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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 , , , , , , , , , , , , 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

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
Pharmacol Ther. 2009 August; 123(2): 151–177.
PMCID: PMC2704947

Ryanodine receptor-mediated arrhythmias and sudden cardiac death

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.
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:

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

and

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?

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

  1. Stéphane Moniotte, MD;
  2. Lester Kobzik, MD;
  3. Olivier Feron, PhD;
  4. Jean-Noël Trochu, MD;
  5. Chantal Gauthier, PhD;
  6. Jean-Luc Balligand, MD, PhD

+Author Affiliations


  1. 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.
  1. 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 Gαi-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.

  1. S M Heilbrunn;
  2. P Shah;
  3. M R Bristow;
  4. H A Valantine;
  5. R Ginsburg;
  6. M B Fowler

+Author Affiliations


  1. 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.

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

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

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

  1. Mark E. Anderson

+Author Affiliations


  1. From the University of Iowa, Carver College of Medicine, Iowa City.
  1. 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 arrhythmias2,3 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 (ICa), 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 ICa 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.

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 (ICa) 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

References

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    Zhang T, Brown JH. Role of Ca2+/calmodulin-dependent protein kinase II in cardiac hypertrophy and heart failure. Cardiovasc Res. 2004; 63: 476–486.
  2. ↵
    Mazur A, Roden DM, Anderson ME. Systemic administration of calmodulin antagonist W-7 or protein kinase A inhibitor H-8 prevents torsade de pointes in rabbits. Circulation. 1999; 100: 2437–2442.
  3. ↵
    Wu Y, Temple J, Zhang R, Dzhura I, Zhang W, Trimble RW, Roden DM, Passier R, Olson EN, Colbran RJ, Anderson ME. Calmodulin kinase II and arrhythmias in a mouse model of cardiac hypertrophy. Circulation. 2002; 106: 1288–1293.
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    Anderson ME, Braun AP, Wu Y, Lu T, Schulman H, Sung RJ. KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase, decreases early afterdepolarizations in rabbit heart. J Pharm Exp Ther. 1998; 287: 996–1006.
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    Maier LS, Zhang T, Chen L, DeSantiago J, Brown JH, Bers DM. Transgenic CaMKIIdeltaC overexpression uniquely alters cardiac myocyte Ca2+ handling: reduced SR Ca2+ load and activated SR Ca2+ release. Circ Res. 2003; 92: 904–911.
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    Schroder F, Handrock R, Beuckelmann DJ, Hirt S, Hullin R, Priebe L, Schwinger RH, Weil J, Herzig S. Increased availability and open probability of single L-type calcium channels from failing compared with nonfailing human ventricle. Circulation.1998; 98: 969–976.
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    Wehrens XH, Lehnart SE, Reiken SR, Deng SX, Vest JA, Cervantes D, Coromilas J, Landry DW, Marks AR. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science. 2004; 304: 292–296.
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 SOURCE

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

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.
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17038644 [PubMed – indexed for MEDLINE] Free Article

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

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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.
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16861697 [PubMed – indexed for MEDLINE] Free Article

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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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
63. Gheorghiade M, Adams KF, Colucci WS. Digoxin in the management of cardiovascular disorders. Circulation. 2004 Jun 22; 109(24):2959-64.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
78. Gheorghiade M, Colucci WS, Swedberg K. Beta-blockers in chronic heart failure. Circulation. 2003 Apr 1; 107(12):1570-5.
View in: PubMed
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.
View in: PubMed
80. Kivikko M, Lehtonen L, Colucci WS. Sustained hemodynamic effects of intravenous levosimendan. Circulation. 2003 Jan 7; 107(1):81-6.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
211. Colucci WS. Cardiovascular effects of milrinone. Am Heart J. 1991 Jun; 121(6 Pt 2):1945-7.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
221. Colucci WS. Myocardial and vascular actions of milrinone. Eur Heart J. 1989 Aug; 10 Suppl C:32-8.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
226. Colucci WS. Positive inotropic/vasodilator agents. Cardiol Clin. 1989 Feb; 7(1):131-44.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
235. Lee RT, Mudge GH, Colucci WS. Coronary artery fistula after mitral valve surgery. Am Heart J. 1988 May; 115(5):1128-30.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
243. Colucci WS. Usefulness of calcium antagonists for congestive heart failure. Am J Cardiol. 1987 Jan 30; 59(3):52B-58B.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
265. Braunwald E, Colucci WS. Evaluating the efficacy of new inotropic agents. J Am Coll Cardiol. 1984 Jun; 3(6):1570-4.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
269. Colucci WS, Braunwald E. Adrenergic receptors: new concepts and implications for cardiovascular therapeutics. Cardiovasc Clin. 1984; 14(3):39-59.
View in: PubMed
270. Colucci WS, Jaski BE, Fifer MA, Wright RF, Braunwald E. Milrinone: a positive inotropic vasodilator. Trans Assoc Am Physicians. 1984; 97:124-33.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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.
View in: PubMed
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
  1. 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.
    View in: PubMed
  2. 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.
    View in: PubMed
  3. 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.
    View in: PubMed
  4. 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.
    View in: PubMed
  5. 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.
    View in: PubMed
  6. 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.
    View in: PubMed
  7. Michaud GF, Stevenson WG. Feeling a little loopy? J Cardiovasc Electrophysiol. 2013 May; 24(5):553-5.
    View in: PubMed
  8. 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.
    View in: PubMed
  9. 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.
    View in: PubMed
  10. 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.
    View in: PubMed
  11. 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.
    View in: PubMed
  12. 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.
    View in: PubMed
  13. 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.
    View in: PubMed
  14. 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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  15. 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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  16. Tedrow UB, Sobieszczyk P, Stevenson WG. Transvenous ethanol ablation of ventricular tachycardia. Heart Rhythm. 2012 Oct; 9(10):1640-1.
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  17. Stevenson WG, Tedrow UB. Ablation for ventricular tachycardia during stable sinus rhythm. Circulation. 2012 May 8; 125(18):2175-7.
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  18. 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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  19. 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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  20. 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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  21. 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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  22. 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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  23. Stevenson WG, John RM. Ventricular arrhythmias in patients with implanted defibrillators. Circulation. 2011 Oct 18; 124(16):e411-4.
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  24. 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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  25. John RM, Stevenson WG. Catheter-based ablation for ventricular arrhythmias. Curr Cardiol Rep. 2011 Oct; 13(5):399-406.
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  26. 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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  27. 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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  28. 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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  29. 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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  30. 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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  31. 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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  32. 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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  33. 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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  34. 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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  35. 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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  36. 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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  37. 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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  38. 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.
    View in: PubMed
  39. 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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  40. 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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  41. 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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  42. 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.
    View in: PubMed
  43. 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.
    View in: PubMed
  44. 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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  45. Stevenson WG, Asirvatham SJ. Teaching rounds in cardiac electrophysiology. Circ Arrhythm Electrophysiol. 2010 Dec; 3(6):563.
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  46. 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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  47. 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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  48. 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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  49. 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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  50. 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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  51. 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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  52. 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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  53. 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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  54. 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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  55. 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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  56. Stevenson WG, Tedrow U. Preventing ventricular tachycardia with catheter ablation. Lancet. 2010 Jan 2; 375(9708):4-6.
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  57. 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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  58. Seiler J, Stevenson WG. Atrial fibrillation in congestive heart failure. Cardiol Rev. 2010 Jan-Feb; 18(1):38-50.
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  59. 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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  60. 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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  61. 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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  62. 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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  63. 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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  64. Stevenson WG, Saltzman JR. Gastroesophageal reflux and atrial-esophageal fistula. Heart Rhythm. 2009 Oct; 6(10):1463-4.
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  65. 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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  66. 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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  67. 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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  68. 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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  69. 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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  70. 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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  71. Koplan BA, Stevenson WG. Ventricular tachycardia and sudden cardiac death. Mayo Clin Proc. 2009 Mar; 84(3):289-97.
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  72. Khairy P, Stevenson WG. Catheter ablation in tetralogy of Fallot. Heart Rhythm. 2009 Jul; 6(7):1069-74.
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  73. Stevenson WG, Tedrow UB, Koplan BA. Management of ventricular tachycardia complicating cardiac surgery. Heart Rhythm. 2009 Aug; 6(8 Suppl):S66-9.
    View in: PubMed
  74. 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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  75. 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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  76. Stevenson WG. Ventricular scars and ventricular tachycardia. Trans Am Clin Climatol Assoc. 2009; 120:403-12.
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  77. 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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  78. 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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  79. 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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  80. 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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  81. 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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  82. 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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  83. 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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  84. 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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  85. 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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  86. 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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  87. Stevenson WG, Berul CI. Arrhythmia and Electrophysiology: the eagle can land. Circ Arrhythm Electrophysiol. 2008 Apr; 1(1):1.
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  88. 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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  89. 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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  90. 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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  91. 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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  92. 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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  93. 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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  94. 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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  95. 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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  96. Stevenson WG, Soejima K. Catheter ablation for ventricular tachycardia. Circulation. 2007 May 29; 115(21):2750-60.
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  97. Koplan BA, Stevenson WG. Sudden arrhythmic death syndrome. Heart. 2007 May; 93(5):547-8.
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  98. 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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  99. 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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  100. 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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  101. 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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  102. 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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  103. 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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  104. Tedrow U, Stevenson WG. Substrate mapping and the aging atrium. Heart Rhythm. 2007 Feb; 4(2):145-6.
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  105. 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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  106. 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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  107. 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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  108. 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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  109. 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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  110. 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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  111. 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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  112. 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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  113. Ames A, Stevenson WG. Cardiology patient page. Catheter ablation of atrial fibrillation. Circulation. 2006 Apr 4; 113(13):e666-8.
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  114. 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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  115. Zei PC, Stevenson WG. Epicardial catheter mapping and ablation of ventricular tachycardia. Heart Rhythm. 2006 Mar; 3(3):360-3.
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  116. 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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  117. 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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  118. Stevenson WG, Epstein LM. Endpoints for ablation of atrial fibrillation. Heart Rhythm. 2006 Feb; 3(2):146-7.
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  119. 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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  120. 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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  121. 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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  122. 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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  123. 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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  124. Stevenson WG, Soejima K. Recording techniques for clinical electrophysiology. J Cardiovasc Electrophysiol. 2005 Sep; 16(9):1017-22.
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  125. 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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  126. 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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  127. Stevenson WG. Catheter ablation of monomorphic ventricular tachycardia. Curr Opin Cardiol. 2005 Jan; 20(1):42-7.
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  128. Stevenson WG. To freeze or burn the epicardium? Heart Rhythm. 2005 Jan; 2(1):91-2.
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  129. 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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  130. 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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  131. 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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  132. 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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  133. 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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  134. 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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  135. 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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  136. 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.
    View in: PubMed
  137. 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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  138. 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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  139. 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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  140. 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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  141. 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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  142. Tedrow U, Sweeney MO, Stevenson WG. Physiology of cardiac resynchronization. Curr Cardiol Rep. 2004 May; 6(3):189-93.
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  143. 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.
    View in: PubMed
  144. Stevenson WG, Sweeney MO. Single site left ventricular pacing for cardiac resynchronization. Circulation. 2004 Apr 13; 109(14):1694-6.
    View in: PubMed
  145. 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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  146. 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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  147. 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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  148. 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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  149. 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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  150. 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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  151. 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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  152. 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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  153. 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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  154. 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.
    View in: PubMed
  155. 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.
    View in: PubMed
  156. 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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  157. 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.
    View in: PubMed
  158. 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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  159. 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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  160. 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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  161. 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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  162. 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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  163. 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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  164. 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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  165. 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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  166. 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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  167. 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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  168. 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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  169. Sweeney MO, Ellison KE, Stevenson WG. Implantable cardioverter defibrillators in heart failure. Cardiol Clin. 2001 Nov; 19(4):653-67.
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  170. 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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  171. 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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  172. 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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  173. 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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  174. 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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  175. 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.
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  176. 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.
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  177. 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.
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  178. 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.
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  179. 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.
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  180. Stevenson WG, Soejima K. Knowing where to look. J Cardiovasc Electrophysiol. 2001 Mar; 12(3):367-8.
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  181. Stevenson WG, Stevenson LW. Prevention of sudden death in heart failure. J Cardiovasc Electrophysiol. 2001 Jan; 12(1):112-4.
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  182. Stevenson WG, Delacretaz E. Radiofrequency catheter ablation of ventricular tachycardia. Heart. 2000 Nov; 84(5):553-9.
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  183. Stevenson WG, Delacretaz E. Strategies for catheter ablation of scar-related ventricular tachycardia. Curr Cardiol Rep. 2000 Nov; 2(6):537-44.
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  184. 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.
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  185. 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.
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  186. Maisel WH, Stevenson WG. Sudden death and the electrophysiological effects of angiotensin-converting enzyme inhibitors. J Card Fail. 2000 Jun; 6(2):80-2.
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  187. 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.
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  188. 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.
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  189. 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.
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  190. 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.
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  191. Stevenson WG, Stevenson LW. Atrial fibrillation in heart failure. N Engl J Med. 1999 Sep 16; 341(12):910-1.
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  192. 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.
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  193. 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.
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  194. Delacretaz E, Stevenson WG, Winters GL, Friedman PL. Radiofrequency ablation of atrial flutter. Circulation. 1999 Apr 13; 99(14):E1-2.
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  195. Friedman PL, Stevenson WG. Proarrhythmia. Am J Cardiol. 1998 Oct 16; 82(8A):50N-58N.
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  196. 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.
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  197. 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.
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  198. 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.
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  199. 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.
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  200. 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.
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  201. 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.
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  202. 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.
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  203. Stevenson WG, Ellison KE, Lefroy DC, Friedman PL. Ablation therapy for cardiac arrhythmias. Am J Cardiol. 1997 Oct 23; 80(8A):56G-66G.
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  204. 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.
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  205. 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.
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  206. Stevenson WG, Sweeney MO. Arrhythmias and sudden death in heart failure. Jpn Circ J. 1997 Sep; 61(9):727-40.
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IDO for Commitment of a Life Time: The Origins and Mechanisms of IDO, indolamine 2, 3-dioxygenase

Posted in Advanced Drug Manufacturing Technology, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Human Immune System in Health and in Disease, Infectious Disease & New Antibiotic Targets, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Reproductive Biology & Bio Instrumentation, Stem Cells for Regenerative Medicine, Uncategorized, tagged , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , on August 4, 2013| 2 Comments »

 

Abstract:

The immune response mechanism is the holy grail of the human defense system for health.   IDO, indolamine 2, 3-dioxygenase, is a key gene for homeostasis of immune responses and producing an enzyme catabolizing the first rate-limiting step in tryptophan degradation metabolism. The hemostasis of immune system is complicated.  In this review, the  properties of IDO such as basic molecular genetics, biochemistry and genesis will be discussed.

IDO belongs to globin gene family to carry oxygen and heme.  The main function and genesis of IDO comes from the immune responses during host-microbial invasion and choice between tolerance and immunegenity.  In human there are three kinds of IDOs, which are IDO1, IDO2, and TDO, with distinguished mechanisms and expression profiles. , IDO mechanism includes three distinguished pathways: enzymatic acts through IFNgamma, non-enzymatic acts through TGFbeta-IFNalpha/IFNbeta and moonlighting acts through AhR/Kyn.

