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Li -Fraumeni Syndrome and Pancreatic Cancer

Posted in Cancer Screening, Cell Biology, Genome Biology, Genomic Testing: Methodology for Diagnosis, Li-fraumeni syndrome., Mutagenesis, TP53 - Germline mutations, Variation in human protein-coding regions, tagged gene therapy, Li-fraumeni syndrome., Pancreatic cancer, PRIMA-1, TP53 on December 14, 2016| Leave a Comment »

Li -Fraumeni Syndrome and Pancreatic Cancer

Curator: Marzan Khan, B.Sc.

Li-Fraumeni syndrome (LFS) is a condition that makes individuals prone to developing a wide variety of cancers that occur early on in life, the most common types being- soft tissue sarcoma, osteosarcoma, breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemia. (1) Pancreatic cancer is minimally associated with the condition. (2) A survey found the presence of pancreatic cancer in only 1% of 475 tumor samples collected from 91 families who were carriers of p53 mutations, with half of them having LFS. The incidence of breast cancer amongst them was the highest -24%. (2) Pancreatic carcinoma in LFS patients usually occurs in the later stages of life. (3)

The underlying cause of LFS is germline mutations in TP53 gene on chromosome 17p, that encodes the transcription factor p53, crucial in cell cycle regulation and the repair of damaged and/or abnormal cells. (4) In the majority of cases, this mutation is obtained by inheritance. (5) De-novo germline mutations in p53 occur in 7%-20% of the cases. (5)

A person showing symptoms of any type of cancer at an early age or having first or second-degree relatives with cancer are at risk of developing LFS. (5) That is why tracing family history is an important part of diagnosis in LFS patients. Genetic testing can confirm mutations present in the gene, however, there are controversial ethical issues regarding their use, particularly in children and fetuses.

In patients with LFS, it is important to control the manifestations of the disease. They should be monitored closely so that any new cancers that arise are diagnosed and treated during the early stages. (6) Patients are also at risk of developing radiation-induced second and third primary tumors. (6) Therefore, radiation and alkylating agents should be used minimally (6) People at risk can be cautioned to avoid exposure to carcinogens such as sunlight, cigarette smoke, and alcohol consumption. (5) Therapeutic approaches that are aimed at restoring wild-type p53 by gene therapy as well as reactivating non-functional p53 by the use of small-molecule drugs are currently being investigated in many cancers. (7) Unlike radiation therapy, these small-molecule drugs are non-toxic to healthy cells, thus eliminating the risk of forming new tumors.

So far, PRIMA-1 has proven to be quite effective at correcting non-functional p53. (8) PRIMA-1 is changed to its methylated form, PRIMA-1^METthat forms covalent adducts to thiol groups in the mutated protein and modifies them. (8) As a result, p53 regains its ability to destroy malignant cells. (8) A research study also found that PRIMA-1 induces apoptosis and increases the sensitivity of pancreatic cancer cells to various chemotherapeutic agents. (9)

Magali Olivier, David E. Goldgar, Nayanta Sodha, Hiroko Ohgaki, Paul Kleihues, Pierre Hainaut and Rosalind A. Eeles. Li-Fraumeni and Related Syndromes. Cancer Res October 15 2003 63 (20) 6643-6650 http://cancerres.aacrjournals.org/content/63/20/6643.abstract
Kleihues P, Schauble B, zur Hausen H, et al. Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol 1997; 150:1-13 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1858532/
John P. Neoptolemos, Raul Urrutia, James L. Abbruzzese, Markus W. Buchler. Pancreatic Cancer. 2010.1^st ed, pp-6, 2010, Springer, Verlag, New York
Mishra B and Patel RR. Gene Therapy for Treatment of Pancreatic Cancer. Austin Therapeutics. 2014;1(1): 10. https://books.google.ca/books?id=NmBB5ZoKkk4C&pg=PA6&lpg=PA6&dq=connection+between+li+fraumeni+and+Pancreatic+cancer&source=bl&ots=H0iCeaPP0N&sig=pqJT1tPMR6C-NIig3S_NkFKFsD0&hl=en&sa=X&ved=0ahUKEwi4nLrgzuPQAhUUIWMKHS3wBoc4ChDoAQhNMAg#v=onepage&q=connection%20between%20li%20fraumeni%20and%20Pancreatic%20cancer&f=false
Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni Syndrome. 1999 Jan 19 [Updated 2013 Apr 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. https://www.ncbi.nlm.nih.gov/pubmed/20301488
Elisa Becze BA, ELS, 2011 Mar 1. An introduction to Li-Fraumeni Syndrome, Five-Minute-In-Service. http://connect.ons.org/columns/five-minute-in-service/an-introduction-to-li-fraumeni-syndrome
Sorrell, A. D., Espenschied, C. R., Culver, J. O., & Weitzel, J. N. (2013).TP53Testing and Li-Fraumeni Syndrome: Current Status of Clinical Applications and Future Directions. Molecular Diagnosis & Therapy, 17(1), 31–47. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627545/
Emily J. Lewis. PRIMA-1 as a cancer therapy restoring mutant p53: a reviewBioscience Horizons (2015) 8: hzv006 http://biohorizons.oxfordjournals.org/content/8/hzv006.full
Izetti, Patricia, Agnes Hautefeuille, Ana Lucia Abujamra, Caroline Brunetto de Farias, Juliana Giacomazzi, Bárbara Alemar, Guido Lenz, et al. ‘PRIMA-1, a Mutant p53 Reactivator, Induces Apoptosis and Enhances Chemotherapeutic Cytotoxicity in Pancreatic Cancer Cell Lines’. Investigational New Drugs 32, no. 5 (October 2014): 783–94. https://www.ncbi.nlm.nih.gov/pubmed/24838627

Izetti, Patricia, Agnes Hautefeuille, Ana Lucia Abujamra, Caroline Brunetto de Farias, Juliana Giacomazzi, Bárbara Alemar, Guido Lenz, et al. ‘PRIMA-1, a Mutant p53 Reactivator, Induces Apoptosis and Enhances Chemotherapeutic Cytotoxicity in Pancreatic Cancer Cell Lines’. Investigational New Drugs 32, no. 5 (October 2014): 783–94

Mid Atlantic LRIG 22nd Annual Technology Showcase: Agenda on 3D Bioprinting on Wednesday, May 11, 2016; Somerset NJ

Posted in 3D Plotting Scaffolds, 3D Printing for Medical Application, Drug Delivery Platform Technology, tagged 3D bioprinting, advances in drug development, Cell therapy, Clinical Laboratory Automation, gene therapy, scientific meeting on April 16, 2016| Leave a Comment »

Mid Atlantic LRIG 22nd Annual Technology Showcase: Agenda on 3D Bioprinting on Wednesday, May 11, 2016 at Holiday Inn, 195 Davidson Avenue, Somerset, NJ

Reporter: Stephen J. Williams, Ph.D.

