms is slowly creeping in to the atherosclerotic disease lexicon: “Lipid Arc,” “Lipid Core Plaque,” “Lipid-Rich Plaque,” “Lipid Core Burden Index” and other similar phrases. While clinicians and researchers have long been aware of the central importance of lipid in the biology of atherosclerosis, the growing use of these terms is driven by the recent widespread use of novel imaging modalities that provide accurate detection, and even quantification, of the extent of lipid that is contained within the core of an atherosclerotic plaque. Our ability to detect and quantify lipid in plaques is opening up new therapeutic opportunities for modifying the atherosclerotic disease process, which may ultimately be of benefit to patients.

At the present time there are 3 methods that are commonly used to measure the extent of lipid in atherosclerotic plaques. Perhaps most familiar of these is coronary computer tomographic (CT) scanning. While more commonly used to quantitate calcification or luminal stenosis, CT scanning is readily able to quantitate the extent of lipid associated with an atherosclerotic lesion. However, while several studies have reported various Hounsfield Unit (HU)-based criteria to distinguish lipid-rich from fibrous plaques, the HU cut-off points have so far been inconsistent. The use of CT for detecting lipid-rich plaque is further limited by its relatively low spatial resolution and the fact that the HU values for distinguishing between fibrous and lipid-rich plaques are overlapping.1 In contrast, optical coherence tomography (OCT) offers perhaps the greatest spatial resolution of all clinically available coronary imaging devices. OCT can offer exquisite detail of abluminal coronary artery anatomy, including detection of lipid core plaque. However, while automated systems are being developed, at the present time the quantitation of lipid by OCT is a somewhat specialized process that typically involves detailed off-line analysis.

A specific intra-coronary imaging catheter for the quantitation of coronary artery lipid content is now available and FDA approved: diffuse reflectance near-infrared spectroscopy (NIRS). The application of NIRS to identify lipid deposition within coronary arteries has been validated ex vivo2-5 and in vivo.6,7 Although NIRS itself is essentially only able to detect and quantitate lipid, design changes and technological advances to this catheter have now made it possible to combine intravascular ultrasound (IVUS) and NIRS technology on a single instrument. In one of the few clinical studies published to date using this device, NIRS has already shown that a high lipid burden in a target lesion undergoing percutaneous coronary intervention (PCI) is associated with an increased likelihood of peri-procedural myocardial infarction.7

It is well known that the reduction of cholesterol levels by statin therapy is associated with significant decreases in plaque burden. REVERSAL,8 ASTEROID,9 and more recently the SATURN II10 trial showed that in patients with coronary artery disease (CAD), lipid lowering with high-dose statin therapy reduced progression of plaque atheroma burden, even causing plaque regression of some lesions. However, while reduction in atheroma burden and plaque size are important anatomical endpoints, a major unresolved question had been the mechanism of action of statins and the unanswered question of whether they reduce plaque lipid content. Indeed, a high burden of plaque lipid is one of the cardinal features of a rupture-prone vulnerable lesion.11 Therefore, the ability to reduce plaque lipid content may have important effects on lesion stability and therefore, might impact clinical endpoints.

The advent of sensitive imaging tools for the evaluation of plaque lipid content has paved the way for the investigation of potential pharmacological therapies for lipid core plaque. In particular, the ability of NIRS to provide an automated quantitation of plaque lipid provides a ready-made platform for this task. We recently completed the YELLOW study of high-dose statin therapy for the potential reduction of coronary artery lipid content as assessed by NIRS. We randomized 87 patients with multivessel CAD undergoing elective PCI to rosuvastatin 40 mg daily vs conventional statin therapy. Following PCI of the culprit lesion, non-culprit lesions with a fractional flow reserve (FFR) <0.8 were interrogated using IVUS and NIRS. Changes in plaque composition were assessed after 6-12 weeks during follow-up angiography. The core finding of this study was that high-dose statin therapy was associated with significant reductions in the lipid content of coronary atherosclerotic plaques. Interestingly, despite reduced plaque lipid content, in this relatively short time period concordant changes in gross lesion characteristics such as total atheroma volume or % plaque burden were not observed.12 In short, the YELLOW study identified that even before gross atheroma regression occurs, lipid removal from plaques is an early event upon initiation of high-dose statin therapy. Furthermore, the results of the YELLOW study are concordant with the known acute benefits of statin therapy in patients presenting with acute coronary syndromes, where the early introduction of these agents is known to be of clinical benefit.13 While the YELLOW study was the first of this nature and the results remain to be replicated in a larger trial, these findings have revived interest in the concept of the “vulnerable plaque” because it appears possible that by causing lipid core reduction over a just few weeks, high-dose statin therapy may have rapid plaque stabilizing effects. We are now embarking on the YELLOW II study, where we will further explore the utility of high-dose rosuvastatin for the early reduction of plaque lipid content and potential mechanistic pathways.