The well understood functional genomics and mechanisms is important to translate basic science for clinical interventions of human health needs. In conclusion, overall purpose is to find a method to manipulate IDO to correct/fix/modulate immune responses for clinical applications.

The first part of the review concerns the basic science information gained overall several years that lay the foundation where translational research scientist should familiar to develop a new technology for clinic. The first connection of IDO and human health came from a very natural event that is protection of pregnancy in human. The focus of the translational medicine is treatment of cancer or prevention/delay cancer by stem cell based Dendritic Cell Vaccine (DCvax) development.

Table of Contents:

  • Abstract

1         Introduction: IDO gene encodes a heme enzyme

2        Location, location, location

3        Molecular genetics

4        Types of IDO:

4.1       IDO1,

4.2       IDO2,

4.3       IDO-like proteins

5        Working mechanisms of IDO

6        Infection Diseases and IDO

7. Conclusion

  1. 1.     Indoleamine 2, 3-dioxygenase (IDO) gene encodes a heme enzyme

IDO is a key homeostatic regulator and confined in immune system mechanism for the balance between tolerance and immunity.  This gene encodes indoleamine 2, 3-dioxygenase (IDO) – a heme enzyme (EC=1.13.11.52) that catalyzes the first rate-limiting step in tryptophan catabolism to N-formyl-kynurenine and acts on multiple tryptophan substrates including D-tryptophan, L-tryptophan, 5-hydroxy-tryptophan, tryptamine, and serotonin.

The basic genetic information describes indoleamine 2, 3-dioxygenase 1 (IDO1, IDO, INDO) as an enzyme located at Chromosome 8p12-p11 (5; 6) that active at the first step of the Tryptophan catabolism.    The cloned gene structure showed that IDO contains 10 exons ad 9 introns (7; 8) producing 9 transcripts.

After alternative splicing only five of the transcripts encode a protein but the other four does not make protein products, three of transcripts retain intron and one of them create a nonsense code (7).  Based on IDO related studies 15 phenotypes of IDO is identified, of which, twelve in cancer tumor models of lung, kidney, endometrium, intestine, two in nervous system, and one HGMD- deletion.

  1. 2.     Location, Location and Location

The specific cellular location of IDO is in cytosol, smooth muscle contractile fibers and stereocilium bundle. The expression specificity shows that IDO is present very widely in all cell types but there is an elevation of expression in placenta, pancreas, pancreas islets, including dendritic cells (DCs) according to gene atlas of transcriptome (9).  Expression of IDO is common in antigen presenting cells (APCs), monocytes (MO), macrophages (MQs), DCs, T-cells, and some B-cells. IDO present in APCs (10; 11), due to magnitude of role play hierarchy and level of expression DCs are the better choice but including MOs during establishment of three DC cell subset, CD14+CD25+, CD14++CD25+ and CD14+CD25++ may increase the longevity and efficacy of the interventions.

IDO is strictly regulated and confined to immune system with diverse functions based on either positive or negative stimulations. The positive stimulations are T cell tolerance induction, apoptotic process, and chronic inflammatory response, type 2 immune response, interleukin-12 production (12).  The negative stimulations are interleukin-10 production, activated T cell proliferation, T cell apoptotic process.  Furthermore, there are more functions allocating fetus during female pregnancy; changing behavior, responding to lipopolysaccharide or multicellular organismal response to stress possible due to degradation of tryptophan, kynurenic acid biosynthetic process, cellular nitrogen compound metabolic process, small molecule metabolic process, producing kynurenine process (13; 14; 15).

IDO plays a role in a variety of pathophysiological processes such as antimicrobial and antitumor defense, neuropathology, immunoregulation, and antioxidant activity (16; 17; 18; 19).

 

 3.     Molecular Genetics of IDO:

A: Structure of human IDO2 gene and transcripts. Complete coding region is 1260 bps encoding a 420 aa polypeptide. Alternate splice isoforms lacking the exons indicated are noted. Hatch boxes represent a frameshift in the coding region to an alternate reading frame leading to termination. Black boxes represent 3' untranslated regions. Nucleotide numbers, intron sizes, and positioning are based on IDO sequence files NW_923907.1 and GI:89028628 in the Genbank database. (reference: http://atlasgeneticsoncology.org/Genes/IDO2ID44387ch8p11.html)

A: Structure of human IDO2 gene and transcripts. Complete coding region is 1260 bps encoding a 420 aa polypeptide. Alternate splice isoforms lacking the exons indicated are noted. Hatch boxes represent a frameshift in the coding region to an alternate reading frame leading to termination. Black boxes represent 3′ untranslated regions. Nucleotide numbers, intron sizes, and positioning are based on IDO sequence files NW_923907.1 and GI:89028628 in the Genbank database.
(reference: http://atlasgeneticsoncology.org/Genes/IDO2ID44387ch8p11.html)

Molecular genetics data from earlier findings based on reporter assay results showed that IDO promoter is regulated by ISRE-like elements and GAS-sequence at -1126 and -1083 region (20).  Two cis-acting elements are ISRE1 (interferon sequence response element 1) and interferon sequence response element 2 (ISRE2).

Analyses of site directed and deletion mutation with transfected cells demonstrated that introduction of point mutations at these elements decreases the IDO expression. Removing ISRE1 decreases the effects of IFNgamma induction 50 fold and deleting ISRE1 at -1126 reduced by 25 fold (3). Introducing point mutations in conserved t residues at -1124 and -1122 (from T to C or G) in ISRE consensus sequence NAGtttCA/tntttNCC of IFNa/b inducible gene ISG4 eliminates the promoter activity by 24 fold (21).

ISRE2 have two boxes, X box (-114/1104) and Y Box 9-144/-135), which are essential part of the IFNgamma response region of major histocompatibility complex class II promoters (22; 23).  When these were removed from ISRE2 or introducing point mutations at two A residues of ISRE2 at -111 showed a sharp decrease after IFNgamma treatment by 4 fold (3).

The lack of responses related to truncated or deleted IRF-1 interactions whereas IRF-2, Jak2 and STAT91 levels were similar in the cells, HEPg2 and ME180 (3). Furthermore, 748 bp deleted between these elements did not affect the IDO expression, thus the distance between ISRE1 and ISRE2 elements have no function or influence on IDO (3; 24)

B: Amino acid alignment of IDO and IDO2. Amino acids determined by mutagenesis and the crystal structure of IDO that are critical for catalytic activity are positioned below the human IDO sequence. Two commonly occurring SNPs identified in the coding region of human IDO2 are shown above the sequence which alter a critical amino acid (R248W) or introduce a premature termination codon (Y359stop).

B: Amino acid alignment of IDO and IDO2. Amino acids determined by mutagenesis and the crystal structure of IDO that are critical for catalytic activity are positioned below the human IDO sequence. Two commonly occurring SNPs identified in the coding region of human IDO2 are shown above the sequence which alter a critical amino acid (R248W) or introduce a premature termination codon (Y359stop).

4.     There are three types of IDO in human genome:

IDO was originally discovered in 1967 in rabbit intestine (25). Later, in 1990 the human IDO gene is cloned and sequenced (7).  However, its importance and relevance in immunology was not created until prevention of allocation of fetal rejection and founding expression in wide range of human cancers (26; 27).

There are three types of IDO, pro-IDO like, IDO1, and IDO2.  In addition, another enzyme called TDO, tryptophan 2, 3, dehydrogenase solely degrade L-Trp at first-rate limiting mechanism in liver and brain.

4.1.  IDO1:

IDO1 mechanism is the target for immunotherapy applications. The initial discovery of IDO in human physiology is protection of pregnancy (1) since lack of IDO results in premature recurrent abortion (28; 26; 29).   The initial rate-limiting step of tryptophan metabolism is catalyzed by either IDO or tryptophan 2, 3-dioxygenase (TDO).

Structural studies of IDO versus TDO presenting active site environments, conserved Arg 117 and Tyr113, found both in TDO and IDO for the Tyr-Glu motif, but His55 in TDO replaced by Ser167b in IDO (30; 2). As a result, they are regulated with different mechanisms (1; 2) (30).  The short-lived TDO, about 2h, responds to level of tryptophan and its expression regulated by glucorticoids (31; 32).  Thus, it is a useful target for regulation and induced by tryptophan so that increasing tryptophan induces NAD biosynthesis. Whereas, IDO is not activated by the level of Trp presence but inflammatory agents with its interferon stimulated response elements (ISRE1 and ISRE2) in its (33; 34; 35; 36; 3; 10) promoter.

TDO promoter contains glucorticoid response elements (37; 38) and regulated by glucocorticoids and other available amino acids for gluconeogenesis. This is how IDO binds to only immune response cells and TDO relates to NAD biosynthesis mechanisms. Furthermore, TDO is express solely in liver and brain (36).  NAD synthesis (39) showed increased IDO ubiquitous and TDO in liver and causing NAD level increase in rat with neuronal degeneration (40; 41).  NAM has protective function in beta-cells could be used to cure Type1 diabetes (40; 42; 43). In addition, knowledge on NADH/NAD, Kyn/Trp or Trp/Kyn ratios as well as Th1/Th2, CD4/CD8 or Th17/Threg are equally important (44; 40).

Active site of IDO–PI complex. (A) Stereoview of the residues around the heme of IDO viewed from the side of heme plane. The proximal ligand H346 is H-bonded to wa1. The 6-propionate of the heme contacts with wa2 and R343 Nε. The wa2 is H-bonded to wa1, L388 O, and 6-propionate. Mutations of F226, F227, and R231 do not lose the substrate affinity but produce the inactive enzyme. Two CHES molecules are bound in the distal pocket. The cyclohexan ring of CHES-1 (green) contacts with F226 and R231. The 7-propionate of the heme interacts with the amino group of CHES-1 and side chain of Ser-263. The mutational analyses for these distal residues are shown in Table 1. (B) Top view of A by a rotation of 90°. The proximal residues are omitted. (http://www.pnas.org/content/103/8/2611/F3.expansion.html)

Active site of IDO–PI complex. (A) Stereoview of the residues around the heme of IDO viewed from the side of heme plane. The proximal ligand H346 is H-bonded to wa1. The 6-propionate of the heme contacts with wa2 and R343 Nε. The wa2 is H-bonded to wa1, L388 O, and 6-propionate. Mutations of F226, F227, and R231 do not lose the substrate affinity but produce the inactive enzyme. Two CHES molecules are bound in the distal pocket. The cyclohexan ring of CHES-1 (green) contacts with F226 and R231. The 7-propionate of the heme interacts with the amino group of CHES-1 and side chain of Ser-263. The mutational analyses for these distal residues are shown in Table 1. (B) Top view of A by a rotation of 90°. The proximal residues are omitted. (http://www.pnas.org/content/103/8/2611/F3.expansion.html)

4.2. IDO2:

The third type of IDO, called IDO2 exists in lower vertebrates like chicken, fish and frogs (45) and in human with differential expression properties. The expression of IDO2 is only in DCs, unlike IDO1 expresses on both tumors and DCs in human tissues.  Yet, in lower invertebrates IDO2 is not inhibited by general inhibitor of IDO, D-1-methyl-tryptophan (1MT) (46).   Recently, two structurally unusual natural inhibitors of IDO molecules, EXIGUAMINES A and B, are synthesized (47).  LIP mechanism cannot be switch back to activation after its induction in IDO2 (46).

Crucial cancer progression can continue with production of IL6, IL10 and TGF-beta1 to help invasion and metastasis.  Inclusion of two common SNPs affects the function of IDO2 in certain populations.  SNP1 reduces 90% of IDO2 catalytic activity in 50% of European and Asian descent and SNP2 produce premature protein through inclusion of stop-codon in 25% of African descent lack functional IDO2 (Uniport).

4.3. IDO-like proteins: The Origin of IDO:

Knowing the evolutionary steps will helps us to identify how we can manage the regulator function to protect human health in cancer, immune disorders, diabetes, and infectious diseases.

Bacterial IDO has two types of IDOs that are group I and group II IDO (48).  These are the earliest version of the IDO, pro-IDO like, proteins with a quite complicated function.  Each microorganism recognized by a specific set of receptors, called Toll-Like Receptors (TLR), to activate the IDO-like protein expression based on the origin of the bacteria or virus (49; 35).   Thus, the genesis of human IDO originates from gene duplication of these early bacterial versions of IDO-like proteins after their invasion interactions with human host.  IDO1 only exists in mammals and fungi.

Fungi also has three types of IDO; IDOa, IDO beta, and IDO gamma (50) with different properties than human IDOs, perhaps multiple IDO is necessary for the world’s decomposers.

All globins, haemoglobins and myoglobins are destined to evolve from a common ancestor, which  is only 14-16kDa (51) length. Binding of a heme and being oxygen carrier are central to the enzyme mechanism of this family.  Globins are classified under three distinct origins; a universal globin, a compact globin, and IDO-like globin (52).  IDO like globin widely distributed among gastropodic mollusks (53; 51).  The indoleamine 2, 3-dioxygenase 1–like “myoglobin” (Myb) was discovered in 1989 in the buccal mass of the abalone Sulculus diversicolor (54).

The conserved region between Myb and IDO-like Myb existed for at least 600 million years (53).  Even though the splice junction of seven introns was kept intact, the overall homolog region between Myb and IDO is only about 35%.

No significant evolutionary relationship is found between them after their amino acid sequence of each exon is compared to usual globin sequences. This led the hint that molluscan IDO-like protein must have other functions besides carrying oxygen, like myoglobin.   Alignment of S. cerevisiae cDNA, mollusk and vertebrate IDO–like globins show the key regions for controlling IDO or myoglobin function (55). These data suggest that there is an alternative pathways of myoglobin evolution.  In addition, understanding the diversity of globin may help to design better protocols for interventions of diseases.

Mechanisms of IDO:

The dichotomy of IDO mechanism lead the discovery that IDO is more than an enzyme as a versatile regulator of innate and adaptive immune responses in DCs (66; 67; 68). Meantime IDO also involve with Th2 response and B cell mediated autoimmunity showing that it has three paths, short term (acute) based on enzymatic actions, long term (chronic) based on non-enzymatic role, and moonlighting relies of downstream metabolites of tryptophan metabolism (69; 70).

IFNgamma produced by DC, MQ, NK, NKT, CD4+ T cells and CD8+ T cells, after stimulation with IL12 and IL8.  Inflammatory cytokine(s) expressed by DCs produce IFNgamma to stimulate IDO’s enzymatic reactions in acute response.  Then, TDO in liver and tryptophan catabolites act through Aryl hydrocarbon receptor induction for prevention of T cell proliferation. This mechanism is common among IDO, IDO2 (expresses in brain and liver) and TDO expresses in liver) provide an acute response for an innate immunity (30). When the pDCs are stimulated with IFNgamma, activation of IDO is go through Jak, STAT signaling pathway to degrade Trp to Kyn causing Trp depletion. The starvation of tryptophan in microenvironment inhibits generation of T cells by un-read t-RNAs and induce apoptosis through myc pathway.  In sum, lack of tryptophan halts T cell proliferation and put the T cells in apoptosis at S1 phase of cell division (71; 62).

The intermediary enzymes, functioning during Tryptophan degradation in Kynurenine (Kyn) pathway like kynurenine 3-hydroxylase and kynureninase, are also induced after stimulation with liposaccaride and proinflammatory cytokines (72). They exhibit their function in homeostasis through aryl-hydrocarbon receptor (AhR) induction by kynurenine as an endogenous signal (73; 74).  The endogenous tumor-promoting ligand of AhR are usually activated by environmental stress or xenobiotic toxic chemicals in several cellular processes like tumorigenesis, inflammation, transformation, and embryogenesis (Opitz ET. Al, 2011).