Symposium Speakers and Topics:

Human Organoids
Hatem E. Sabaawy-Director, Production GMP Facility for Cell and Gene Therapy, RBHS-Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey

Intestinal Organoids for Drug Discovery
Richard Visconti-Associate Principal Scientist, Cellular Pharmacology, Merck Research Laboratories, Kenilworth, New Jersey

3D Bioprinting
Elizabeth Wu-President, WuZenTech, Edison, New Jersey

Building Your Brand Through LinkedIn
Stan Robinson, Jr., LinkedIn Consultant, Helping Professionals with Social Selling, Personal Branding

Register at EventBrite here: https://www.eventbrite.com/e/mid-atlantic-22nd-annual-technology-and-exhibition-tickets-21359945171

To sign up to be an LRIG member or update your profile, please visit us at http://lrig.org
Hoping to see you on May 11th.
R eserve your spot today!

AGTC (AGTC) , An adenoviral gene therapy startup, expands in Florida with help from $1 billion deal with Biogen

Posted in Genetics & Innovations in Treatment, Genome Biology, Investment in Technological Breakthrough, Medical Devices R&D Investment, tagged AAV, adenovirus, biotech startup, gene therapy, genetic diseases, Global Partnering & Biotech Investment, startup, Venture capital on February 17, 2016| Leave a Comment »

AGTC (AGTC) , An adenoviral gene therapy startup, expands in Florida with help from $1 billion deal with Biogen

Reporter: Stephen J. Williams, Ph.D.

from Biospace News

AGTC Sets Up Shop in Florida, New Facility to House 75 Employees
February 17, 2016
By Alex Keown, BioSpace.com Breaking News Staff

GAINESVILLE, Fla. — Applied Genetic Technologies Corporation (AGTC), a biotechnology company researching adeno-associated virus (AAV)-based gene therapies for the treatment of rare diseases, is expanding into the rapidly growing north central Florida biotech corridor.

The company, which was founded on technology developed at the University of Florida, is opening a combined use corporate office and laboratory facility in Alachua, Fla. AGTC’s portion of the new multi-tenant facility is expected to accommodate up to about 75 people and consists of approximately 20,000 square feet including state-of-the-art lab and office space as well as space for future expansion, the company announced this morning.

“The new facility will help us to accelerate our research and development efforts for novel AAV-based gene therapies for rare diseases and house critical corporate functions including finance, quality assurance and project management, while providing ample space as we continue to bring new talent to our team,” Sue Washer, president and chief executive officer of AGTC said in a statement.

AGTC’s lead product candidates focus on X-linked retinoschisis, achromatopsia and X-linked retinitis pigmentosa, which are inherited orphan diseases of the eye, caused by mutations in single genes that significantly affect visual function and currently lack effective medical treatments. Retinoschisis is a condition in which an area of the retina has separated into two layers. The part of the retina that is affected by retinoschisis will have suboptimal vision, according to the University of Michigan’s Kellogg Eye Center. Achromatopsia is a condition of the eye that is characterized by an absence (partial or total) of color vision. People with the complete form of achromatopsia are unable to perceive any colors and can only see black, white and shades of gray.

AGTC is also pursuing pre-clinical development of treatments for wet AMD using the company’s experience in ophthalmology to expand into disease indications with larger markets.

In August, AGTC’s research was bolstered by a $1 billion deal withBiogen (BIIB) to support the company’s gene-based therapies. As part of the deal, Biogen holds a license to AGTC’s XLRS and XLRP programs and an additional three licenses, BioSpace (DHX) reported in August.

David Day, assistant vice president & director of the Office of Technology Licensing at the University of Florida, touted the growth of the biotech sector in north central Florida.

“AGTC’s progress in developing novel treatments for rare diseases without adequate therapeutic options is a particularly good model for the entire biotechnology sector,” Day said in a statement.

FDA Cellular & Gene Therapy Guidances: Implications for CRSPR/Cas9 Trials

Posted in 3D Printing for Medical Application, CRISPR/Cas9 & Gene Editing, FDA, FDA Regulatory Affairs, Tissue Engineering, tagged Clinical trial, CRISPR-Cas9, Editas, FDA, FDA guidance, Food and Drug Administration, gene, gene expression, gene therapy, genetics, medicine on November 10, 2015| Leave a Comment »

FDA Cellular & Gene Therapy Guidances: Implications for CRSPR/Cas9 Trials

Reporter: Stephen J. Williams, PhD

The recent announcement by Editas CEO Katrine Bosley to pursue a CRSPR/Cas9 gene therapy trial to correct defects in an yet to be disclosed gene to treat one form of a rare eye disease called Leber congenital amaurosis (multiple mutant genes have been linked to the disease) have put an interesting emphasis on the need for a regulatory framework to initiate these trials. Indeed at the 2015 EmTechMIT Conference Editas CEO Katrine Bosley had mentioned this particular issue: the need for discourse with FDA and regulatory bodies to establish guidelines for design of clinical trials using the CRSPR gene editing tool.

See the LIVE NOTES from Editas CEO Katrine Bosley on using CRSPR as a gene therapy from the 2015 EmTechMIT Conference at http://pharmaceuticalintelligence.com/2015/11/03/live-1132015-130pm-the-15th-annual-emtech-mit-mit-media-lab-top-10-breakthrough-technologies-2015-innovators-under-35/

To this effect, I have listed below, the multiple FDA Guidance Documents surrounding gene therapy to show that, in the past year, the FDA has shown great commitment to devise a regulatory framework for this therapeutic area.

Cellular & Gene Therapy Guidance Documents

Homologous Use of Human Cells, Tissue, and Cellular and Tissue-Based Products; Draft guidance for Industry and FDA Staff (PDF – 120KB)
10/2015
Recommendations for Microbial Vectors Used for Gene Therapy; Draft Guidance for Industry (PDF – 447KB)
10/2015
Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products; Guidance for Industry (PDF – 120KB)
8/2015
Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products; Guidance for Industry (PDF – 313KB)
6/2015
Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products; Guidance for Industry
3/2015
Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) from Adipose Tissue: Regulatory Considerations; Draft Guidance for Industry
12/2014. For more information, please refer to footnote 1 in the 2015 GUIDANCE AGENDA under RESOURCES FOR YOU.
Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products: Draft Guidance for Industry and Food and Drug Administration Staff
12/2014. When finalized, this guidance will supersede the FDA guidance entitled, “Minimal Manipulation of Structural Tissue Jurisdictional Update,” September 2006. Please refer to footnote 1 in the 2015 GUIDANCE AGENDA under RESOURCES FOR YOU.
Draft Guidance for Industry: Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception
10/2014. For more information, please refer to footnote 1 in the 2015 GUIDANCE AGENDA under RESOURCES FOR YOU.
Guidance for Industry: BLA for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System (PDF – 385KB)
3/2014. (This guidance finalizes the draft guidance of the same title dated June 2013.)
Guidance for Industry and FDA Staff: IND Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System
3/2014. (This guidance finalizes the draft guidance of the same title dated June 2013.)
Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products
November 2013. (This guidance finalizes the draft guidance entitled “Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products” dated November 2012)
Guidance for Industry: Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage (PDF – 157KB)
12/2011. (This guidance finalizes the draft guidance of the same title dated July 2007.)
Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines (PDF – 75KB)
10/2011. (This guidance finalizes the draft guidance of the same title dated September 2009.)
Guidance for Industry and FDA Staff: Investigational New Drug Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications. (PDF – 104KB)
6/2011
Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products (PDF – 311KB)
1/2011. (This guidance finalizes the draft document of the same name, dated October 2008.)
Guidance for Industry: Cellular Therapy for Cardiac Disease
10/2010. (This guidance finalizes the draft guidance entitled “Guidance for Industry: Somatic Cell Therapy for Cardiac Disease” dated March 2009 (April 2, 2009, 74 FR 14992).
Draft Guidance for Industry: Assay Development for Immunogenicity Testing of Therapeutic Proteins (PDF – 161KB)
12/2009
Guidance for Industry – Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications (PDF – 462KB)
10/2009
Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products
9/2009
Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)
4/2008
Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)
4/2008
Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products
8/2007
Guidance for Industry: Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events
11/2006
Guidance for Industry: Supplemental Guidance on Testing for Replication Competent Retrovirus in Retroviral Vector Based Gene Therapy Products and During Follow-up of Patients in Clinical Trials Using Retroviral Vectors
11/2006
Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy
3/1998