What other agents might have therapeutic efficacy for lipid core reduction? This question is perhaps more complex than it might first appear, because at the present time we do not know the specific mechanism whereby high-dose rosuvastatin causes lipid reduction in plaques. Theoretically it may be due to reduced LDL, increased HDL, other mechanisms or a combination of these effects. Potentially, other agents that are already available such as bile acid sequestrants, ezetimibe, and fibrates may have a weak lipid core reducing effect. However, we would underscore the fact that at the present time the utility of these agents is speculative, and no other agent (apart from high-dose rosuvastatin in the YELLOW study) has been shown to reduce lipid content in vivo in human plaques. Furthermore, given the fact that these other agents are far less potent in their overall effect than rosuvastatin 40 mg/day, it may be clinically challenging to determine if they have efficacy for lipid core reduction beyond that of statins.

In addition to pharmacotherapy, it must be remembered that we have several non-pharmacological treatments in our armamentarium that may impact lipid core reduction. For example, exercise is known to be associated with reduced plaque lipid content,14 and proper adherence to current guidelines with respect to lifestyle and diet are of paramount importance in any patient in whom it is considered desirable to reduce plaque lipid content.

Looking ahead, there are several emerging and investigational agents that may hold promise for lipid core reduction. Microsomal triglyceride transfer protein (MTP) is expressed in the liver, intestine, and the heart and is required for the proper assembly of VLDL and chylomicrons. In animals, treatment with an MTP inhibitor leads to a rapid reduction in plasma lipid levels, with a significant decrease in lipid content and monocyte-derived (CD68+) cells in atherosclerotic plaques.15 On December 21, 2012, the first of the MTP inhibitors was approved for clinical use. Lomitapide (marketed as Juxtapid) was approved by the FDA as an adjunct to a low fat diet and other lipid-lowering treatments for patients with homozygous familial hypercholesterolemia. However, concerns have been raised due to hepatic side effects and liver toxicity. As a result, lomitapide will carry a boxed warning and will only be available through a restricted program.16 Another new drug that was recently given restricted approval in the US for homozygous familial hypercholesterolemia is mipomersen. This agent is an antisense therapeutic that targets messenger RNA for apolipoprotein B, leading to reduced apoB protein and LDL levels. While showing efficacy for lowering LDL,17 safety concerns have thus far prohibited this agent from gaining approval for use in Europe. PCSK9 inhibitors are yet another novel class of agents that may hold promise for reducing lipid core plaque. PCSK9 is involved in the degradation of the LDL receptor (LDLR), and by inhibiting PCSK9 it is believed that this permits more LDL receptors to remain active and participate in LDL removal from the blood, thereby reducing plasma LDL and cholesterol levels. Denis et al18 recently demonstrated that gene inactivation of PCSK9 in mice reduced aortic cholesterol accumulation and atherosclerotic lesion development in atherosclerosis-prone mice. Based on their powerful LDL lowering effect, intense efforts are currently underway to develop clinically efficacious PCSK9 inhibitors with several agents already moving to phase II/III human studies.19 While all of these new and emerging therapies are cause for optimism, the recent experience with CETP-inhibitors and the overall failure of this class so far to stand up to rigorous testing as HDL raising agents in phase III studies20,21 serves to remind us that not all “promising future therapies” survive through the arduous clinical testing pipeline.

In conclusion, there is renewed interest in the concept of “plaque regression” and pharmacological therapy for “lipid core reduction.” This has been driven by our increasing ability to image and quantify these phenomena, and more recently by the provocative findings that high-dose statin therapy may achieve both of these clinical endpoints. Further studies are now required to evaluate novel agents, define mechanisms of action and, most importantly, to confirm that atherosclerotic lipid core reduction is associated with plaque stabilization and fewer clinical endpoints.

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5. Wang J, Geng YJ, Guo B, et al. Near-infrared spectroscopic characterization of human advanced atherosclerotic plaques. J Am Coll Cardiol. 2002;39:1305-1313.