Human tumor cells constitutively produce TDO also contributes to production of Kyn as an endogenous ligand of the AhR (75; 27).  Degradation of tryptophan by IDO1/2 in tumors and tumor-draining lymph nodes occur. As a result, there are animal studies and Phase I/II clinical trials to inhibit the IDO1/2 to prevent cancer and poor prognosis (NewLink Genetics Corp. NCT00739609, 2007).

 IDO mechanism for immune response

Systemic inflammation (like in sepsis, cerebral malaria and brain tumor) creates hypotension and IDO expression has the central role on vascular tone control (63).  Moreover, inflammation activates the endothelial coagulation activation system causing coagulopathies on patients.  This reaction is namely endothelial cell activation of IDO by IFNgamma inducing Trp to Kyn conversion. After infection with malaria the blood vessel tone has decreases, inflammation induce IDO expression in endothelial cells producing Kyn causing decreased trp, lower arterial relaxation, and develop hypotension (Wang, Y. et. al 2010).  Furthermore, existing hypotension in knock out Ido mice point out a secondary mechanism driven by Kyn as an endogenous ligand to activate non-canonical NfKB pathway (63).

Another study also hints this “back –up” mechanism by a significant outcome with a differential response in pDCs against IMT treatment.  Unlike IFN gamma conditioned pDC blocks T cell proliferation and apoptosis, methyl tryptophan fails to inhibit IDO activity for activating naïve T cells to make Tregs at TGF-b1 conditioned pDCs (77; 78).

 Indoleamine-Pyrrole 2,3,-Dioxygenase; IDO dioxygenase; Indeolamine-2,3

The second role of the IDO relies on non-enzymatic action as being a signal molecule. Yet, IDO2 and TDO are devoid of this function. This role mainly for maintenance of microenvironment condition. DCs response to TGFbeta-1 exposure starts the kinase Fyn induce phosphorylation of IDO-associated immunoreceptor tyrosine–based inhibitory motifs (ITIMs) for propagation of the downstream signals involving non-canonical (anti-inflammatory) NF-kB pathway for a long term response. When the pDCs are conditioned with TGF-beta1 the signaling (68; 77; 78) Phospho Inositol Kinase3 (PIK-3)-dependent and Smad independent pathways (79; 80; 81; 82; 83) induce Fyn-dependent phosphorylation of IDO ITIMs.  A prototypic ITIM has the I/V/L/SxYxxL/V/F sequence (84), where x in place of an amino acid and Y is phosphorylation sites of tyrosines (85; 86).

Smad independent pathway stimulates SHP and PIK3 induce both SHP and IDO phosphorylation. Then, formed SHP-IDO complex can induce non-canonical (non-inflammatory) NF-kB pathway (64; 79; 80; 82) by phosphorylation of kinase IKKa to induce nuclear translocation of p52-Relb towards their targets.  Furthermore, the SHP-IDO complex also may inhibit IRAK1 (68). SHP-IDO complex activates genes through Nf-KB for production of Ido1 and Tgfb1 genes and secretion of IFNalpha/IFNbeta.  IFNa/IFNb establishes a second short positive feedback loop towards p52-RelB for continuous gene expression of IDO, TGFb1, IFNa and IFNb (87; 68).  However, SHP-IDO inhibited IRAK1 also activates p52-RelB.  Nf-KB induction at three path, one main and two positive feedback loops, is also critical.  Finally, based on TGF-beta1 induction (76) cellular differentiation occurs to stimulate naïve CD4+ T cell differentiation to regulatory T cells (Tregs).  In sum, TGF-b1 and IFNalpha/IFNbeta stimulate pDCs to keep inducing naïve T cells for generation of Treg cells at various stages, initiate, maintain, differentiate, infect, amplify, during long-term immune responses (67; 66).

Moonlighting function of Kyn/AhR is an adaptation mechanism after the catalytic (enzymatic) role of IDO depletes tryptophan and produce high concentration of Kyn induce Treg and Tr1 cell expansion leading Tregs to use TGFbeta for maintaining this environment (67; 76). In this role, Kyn pathway has positive-feedback-loop function to induce IDO expression.

In T cells, tryptophan starvation induces Gcn2-dependent stress signaling pathway, which initiates uncharged Trp-tRNA binding onto ribosomes. Elevated GCN2 expression stimulates elF2alfa phosphorylation to stop translation initiation (88). Therefore, most genes downregulated and LIP, an alternatively initiated isoform of the b/ZIP transcription factor NF-IL6/CEBP-beta (89).

This mechanism happens in tumor cells based on Prendergast group observations. As a result, not only IDO1 propagates itself while producing IFNalpha/IFNbeta, but also demonstrates homeostasis choosing between immunegenity by production of TH17or tolerance by Tregs. This mechanism acts like a see-saw. Yet, tolerance also can be broken by IL6 induction so reversal mechanism by SOC-3 dependent proteosomal degradation of the enzyme (90).  All proper responses require functional peripheral DCs to generate mature DCs for T cells to avoid autoimmunity (91).

Niacin (vitamin B3) is the final product of tryptophan catabolism and first molecule at Nicotinomic acid (NDA) Biosynthesis.  The function of IDO in tryptophan and NDA metabolism has a great importance to develop new clinical applications (40; 42; 41).  NAD+, biosynthesis and tryptophan metabolisms regulate several steps that can be utilize pharmacologically for reformation of healthy physiology (40).

IDO for protection in Microbial Infection with Toll-like Receptors

The mechanism of microbial response and infectious tolerance are complex and the origination of IDO based on duplication of microbial IDO (49).  During microbial responses, Toll-like receptors (TLRs) play a role to differentiate and determine the microbial structures as a ligand to initiate production of cytokines and pro-inflammatory agents to activate specific T helper cells (92; 93; 94; 95). Uniqueness of TLR comes from four major characteristics of each individual TLR by ligand specificity, signal transduction pathways, expression profiles and cellular localization (96). Thus, TLRs are important part of the immune response signaling mechanism to initiate and design adoptive responses from innate (naïve) immune system to defend the host.

TLRs are expressed cell type specific patterns and present themselves on APCs (DCs, MQs, monocytes) with a rich expression levels (96; 97; 98; 99; 93; 100; 101; 102; 87). Induction signals originate from microbial stimuli for the genesis of mature immune response cells.  Co-stimulation mechanisms stimulate immature DCs to travel from lymphoid organs to blood stream for proliferation of specific T cells (96).  After the induction of iDCs by microbial stimuli, they produce proinflammatory cytokines such as TNF and IL-12, which can activate differentiation of T cells into T helper cell, type one (Th1) cells. (103).

Utilizing specific TLR stimulation to link between innate and acquired responses can be possible through simple recognition of pathogen-associated molecular patterns (PAMPs) or co-stimulation of PAMPs with other TLR or non-TLR receptors, or even better with proinflammatory cytokines.   Some examples of ligand- TLR specificity shown in Table1, which are bacterial lipopeptides, Pam3Cys through TLR2 (92; 104; 105).  Double stranded (ds) RNAs through TLR3 (106; 107), Lipopolysaccharide (LPS) through TLR4, bacterial flagellin through TLR5 (108; 109), single stranded RNAs through TLR7/8 (97; 98), synthetic anti-viral compounds imiquinod through TLR 7 and resiquimod through TLR8, unmethylated CpG DNA motifs through TLR9 (Krieg, 2000).

IDO action

Then, the specificity is established by correct pairing of a TLR with its proinflammatory cytokines, so that these permutations influence creation and maintenance of cell differentiation. For example, leading the T cell response toward a preferred Th1 or Th2 response possible if the cytokines TLR-2 mediated signals induce a Th2 profile when combined with IL-2 but TLR4 mediated signals lean towards Th1 if it is combined with IL-10 or Il-12, (110; 111)  (112).

TLR ligand TLR Reference
Lipopolysaccharide, LPS TLR4 (96).  (112).
Lipopeptides, Pam3Cys TLR2 (92; 104; 105)
Double stranded (ds) RNAs TLR3 (106; 107)
Bacterial flagellin TLR5 (108; 109)
Single stranded RNAs TLR7/8 (97; 98)
Unmethylated CpG DNA motifs TLR9 (Krieg, 2000)
Synthetic anti-viral compounds imiquinod and resiquimod TLR7 and TLR8 (Lee J, 2003)

Furthermore, if the DCs are stimulated with IL-6, DCs relieve the suppression of effector T cells by regulatory T cells (113).

The modification of IDO+ monocytes manage towards specific subset of T cell activation with specific TLRs are significantly important (94).

The type of cell with correct TLR and stimuli improves or decreases the effectiveness of stimuli. Induction of IDO in monocytes by synthetic viral RNAs (isRNA) and CMV was possible, but not in monocyte derived DCs or TLR2 ligand lipopeptide Pam3Cys since single- stranded RNA ligands target TLR7/8 in monocytes derive DCs only (Lee J, 2003).  These data show that TLRs has ligand specificity, signal transduction pathways, expression profiles and cellular localization so design of experiments should follow these rules.

Conclusion:

Overall our purpose of this information is to find a method to manipulate IDO to correct/fix/modulate immune responses for clinical applications.  This first part of the review concerns the basic science information gained overall several years that lay the foundation that translational research scientist should familiar to develop a new technology for clinic. The first connection of IDO and human health came from a very natural event that is protection of pregnancy in human. The focus of the translational medicine is treatment of cancer or prevention/delay cancer by stem cell based Dendritic Cell Vaccine (DCvax) development.

References

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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

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Drug Delivery Platform Technology, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Interviews with Scientific Leaders, Medical and Population Genetics, Medical Devices R&D Investment, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, PCI, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stem Cells for Regenerative Medicine, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , , , , , , , , on August 1, 2013| 11 Comments »

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

Curator: Aviva Lev-Ari, PhD, RN

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Article VI Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart

Image created by Adina Hazan 06/30/2021

This article is Part VI in a Series of articles on 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-differen/

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

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 has THREE parts:

Part I: Scientific Leader in Cardiology, Contributions by Roger J. Hajjar, MD to Gene Therapy

Part II: Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension

Part III: Cardiac Gene Therapy: Percutaneous Intra-coronary Artery Infusion for Heart Failure

The following two discoveries in Cardiac Gene Therapies represent the FRONTIER IN CARDIOLOGY for 2012 – 2013: Solution Advancement for Improving Myocardial Contractility

Part I: Scientific Leader in Cardiology, Contributions by Roger J. Hajjar, MD to Gene Therapy

Roger J. Hajjar, MD, a pioneering Mount Sinai researcher who has published cutting-edge studies on heart failure, has been named the recipient of the 2013 BCVS Distinguished Achievement Award by theAmerican Heart Association and the Council on Basic Cardiovascular Sciences. Dr. Hajjar, who is The Arthur and Janet C. Ross Professor of Medicine and Director of The Helmsley Trust Translational Research Center, will be honored at the American Heart Association’s Scientific Sessions Annual Conference later this year.

“Dr. Hajjar will receive the award for his groundbreaking contributions to developing gene therapy treatments for cardiac disease,” says Joshua Hare, MD, who is President-elect of the Council on Basic Cardiovascular Sciences. He will also be recognized for his work on behalf of the Council.

Over the years, Dr. Hajjar’s laboratory has made important basic science discoveries that were translated into clinical trials. Most recently, Dr. Hajjar and his researchers identified a possible new drug target for treating or preventing heart failure. Says Mark A. Sussman, PhD, a former president of the Council, “Dr. Hajjar was among the first, and certainly the most successful, in combining gene therapy and treatment of heart failure. He shows a relentless pursuit of translating basic science into real-world treatment of heart disease.”

This article was first published in Inside Mount Sinai.

http://blog.mountsinai.org/blog/roger-j-hajjar-md-to-be-honored-for-research/

John Hopkins, Distinguished Alumnus Award 2011

Roger J. Hajjar, Engr ’86
Dr. Roger Hajjar received his bachelor’s degree in biomedical engineering from Johns Hopkins University in 1986. A cardiologist and translational scientist, he is a leader in gene therapy techniques and model testing for cardiovascular diseases. Dr. Hajjar is professor of medicine and cardiology, and professor of gene and cell medicine at Mount Sinai Medical Center in New York, as well as research director of Mount Sinai’s Wiener Family Cardiovascular Research Laboratories. Dr. Hajjar was recruited to Mt. Sinai from Harvard Medical School where he was assistant professor of medicine and staff cardiologist in the Heart Failure & Cardiac Transplantation Center. He received his medical degree from Harvard Medical School and trained in internal medicine and cardiology at Massachusetts General Hospital in Boston. Dr. Hajjar has concentrated his research efforts on understanding the basic mechanisms of heart failure. He has developed gene transfer methods and techniques in the heart to improve contractility. Dr. Hajjar’s laboratory focuses on targeting signaling pathways in cardiac myocytes to improve contractile function in heart failure and to block signaling pathways in hypertrophy and apoptosis. Dr. Hajjar has significant expertise in gene therapy. In 1996, he won the Young Investigator Award of the American Heart Association (Council on Circulation). In 1999, Dr. Hajjar was awarded the prestigious Doris Duke Clinical Scientist award and won first prize at the Astra Zeneca Young Investigator Forum. Dr. Hajjar holds a number of NIH grants.

http://alumni.jhu.edu/distinguishedalumni2011

Dr Hajjar is the Director of the Cardiovascular Research Center, and the Arthur & Janet C. Ross Professor of Medicine at Mount Sinai School of Medicine, New York, NY. He received his BS in Biomedical Engineering from Johns Hopkins University and his MD from Harvard Medical School and the Harvard-MIT Division of Health Sciences & Technology. He completed his training in internal medicine, cardiology and research fellowships at Massachusetts General Hospital in Boston.

Dr. Hajjar is an internationally renowned scientific leader in the field of cardiac gene therapy for heart failure. His laboratory focuses on molecular mechanisms of heart failure and has validated the cardiac sarcoplasmic reticulum calcium ATPase pump, SERCA2a, as a target in heart failure, developed methodologies for cardiac directed gene transfer that are currently used by investigators throughout the world, and examined the functional consequences of SERCA2a gene transfer in failing hearts. His basic science laboratory remains one of the preeminent laboratories for the investigation of calcium cycling in failing hearts and targeted gene transfer in various animal models. The significance of Dr Hajjar’s research has been recognized with the initiation and recent successful completion of phase 1 and phase 2 First-in-Man clinical trials of SERCA2a gene transfer in patients with advanced heart failure under his guidance.

Prior to joining Mount Sinai, Dr. Hajjar served as Director of the Cardiovascular Laboratory of Integrative Physiology and Imaging at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. Dr. Hajjar has also been a staff cardiologist in the Heart Failure & Cardiac Transplantation Center at Massachusetts General Hospital.

Dr. Hajjar has won numerous awards and distinctions, including the Young Investigator Award of the American Heart Association. He was awarded a Doris Duke Clinical Scientist award and has won first prize at the Astra Zeneca Young Investigator Forum. He is a member of the American Society for Clinical Investigation. He was recently awarded the Distinguished Alumnus Award from Johns Hopkins University and the Mount Sinai Dean’s award for Excellence in Translational Science. He has authored over 260 peer-reviewed publications.

http://heart.sdsu.edu/~website/IRRI/Pages/faculty/roger-hajjar-md.html

Meet the Director of Mount Sinai’s Cardiovascular Research Center

“Cardiovascular diseases are the number one cause of death globally. In order to tackle them in all aspects, we must unite improved diagnostic techniques with more refined therapies.”