Withdrawn Guidance Documents

Withdrawn – Draft Guidance for Industry: Validation of Growth-Based Rapid Microbiological Methods for Sterility Testing of Cellular and Gene Therapy Products
May 2015

Three other posts on this site goes into detail into three of the above-mentioned Guidance Documents

FDA Guidance on Use of Xenotransplanted Products in Human: Implications in 3D Printing

New FDA Draft Guidance On Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products – Implications for 3D BioPrinting of Regenerative Tissue

FDA Guidance Documents Update Nov. 2015 on Devices, Animal Studies, Gene Therapy, Liposomes

10/14/15: General Considerations for Animal Studies for Medical Devices – Draft Guidance for Industry and Food and Drug Administration Staff

FDA Guidance Documents Update Nov. 2015 on Devices, Animal Studies, Gene Therapy, Liposomes

Posted in FDA, FDA Regulatory Affairs, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Lipidomics, Liposome, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Uncategorized, tagged animal testing, Clinical trial, FDA, Food and Drug Administration, gene therapy, health on November 3, 2015| Leave a Comment »

FDA Guidance Documents Update

Reporter: Stephen J. Williams, Ph.D.

10/30/2015

You are subscribed to FDA Guidance Documents for U.S. Food & Drug Administration (FDA).

This information has recently been updated and is now available.

Recently posted guidance documents

10/14/15: Recommendations for Microbial Vectors Used for Gene Therapy; Draft Guidance for Industry

10/15/15: Draft PDEs for Triethylamine and for Methylisobutylketone

10/15/15: ICH Q3C Maintenance Procedures for the Guidance for Industry Q3C Impurities: Residual Solvents

10/19/15: CVM GFI #229 – Evaluating the Effectiveness of New Animal Drugs for the Reduction of Pathogenic Shiga Toxin-Producing E. coli in Cattle

10/21/15: Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use

10/21/15: Manufacturing Site Change Supplements: Content and Submission – Draft Guidance for Industry and Food and Drug Administration Staff

10/26/15: Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry

10/26/15: Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act

10/26/15: Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance

10/27/15: Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route

10/27/15: Product Development Under the Animal Rule

10/28/15: DSCSA Implementation: Product Tracing Requirements for Dispensers — Compliance Policy (Revised) Guidance for Industry

10/29/15: Liposome Drug Products: Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation

Guidance Document Search

• Search all FDA official guidance documents and other regulatory guidance

Source: https://www.fiercepharma.com/ai-and-machine-learning/oncologists-have-shopping-car-t-full-complaints-safety-questions-cell?utm_medium=email&utm_source=nl&utm_campaign=LS-NL-FiercePharma+Tracker&oly_enc_id=2360C5096034F3G

NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

Posted in Autologous Cell Therapy, Bioengineering & reverse engineering design, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, Computational Biology/Systems and Bioinformatics, Disease Biology, Drug Toxicity, FDA, FDA Regulatory Affairs, Genetics & Pharmaceutical, GLP, Human Immune System in Health and in Disease, Immunodiagnostics, Innovation in Immunology Diagnostics, Innovations, ISO 14155, Personalized and Precision Medicine & Genomic Research, Quality Assurance, Translational Research, tagged Adult ALL, Adverse event, Alliance for Clinical Trials in Oncology, Apoptosis, autologous transplant, B and T cell gene rearrangements, Cancer - General, CD8+ T cells, Clinical trial, clinical trial guidelines, Food and Drug Administration, gene expression, gene therapy, health, insertional mutagenesis, interleukins, medicine, National Institutes of Health, Personalized medicine, Pharmacovigilance, research, safety guidelines on September 23, 2014| Leave a Comment »

NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

Reporter: Stephen J. Williams, Ph.D.

UPDATED 5/27/2024

The practice of pharmacovigilence, both premarketing and postmarketing, has very well defined best practices concerning most small molecule drugs and even medical devices. However, for many cell based therapies and many gene based therapies, often still administered within the university, academic setting, pharmacovigilence reporting and adherence may be a not as efficient and thorough as conducted by large big pharmaceutical firms. Big pharma will devote massive resources for the conduct of pharmacovigilence data collecting and analysis. For many cell based therapies, like CAR-T therapies and some gene therapies are almost conducted as clinical trials within university medical centers, which may not have the resources for a large pharmacovigilence program.

In a report by IQVIA, oncologists were asked about their concerns with cell based therapies. A recurring concern involved the lack of information on the adverse events related to these therapies, especially after an oncologist’s patient would return from administration of their CAR-T therapy and then both patient and oncologist felt ‘on their own’.

Most recently the FDA has issued black box warning on many CAR-T therapies for their risk in inducing secondary malignancies (see What does this mean for Immunotherapy? FDA put a temporary hold on Juno’s JCAR015, Three Death of Cerebral Edema in CAR-T Clinical Trial and Kite Pharma announced Phase II portion of its CAR-T ZUMA-1 trial).

Note: the IQVIA will be submitted as an abstract at the current ASCO meeting

UPDATED 5/10/2022

In the mid to late 1970’s a public debate (and related hysteria) had emerged surrounding two emerging advances in recombinant DNA technology;

the development of vectors useful for cloning pieces of DNA (the first vector named pBR322) and
the discovery of bacterial strains useful in propagating such vectors

As discussed by D. S, Fredrickson of NIH’s Dept. of Education and Welfare in his historical review” A HISTORY OF THE RECOMBINANT DNA GUIDELINES IN THE UNITED STATES” this international concern of the biological safety issues of this new molecular biology tool led the National Institute of Health to coordinate a committee (the NIH Recombinant DNA Advisory Committee) to develop guidelines for the ethical use, safe development, and safe handling of such vectors and host bacterium. The first conversations started in 1974 and, by 1978, initial guidelines had been developed. In fact, as Dr. Fredrickson notes, public relief was voiced even by religious organizations (who had the greatest ethical concerns)

On December 16, 1978, a telegram purporting to be from the Vatican was hand delivered to the office of Joseph A. Califano, Jr., Secretary of Health, Education,

and Welfare. “Habemus regimen recombinatum,” it proclaimed, in celebration of the

end of a long struggle to revise the NIH Guidelines for Research Involving

Recombinant DNA Molecules

The overall Committee resulted in guidelines (2013 version) which assured the worldwide community that

organisms used in such procedures would have limited pathogenicity in humans
vectors would be developed in a manner which would eliminate their ability to replicate in humans and have defined antibiotic sensitivity

So great was the success and acceptance of this committee and guidelines, the NIH felt the Recombinant DNA Advisory Committee should meet regularly to discuss and develop ethical guidelines and clinical regulations concerning DNA-based therapeutics and technologies.