6. Waxman S, Dixon SR, L’Allier P, et al. In vivo validation of a catheter-based near-infrared spectroscopy system for detection of lipid core coronary plaques: initial results of the SPECTACL study. JACC Cardiovasc Imaging. 2009;2:858-868.

7. Goldstein JA, Maini B, Dixon SR, et al. Detection of lipid-core plaques by intracoronary near-infrared spectroscopy identifies high risk of periprocedural myocardial infarction. Circ Cardiovasc Interv. 2011;4:429-437.

8. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005;352:29-38.

9. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556-1565.

10. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365:2078-2087.

11. Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodeling and plaque vulnerability. Circulation. 2002;105:939-943.

12. Kini AS, Baber U, Kovacic JC, et al. Changes in plaque lipid content after short-term, intensive versus standard statin therapy: The YELLOW Trial. J Am Coll Cardiol. 2013;62:21-29.

13. Hulten E, Jackson JL, Douglas K, et al. The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166:1814-1821.

14. Yoshikawa D, Ishii H, Kurebayashi N, et al. Association of cardiorespiratory fitness with characteristics of coronary plaque: assessment using integrated backscatter intravascular ultrasound and optical coherence tomography. Int J Cardiol. 2013;162:123-128.

15. Hewing B, Parathath S, Mai CK, et al. Rapid regression of atherosclerosis with MTP inhibitor treatment. Atherosclerosis. 2013;227:125-129.

16. Cuchel M, Bloedon LT, Szapary PO, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007;356:148-156.

17. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:998-1006.

18. Denis M, Marcinkiewicz J, Zaid A, et al. Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation. 2012;125:894-901.

19. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367:1891-1900.

20. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089-2099.

21. Kovacic JC, Fuster V. From Treating Complex Coronary Artery Disease to Promoting Cardiovascular Health: Therapeutic Transitions and Challenges, 2010-2020. Clin Pharmacol Ther. 2011;90:509-518.

KOVACIC and KINI

28A

The Journal of Invasive Cardiology^®

KEY SOURCE for this Article

Journal of Invasive Cardiology, August 2013, Vol 25/Supplement A

Print ISSN 1042-3931 / Electronic ISSN 1557-2501

Introduction

NIRS-IVUS Imaging To Characterize the Composition and Structure of Coronary Plaques

D. RIZIK AND J.A. GOLDSTEIN……………………………………..2A

Background

Imaging of Plaque Composition and Structure with the TVC Imaging System™ and TVC Insight™ Catheter

B. SHYDO, ET AL…………………………………………………………5A

Comparative Intravascular Imaging for Lipid Core Plaque: NIRS vs VH-IVUS vs OCT

E. FUH AND E.S. BRILAKIS……………………………………………9A

Plaque Characterization and PCI Procedural Outcomes

NIRS-IVUS Imaging Identifies Lesions at High Risk of

Peri-Procedural Myocardial Infarction

J.A. GOLDSTEIN, ET AL……………………………………………..14A

Case Vignettes:

Multiple Plaque Ruptures in a Patient with ST-Segment Elevation Myocardial Infarction: Does Infrared Spectroscopy Evidence Explain a Significant Change in the Angiogram?

M.J. LIM AND J.M. STOLKER……………………………………….16A

Missing the Culprit Yellow Plaque

D. ERLINGE…………………………………………………………….18A

The Use of Near-Infrared Spectroscopy to Optimize Stent Length

G.A. STOUFFER ………………………………………………………19A

Employing NIRS-IVUS to Guide Optimal Lesion Coverage—Avoidance of Geographic Miss

I. HANSON, ET AL……………………………………………………..20A

Peri-Procedural Myocardial Injury Unraveled: Combined

Assessment by Optical Coherence Tomography, Near-Infrared

Spectroscopy, and IVUS

A. KARANASOS, ET AL………………………………………………..22A

Plaque Characterization and Long-Term

Clinical Outcomes

Long-term Consequences of a Lipid Core Plaque

C.V. BOURANTAS, ET AL…………………………………………….24A

Pharmacological Therapy of Lipid Core Plaque

J.C. KOVACIC AND A. KINI………………………………………….27A

The Search for Vulnerable Plaque — The Pace Quickens

R.D. MADDER, ET AL…………………………………………………29A

Case Vignettes:

Observations from Intracoronary Near-Infrared Spectroscopy in Patients with ST-Segment Elevation Myocardial Infarction

R.D. MADDER…………………………………………………………34A

NIRS Imaging of Cardiac Allograft Vasculopathy

G. WEISZ ……………………………………………………………….35A

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Archive for August, 2013

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Following (or not) the guidelines for use of imaging in management of prostate cancer.