Roger J. Hajjar, MD, Director of the Cardiovascular Research Center, 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.

In the late 1990s, the possibility that discoveries in genetics and genomics could have a positive impact on the diagnosis, treatment, and prevention of cardiovascular diseases seemed to be just a distant promise. Today, a little more than a decade later, the promise is beginning to take shape. Roger J. Hajjar, MD and his multidisciplinary team of investigators are beginning to translate scientific findings into real therapies for cardiovascular diseases. As Director of the Cardiovascular Research Institute and a cardiologist by training, Dr. Hajjar guides the growth of a cutting-edge translational research laboratory, which is positioning Mount Sinai as the leader in cardiovascular genomics.

An internationally recognized scientific leader in the field of cardiac gene therapy for heart failure, Dr. Hajjar is expanding studies of the basic mechanisms of cardiac diseases and identification of high-risk groups and genomic predictors so that they can be part of the daily clinical care of patients. Unique biorepositories combined with cardiovascular areas of excellence across Mount Sinai make possible crucial genetic studies.

First Gene Therapy for Heart Failure

Under Dr. Hajjar’s leadership, the Cardiovascular Research Center has already developed the world’s first potential gene therapy for heart failure. Known as AAV1.SERCA2a, this therapy actually revives heart tissue that has stopped working properly. It has led to new treatment possibilities for patients with advanced heart failure, whose options used to be severely limited. The significance of this research has been recognized with the initiation and successful completion Phase 1 and Phase 2 First-in-Man clinical trials of SERCA2a gene transfer in patients with advanced heart failure. Phase 3 validation begins in 2011.

The Cardiovascular Research Center’s next research projects, already underway, focus on using novel gene therapy vectors to target diastolic heart failure, ventricular arrhythmias, pulmonary hypertension, and myocardial infarctions.

In addition to targeting signaling pathways to aid failing heart cells, ongoing work at the Cardiovascular Research Center involves studying how to block signaling pathways in cardiac hypertrophy as well as apoptosis. The laboratory team is also targeting a number of signaling pathways in the aging heart to improve dystolic function.

Prior to joining Mount Sinai in 2007, Dr. Hajjar served as Director of the Cardiovascular Laboratory of Integrative Physiology and Imaging at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. Dr. Hajjar has also been a staff cardiologist in the Heart Failure & Cardiac Transplantation Center at Massachusetts General Hospital. After earning a bachelors of science degree in Biomedical Engineering from Johns Hopkins University and a medical degree from Harvard Medical School and the Harvard-MIT Division of Health Sciences and Technology, he completed his training in internal medicine, cardiology and research fellowships at Massachusetts General Hospital in Boston.

Scientific Advisors
Roger J. Hajjar, MD, Co-Founder and a Scientific Advisor of Celladon Co, plans to commercialize AAV1.SERCA2a for the treatment of heart failure.
Dr. Roger J. Hajjar is the Director of the Cardiovascular Research Center at the Mt. Sinai School of Medicine. Previously, he was the Director of the Cardiovascular Laboratory of Integrative Physiology and Imaging at Massachusetts General Hospital (MGH) and Associate Professor of Medicine at Harvard Medical School. Dr. Hajjar has an active basic science laboratory and concentrates his research efforts on understanding the basic mechanisms of heart failure. He has developed gene transfer methods and techniques targeting the heart as a therapeutic modality to improve contractility in heart failure. Dr. Hajjar’s laboratory focuses on targeting signaling pathways in cardiac myocytes to improve contractile function in heart failure and to block signaling pathways in hypertrophy and apoptosis.

Gene Therapy: Volume 19, Issue 6 (June 2012)

Special Issue: Cardiovascular Gene Therapy

Guest Editor

Roger J Hajjar MD, Mount Sinai School of Medicine, New York, NY Director, Cardiovascular Research Institute, Arthur & Janet C Ross Professor of Medicine

SDF-1 in myocardial repair  

M S Penn, J Pastore, T Miller and R Aras

Gene Ther 19: 583-587; doi:10.1038/gt.2012.32

Abstract | Full Text | PDF

Gene- and cell-based bio-artificial pacemaker: what basic and translational lessons have we learned?  

R A Li

Gene Ther 19: 588-595; doi:10.1038/gt.2012.33

Abstract | Full Text | PDF

Sarcoplasmic reticulum and calcium cycling targeting by gene therapy  

J-S Hulot, G Senyei and R J Hajjar

Gene Ther 19: 596-599; advance online publication, May 17, 2012; doi:10.1038/gt.2012.34

Abstract | Full Text | PDF

Gene therapy for ventricular tachyarrhythmias  

J K Donahue

Gene Ther 19: 600-605; advance online publication, April 26, 2012; doi:10.1038/gt.2012.35

Abstract | Full Text | PDF

Prospects for gene transfer for clinical heart failure  

T Tang, M H Gao and H Kirk Hammond

Gene Ther 19: 606-612; advance online publication, April 26, 2012; doi:10.1038/gt.2012.36

Abstract | Full Text | PDF

Targeting S100A1 in heart failure  

J Ritterhoff and P Most

Gene Ther 19: 613-621; advance online publication, February 16, 2012; doi:10.1038/gt.2012.8

Abstract | Full Text | PDF

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond  

M Giacca and S Zacchigna

Gene Ther 19: 622-629; advance online publication, March 1, 2012; doi:10.1038/gt.2012.17

Abstract | Full Text | PDF

Vein graft failure: current clinical practice and potential for gene therapeutics  

S Wan, S J George, C Berry and A H Baker

Gene Ther 19: 630-636; advance online publication, March 29, 2012; doi:10.1038/gt.2012.29

Abstract | Full Text | PDF

Percutaneous methods of vector delivery in preclinical models  

D Ladage, K Ishikawa, L Tilemann, J Müller-Ehmsen and Y Kawase

Gene Ther 19: 637-641; advance online publication, March 15, 2012; doi:10.1038/gt.2012.14

Abstract | Full Text | PDF

Lentiviral vectors and cardiovascular diseases: a genetic tool for manipulating cardiomyocyte differentiation and function  

E Di Pasquale, M V G Latronico, G S Jotti and G Condorelli

Gene Ther 19: 642-648; advance online publication, March 1, 2012; doi:10.1038/gt.2012.19

Abstract | Full Text | PDF

Intracellular transport of recombinant adeno-associated virus vectors  

M Nonnenmacher and T Weber

Gene Ther 19: 649-658; advance online publication, February 23, 2012; doi:10.1038/gt.2012.6

Abstract | Full Text | PDF

Gene delivery technologies for cardiac applications  

M G Katz, A S Fargnoli, L A Pritchette and C R Bridges

Gene Ther 19: 659-669; advance online publication, March 15, 2012; doi:10.1038/gt.2012.11

Abstract | Full Text | PDF

Cardiac gene therapy in large animals: bridge from bench to bedside  

K Ishikawa, L Tilemann, D Ladage, J Aguero, L Leonardson, K Fish and Y Kawase

Gene Ther 19: 670-677; advance online publication, February 2, 2012; doi:10.1038/gt.2012.3

Abstract | Full Text | PDF

Progress in gene therapy of dystrophic heart disease  

Y Lai and D Duan

Gene Ther 19: 678-685; advance online publication, February 9, 2012; doi:10.1038/gt.2012.10

Abstract | Full Text | PDF

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade  

J Reinkober, H Tscheschner, S T Pleger, P Most, H A Katus, W J Koch and P W J Raake

Gene Ther 19: 686-693; advance online publication, February 16, 2012; doi:10.1038/gt.2012.9

Abstract | Full Text | PDF

Directed evolution of novel adeno-associated viruses for therapeutic gene delivery  

M A Bartel, J R Weinstein and D V Schaffer

Gene Ther 19: 694-700; advance online publication, March 8, 2012; doi:10.1038/gt.2012.20

Abstract | Full Text | PDF

http://www.nature.com/gt/journal/v19/n6/index.html

Part II: Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension

Public release date: 30-Jul-2013

Contact: Lauren Woods
lauren.woods@mountsinai.org
212-241-2836
The Mount Sinai Hospital / Mount Sinai School of Medicine

Inhalable gene therapy may help pulmonary arterial hypertension patients

Gene therapy when inhaled may restore function of a crucial enzyme in the lungs to reverse deadly PAH

The deadly condition known as pulmonary arterial hypertension (PAH), which afflicts up to 150,000 Americans each year, may be reversible by using an inhalable gene therapy, report an international team of researchers led by investigators at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai.

In their new study, reported in the July 30 issue of the journal Circulation, scientists demonstrated that gene therapy administered through a nebulizer-like inhalation device can completely reverse PAH in rat models of the disease. In the lab, researchers also showed in pulmonary artery PAH patient tissue samples reduced expression of the SERCA2a, an enzyme critical for proper pumping of calcium in calcium compartments within the cells. SERCA2a gene therapy could be sought as a promising therapeutic intervention in PAH.

“The gene therapy could be delivered very easily to patients through simple inhalation — just like the way nebulizers work to treat asthma,” says study co-senior investigator Roger J. Hajjar, MD, Director of the Cardiovascular Research Center and the Arthur & Janet C. Ross Professor of Medicine and Professor of Gene & Cell at Icahn School of Medicine at Mount Sinai. “We are excited about testing this therapy in PAH patients who are in critical need of intervention.”

This same SERCA2a dysfunction also occurs in heart failure. This new study utilizes the same gene therapy currently being tested in patients to reverse congestive heart failure in a large phase III clinical trial in the United States and Europe.

“What we have shown is that gene therapy restores function of this crucial enzyme in diseased lungs,” says Dr. Hajjar. “We are delighted with these new findings because it suggests that a gene therapy that is already showing great benefit in congestive heart failure patients may be able to help PAH patients who currently have no good treatment options — and are in critical need of a life sustaining therapy.”

When SERCA2a is down-regulated, calcium stays longer in the cells than it should, and it induces pathways that lead to overgrowth of new and enlarged cells. According to researchers, the delivery of the SERCA2a gene produces SERCA2a enzymes, which helps both heart and lung cells restore their proper use of calcium.

“We are now on a path toward PAH patient clinical trials in the near future,” says Dr. Hajjar, who developed the gene therapy approach. Studies in large animal models are now underway. SERCA2a gene therapy has already been approved by the National Institutes of Health for human study.

A Simple Inhalation Corrects Deadly Dysfunction

PAH most commonly results from heart failure in the left side of the heart or from a pulmonary embolism, when clots in the legs travel to the lungs and cause blockages. When the lung is damaged from these conditions, the tissue starts to quickly produce new and enlarged cells, which narrows pulmonary arteries. This increases the pressure inside them. The high pressure in these arteries resists the heart’s effort to pump through them and the blood flow between the heart and lungs is reduced. The right side of the heart then must overcome the resistance and work harder to push the blood through the pulmonary arteries into the lungs. Over time, the right ventricle becomes thickened and enlarged and heart failure develops.

The gene therapy that Dr. Hajjar developed uses a modified adeno-associated viral-vector that is derived from a parvovirus. It works by introducing a healthy SERCA2a gene into cells, but this gene does not incorporate into a patient’s chromosome, according to the study’s lead author, Lahouaria Hadri, PhD, an Instructor of Medicine in Cardiology at Icahn School of Medicine at Mount Sinai.

“The clinical trials in congestive heart failure have shown already that the gene therapy is very safe,” says Dr. Hadri. Between 40-50 percent of individuals have antecedent antibodies to the adeno-associated vectors, so potential patients need to be screened before gene therapy to make sure they are eligible to receive the vectors. In patients without antibodies, the restorative enzyme gene therapy does not cause an immune response, according to Dr. Hadri.

The clinical application of the gene therapy for patients with PAH will most likely differ from those with heart failure. The replacement gene needs to be injected through the coronary arteries of heart failure patients using catheters, while in PAH patients, the gene will need to be administered through inhalation.

This study was supported by National Institutes of Health grants (K01HL103176, K08111207, R01 HL078691, HL057263, HL071763, HL080498, HL083156, and R01 HL105301).

Other study co-authors include Razmig G. Kratlian, MD, Ludovic Benard, PhD, Kiyotake Ishikawa, MD, Jaume Aguero, MD, Dennis Ladage, MD, Irene C.Turnbull, MD, Erik Kohlbrenner, BA, Lifan Liang, MD, Jean-Sébastien Hulot, MD, PhD, and Yoshiaki Kawase, MD, from Icahn School of Medicine at Mount Sinai; Bradley A. Maron, MD and the study’s co-senior author Jane A. Leopold, MD, from Brigham and Women’s Hospital and Harvard Medical School in Boston, MA; Christophe Guignabert, PhD, from Hôpital Antoine-Béclère, Clamart, France; Peter Dorfmüller, MD, PhD, and Marc Humbert, MD, PhD, both of the Hôpital Antoine-Béclère and INSERM U999, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France; Borja Ibanez, MD, from Fundación Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain; and Krisztina Zsebo, PhD, of Celladon Corporation, San Diego, CA.

  • Dr. Hajjar and co-author Dr. Zsebo, have ownership interest in Celladon Corporation, which is developing AAV1.SERCA2a for the treatment of heart failure. Also,
  • Dr. Hajjar and co-authors Dr. Kawase and Dr. Ladage hold intellectual property around SERCA2a gene transfer as a treatment modality for PAH. In addition,
  • co-author Dr. Maron receives funding from Gilead Sciences, Inc. to study experimental pulmonary hypertension.
  • Other study co-authors have no financial interests to declare.

Therapeutic Efficacy of AAV1.SERCA2a in Monocrotaline-Induced Pulmonary Arterial Hypertension

  1. Lahouaria Hadri, PhD;
  2. Razmig G. Kratlian, MD;
  3. Ludovic Benard, PhD;
  4. Bradley A. Maron, MD;
  5. Peter Dorfmüller, MD, PhD;
  6. Dennis Ladage, MD;
  7. Christophe Guignabert, PhD;
  8. Kiyotake Ishikawa, MD;
  9. Jaume Aguero, MD;
  10. Borja Ibanez, MD;
  11. Irene C. Turnbull, MD;
  12. Erik Kohlbrenner, BA;
  13. Lifan Liang, MD;
  14. Krisztina Zsebo, PhD;
  15. Marc Humbert, MD, PhD;
  16. Jean-Sébastien Hulot, MD, PhD;
  17. Yoshiaki Kawase, MD;
  18. Roger J. Hajjar, MD*;
  19. Jane A. Leopold, MD*

+Author Affiliations


  1. From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.H., R.G.K., L.B., D.L., K.I., J.A., I.C.T., E.K., L.L., J.-S.H., Y.K., R.J.H.); Cardiovascular Medicine Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (B.A.M., J.A.L.); Hôpital Antoine-Béclère, Clamart, France (P.D., C.G., M.H.); INSERM U999, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France (P.D., M.H.); Fundación Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain (B.I.); and Celladon Corporation, San Diego, CA (K.Z.).
  1. Correspondence to Lahouaria Hadri, PhD, Cardiovascular Research Center, Box 1030, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, New York, NY 10029. E-mail lahouaria.hadri@mssm.edu

Abstract

Background—Pulmonary arterial hypertension (PAH) is characterized by dysregulated proliferation of pulmonary artery smooth muscle cells leading to (mal)adaptive vascular remodeling. In the systemic circulation, vascular injury is associated with downregulation of sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) and alterations in Ca2+homeostasis in vascular smooth muscle cells that stimulate proliferation. We, therefore, hypothesized that downregulation of SERCA2a is permissive for pulmonary vascular remodeling and the development of PAH.