A PowerPoint Slideshow: Introduction to NIH OBA and the History of Recombinant DNA Oversight can be viewed at the following link:

http://www.powershow.com/view1/e1703-ZDc1Z/Introduction_to_NIH_OBA_and_the_History_of_Recombinant_DNA_Oversight_powerpoint_ppt_presentation

Please see the following link for a video discussion between Dr. Paul Berg, who pioneered DNA recombinant technology, and Dr. James Watson (Commemorating 50 Years of DNA Science):

http://media.hhmi.org/interviews/berg_watson.html

The Recombinant DNA Advisory Committee has met numerous times to discuss new DNA-based technologies and their biosafety and clinical implication including:

January 24, 2013 Biosafety Considerations for Research with Highly Pathogenic Avian Influenza Virus H5N1 that is Transmissible between Mammals by Respiratory Droplets

2012 Discussion of Gene Transfer Protocols

2008 Guidelines for HIV Vaccination Protocols Appendix M-VI-A of the NIH Guidelines (the “Vaccine Exemption”)

2006 Guidance on Biosafety Considerations for Research with Lentiviral Vectors

A recent Symposium was held in the summer of 2010 to discuss ethical and safety concerns and discuss potential clinical guidelines for use of an emerging immunotherapy technology, the Chimeric Antigen Receptor T-Cells (CART), which at that time had just been started to be used in clinical trials.

Considerations for the Clinical Application of Chimeric Antigen Receptor T Cells: Observations from a Recombinant DNA Advisory Committee Symposium Held June 15, 2010[1]

Contributors to the Symposium discussing opinions regarding CAR-T protocol design included some of the prominent members in the field including:

Drs. Hildegund C.J. Ertl, John Zaia, Steven A. Rosenberg, Carl H. June, Gianpietro Dotti, Jeffrey Kahn, Laurence J. N. Cooper, Jacqueline Corrigan-Curay, And Scott E. Strome.

The discussions from the Symposium, reported in Cancer Research[1]. were presented in three parts:

Summary of the Evolution of the CAR therapy
Points for Future Consideration including adverse event reporting
Considerations for Design and Implementation of Trials including mitigating toxicities and risks

1. Evolution of Chimeric Antigen Receptors

Early evidence had suggested that adoptive transfer of tumor-infiltrating lymphocytes, after depletion of circulating lymphocytes, could result in a clinical response in some tumor patients however developments showed autologous T-cells (obtained from same patient) could be engineered to express tumor-associated antigens (TAA) and replace the TILS in the clinical setting.

However there were some problems noticed.

Problem: HLA restriction of T-cells. Solution: genetically engineer T-cells to redirect T-cell specificity to surface TAAs
Problem: 1^st generation vectors designed to engineer T-cells to recognize surface epitopes but engineered cells had limited survival in patients. Solution: development of 2^nd generation vectors with co-stimulatory molecules such as CD28, CD19 to improve survival and proliferation in patients

A summary table of limitations of the two types of genetically-modified T-cell therapies were given and given (in modified form) below

Type of Gene-modified T-Cell

Limitations	aβ TCR	CAR
Affected by loss or decrease of HLA on tumor cells	yes	no
Affected by altered tumor cell antigen processing?	yes	no
Need to have defined tumor target antigen?	no	yes
Vector recombination with endogenous TCR	yes	no

A brief history of construction of 2^nd and 3^rd generation CAR-T cells given by cancer.gov:

http://www.cancer.gov/cancertopics/research-updates/2013/CAR-T-Cells

Differences between second- and third-generation chimeric antigen receptor T cells. (Adapted by permission from the American Association for Cancer Research: Lee, DW et al. The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer. Clin Cancer Res; 2012;18(10); 2780–90. doi:10.1158/1078-0432.CCR-11-1920)

Constructing a CAR T Cell (from cancer.gov)

The first efforts to engineer T cells to be used as a cancer treatment began in the early 1990s. Since then, researchers have learned how to produce T cells that express chimeric antigen receptors (CARs) that recognize specific targets on cancer cells.

The T cells are genetically modified to produce these receptors. To do this, researchers use viral vectors that are stripped of their ability to cause illness but that retain the capacity to integrate into cells’ DNA to deliver the genetic material needed to produce the T-cell receptors.

The second- and third-generation CARs typically consist of a piece of monoclonal antibody, called a single-chain variable fragment (scFv), that resides on the outside of the T-cell membrane and is linked to stimulatory molecules (Co-stim 1 and Co-stim 2) inside the T cell. The scFv portion guides the cell to its target antigen. Once the T cell binds to its target antigen, the stimulatory molecules provide the necessary signals for the T cell to become fully active. In this fully active state, the T cells can more effectively proliferate and attack cancer cells.

2. Adverse Event Reporting and Protocol Considerations

The symposium had been organized mainly in response to two reported deaths of patients enrolled in a CART trial, so that clinical investigators could discuss and formulate best practices for the proper conduct and analysis of such trials. One issue raised was lack of pharmacovigilence procedures (adverse event reporting). Although no pharmacovigilence procedures (either intra or inter-institutional) were devised from meeting proceedings, it was stressed that each institution should address this issue as well as better clinical outcome reporting.

Case Report of a Serious Adverse Event Following the Administration of T Cells Transduced With a Chimeric Antigen Receptor Recognizing ERBB2[2] had reported the death of a patient on trial.

In A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer[3] authors: Lana E Kandalaft^*, Daniel J Powell and George Coukos from University of Pennsylvania recorded adverse events in pilot studies using a CART modified to recognize the folate receptor, so it appears any adverse event reporting system is at the discretion of the primary investigator.

Other protocol considerations suggested by the symposium attendants included:

Plan for translational clinical lab for routine blood analysis
Subject screening for pulmonary and cardiac events
Determine possibility of insertional mutagenesis
Informed consent
Analysis of non T and T-cell subsets, e.g. natural killer cells and CD*8 cells

3. Consideration for Design of Trials and Mitigating Toxicities

Early Toxic effects– Cytokine Release Syndrome– The effectiveness of CART therapy has been manifested by release of high levels of cytokines resulting in fever and inflammatory sequelae. One such cytokine, interleukin 6, has been attributed to this side effect and investigators have successfully used an IL6 receptor antagonist, tocilizumab (Acterma™), to alleviate symptoms of cytokine release syndrome (see review Adoptive T-cell therapy: adverse events and safety switches by Siok-Keen Tey).