Writer and curator: Dror Nir, PhD

Similar items I have covered on this this Open Access Online Scientific Journal:

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Cardiac Contractility & Myocardial Performance: Therapeutic Implications of Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Image created by Adina Hazan 06/30/2021

This article is Part VII in a continuation to the following article series on tightly related topics of the Calcium Release Mechanism.

This article has the following sections:

Introduction to Calcium Release Mechanism in Vascular Smooth Muscle and in Cardiomyocytes

I. Cellular Contractility Capacity — Actin, Cellular Dynamics and Calcium Efflux: Emergence of the Calcium Release-related Contractile Dysfunction

II. Integration and Interpretation of Research Results in Two Labs: Mark E Anderson’s and Roger Hajjar’s Lab

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

III. Therapeutic Implications of Pharmacological Agents for Cardiac Contractility Dysfunction: “The Fire From Within The Biggest Ca2+ Channel Erupts and Dribbles” by Anderson, ME

Treatment Selection

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

Negative inotropic agents

Therapeutic Implications

PENDING

Therapeutic Implications

IV. Selective Research Contributions on Calcium Release-related Contractile Dysfunction

Ischemic versus non-ischemic heart failure: should the etiology be determined?

Source

Abstract

Upregulation of β3-Adrenoceptors and Altered Contractile Response to Inotropic Amines in Human Failing Myocardium

Abstract

Increased beta-receptor density and improved hemodynamic response to catecholamine stimulation during long-term metoprolol therapy in heart failure from dilated cardiomyopathy.

Ryanopathy: causes and manifestations of RyR2 dysfunction in heart failure

Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure.

Source

Abstract

Editorial Comment on the above article abstract made by Anderson, ME

The Fire From Within – The Biggest Ca2+ Channel Erupts and Dribbles

CaMKII Is a Pluripotent Signaling Molecule in Heart

Ryanodine Receptors Are Central

Kinases Facilitate Communication Between LTCCs and RyRs

Heart Failure Is a Disease of Disordered Ca2+i Homeostasis

Is Heart Failure a Disease of Enzymatic Over-Activity?

What We Learned and What We Need to Know

References

Summary

V. Bibliography on Calcium Release Mechanisms in Vascular Smooth Muscle, in Cardiomyocytes and the Role in Heart Failure

Curator: Aviva Lev-Ari, PhD, RN

Anderson ME, General Hospital Iowa City and University of Iowa

Latest 20 Publications by Prof. Anderson ME on Heart Failure, Calcium and Calmodulin-dependent protein kinase II: linking heart failure and arrhythmias.

Contact Information

Results: 1 to 20 of 419

Publications by Prof. Wilson S. Colucci, MD on Heart Failure

Publications on Heart Failure by Prof. William Gregory Stevenson, M.D.

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Leaving Hospital Against Medical Advice (AMA): Higher Rates of Hospital Readmission and Death

Reporter: Aviva Lev-Ari, PhD, RN

Rates of readmission and death associated with leaving hospital against medical advice: a population-based study

Abstract

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Cardiovascular Genetics: Functional Characterization and Clinical Applications @ 2013 Annual Conference of American Society of Human Genetics in Boston, 10/22-26, 2013

The 63rd Annual Conference of American Society of Human Genetics in Boston, 10/22-26, 2013

We express a special interest in Session 58

SESSION 58 – Cardiovascular Genetics: Functional Characterization and Clinical Applications

Human Syndromic Atrioventricular Septal Defect

Left Ventricular Noncompaction – Model in Zebrafish

Genetics of Cerebral Small Vessel Disease

Genetics & Brugada Syndrome

Mutations, Vasculopathy with Fever and Early Onset Strokes

Genetics of Atherosclerotic Plaque in Patients with Chronic Coronary Artery Disease

Genetics of influence IL-18 regulation in patients with Acute Coronary Syndrome

Thoracic Aortic Aneurysmal Genes

III. Therapeutic Implications of Pharmacological Agents for Cardiac Contractility Dysfunction: “The Fire From Within The Biggest Ca²⁺ Channel Erupts and Dribbles” by Anderson, ME

Upregulation of β₃-Adrenoceptors and Altered Contractile Response to Inotropic Amines in Human Failing Myocardium

The Fire From Within – The Biggest Ca²⁺ Channel Erupts and Dribbles

Heart Failure Is a Disease of Disordered Ca²⁺_i Homeostasis