Methods and Results—SERCA2a expression was decreased significantly in remodeled pulmonary arteries from patients with PAH and the rat monocrotaline model of PAH in comparison with controls. In human pulmonary artery smooth muscle cells in vitro, SERCA2a overexpression by gene transfer decreased proliferation and migration significantly by inhibiting NFAT/STAT3. Overexpresion of SERCA2a in human pulmonary artery endothelial cells in vitro increased endothelial nitric oxide synthase expression and activation. In monocrotaline rats with established PAH, gene transfer of SERCA2a via intratracheal delivery of aerosolized adeno-associated virus serotype 1 (AAV1) carrying the human SERCA2a gene (AAV1.SERCA2a) decreased pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and fibrosis in comparison with monocrotaline-PAH rats treated with a control AAV1 carrying β-galactosidase or saline. In a prevention protocol, aerosolized AAV1.SERCA2a delivered at the time of monocrotaline administration limited adverse hemodynamic profiles and indices of pulmonary and cardiac remodeling in comparison with rats administered AAV1 carrying β-galactosidase or saline.

Conclusions—Downregulation of SERCA2a plays a critical role in modulating the vascular and right ventricular pathophenotype associated with PAH. Selective pulmonary SERCA2a gene transfer may offer benefit as a therapeutic intervention in PAH.

Key Words:

  • Received January 24, 2013.
  • Accepted June 13, 2013.

http://circ.ahajournals.org/content/128/5/512.abstract?sid=9b3b4fcc-e158-4e5d-bb8b-125586e2ec12

Circulation.2013; 128: 512-523 Published online before print June 26, 2013,doi: 10.1161/​CIRCULATIONAHA.113.001585

Part III: Cardiac Gene Therapy: Percutaneous Intra-coronary Artery Infusion for Heart Failure

Etiology of Heart Failure

  • Alcoholic
  • Hypertensive
  • Idiopathic
  • Inflammatory
  • Ischemic
  • Pregnancy-related
  • Toxic
  • Valvular Heart DIsease

Administration of Cardiac Gene Therapy for Heart Failure: via Percutaneous Intra-coronary Artery Infusion

  • Gene delivery to viable myocardium

dominance and coronary artery anatomy from angiography determines infusion scenario

  • Antegrade epicardial coronary artery infusion over 10 minutes

60 mL divided into 1,2,3 infusions depending on anatomy

Delivered via commercially available angiographic injection system & guide or diagnostic catheters

Dr. Roger J. Hajjar of the Mount Sinai School of Medicine will present at the ASGCT 15th Annual Meeting during a Scientific Symposium entitled: Cell and Gene Therapy in Cardiovascular Disease on Wednesday, May 16, 2012 at 8:00 am. Below is a brief preview of his presentation.

Roger J. Hajjar, MD

Mount Sinai School of Medicine

New York, NY

Novel Developments in Gene Therapy for Cardiovascular Diseases

Chronic heart failure is a leading cause of hospitalization affecting nearly 6 million people in the U.S. with 670,000 new cases diagnosed every year. Heart failure leads to about 280,000 deaths annually.

Congestive heart failure remains a progressive disease with a desperate need for innovative therapies to reverse the course of ventricular dysfunction. The most common symptoms of heart failure are shortness of breath, feeling tired and swelling in the ankles, feet, legs and sometimes the abdomen. Recent advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology have placed heart failure within reach of gene-based therapies.

One of the key abnormalities in both human and experimental HF is a defect in sarcoplasmic reticulum (SR) function, which controls Ca2+ handling in cardiac myocytes on a beat to beat basis. Deficient SR Ca2+ uptake during relaxation has been identified in failing hearts from both humans and animal models and has been associated with a decrease in the activity of the SR Ca2+-ATPase (SERCA2a).

Over the last ten years we have undertaken a program of targeting important calcium cycling proteins in experimental models of heart by somatic gene transfer. This has led to the completion of a first-in-man phase 1 clinical trial of gene therapy for heart failure using adeno-associated vector (AAV) type 1 carrying SERCA2a. In this Phase I trial, there was evidence of clinically meaningful improvements in functional status and/or cardiac function which were observed in the majority of patients at various time points. The safety profile of AAV gene therapy along with the positive biological signals obtained from this phase 1 trial has led to the initiation and recent completion of a phase 2 trial of AAV1.SERCA2a in NYHA class III/IV patients. In the phase 2 trial, gene transfer of SERCA2a was found to be safe and associated with benefit in clinical outcomes, symptoms, functional status, NT-proBNP and cardiac structure.

The 12 month data presented showed that heart failure, which is a progressive disease, became stabilized in high dose AAV1.SERCA2a-treated patients: heart failure symptoms, exercise tolerance, serum biomarkers and cardiac function essentially improved or remained the same while these parameters deteriorated substantially in patients treated with placebo and concurrent optimal drug and device therapy. More recently, the 2-year CUPID data from long-term follow-up demonstrate a durable benefit in preventing major cardiovascular events.

The recent successful and safe completion of the CUPID trial along with the start of more recent phase 1 trials usher a new era for gene therapy for the treatment of heart failure. Furthermore, novel AAV derivatives with high cardiotropism and resistant to neutralizing antibodies are being developed to target a large number of cardiovascular diseases.

http://www.execinc.com/hosted/emails/asgct/file/Hajjar2(1).pdf

Power Point Presentation on Cardiac Gene Therapy –

VIEW SLIDE SHOW

http://my.americanheart.org/idc/groups/heart-public/@wcm/@global/documents/downloadable/ucm_311680.pdf

Gene Therapy for Heart Failure

  1. Lisa Tilemann,
  2. Kiyotake Ishikawa,
  3. Thomas Weber,
  4. Roger J. Hajjar

+Author Affiliations


  1. From the Cardiovascular Research Center, Mount Sinai Medical Center, New York, NY.
  1. Correspondence to Roger J. Hajjar, MD, Mount Sinai Medical Center, One Gustave Levy Place, Box 1030, New York, NY 10029. E-mail roger.hajjar@mssm.edu

Abstract

Congestive heart failure accounts for half a million deaths per year in the United States. Despite its place among the leading causes of morbidity, pharmacological and mechanic remedies have only been able to slow the progression of the disease. Today’s science has yet to provide a cure, and there are few therapeutic modalities available for patients with advanced heart failure. There is a critical need to explore new therapeutic approaches in heart failure, and gene therapy has emerged as a viable alternative. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a), along with the start of more recent phase 1 trials, opens a new era for gene therapy for the treatment of heart failure.

Circulation Research.2012; 110: 777-793 doi: 10.1161/​CIRCRESAHA.111.252981

Key Words:

  • Received December 8, 2011.
  • Revision received January 29, 2012.
  • Accepted January 30, 2012.

Conclusions 

With a better understanding of the molecular mechanisms associated with heart failure and improved vectors with cardiotropic properties, gene therapy can now be considered as a viable adjunctive treatment to mechanical and pharmacological therapies for heart failure. In the coming years, more targets will emerge that are amenable to genetic manipulations, along with more advanced vector systems, which will undoubtedly lead to safer and more effective clinical trials in gene therapy for heart failure.

http://circres.ahajournals.org/content/110/5/777.full.pdf+html

Hijjar1
Figure 1.

AAV entry. 1 indicates receptor binding and endocytosis; 2, escape into cytoplasm; 3, nuclear import; 4, capsid disassembly; 5, double-strand synthesis; and 6, transcription.

Hijjar2

Figure 2.

Generation of mutant AAV library and directed evolution to identify cardiotropic AAVs. A, Creation of a library of AAVs through DNA shuffling.B, Selection of cardiotropic AAVs through directed evolution.

Hijjar3

Figure 3.

Antegrade coronary artery infusion. A, Coronary artery infusion. The vector is injected through a catheter without interruption of the coronary flow. B, Coronary artery infusion with occlusion of a coronary artery: The vector is injected through the lumen of an inflated angioplasty catheter. C, Coronary artery infusion with simultaneous blocking of a coronary artery and a coronary vein: The vector is injected through an inflated angioplasty catheter and resides in the coronary circulation until both balloons are deflated.

Hijjar4

Figure 4.

V-Focus system and retrograde coronary venous infusion. A, Recirculating antegrade coronary artery infusion: The vector is injected into a coronary artery, collected from the coronary sinus and after oxygenation readministered into the coronary artery. B, Retrograde coronary venous infusion with simultaneous blocking of a coronary artery and a coronary vein: The vector is injected into a coronary vein and resides in the coronary circulation until both balloons are deflated.

Hijjar5

Figure 5.

Direct myocardial injection and pericardial injection. A, Percutaneous myocardial injection: The vector is injected with an injection catheter via an endocardial approach.B, Surgical myocardial injection: The vector is injected via an epicardial approach. C, Percutaneous pericardial injection: The vector is injected via a substernal approach.

Hijjar6

Figure 6.

Excitation-contraction coupling in cardiac myocytes provides multiple targets for gene therapy.

SOURCE

http://circres.ahajournals.org/content/110/5/777.figures-only

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  • Up-regulation of sarcoplasmic reticulum Ca2+ uptake leads to cardiac hypertrophy, contractile dysfunction and early mortality in mice deficient in CASQ2Cardiovasc Res. 2013;98:297-306,
  • Myocardial Delivery of Stromal Cell-Derived Factor 1 in Patients With Ischemic Heart Disease: Safe and PromisingCirc. Res.. 2013;112:746-747,
  • Circulation Research Thematic Synopsis: Cardiovascular GeneticsCirc. Res.. 2013;112:e34-e50,
  • Gene and cytokine therapy for heart failure: molecular mechanisms in the improvement of cardiac functionAm. J. Physiol. Heart Circ. Physiol.. 2012;303:H501-H512,
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http://circres.ahajournals.org/content/110/5/777.figures-only

For 154 References on Cardiac Gene Therapy

http://circres.ahajournals.org/content/110/5/777.full.pdf+html

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Nanotechnology and HIV/AIDS Treatment

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, BioSimilars, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Human Immune System in Health and in Disease, Infectious Disease & New Antibiotic Targets, Nanotechnology for Drug Delivery, Pharmaceutical R&D Investment, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Uncategorized, tagged , , , , , , , , , , , , , , , , , , , , , , , , , on December 25, 2012| 5 Comments »

Nanotechnology and HIV/AIDS Treatment

Author: Tilda Barliya, PhD

 

AIDS was first reported in 1981 followed by the identification of HIV as the cause of the disease in 1983 and is now a global pandemic that has become the leading infectious killer of adults worldwide. By 2006, more than 65 million people had been infected with the HIV virus worldwide and 25 million had died of AIDS (Merson MH. The HIV-AIDS pandemic at 25 – the global response. (1, 2). This has caused tremendous social and economic damage worldwide, with developing countries, particularly Sub-Saharan Africa, heavily affected.

A cure for HIV/AIDS has been elusive in almost 30 years of research. Early treatments focused on antiretroviral drugs that were effective only to a certain degree. The first drug, zidovudine, was approved by the US FDA in 1987, leading to the approval of a total of 25 drugs to date, many of which are also available in fixed-dose combinations and generic formulations for use in resource-limited settings (to date, only zidovudine and didanosine are available as true generics in the USA).

However, it was the advent of a class of drugs known as protease inhibitors and the introduction of triple-drug therapy in the mid-1990s that revolutionized HIV/AIDS treatment (3,4). This launched the era of highly active antiretroviral therapy (HAART), where a combination of three or more different classes of drugs are administered simultaneously.

Challenges of HIV/AIDS treatment

  • HIV resides in latent cellular and anatomical reservoirs where current drugs are unable to completely eradicate the virus.
  • Macrophages are major cellular reservoirs, which also contribute to the generation of elusive mutant viral genotypes by serving as the host for viral genetic recombination.
  • Anatomical latent reservoirs include secondary lymphoid tissue, testes, liver, kidney, lungs, the gut and the brain.
  • The major challenge facing current drug regimens is that they do not fully eramacrdicate the virus from these reservoirs; requiring patients take medications for life. Under current treatment, pills are taken daily, resulting in problems of patient adherence. The drugs also have side effects and in some people the virus develops resistance against certain drugs.

Current treatment in HIV/AIDS

The use of the HAART regimen, particularly in the developed world, has resulted in tremendous success in improving the expectancy and quality of lives for patients. However, some HAART regimens have serious side effects and, in all cases, HAART has to be taken for a lifetime, with daily dosing of one or more pills. Due to the need to take the medication daily for a lifetime, patients fail to adhere to the treatment schedule, leading to ineffective drug levels in the body and rebound of viral replication.Some patients also develop resistance to certain combinations of drugs, resulting in failure of the treatment. The absence of complete cure under current treatment underscores the great need for continued efforts in seeking innovative approaches for treatment of HIV/AIDS.

Drug resistance is mainly caused by the high genetic diversity of HIV-1 and the continuous mutation it undergoes. This problem is being addressed with individualized therapy, whereby resistance testing is performed to select a combination of drugs that is most effective for each patient (5). In addition, side effects due to toxicities of the drugs are also a concern. There are reports that patients taking HAART experience increased rates of heart disease, diabetes, liver disease, cancer and accelerated aging. Most experts agree that these effects could be due to the HIV infection itself or co-infection with another virus, such as co-infection with hepatitis C virus resulting in liver disease. However, the toxicities resulting from the drugs used in HAART could also contribute to these effects.

Under current treatment, complete eradication of the virus from the body has not been possible. The major cause for this is that the virus resides in ‘latent reservoirs’ within memory CD4+ T cells and cells of the macrophage–monocyte lineage. A major study recently found that, in addition to acting as latent reservoirs, macrophages significantly contribute to the generation of elusive mutant viral genotypes by serving as the host for viral genetic recombination (6).  The cells that harbor latent HIV are typically concentrated in specific anatomic sites, such as secondary lymphoid tissue, testes, liver, kidney, lungs, gut and the CNS. The eradication of the virus from such reservoirs is critical to the effective long-term treatment of HIV/AIDS patients.

Therefore, there is a great need to explore new approaches for developing nontoxic, lower-dosage treatment modalities that provide more sustained dosing coverage and effectively eradicate the virus from the reservoirs, avoiding the need for lifetime treatments.

Nanotechnology for HIV/AIDS treatment

The use of nanotechnology platforms for delivery of drugs is revolutionizing medicine in many areas of disease treatment.

Nanotechnology-based platforms for systemic delivery of antiretroviral drugs could have similar advantages.

  • Controlled-release delivery systems can enhance their half-lives, keeping them in circulation at therapeutic concentrations for longer periods of time. This could have major implications in improving adherence to the drugs.
  • Nanoscale delivery systems also enhance and modulate the distribution of hydrophobic and hydrophilic drugs into and within different tissues due to their small size. This particular feature of nanoscale delivery systems appears to hold the most promise for their use in clinical treatment and prevention of HIV. Specifically, targeted delivery of antiretroviral drugs to CD4+ T cells and macrophages as well as delivery to the brain and other organ systems could ensure that drugs reach latent reservoirs
  • Moreover, by controlling the release profiles of the delivery systems, drugs could be released over a longer time and at higher effective doses to the specific targets. Figure 1. Various nanoscale drug delivery systems.