Below is a video form Dr. Renier Brentjens, M.D., Ph.D. for Memorial Sloan Kettering concerning the finding he made that the adverse event from cytokine release syndrome may be a function of the tumor cell load, and if they treat the patient with CAR-T right after salvage chemotherapy the adverse events are alleviated..

Please see video below:

http link: https://www.youtube.com/watch?v=4Gg6elUMIVE

Early Toxic effects – Over-activation of CAR T-cells; mitigation by dose escalation strategy (as authors in reference [3] proposed). Most trials give billions of genetically modified cells to a patient.
Late Toxic Effects – long-term depletion of B-cells . For example CART directing against CD19 or CD20 on B cells may deplete the normal population of CD19 or CD20 B-cells over time; possibly managed by IgG supplementation

Below is a curation of various examples of the need for developing a Pharmacovigilence Framework for Engineered T-Cell Therapies

As shown above the first reported side effects from engineered T-cell or CAR-T therapies stemmed from the first human trial occuring at University of Pennsylvania, the developers of the first CAR-T therapy. The clinical investigators however anticipated the issue of a potential cytokine storm and had developed ideas in the pre-trial phase of how to ameliorate such toxicity using anti-cytokine antibodies. However, until the trial was underway they were unsure of which cytokines would be prominent in causing a cytokine storm effect from the CAR-T therapy. Fortunately, the investigators were able to save patient 1 (described here in other posts) using anti-IL1 and 10 antibodies.

Over the years, however, multiple trials had to be discontinued as shown below in the following posts:

What does this mean for Immunotherapy? FDA put a temporary hold on Juno’s JCAR015, Three Death of Celebral Edema in CAR-T Clinical Trial and Kite Pharma announced Phase II portion of its CAR-T ZUMA-1 trial

The NIH has put a crimp in the clinical trial work of Steven Rosenberg, Kite Pharma’s star collaborator at the National Cancer Institute. The feds slammed the brakes on the production of experimental drugs at two of its facilities–including cell therapies that Rosenberg works with–after an internal inspection found they weren’t in compliance with safety and quality regulations.

In this instance Kite was being cited for manufacturing issues, apparantly fungal contamination in their cell therapy manufacturing facility. However shortly after other CAR-T developers were having tragic deaths in their initial phase 1 safety studies.

Juno Halts Cancer Trial Using Gene-Altered Cells After 3 Deaths

By ANDREW POLLACKJULY 7, 2016

http://www.nytimes.com/2016/07/08/business/juno-halts-cancer-trial-using-gene-altered-cells-after-3-deaths.html?rref=collection%2Ftimestopic%2FFood%20and%20Drug%20Administration&action=click&contentCollection=timestopics&region=stream&module=stream_unit&version=latest&contentPlacement=2&pgtype=collection

Juno halts its immunotherapy trial for cancer after three patient deaths

By DAMIAN GARDE @damiangarde and MEGHANA KESHAVAN @megkesh

JULY 7, 2016

Juno halts its immunotherapy trial for cancer after three patient deaths

In Juno patient deaths, echoes seen of earlier failed company

By SHARON BEGLEY @sxbegle

JULY 8, 2016

https://www.statnews.com/2016/07/08/juno-echoes-of-dendreon/

After a deadly clinical trial, will immune therapies for cancer be a bust?

By DAMIAN GARDE @damiangarde

JULY 8, 2016

After a deadly clinical trial, will immune therapies for cancer be a bust?

This led to warnings by FDA and alteration of their trials as well as the use of their CART as a monotherapy

Hours after Juno CAR-T study deaths announced, Kite enrolls CAR-T PhII

Well That Was Quick! FDA Lets Juno Restart Trial With a New Combination Chemotherapuetic

Rachel Lerman at Seattle Times

FDA lets Juno restart cancer-treatment trial

Originally published July 12, 2016 at 4:07 pm Updated July 13, 2016 at 11:21 am

SOURCE: http://www.seattletimes.com/business/technology/fda-lets-juno-restart-cancer-treatment-trial/

Juno Therapeutics said Tuesday it will restart one of its most prominent clinical trials after the Food and Drug Administration lifted a hold that had been placed last week on the trial.

The FDA halted Juno’s “Rocket” clinical trial after the company reported thattwo patients undergoing treatment had died. Juno determined the deaths resulted from swelling in the brain caused by a new drug that had been added to the treatment.

he trial seeks to treat patients with relapsed acute lymphoblastic leukemia by using engineered T-cells to attack cancer cells.

Juno added the chemotherapy drug fludarabine to the treatment plan as part of an early step that gets the patient’s body ready for the T-cell injection. Previously, Juno was using only cyclophosphamide in that part of the treatment.

Under an agreement with the FDA, Juno will continue the trial without fludarabine, using only cyclophosphamide instead.

So What Did this all mean for the CAR-T world? Is it end for CAR-T Therapies?

NO!

This, as I have posted before is a matter of pharmacovigilence, the part of drug development and premarketing trials and postmarketing analysis that deals with adverse events and safety

see post of FDA guidelines for CAR-T therapy here

https://pharmaceuticalintelligence.com/2014/09/23/nih-considers-guidelines-for-car-t-therapy-report-from-recombinant-dna-advisory-committee/

The JUNO trial called for co-treatment with the drug fludarabine, and antimetabolite known, in some cases to promote a cytotoxic lysis syndrome and central nervous system complications. GRANTED these two side effects were deemed RARE however it appears that the addition of fludarabine pre CART therapy aggravated either the side effect of fludarabine pretreatment or a cytoxic lysis syndrome from CAR-T (an adverse event from CAR-T therapy as I had posted here INCLUDING REPORTS OF TWO DEATHS DURING THE MSK CAR-t TRIAL

https://pharmaceuticalintelligence.com/2015/09/14/steroids-inflammation-and-car-t-therapy/

Certainly with so many issues there would seem to be more rigorous work to either establish a pharmacovigilence framework or to develop alternative engineered T cells with a safer profile

However here we went again

New paper sheds fresh light on Tmunity’s high-profile CAR-T deaths
Jason Mast
Editor
The industry-wide effort to push CAR-T therapies — wildly effective in several blood cancers — into solid tumors took a hit last year when Tmunity, a biotech founded by CAR-T pioneer Carl June and backed by several blue-chip VCs, announced it shut down its lead program for prostate cancer after two patients died.

On a personal note this trial was announced in a Bio International meeting here in Philadelphia a few years ago in 2019

see Live Conference Coverage on this site

eProceedings for BIO 2019 International Convention, June 3-6, 2019 Philadelphia Convention Center; Philadelphia PA, Real Time Coverage by Stephen J. Williams, PhD @StephenJWillia2

and the indication was for prostate cancer, in particular hormone resistant castration resistant. Another one was planned for pancreatic cancer from the same group and the early indications were favorable.

From Onclive

Source: https://www.onclive.com/view/car-t-cell-therapy-trial-in-solid-tumors-halted-following-2-patient-deaths

Tmunity Therapeutics, a clinical-stage biotherapeutics company, has halted the development of its lead CAR T-cell product following the deaths of 2 patients who were enrolled to a trial investigating its use in solid tumors.¹

The patients reportedly died from immune effector cell-associated neurotoxicity syndrome (ICANS), which is a known adverse effect associated with CAR T-cell therapies.

“What we are discovering is that the cytokine profiles we see in solid tumors are completely different from hematologic cancers,” Oz Azam, co-founder of Tmunity said in an interview with Endpoints News. “We observed ICANS. And we had 2 patient deaths as a result of that. We navigated the first event and obviously saw the second event, and as a result of that we have shut down the version one of that program and pivoted quickly to our second generation.”

Previously, with first-generation CAR T-cell therapies in patients with blood cancers, investigators were presented with the challenge of overcoming cytokine release syndrome. Now ICANS, or macrophage activation, is proving to have deadly effects in the realm of solid tumors. Carl June, the other co-founder of Tmunity, noted that investigators will now need to dedicate their efforts to engineering around this, as had been done with tocilizumab (Actemra) in 2012.

The company is dedicated to the development of novel approaches that produce best-in-class control over T-cell activation and direction in the body.² The product examined in the trial was developed to utilize engineered patient cells to target prostate-specific membrane antigen; it was also designed to use a dominant TGFβ receptor to block an important checkpoint involved in cancer.

Twenty-four patients were recruited for the dose-escalating study and the company plans to release data from high-dose cohorts later in 2021.

“We are going to present all of this in a peer-reviewed publication because we want to share this with the field,” Azam said. “Because everything we’ve encountered, no matter what…people are going to encounter this when they get into the clinic, and I don’t think they’ve really understood yet because so many are preclinical companies that are not in the clinic with solid tumors. And the rubber meets the road when you get in the clinic, because the ultimate in vivo model is the human model.”

Azam added that the company plans to develop a new investigational new drug for version 2, which they hope will result in a safer product.

References

Carroll J. Exclusive: Carl June’s Tmunity encounters a lethal roadblock as 2 patient deaths derail lead trial, raise red flag forcing rethink of CAR-T for solid tumors. Endpoints News. June 2, 2021. Accessed June 3, 2021. https://bit.ly/3wPYWm0
Research and Development. Tmunity Therapeutics website. Accessed June 3, 2021. https://bit.ly/3fOH3OR

Forward to 2022

Reprogramming a new type of T cell to go after cancers with less side effects, longer impact

By Sophia SorensenApr 25, 2022 09:30am

A Sloan Kettering Institute research team thinks new, killer, innate-like T cells could make promising candidates to treat cancers that so far haven’t responded to immunotherapy treatments. (koto_feja)

Immunotherapy is one of the more appealing and effective kinds of cancer treatment when it works, but the relatively new approach is still fairly limited in the kinds of cancer it can be used for. Researchers at the Sloan Kettering Institute have discovered a new kind of immune cell and how it could be used to expand the reach of immunotherapy treatments to a much wider pool of patients.

The cells in question are called killer innate-like T cells, a threatening name for a potentially lifesaving innovation. Unlike normal killer T cells, killer innate-like T cells stay active much longer and can burrow further into potentially cancerous tissue to attack tumors. The research team first reported these cells in 2016, but it’s only recently that they were able to properly understand and identify them.

“We think these killer innate-like T cells could be targeted or genetically engineered for cancer therapy,” said the study’s lead author, Ming Li, Ph.D., in a press release. “They may be better at reaching and killing solid tumors than conventional T cells.”

Below is the referenced paper from Pubmed:

Evaluation of the safety and efficacy of humanized anti-CD19 chimeric antigen receptor T-cell therapy in older patients with relapsed/refractory diffuse large B-cell lymphoma based on the comprehensive geriatric assessment system

Huan Zhang¹, Man Liu², Qing Li¹, Cuicui Lyu¹, Yan-Yu Jiang¹, Juan-Xia Meng¹, Jing-Yi Li¹, Qi Deng¹

Affiliations

PMID: 34587859
DOI: 10.1080/10428194.2021.1986216

Abstract

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has led to unprecedented results to date in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), yet its clinical application in elderly patients with R/R DLBCL remains somewhat limited. In this study, a total of 31 R/R DLBCL patients older than 65 years of age were enrolled and received humanized anti-CD19 CAR T-cell therapy. Patients were stratified into a fit, unfit, or frail group according to the comprehensive geriatric assessment (CGA). The fit group had a higher objective response (OR) rate (ORR) and complete response (CR) rate than that of the unfit/frail group, but there was no difference in the part response (PR) rate between the groups. The unfit/frail group was more likely to experience AEs than the fit group. The peak proportion of anti-CD19 CAR T-cells in the fit group was significantly higher than that of the unfit/frail group. The CGA can be used to effectively predict the treatment response, adverse events, and long-term survival.

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for 30–40% of cases, with the median age of onset being older than 65 years [1]. Although the five-year survival rate for patients with DLBCL has risen to more than 60% with the application of standardized treatments and hematopoietic stem cell transplantation, nearly half of patients progress to relapsed/refractory (R/R) DLBCL. Patients with R/R DLBCL, especially elderly individuals, have a poor prognosis [2,3], so new treatments are needed to prolong survival and improve the prognosis of this population.

As a revolutionary immunotherapy therapy, anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has achieved unprecedented results in hematological tumors [4]. As CD19 is expressed on the surface of most B-cell malignant tumors but not on pluripotent bone marrow stem cells, CD19 has been used as a target for B-cell malignancies, including B-cell acute lymphoblastic leukemia, NHL, multiple myeloma, and chronic lymphocytic leukemia [5]. Despite the wide application and high efficacy of anti-CD19 CAR T-cell therapy, reports of adverse events (AEs) such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxic syndrome (ICANS) have influenced its use [6]. Especially in elderly patients, AEs associated with anti-CD19 CAR T-cell therapy might be more obvious.

Although anti-CD19 CAR T-cell therapy has been reported in the treatment of NHL, including R/R DLBCL, few studies to date have assessed the safety of anti-CD19 CAR T-cell therapy in elderly R/R DLBCL patients, and its clinical application in the elderly R/R DLBCL population is limited. In ZUMA-1 [7] to R/R DLBCL patients who received CAR T-cell therapy, the CR rate in patients ≥65 years was higher than that of in patients <65 years (75% vs. 53%). Lin et al. [8] reported 49 R/R DLBCL patients (24 patients >65 years, 25 patients <65 years) who received CAR T-cell therapy with a median follow-up of 179 days. The CR rate at 100 days was 51%, while the 6-month progression-free survival (PFS) and overall survival (OS) were 48% and 71%, respectively. Neither of the two studies carried out a comprehensive geriatric assessment (CGA) of fit, unfit, and frail groups of R/R DLBCL patients over 65 years of age and further analyzed the differences in efficacy and side effects in the three groups. The CGA is an effective system designed to evaluate the prognosis and improve the survival of elderly patients with cancer. The CGA system includes age, activities of daily living (ADL), instrumental ADL (IADL), and the Cumulative Illness Rating Score for Geriatrics (CIRS-G) [9].