Optional treatments:

  •    Antiretroviral drugs
  •    Gene Therapy
  •    Immune Therapy
  •    Prevention

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The use of nanotechnology systems for delivery of antiretroviral drugs has been extensively reviewed by Nowacek et al. and Amiji et al. (7,8).

In a recent study based on polymeric systems, nanosuspensions (200 nm) of the drug rilpivirine (TMC278) stabilized by polyethylene. A series of experiments by Dou et al. showed that nanosuspension of the drug indinavir can be stabilized by a surfactant system comprised of Lipoid E80 for effective delivery to various tissues. The indinavir nanosuspensions were loaded into macrophages and their uptake was investigated. Macrophages loaded with indinavir nanosuspensions were then injected intravenously into mice, resulting in a high distribution in the lungs, liver and spleen. More significantly, the intravenous administration of a single dose of the nanoparticle-loaded macrophages in a rodent mouse model of HIV brain infection resulted in significant antiviral activity in the brain and produced measureable drug levels in the blood up to 14 days post-treatment.polypropylene glycol (poloxamer 338) and PEGylated tocopheryl succinate ester (TPGS 1000) were studied in dogs and mice. A single-dose administration of the drug in nanosuspensions resulted in sustained release over 3 months in dogs and 3 weeks in mice, compared with a half-life of 38 h for free drug. These results serve as a proof-of-concept that nanoscale drug delivery may potentially lower dosing frequency and improve adherence.

Active targeting strategies have also been employed for antiretroviral drug delivery. Macrophages, which are the major HIV reservoir cells, have various receptors on their surface such as formyl peptide, mannose, galactose and Fc receptors, which could be utilized for receptor-mediated internalization. The drug stavudine was encapsulated using various liposomes (120–200 nm) conjugated with mannose and galactose, resulting in increased cellular uptake compared with free drug or plain liposomes, and generating significant level of the drug in liver, spleen and lungs. Stavudine is a water-soluble drug with a very short serum half-life (1 h). Hence, the increased cellular uptake and sustained release in the tissues afforded by targeted liposomes is a major improvement compared with free drug. The drug zidovudine, with half-life of 1 h and low solubility, was also encapsulated in a mannose-targeted liposome made from stearylamine, showing increased localization in lymph node and spleen. An important factor to consider here is that although most of the nucleoside drugs such as stavudine and zidovudine have short serum half-lives, the clinically relevant half-life is that of the intracellular triphosphate form of the drug. For example, despite zidovudine’s 1 h half-life in plasma, it is dosed twice daily based on intracellular pharmacokinetic and clinical efficacy data. Therefore, future nanotechnology-based delivery systems will have to focus in showing significant increase of the half-lives of the encapsulated drugs to achieve a less frequent dosing such as once weekly, once-monthly or even less.

Gene Therapy for HIV/AIDS

In addition to improving existing antiretroviral therapy, there are ongoing efforts to discover alternative approaches for treatment of HIV/AIDS. One promising alternative approach is gene therapy, in which a gene is inserted into a cell to interfere with viral infection or replication. Other nucleic acid-based compounds, such as DNA, siRNA, RNA decoys, ribozymes and aptamers or protein-based agents such as fusion inhibitors and zinc-finger nucleases can also be used to interfere with viral replication.

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RNAi is also considered to have therapeutic potential for HIV/AIDS. Gene silencing is induced by double stranded siRNA, which targets for destruction

he mRNA of the gene of interest. For HIV/AIDS, RNAi can either target the various stages of the viral replication cycle or various cellular targets involved in viral infection such as CD4, CCR5, and/or CXCR4, the major cell surface co-receptors responsible for viral entry. HIV replicates by reverse transcription to form DNA and uses the DNA to produce copies of its mRNA for protein synthesis; siRNA therapy could be used to knock down this viral mRNA. As with other gene therapy techniques, delivery of siRNA to specific cells and tissues has been the major challenge in realizing the potential of RNAi.

New nanotechnology platforms are tackling this problem by providing nonviral alternatives for effective and safe delivery. The first nontargeted delivery of siRNA in humans via self-assembling, cyclodextrin polymer-based nanoparticles for cancer treatment have recently entered Phase I clinical trials.

Although at an early stage, nonviral delivery of siRNA for treatment of HIV infection is also gaining ground. A fusion protein, with a peptide transduction domain and a double stranded RNA-binding domain, was used to encapsulate and deliver siRNA to T cells in vivo. CD4- and CD8-specific siRNA delivery caused RNAi responses with no adverse effects such as cyto-toxicity or immune stimulation. Similarly, a protamine-antibody fusion protein-based siRNA delivery demonstrated that siRNA knockdown of the gag gene can inhibit HIV replication in primary T cells. 

Single-walled nanotubes were shown to deliver CXCR4 and CD4 specific siRNA to human T cells and peripheral blood mononuclear cells. Up to 90% knockdown of CXCR4 receptors and up to 60% knockdown of CD4 expression on T cells was observed while the knockdown of CXCR4 receptors on peripheral blood mononuclear cells was as high as 60%. In a separate study, amino-terminated carbosilane dendrimers (with interior carbon-silicon bonds) were used for delivery of siRNA to HIV-infected lymphocytes.

These pioneering studies demonstrate that nonviral siRNA delivery is possible for HIV/AIDS treatment. However, more work needs to be done in optimizing the delivery systems and utilizing designs for efficient targeting and intracellular delivery. The recent developments in polymer- and liposome-based siRNA delivery systems could be optimized for targeting cells that are infected with HIV, such as T cells and macrophages. Moreover, since HIV mutates and has multiple strains with different genetic sequences, combination siRNA therapy targeting multiple genes should be pursued. For these applications, nanotechnology platforms with capability for co-delivery and targeting need to be developed specifically for HIV-susceptible cells. A macrophage and T-cell-targeted and nanotechnology-based combination gene therapy may be a promising platform for efficient HIV/AIDS treatment.

Immunotherapy for HIV/AIDS

The various treatment approaches described above focus on treating HIV/AIDS by directly targeting HIV at the level of the host cell or the virus itself. An alternative approach is immunotherapy aimed at modulating the immune response against HIV. CD8+ cytotoxic T-cell responses to acute HIV infection appear to be relatively normal, while neutralizing antibody production by B cells is delayed or even absent.

Immunotherapy is a treatment approach involving the use of immunomodulatory agents to modulate the immune response against a disease. Similar to vaccines, it is based on immunization of individuals with various immunologic formulations; however, the purpose is to treat HIV-infected patients as opposed to protect healthy individuals (preventive vaccines will be discussed in an upcoming section). The various immunotherapy approaches for HIV/AIDS could be based on delivering cytokines (such as IL-2, IL-7 and IL-15) or antigens. The development of cellular immunity, and to a large degree humoral immunity, requires antigen-presenting cells (APCs) to process and present antigens to CD4+and CD8+ T cells. Dendritic cells (DCs) are the quintessential professional APCs responsible for initiating and orchestrating the development of cellular and humoral (antibody) immunity.

Various polymeric systems have been explored for in vivo targeting of DCs and delivery of small molecules, proteins or DNAs showing potential for immunotherapy. Poly(ethylene glycol) (PEG) stabilized poly(propylene sulfide) polymer nanoparticles accumulated in DCs in lymph nodes. Following nanoparticle injection, DCs containing nanoparticles accumulated in lymph nodes, peaking at 4 days with 40–50% of DCs and other APCs having internalized nanoparticles.

In another study, nanoparticles of the copolymer poly(D,L-lacticide-co-glycolide) (PLGA) showed efficient delivery of antigens to murine bone marrow-derived DCs in vitro, suggesting their potential use in immunotherapy. More recently, a very interesting work showed that HIV p24 protein adsorbed on the surface of surfactant-free anionic poly(D,L-lactide) (PLA) nanoparticles were efficiently taken-up by mouse DCs, inducing DC maturation. he p24-nanoparticles induced enhanced cellular and mucosal immune responses in mice. Although this targeting is seen in ex vivo-generated DCs and not in vivo DCs, the efficient delivery of the antigen to DCs through the nanoparticles is an important demonstration that may eventually be applied to in vivo DC targeting.

Clinical Trial

he most clinically advanced application of nanotechnology for immunotherapy of HIV/AIDS is the DermaVir patch that has reached Phase II clinical trials (9). DermaVir is a targeted nanoparticle system based on polyethyleimine mannose (PEIm), glucose and HIV antigen coding DNA plasmid formulated into nanoparticles (~100 nm) and administered under a patch after a skin preparation. The nanoparticles are delivered to epidermal Langerhans cells that trap the nanoparticles and mature to become highly immunogenic on their way to the lymph nodes. Mature DCs containing the nanoparticles present antigens to T cells inducing cellular immunity. Preclinical studies and Phase I clinical trials showed safety and tolerability of the DermaVir patch, which led the progression to Phase II trials. This is the first nanotechnology-based immunotherapy for HIV/AIDS that has reached the clinic and encourages further work in this area.

Table 1

Summary of nanotechnology-based treatment approaches for HIV/AIDS.

Type of therapy Therapeutic agent (drug or gene) Nanotechnology delivery platform Development stage Refs.
Antiretroviral therapy Rilpivirine (TMC278) Poloxamer 338/TPGS 1000 Preclinical [35]
Indinavir Liposome-laden macrophages Preclinical [36–38]
Stavudine Mannose- and galactose-targeted liposome Preclinical [39–41]
Zidovudine Mannose-targeted liposome Preclinical [42]
Efavirenz Mannose-targeted dendrimer Preclinical [43,45]
Lamivudine Mannose-targeted dendrimer Preclinical [46]
Nanomaterials Fullerene derivatives – Preclinical [49–55]
Dendrimers – Preclinical [56,57]
Silver nanoparticles – Preclinical [58,59]
SDC-1721/gold nanoparticles Gold nanoparticles Preclinical [60]
Gene therapy siRNA Peptide fusion proteins, protamine–antibody fusion proteins, dendrimers, single walled carbon nanotubes, peptide–antibody conjugates Preclinical [77–81]
Immunotherapy P24 protein Poly (D,L-lactide) nanoparticles/dendritic cells Preclinical [98]
Plasmid DNA Mannose-targeted polyethyleimine polymers Phase II clinical trials [99]

Note:  to open the references in the table 1, please go to ref 1 in this post to see full ref info.

Nanotechnology for HIV/AIDS prevention

The search for a safe and effective HIV/AIDS vaccine has been challenging in the almost three decades since the discovery of the disease. Recently, high-profile clinical trial failures have prompted great debate over the vaccine research, with some suggesting the need for a major focus on fundamental research, with fewer efforts on clinical trials.

The major challenges in the development of a preventive HIV/AIDS vaccine have been the extensive viral strain and sequence diversity, viral evasion of humoral and cellular immune responses, coupled with the lack of methods to elicit broadly reactive neutralizing antibodies and cytotoxic T cells. The challenge associated with delivery of any exogenous antigen (such as nanoparticles) to APCs, is that exogenous antigens require specialized ‘cross-presentation’ in order to be presented by MHC class I and activate CD8+cytotoxic T cells.

his requirement for cytosolic delivery of antigens and cross-presentation represents yet another hurdle for HIV intracellular antigen vaccine, but potentially an advantage of nanodelivery. Humoral responses (neutralizing antibodies produced by B cells) are generated to intact antigen presented on the surface for the virus, or nanoparticles, but these humoral responses typically require ‘help’ from CD4+ T cells, but rather both. Nanoparticles have potential as adjuvants and delivery systems for vaccines. Table 2 present the different approaches.

Table 2

Summary of nanotechnology developments for prevention of HIV/AIDS.

Type of preventive agent Antigen/adjuvant or drug Nanotechnology platform Development stage Refs.
Protein or peptide vaccine gp41, gp120, gp160, p24, Env, Gag, Tat Liposomes, nanoemulsion, MF59, PLA nanoparticles, poly(γ-glutamic acid) nanoparticles Preclinical [108–111]
[119–120]
[122–125]
[128–130]
DNA vaccine env, rev, gag, tat, CpG ODN Liposomes, nanoemulsion, PLA nanoparticles Preclinical [115,121]
Inactivated viral particle Inactivated HIV viral particle Polystyrene nanospheres Preclinical [126–127]
Microbicides L-lysine dendrimer L-lysine dendrimer Phase I/II [136–138]
PLGA nanoparticles
PSC-RANTES PLGA Preclinical [139]
siRNA Nanoparticles, lipids, cholesterol conjugation Preclinical [141–144]

ODN: Oligonucleotides; PLA: Poly(D,L-lactide); PLGA: Poly(D,L-lacticide-co-glycolide).

Note:  to open the references in the table 2, please go to ref 1 in this post to see full ref info.

 

Summary

Nanotechnology can impact the treatment and prevention of HIV/AIDS with various innovative approaches. Treatment options may be improved using nanotechnology platforms for delivery of antiretroviral drugs. Controlled and sustained release of the drugs could improve patient adherence to drug regimens, increasing treatment effectiveness.

While there is exciting potential for nanomedicine in the treatment of HIV/AIDS, challenges remain to be overcome before the potential is realized. These include toxicity of nanomaterials, stability of nanoparticles in physiological conditions and their scalability for large-scale production. These are challenges general to all areas of nanomedicine and various works are underway to tackle them.

Another important consideration in investigating nanotechnology-based systems for HIV/AIDS is the economic aspect, as the hardest hit and most vulnerable populations reside in underdeveloped and economically poor countries. In the case of antiretroviral therapy, nanotherapeutics may increase the overall cost of treatment, reducing the overall value. However, if the nanotherapeutics could improve patient adherence by reducing dosing frequency as expected, and furthermore, if they can eradicate viral reservoirs leading to a sterile immunity, these advantages may effectively offset the added cost.

 

Ref:

1. Mamo T, Moseman EA., Kolishetti N., Salvadoe-Morales C., Shi J., Kuritzkes DR., Langer R., von-Adrian U and Farokhzad OF.   Emerging nanotechnology approaches for HIV/AIDS treatment and prevention. Nanomedicine (Lond) 2010; 5(2): 269-295.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861897/

2. Merson MH. The HIV-AIDS pandemic at 25 – the global response. N Engl J Med.2006;354(23):2414–2417

3. Walensky RP, Paltiel AD, Losina E, et al. The survival benefits of AIDS treatment in the United States. J Infect Dis. 2006;194(1):11–19

4. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ. The challenge of finding a cure for HIV infection. Science. 2009;323(5919):1304–1307)

5.Sax PE, Cohen CJ, Kuritzkes DR. HIV Essentials. Physicians’ Press; Royal Oak, MI, USA: 2007.

6. Lamers SL, Salemi M, Galligan DC, et al. Extensive HIV-1 intra-host recombination is common in tissues with abnormal histopathology. PLoS One. 2009;4(3):E5065.

7. Vyas TK, Shah L, Amiji MM. Nanoparticulate drug carriers for delivery of HIV/AIDS therapy to viral reservoir sites. Expert Opin Drug Deliv. 2006;3(5):613–628.