In this study, elderly R/R DLBCL patients were grouped according to their CGA results (fit vs. unfit/frail) before receiving humanized anti-CD19 CAR T-cell therapy. We then analyzed the efficacy and AEs of anti-CD19 CAR T-cell therapy and compared findings between these groups.

Well it appears that the discriminator was only fitness going into the trial a bit odd that the whole field appears to be lacking in development of Safety Biomarkers.

However Genentech (subsidiary of Roche) may now be using some data to develop therapies which may combat resistance to CART therapies which may provide at least, for now, a toxicokinetic approach to reducing AEs by lowering the amount of CARTs needed to be administered.

Source: https://www.fiercebiotech.com/research/genentech-uncovers-how-cancer-cells-resist-t-cell-attack-potential-boon-immunotherapy

Roche’s Genentech is exploring inhibiting ESCRT as an anticancer strategy, said Ira Mellman, Ph.D., Genentech’s vice president of cancer immunology. (Roche)

Cancer cells deploy various tactics to avoid being targeted and killed by the immune system. A research team led by Roche’s Genentech has now identified one such method that cancer cells use to resist T-cell assault by repairing damage.

To destroy their targets, cancer-killing T cells known as cytotoxic T lymphocytes (CTLs) secrete the toxin perforin to form little pores in the target cells’ surface. Another type of toxin called granzymes are delivered directly into the cells through those portals to induce cell death.

By using high-res imaging in live cells, the Genentech-led team found that the membrane damage caused by perforin could trigger a repair response. The tumor cells could recruit endosomal sorting complexes required for transport (ESCRT) proteins to remove the lesions, thereby preventing granzymes from entering, the team showed in a new study published in Science.

The following is the Science paper

Source: https://www.science.org/doi/10.1126/science.abl3855

Membrane repair in target cell defenses

Killer T cells destroy virus-infected and cancer cells by secreting two protein toxins that act as a powerful one-two punch. Pore-forming toxins, perforins, form holes in the plasma membrane of the target cell. Cytotoxic proteins released by T cells then pass through these portals, inducing target cell death. Ritter et al. combined high-resolution imaging data with functional analysis to demonstrate that tumor-derived cells fight back (see the Perspective by Andrews). Protein complexes of the ESCRT family were able to repair perforin holes in target cells, thereby delaying or preventing T cell–induced killing. ESCRT-mediated membrane repair may thus provide a mechanism of resistance to immune attack. —SMH

Abstract

Cytotoxic T lymphocytes (CTLs) and natural killer cells kill virus-infected and tumor cells through the polarized release of perforin and granzymes. Perforin is a pore-forming toxin that creates a lesion in the plasma membrane of the target cell through which granzymes enter the cytosol and initiate apoptosis. Endosomal sorting complexes required for transport (ESCRT) proteins are involved in the repair of small membrane wounds. We found that ESCRT proteins were precisely recruited in target cells to sites of CTL engagement immediately after perforin release. Inhibition of ESCRT machinery in cancer-derived cells enhanced their susceptibility to CTL-mediated killing. Thus, repair of perforin pores by ESCRT machinery limits granzyme entry into the cytosol, potentially enabling target cells to resist cytolytic attack.

Cytotoxic lymphocytes, including cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, are responsible for identifying and destroying virus-infected or tumorigenic cells. To kill their targets, CTLs and NK cells secrete a pore-forming toxin called perforin through which apoptosis-inducing serine proteases (granzymes) are delivered directly into the cytosol. Successful killing of target cells often requires multiple hits from single or multiple T cells (1). This has led to the idea that cytotoxicity is additive, often requiring multiple rounds of sublethal lytic granule secretion events before a sufficient threshold of cytosolic granzyme activity is reached to initiate apoptosis in the target (2).

Loss of plasma membrane integrity induced by cytolytic proteins or mechanical damage leads to a membrane repair response. Damage results in an influx of extracellular Ca²⁺, which has been proposed to lead to the removal of the membrane lesion by endocytosis, resealing of the lesions by lysosomal secretion, or budding into extracellular vesicles (3). Perforin pore formation was initially reported to enhance endocytosis of perforin (4), but subsequent work has challenged this claim (5). Endosomal sorting complexes required for transport (ESCRT) proteins can repair small wounds and pores in the plasma membrane caused by bacterial pore-forming toxins, mechanical wounding, and laser ablation (6, 7). ESCRT proteins are transiently recruited to sites of membrane damage in a Ca²⁺-dependent fashion, where they assemble budding structures that shed to eliminate the wound and restore plasma membrane integrity. ESCRT-dependent membrane repair has been implicated in the resealing of endogenous pore-mediated plasma membrane damage during necroptosis (8) and pyroptosis (9).

Localization of target-derived ESCRT proteins to the cytolytic synapse

To investigate whether ESCRT-mediated membrane repair might be involved in the removal of perforin pores during T cell killing, we first determined whether ESCRT proteins in cancer-derived cells were recruited to sites of CTL engagement after perforin secretion. We used CTLs from OT-I mice that express a high-affinity T cell receptor (TCR) that recognizes the ovalbumin peptide SIINFEKL (OVA_257-264) bound to the major histocompatibility complex (MHC) allele H-2Kb (10). We performed live-cell microscopy of OT-I CTLs engaging SIINFEKL-pulsed target cells that express enhanced green fluorescent protein (EGFP)–tagged versions of Tsg101 or Chmp4b, two ESCRT proteins implicated in membrane repair (6). To correlate recruitment of ESCRT proteins with perforin exposure in time, we monitored CTL-target interaction in media with a high concentration of propidium iodide (PI), a cell-impermeable fluorogenic dye that can rapidly diffuse through perforin pores to bind and illuminate nucleic acids in the cytosol and nucleus of the target (5). EGFP-tagged ESCRT proteins were consistently recruited to the site of CTL engagement within 30 to 60 s after PI influx (Fig. 1, A and B). EGFP-Tsg101 and EGFP-Chmp4b in target cells accumulated at the cytolytic synapse after PI influx in 25 of 27 (92.6%) and 31 of 33 (93.9%) of conjugates monitored, respectively, compared with a cytosolic EGFP control, which was not recruited (Fig. 1C and movies S1 to S3). Notably, ESCRT-laden material, presumably membrane fragments, frequently detached from the target cell and adhered to the surface of the CTL (Fig. 1, D and E, and movie S2). We observed this phenomenon in ~60% of conjugates imaged in which targets expressed EGFP-Tsg101 or EGFP-Chmp4b (17 of 27 and 20 of 33 conjugates, respectively; Fig. 1D). Shedding of ESCRT-positive membrane from the cell after repair occurs after laser-induced plasma membrane wounding (6, 7). Plasma membrane fragments shed from the target cell into the synaptic cleft likely contain ligands for CTL-resident receptors. Target cell death would separate the CTL and target, revealing target-derived material on the CTL surface.

FIG. 1. Fluorescently tagged ESCRT proteins in targets localize to site of CTL killing after perforin secretion.