8. Amiji MM, Vyas TK, Shah LK. Role of nanotechnology in HIV/AIDS treatment: Potential to overcome the viral reservoir challenge. Discov Med. 2006;6(34):157–162

9. Lori F, Calarota SA, Lisziewicz J. Nanochemistry-based immunotherapy for HIV-1. Curr Med Chem. 2007;14(18):1911–1919

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Targeted delivery of therapeutics to bone and connective tissues: current status and challenges- Part II

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Bone Disease and Musculoskeletal Disease, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Nanotechnology for Drug Delivery, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , , , , , , , , , , , , on September 30, 2012| 8 Comments »

Curator/Reporter: Aviral Vatsa PhD MBBS

This post is in the second part of the reviews that focuses on the current status of drug delivery to bone and the issues facing this field. The first part can be accessed here

Annual treatment costs for musculoskeletal diseases in the US are roughly 7.7% (~ $849 billion) of total gross domestic product. Such disorders are the main cause of physical disability in US. Almost half of all chronic conditions in people can be attributed to bone and joint disorders. In addition there is increasing ageing population and associated increases in osteoporosis and other diseases, rising incidences of degenerative intervertebral disk diseases and numbers of revision orthopedic arthroplasty surgeries, and increases in spinal fusions. All these factors contribute towards the increasing requirement of bone regeneration and reconstruction methods and products. Delivery of therapeutic grade products to bone has various challenges. Parenteral administration limits the efficient delivery of drugs to the required site of injury and local delivery methods are often expensive and invasive. The theme issue of Advance Drug Delivery reviews focuses on the current status of drug delivery to bone and the issues facing this field. Here is the second part of these reviews and research articles.

1. Targeting polymer therapeutics to bone [1]

Abstract

An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic. Bone, however, provides a unique environment of inorganic solids, which can be exploited in order to effectively target drugs to diseased tissue. By integration of bone targeting moieties to drug-carrying water-soluble polymers, the payload to diseased area can be increased while side effects decreased. The realization of clinically relevant bone targeted polymer therapeutics depends on (1) understanding bone targeting moiety interactions, (2) development of controlled drug delivery systems, as well as (3) understanding drug interactions. The latter makes it possible to develop bone targeted synergistic drug delivery systems.


2. Development of macromolecular prodrug for rheumatoid arthritis [2]

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is considered to be one of the major public health problems worldwide. The development of therapies that target tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and co-stimulatory pathways that regulate the immune system have revolutionized the care of patients with RA. Despite these advances, many patients continue to experience symptomatic and functional impairment. To address this issue, more recent therapies that have been developed are designed to target intracellular signaling pathways involved in immunoregulation. Though this approach has been encouraging, there have been major challenges with respect to off-target organ side effects and systemic toxicities related to the widespread distribution of these signaling pathways in multiple cell types and tissues. These limitations have led to an increasing interest in the development of strategies for the macromolecularization of anti-rheumatic drugs, which could target them to the inflamed joints. This approach enhances the efficacy of the therapeutic agent with respect to synovial inflammation, while markedly reducing non-target organ adverse side effects. In this manuscript, we provide a comprehensive overview of the rational design and optimization of macromolecular prodrugs for treatment of RA. The superior and the sustained efficacy of the prodrug may be partially attributed to their Extravasation through Leaky Vasculature and subsequent Inflammatory cell-mediated Sequestration (ELVIS) in the arthritic joints. This biologic process provides a plausible mechanism, by which macromolecular prodrugs preferentially target arthritic joints and illustrates the potential benefits of applying this therapeutic strategy to the treatment of other inflammatory diseases.

 

3. Peptide-based delivery to bone [3]

Abstract

Peptides are attractive as novel therapeutic reagents, since they are flexible in adopting and mimicking the local structural features of proteins. Versatile capabilities to perform organic synthetic manipulations are another unique feature of peptides compared to protein-based medicines, such as antibodies. On the other hand, a disadvantage of using a peptide for a therapeutic purpose is its low stability and/or high level of aggregation. During the past two decades, numerous peptides were developed for the treatment of bone diseases, and some peptides have already been used for local applications to repair bone defects in the clinic. However, very few peptides have the ability to form bone themselves. We herein summarize the effects of the therapeutic peptides on bone loss and/or local bone defects, including the results from basic studies. We also herein describe some possible methods for overcoming the obstacles associated with using therapeutic peptide candidates.


4. Growth factor delivery: How surface interactions modulate release in vitro and in vivo [4]

Abstract

Biomaterial scaffolds have been extensively used to deliver growth factors to induce new bone formation. The pharmacokinetics of growth factor delivery has been a critical regulator of their clinical success. This review will focus on the surface interactions that control the non-covalent incorporation of growth factors into scaffolds and the mechanisms that control growth factor release from clinically relevant biomaterials. We will focus on the delivery of recombinant human bone morphogenetic protein-2 from materials currently used in the clinical practice, but also suggest how general mechanisms that control growth factor incorporation and release delineated with this growth factor could extend to other systems. A better understanding of the changing mechanisms that control growth factor release during the different stages of preclinical development could instruct the development of future scaffolds for currently untreatable injuries and diseases.


5. Biomaterial delivery of morphogens to mimic the natural healing cascade in bone[5]

Abstract

Complications in treatment of large bone defects using bone grafting still remain. Our understanding of the endogenous bone regeneration cascade has inspired the exploration of a wide variety of growth factors (GFs) in an effort to mimic the natural signaling that controls bone healing. Biomaterial-based delivery of single exogenous GFs has shown therapeutic efficacy, and this likely relates to its ability to recruit and promote replication of cells involved in tissue development and the healing process. However, as the natural bone healing cascade involves the action of multiple factors, each acting in a specific spatiotemporal pattern, strategies aiming to mimic the critical aspects of this process will likely benefit from the usage of multiple therapeutic agents. This article reviews the current status of approaches to deliver single GFs, as well as ongoing efforts to develop sophisticated delivery platforms to deliver multiple lineage-directing morphogens (multiple GFs) during bone healing.

6. Studies of bone morphogenetic protein-based surgical repair[6]

Abstract

Over the past several decades, recombinant human bone morphogenetic proteins (rhBMPs) have been the most extensively studied and widely used osteoinductive agents for clinical bone repair. Since rhBMP-2 and rhBMP-7 were cleared by the U.S. Food and Drug Administration for certain clinical uses, millions of patients worldwide have been treated with rhBMPs for various musculoskeletal disorders. Current clinical applications include treatment of long bone fracture non-unions, spinal surgeries, and oral maxillofacial surgeries. Considering the growing number of recent publications related to clincal research of rhBMPs, there exists enormous promise for these proteins to be used in bone regenerative medicine. The authors take this opportunity to review the rhBMP literature paying specific attention to the current applications of rhBMPs in bone repair and spine surgery. The prospective future of rhBMPs delivered in combination with tissue engineered scaffolds is also reviewed.


7. Strategies for controlled delivery of growth factors and cells for bone regeneration[7]

Abstract

The controlled delivery of growth factors and cells within biomaterial carriers can enhance and accelerate functional bone formation. The carrier system can be designed with pre-programmed release kinetics to deliver bioactive molecules in a localized, spatiotemporal manner most similar to the natural wound healing process. The carrier can also act as an extracellular matrix-mimicking substrate for promoting osteoprogenitor cellular infiltration and proliferation for integrative tissue repair. This review discusses the role of various regenerative factors involved in bone healing and their appropriate combinations with different delivery systems for augmenting bone regeneration. The general requirements of protein, cell and gene therapy are described, with elaboration on how the selection of materials, configurations and processing affects growth factor and cell delivery and regenerative efficacy in both in vitro and in vivo applications for bone tissue engineering.

8. Bone repair cells for craniofacial regeneration[8]

Abstract

Reconstruction of complex craniofacial deformities is a clinical challenge in situations of injury, congenital defects or disease. The use of cell-based therapies represents one of the most advanced methods for enhancing the regenerative response for craniofacial wound healing. Both somatic and stem cells have been adopted in the treatment of complex osseous defects and advances have been made in finding the most adequate scaffold for the delivery of cell therapies in human regenerative medicine. As an example of such approaches for clinical application for craniofacial regeneration, Ixmyelocel-T or bone repair cells are a source of bone marrow derived stem and progenitor cells. They are produced through the use of single pass perfusion bioreactors for CD90+ mesenchymal stem cells and CD14+ monocyte/macrophage progenitor cells. The application of ixmyelocel-T has shown potential in the regeneration of muscular, vascular, nervous and osseous tissue. The purpose of this manuscript is to highlight cell therapies used to repair bony and soft tissue defects in the oral and craniofacial complex. The field at this point remains at an early stage, however this review will provide insights into the progress being made using cell therapies for eventual development into clinical practice.


9. Gene therapy approaches to regenerating bone[9]

Abstract

Bone formation and regeneration therapies continue to require optimization and improvement because many skeletal disorders remain undertreated. Clinical solutions to nonunion fractures and osteoporotic vertebral compression fractures, for example, remain suboptimal and better therapeutic approaches must be created. The widespread use of recombinant human bone morphogenetic proteins (rhBMPs) for spine fusion was recently questioned by a series of reports in a special issue of The Spine Journal, which elucidated the side effects and complications of direct rhBMP treatments. Gene therapy – both direct (in vivo) and cell-mediated (ex vivo) – has long been studied extensively to provide much needed improvements in bone regeneration. In this article, we review recent advances in gene therapy research whose aims are in vivo or ex vivo bone regeneration or formation. We examine appropriate vectors, safety issues, and rates of bone formation. The use of animal models and their relevance for translation of research results to the clinical setting are also discussed in order to provide the reader with a critical view. Finally, we elucidate the main challenges and hurdles faced by gene therapy aimed at bone regeneration as well as expected future trends in this field.

10. Gene delivery to bone[10]

Abstract

Gene delivery to bone is useful both as an experimental tool and as a potential therapeutic strategy. Among its advantages over protein delivery are the potential for directed, sustained and regulated expression of authentically processed, nascent proteins. Although no clinical trials have been initiated, there is a substantial pre-clinical literature documenting the successful transfer of genes to bone, and their intraosseous expression. Recombinant vectors derived from adenovirus, retrovirus and lentivirus, as well as non-viral vectors, have been used for this purpose. Both ex vivo and in vivo strategies, including gene-activated matrices, have been explored. Ex vivo delivery has often employed mesenchymal stem cells (MSCs), partly because of their ability to differentiate into osteoblasts. MSCs also have the potential to home to bone after systemic administration, which could serve as a useful way to deliver transgenes in a disseminated fashion for the treatment of diseases affecting the whole skeleton, such as osteoporosis orosteogenesis imperfecta. Local delivery of osteogenic transgenes, particularly those encoding bone morphogenetic proteins, has shown great promise in a number of applications where it is necessary to regenerate bone. These include healing large segmental defects in long bones and the cranium, as well as spinal fusion and treating avascular necrosis.

11. RNA therapeutics targeting osteoclast-mediated excessive bone resorption[11]

Abstract

RNA interference (RNAi) is a sequence-specific post-transcriptional gene silencing technique developed with dramatically increasing utility for both scientific and therapeutic purposes. Short interfering RNA (siRNA) is currently exploited to regulate protein expression relevant to many therapeutic applications, and commonly used as a tool for elucidating disease-associated genes. Osteoporosis and their associated osteoporotic fragility fractures in both men and women are rapidly becoming a global healthcare crisis as average life expectancy increases worldwide. New therapeutics are needed for this increasing patient population. This review describes the diversity of molecular targets suitable for RNAi-based gene knock down in osteoclasts to control osteoclast-mediated excessive bone resorption. We identify strategies for developing targeted siRNA delivery and efficient gene silencing, and describe opportunities and challenges of introducing siRNA as a therapeutic approach to hard and connective tissue disorders.

Bibliography

[1] S. A. Low and J. Kopeček, “Targeting polymer therapeutics to bone,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1189–1204, Sep. 2012.

[2] F. Yuan, L. Quan, L. Cui, S. R. Goldring, and D. Wang, “Development of macromolecular prodrug for rheumatoid arthritis,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1205–1219, Sep. 2012.

[3] K. Aoki, N. Alles, N. Soysa, and K. Ohya, “Peptide-based delivery to bone,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1220–1238, Sep. 2012.

[4] W. J. King and P. H. Krebsbach, “Growth factor delivery: How surface interactions modulate release in vitro and in vivo,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1239–1256, Sep. 2012.

[5] M. Mehta, K. Schmidt-Bleek, G. N. Duda, and D. J. Mooney, “Biomaterial delivery of morphogens to mimic the natural healing cascade in bone,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1257–1276, Sep. 2012.

[6] K. W.-H. Lo, B. D. Ulery, K. M. Ashe, and C. T. Laurencin, “Studies of bone morphogenetic protein-based surgical repair,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1277–1291, Sep. 2012.

[7] T. N. Vo, F. K. Kasper, and A. G. Mikos, “Strategies for controlled delivery of growth factors and cells for bone regeneration,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1292–1309, Sep. 2012.

[8] G. Pagni, D. Kaigler, G. Rasperini, G. Avila-Ortiz, R. Bartel, and W. V. Giannobile, “Bone repair cells for craniofacial regeneration,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1310–1319, Sep. 2012.

[9] N. Kimelman Bleich, I. Kallai, J. R. Lieberman, E. M. Schwarz, G. Pelled, and D. Gazit, “Gene therapy approaches to regenerating bone,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1320–1330, Sep. 2012.

[10] C. H. Evans, “Gene delivery to bone,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1331–1340, Sep. 2012.

[11] Y. Wang and D. W. Grainger, “RNA therapeutics targeting osteoclast-mediated excessive bone resorption,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1341–1357, Sep. 2012.

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Mitochondria: More than just the “powerhouse of the cell”

Posted in Biological Networks, Gene Regulation and Evolution, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Personalized and Precision Medicine & Genomic Research, tagged , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , on July 9, 2012| 16 Comments »

Author and Curator: Ritu Saxena, Ph.D.

Consultants: Aviva Lev-Ari, PhD, RN and Pnina G. Abir-Am, PhD

CONTENT:

Section I   : Mitochondrial diseases and molecular understanding

Section II  : Diagnosis and therapy of mitochondrial diseases

Section III: Mitochondria, metabolic syndrome and research

I. MITOCHONDRIAL DISEASES and MOLECULAR UNDERSTANDING

Mitochondrial cytopathy in adults – current understanding:

Mitochondrial cytopathies are a diverse group of inherited and acquired disorders that result in inadequate energy production leading to illnesses. Several syndromes have been linked to mutations in mitochondrial DNA. Some key features common to mitochondrial diseases are listed as follows:

  • Diverse manifestations of mitochondrial diseases: Although all mitochondrial diseases have the same characteristic of inadequate energy production as compared to the demand, they seem to show diverse manifestations in the form of organs being affected, age of onset and the rate of progression. Reason lies in the unique genetic makeup of mitochondria. The percentage of mtDNA carrying defects varies when the ovum divides and one daughter cells receiving more defective mtDNA and the other receiving less. Hence, successive divisions may lead to accumulation of defects in one of the developing organs or tissues. Since the process in which defective mtDNA becomes concentrated in an organ is random, this may account for the differing manifestations among patients with the same genetic defect. Also, somatic mutations and mutations occurring as a result of exposure to environmental toxins may cause mitochondrial diseases.

As stated by Robert K. Naviaux, founder and co-director of the Mitochondrial and Metabolic Disease Center (MMDC) at the University of California, San Diego;  

“It is a hallmark of mitochondrial diseases that identical mtDNA mutations may not produce identical diseases…the converse is also true, different mutations can lead to the same diseases.”

  • Postmitotic tissues are more vulnerable to mitochondrial diseases: Postmitotic tissues such as those in the brain, muscles, nerves, retinas, and kidneys, are vulnerable for several reasons. Apart from the fact that these tissues have high-energy demands, healthier neighboring cells unlike that observed in skin cannot replace the diseased cells. Thus, mutations in mtDNA accumulate over a period of time resulting in progressive dysfunction of individual cells and hence the organ itself.
  • High rate of mtDNA mutation: MtDNA mutates at rate that is six-seven times higher than the rate of mutation of nuclear DNA. First reason is the absence of histones on mtDNA and second is the exposure of mtDNA to free radicals due to their close proximity to electron transport chain. Additionally, lack of DNA repair enzymes results in mutant tRNA, rRNA and protein transcripts

Spectrum of mitochondrial diseases:

Following is the list of mitochondrial diseases occurring as a result of either mtDNA mutations, alteration in mitochondrial function or those diseases that sometimes might be associated with mitochondrial dysfunction.

  • Disorders associated with mtDNA mutations-

MELAS, MERRF, NARP, Myoneurogastrointestinal disorder and encephalopathy (MNGIE), Pearson Marrow syndrome Kearns-Sayre-CPEO, Leber hereditary optic neuropathy (LHON), Aminoglycoside-associated deafness, Diabetes with deafness

  • Mendelian disorders of mitochondrial function related to fuel homeostasis-

Luft disease, Leigh syndrome (Complex I, COX, PDH), Alpers Disease, MCAD, SCAD, SCHAD, VLCAD, LCHAD, Glutaric aciduria II, Lethal infantile cardiomyopathy, Friedreich ataxia, Maturity onset diabetes of young Malignant hyperthermia, Disorders of ketone utilization, mtDNA depletion syndrome, Reversible COX deficiency of infancy, Various defects of the Krebs Cycle, Pyruvate dehydrogenase deficiency, Pyruvate carboxylase deficiency, Fumarase deficiency, Carnitine palmitoyl transferase deficiency

  • Disorders sometimes associated with mitochondrial function-

Hemochromatosis, Wilson disease, Batten disease, Huntington disease, Menkes disease, Lesch-Nyhan syndrome, Aging, Type II diabetes mellitus, Atherosclerotic heart disease, Parkinson disease, Alzheimer dementia, Congestive heart failure, Niacin-responsive hypercholesterolemia, Postpartum cardiomyopathy, Alcoholic myopathy, Cancer metastasis, Irritable bowel syndrome Gastroparesis-GI dysmotility, Multiple sclerosis, Systemic lupus erythematosis, Rheumatoid arthritis.

II. DIAGNOSIS AND THERAPY OF MITOCHONDRIAL DISEASES

Diagnosis:

Owing to the diversity of symptoms, there is no accepted criterion for diagnosis. Also, due to overlapping symptoms of several diseases with those of mitochondrial dysfunction illnesses, it is important to evaluate the patient for other conditions. A diagnosis could involve combination of molecular genetic, pathologic, or biochemical data in a patient who has clinical features consistent with the diagnosis including mutational analysis on blood lymphocytes and possibly muscle biopsy for visual and biochemical analysis.

The two main biochemical features in most mtDNA disorders are:

  1. Respiratory chain deficiency and
  2. Lactic acidosis.

Skeletal muscle is chosen to study the pathogenic consequence of mtDNA mutations because of the formation of ragged-red fibers (RRF) through mitochondrial proliferation and massive mitochondrial accumulation in many pathogenic situations. RRF can be detected in two ways. Mitochondrial fibers in a subset of these fibers are shown by red or purple stained area by Gomori trichrome stain; the normal or less-affected fibers stain blue or turquoise. Deep purple areas show accumulations of mitochondria as activity of succinate dehydrogenase (SDH) in the case of mitochondrial mutation.

The primary care physician should remember this relatively simple rule of thumb: “When a common disease has features that set it apart from the pack, or involves 3 or more organ systems, think mitochondria.”

Treatment:

There are no cures for mitochondrial diseases; therefore, the treatment is focused on alleviating symptoms and enabling normal functioning of the affected organs. Most patients have used cofactor and vitamins; however, there is no overwhelming evidence that they are helpful in most patients.

  • Coenzyme Q10 (CoQ10) is the best-known cofactor used in treating mitochondrial cytopathies with no known side effects. CoQ10, residing in the inner mitochondrial membrane, functions as the mobile electron carrier and is a powerful antioxidant with benefits such as reduction in lactic acid levels, improved muscle strength, decreased muscle fatigue and so on.
  • Levocarnitine (L-carnitine, carnitine), is a cofactor required for the metabolism of fatty acids. Levocarnitine therapy improves strength, reversal of cardiomyopathy, and improved gastrointestinal motility, which can be a major benefit to those with poor motility due to their disease. Intestinal cramping and pain are the major side effects.
  • Creatine phosphate, synthesized from creatine can accumulate in small amounts in the body, and can act as storage for a high-energy phosphate bond. Muscular creatine may be depleted in mitochondrial cytopathy, and supplemental creatine phosphate has been shown to be helpful in some patients with weakness due to their disease.
  • B Vitamin, are necessary for the function of several enzymes associated with energy production. The need for supplemental B vitamin therapy is not proven, aside from rare cases of thiamine (vitamin B1)-responsive pyruvate dehydrogenase deficiency.

Research – Restriction enzyme for gene therapy of Mitochondria diseases:

Mitochondrial DNA (mtDNA) is the only extrachromosomal DNA in humans and defects in this genome are now recognized as important causes of various diseases. Presently, there is no effective treatment for patients suffering from diseases that harbor mutations in mtDNA.

Tanaka et al discovered a gene therapy method to treat a mitochondrial disease associated with mtDNA heteroplasmy. Heteroplasmy is where mutant and wild-type mtDNA molecules co-exist within cells. This syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) is caused by mutations in mtDNA leading to amino acid replacement in the resulting protein that codes for a subunit of mitochondrial ATP synthase. Level of mutant mtDNA is crucial for the disease as above a certain threshold level of mtDNA, the disease becomes biochemically and clinically apparent. Authors hypothesized that a possible method to treat patients was by selectively destroying mutant mtDNA, thereby only allowing propagation of wild-type mtDNA. Since restriction endonucleases can recognize highly specific sequences, they were utilized for gene therapy. Tanaka et al utilized Sma1, a restriction endonuclease to destroy mutant mtDNA, leading to increase in wild-type mtDNA levels.

Thus, authors concluded, “ the present results indicate that the use of a mitochondrion-targeted restriction enzyme which specifically recognizes a mutant mtDNA provides a novel strategy for gene therapy of mitochondrial diseases.”

III. MITOCHONDRIA, METABOLIC SYNDROME & RESEARCH

Mitochondria:

Mitochondria are double-membrane organelles located in the cytoplasm and often referred to as the “powerhouse” of the cell. In simple terms, they convert energy into forms that are usable by the cell. Mitochondria are semi-autonomous in that they are only partially dependent on the cell to replicate and grow. They have their own DNA, ribosomes, and can make their own proteins. They are the sites of cellular respiration that generates fuel for the cell’s activities. Mitochondria are also involved in other cell processes such as cell division, cellular growth and cell death. Multiple essential cellular functions are mediated by thousands of mitochondrial-specific proteins, encoded by both the nuclear and mitochondrial genomes.

Interestingly, mitochondria take on many different shapes and along with serving several different metabolic functions. In fact, each mitochondrion’s shape is characteristic of the specialized cell in which it resides. The number of mitochondria too varies in difference cell types, with as high as 500-2000 in some nucleated cells and as low as zero in RBCs and 2-6 in platelets.

The standard sequence to which all human mtNDNA is compared is referred to as the “Cambridge Sequence.” It was sequenced from several different human mtDNAs by a Medical Research Council (MRC) labora- tory based at Cambridge, UK, in 1981 and as a part of this work, Fred Sanger, the received his second Nobel Prize. Several variations in the form of polymorphisms are observed from the Cambridge sequence in the mtDNA of different individuals.

Metabolic syndrome:

Metabolic syndrome is a cluster of conditions — increased blood pressure, a high blood sugar level, excess body fat around the waist or abnormal cholesterol levels — that occur together, increasing your risk of heart disease, stroke and diabetes. Metabolic syndrome is becoming more and more common in the United States. In the future, it may overtake smoking as the leading risk factor for heart disease. In general, a person who has metabolic syndrome is twice as likely to develop heart disease and five times as likely to develop diabetes as someone who doesn’t have metabolic syndrome.

The five conditions described below are metabolic risk factors. You must have at least three metabolic risk factors to be diagnosed with metabolic syndrome.

  • A large waistline. This also is called abdominal obesity or “having an apple shape.” Excess fat in the stomach area is a greater risk factor for heart disease than excess fat in other parts of the body, such as on the hips.
  • A high triglyceride level (or you’re on medicine to treat high triglycerides). Triglycerides are a type of fat found in the blood.
  • A low HDL cholesterol level (or you’re on medicine to treat low HDL cholesterol). HDL sometimes is called “good” cholesterol. This is because it helps remove cholesterol from your arteries. A low HDL cholesterol level raises your risk for heart disease.
  • High blood pressure (or you’re on medicine to treat high blood pressure). Blood pressure is the force of blood pushing against the walls of your arteries as your heart pumps blood. If this pressure rises and stays high over time, it can damage your heart and lead to plaque buildup.
  • High fasting blood sugar (or you’re on medicine to treat high blood sugar). Mildly high blood sugar may be an early sign of diabetes.

Role of Mitochondria in Metabolic Syndrome & Diabetes:

Impaired mitochondrial function has recently emerged as a potential causes of insulin resistance and/or diabetes progression, risk factors of metabolic syndrome.

Mitochondria plays several key functions including generation of ATP, and generating metabolites via Tricarboxylic acid cycle that function in cytosolic pathways, oxidative catabolism of amino acids, ketogenesis, urea cycle; the generation of reactive oxygen species (ROS); the control of cytoplasmic calcium; and the synthesis of all cellular Fe/S clusters, protein cofactors essential for cellular functions such as protein translation and DNA repair. These roles define the mitochondria to be involved in metabolic homeostasis and hence, a major candidate for metabolic syndrome and its associated risk factor including diabetes, obesity and insulin resistance.

Research and Therapeutic relevance:

Understanding the underlying molecular mechanism of aberrant role of mitochondria is important in developing therapeutic agents for mitochondria-associated diseases. In the recent issue of Mitonews, several papers have been published using the products of MitoSciences, which describe research pertaining to the importance of mitochondria in obesity and diabetes. Some recent research articles based on mitochondrial research (also mentioned in MitoNews) have been briefly discussed here:

  • Metabolic inflexibility and Metabolic syndrome: Metabolic inflexibility is defined as the failure of insulin-resistant patients to appropriately adjust mitochondrial fuel selection in response to nutritional cues. Although the phenomenon has been emphasized an important aspect of metabolic syndrome, the molecular mechanisms have not yet been fully deciphered. In a recent article by Muoio et al, published in Cell Metabolism journal, essential role of the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT) has been identified in regulating substrate switching and glucose tolerance. CrAT regulates mitochondrial and intracellular Carbon trafficking by converting acetyl-CoA to its membrane permeant acetylcarnitine ester. Using muscle muscle-specific Crat knockout mice, primary human skeletal myocytes, and human subjects undergoing L-carnitine supplementation, authors have suggested a model wherein CrAT combats nutrient stress, promotes metabolic flexibility, and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase. These findings offer therapeutically relevant insights into the molecular basis of metabolic inflexibility.
  • Rosiglitazone and obesity: Eepicardial adipose tissue (EAT) has been described in humans as a functioning brown adipose tissue (BAT) and has been shown in animal models to have a lower glucose oxidation rate and higher fatty acid (FA) metabolism. In obese individuals, epicardial adipose tissue (EAT) is “hypertrophied”. EAT is a source of BAT may be a source of proinflamatory cytokines. Distel et al published their studies using a rat model of obesity and insulin resistance treated with rosiglitazone. They observed that rosiglitazone, promoted a BAT phenotype in the EAT depot characterized by an increase in the expression levels of genes encoding proteins involved in mitochondrial processing and density PPARγ coactivator 1 alpha (PGC-1α), NADH dehydrogenase 1 and cytochrome oxidase (COX4) resulting in significant up-regulation of PGC1-α and COX4 protein. The authors concluded that PPAR-γ agonist could induce a rapid browning of the EAT that probably contributes to the increase in lipid turnover. Thus, important insights into the mechanism of fat metabolism and involvement of mitochondrial proteins with a therapy were presented in the article.
  • Mitochondrial dysfunction and diabetic neuropathy: Animal models of diabetic neuropathy show that mitochondrial dysfunction occurs in sensory neurons that may contribute to distal axonopathy. The adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of AMPK and PGC-1α is decreased under hyperglycaemia. Chowdhury et al using type 1 and type 2 diabetic rat and mice models studied the hypothesis that deficits in AMPK/PGC-1 signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy. The authors have shown there is a significant reduction in phospho-AMPK, phopho-ACC, total PGC-1α, NDUFS3and COXIV in sensory neurons of the dorsal root ganglia of 14 week old diabetic mice with marked signs of thermal hypoalgesia. These results were associated with an impaired neuronal bioenergetic profile and a decrease in the activity of mitochondrial complex I, complex IV and citrate synthase. The fact that resveratrol treatment reversed the changes observed in vitro and in vivo suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the AMPK/PGC-1α pathway.
  • ROS and diabetes: Mitochondria generated reactive oxygen species (ROS) has been associated with kidney damage occurring in diabetes. Rosca et al, published an article investigating the source and site of ROS production by kidney cortical tubule mitochondria in streptozotocin-induced type 1 diabetes in rats. The authors observed that in diabetic mitochondria, the fatty acid oxidation enzymes were elevated with increased oxidative phosphorylation and increased ROS production. The authors observed ROS production with fatty acid oxidation remained unchanged by limiting electron flow in ETC complexes, changes in ETC substrate processing and that the ROS supported by pyruvate also remained unaltered. The authors hence concluded that mitochondrial fatty acid oxidation is the source of increased ROS production in kidney cortical tubules in early diabetes

Sources:

http://www.ncbi.nlm.nih.gov/pubmed/11453081

http://health.cat/open.php?url=http://biochemgen.ucsd.edu/mmdc/ep-3-10.pdf

http://findarticles.com/p/articles/mi_go2827/is_n6_v27/ai_n28687375/

http://www.columbiamitodiagnostics.org/images/Mitobrochure.pdf

http://www.ncbi.nlm.nih.gov/pubmed?term=12372991

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0004546/

http://www.mayoclinic.com/health/metabolic%20syndrome/DS00522

http://www.nhlbi.nih.gov/health/health-topics/topics/ms/

http://www.ncbi.nlm.nih.gov/pubmed?term=22560225

http://www.ncbi.nlm.nih.gov/pubmed?term=%20%20%20%2022575275

http://www.ncbi.nlm.nih.gov/pubmed?term=%20%20%20%2022561641

http://www.mitosciences.com/mitonews_08_06.html

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