(A) Live-cell spinning disk confocal imaging of a fluorescently labeled OT-I CTL (magenta) engaging an MC38 cancer cell expressing EGFP-Tsg101 (green) in media containing 100 μM PI (red). Yellow arrowheads highlight ESCRT recruitment. T-0:00 is the first frame of PI influx into the target cell (time in minutes:seconds). Scale bar, 10 μm. (B) Graph of EGFP-Tsg101 and PI fluorescence intensity at the IS within the target over time, from example in (A). AU, arbitrary units. (C and D) Quantification of CTL-target conjugates exhibiting accumulation of EGFP at the synapse after PI influx (C) or detectable EGFP-labeled material associated with CTL after target interaction (D) (EGFP condition: N = 22 conjugates in seven independent experiments; EGFP-Tsg101 condition: N = 27 conjugates in nine independent experiments; EGFP-Chmp4b condition: N = 33 conjugates in 24 independent experiments). (E) Live-cell spinning disk confocal imaging of OT-I CTL (magenta) killing MC38 expressing EGFP-Chmp4b (green), demonstrating the presence of target-derived EGFP-Chmp4b material (yellow arrowheads) associated with CTL membrane after a productive target encounter. T-0:00 is the first frame of PI influx into the target cell. Scale bar, 10 μm.

3D cryo-SIM and FIB-SEM imaging of CTLs caught in the act of killing target cells

Although live-cell imaging indicated that ESCRT complexes were rapidly recruited at sites of T cell–target cell contact, light microscopy alone is of insufficient resolution to establish that this event occurred at the immunological synapse (IS). We thus sought to capture a comprehensive view of the IS in the moments immediately after secretion of lytic granules. We used cryo–fluorescence imaging followed by correlative focused ion beam–scanning electron microscopy (FIB-SEM), which can achieve isotropic three-dimensional (3D) imaging of whole cells at 8-nm resolution or better (11–13). To capture the immediate response of target cells after perforin exposure, we developed a strategy whereby cryo-fixed CTL-target conjugates were selected shortly after perforation, indicated by the presence of a PI gradient in the target (fig. S1A). In live-cell imaging experiments, PI fluorescence across the nucleus of SIINFEKL-pulsed ID8 target cells began as a gradient and became homogeneous 158 ± 64 s, on average, after initial PI influx (N = 31 conjugates; fig. S1, B and C, and movie S4). Thus, fixed CTL-target conjugates that exhibited a gradient of PI across the nucleus would have been captured within ~3 min of perforin exposure.

Coverslips of CTL-target conjugates underwent high-pressure freezing and were subsequently imaged with wide-field cryogenic fluorescence microscopy followed by 3D cryo–structured illumination microscopy (3D cryo-SIM) performed in a customized optical cryostat (14). We selected candidate conjugates for FIB-SEM imaging on the basis of whether a gradient of PI fluorescence was observed across the nucleus of the target emanating from an attached CTL (movie S5). FIB-SEM imaging of the CTL-target conjugate at 8-nm isotropic voxels resulted in a stack of >10,000 individual electron microscopy (EM) images. The image stack was then annotated using a human-assisted machine learning–computer vision platform to segment the plasma membranes of each cell along with cell nuclei and various organelles (https://ariadne.ai/).

We captured four isotropic 3D 8-nm-resolution EM datasets of CTLs killing cancer cells moments after the secretion of lytic granule contents (Fig. 2A and movie S6). Semiautomated segmentation of the cell membranes, nuclei, lytic granules, Golgi apparatus, mitochondria, and centrosomes of the T cells allow for easier visualization and analysis of the 3D EM data. All FIB-SEM datasets and segmentations can be explored online at https://openorganelle.janelia.org (see links in the supplementary materials). Reconstructed views of the segmented data clearly demonstrate the polarization of the centrosome, Golgi apparatus, and lytic granules to the IS—all of which are hallmarks of CTL killing [Fig. 2A, i to iii, and movie S6, time stamp (TS) 1:33] (15, 16). On the target cell side, we noted cytoplasmic alterations consistent with cell damage including enhanced electron density of mitochondria adjacent to the IS (fig. S2A). Close visual scanning of the postsynaptic target cell membrane in the raw EM data failed to reveal obvious perforin pores, which have diameters (16 to 22 nm) close to the limit of resolution for this technique (17).

FIG. 2. Eight-nm-resolution 3D FIB-SEM imaging of whole CTL-target conjugate.

(A) 3D rendering of segmented plasma membrane predictions derived from isotropic 8-nm-resolution FIB-SEM imaging of a high-pressure frozen OT-I CTL (red) captured moments after secretion of lytic granules toward a peptide-pulsed ID8 ovarian cancer cell (blue). (i) Side-on sliced view corresponding to the gray horizontal line within the inset box in (A). Seen here are 3D renderings of the segmented plasma membrane of the cancer cell (blue) as well as the CTL plasma membrane (red), centrosome (gold), Golgi apparatus (cyan), lytic granules (purple), mitochondria (green), and nucleus (gray). (ii and iii) A zoomed-in view from the dashed white box in (i) shows the details of the IS (ii) and a single corresponding FIB-SEM slice docked onto the segmented data (iii). (B) Single top-down FIB-SEM slice showing overlaid target cell (blue) and CTL (red) segmentation. (i) Zoomed-in view from dashed white box in (B) details the intercellular material (IM) (gray) between the CTL and target at the IS. (C) Zoomed-in image of a 3D rendering of the surface of the target cell plasma membrane (white) opposite the intercellular material (IM) at the IS. Yellow arrowheads mark plasma membrane buds protruding into the synaptic cleft. (i and ii) Accompanying images demonstrate the orientation of the view in (C) with the rendering of the CTL (red) present (i) and removed (ii), and the dashed yellow box in (ii) indicates the area of detail shown in (C).

The segmentation of the two cells illustrates the detailed topography of the plasma membrane of the CTL and target at the IS (fig. S2B). The raw EM and segmentation data reveal a dense accumulation of particles, vesicles, and multilamellar membranous materials, which crowd the synaptic cleft between the CTL and the target (Fig. 2B and movie S6, TS 0:40 to 0:50). The source of this intercellular material (IM) was likely in part the lytic granules because close inspection revealed similar particles and dense vesicles located within as-yet-unreleased granules (fig. S2C). To determine whether some of the membranous material within the intercellular space might also have been derived from the target cell, we examined the surface topology of the postsynaptic target cell. We noted multiple tubular and bud-like protrusions of the target cell membrane that extended into the synaptic space; thus, at least some of the membrane structures observed were still in continuity with the target cell (Fig. 2C and movie S6, TS 0:58 to 1:11). ESCRT proteins have been shown to generate budding structures in the context of plasma membrane repair (6), which led us to next assess where target-derived ESCRT proteins are distributed in the context of the postsecretion IS.

To map the localization of target-derived ESCRT proteins onto a high-resolution landscape of the IS, we captured three FIB-SEM datasets that have associated 3D cryo-SIM fluorescence data for mEmerald-Chmp4b localization (Fig. 3A, fig. S3, and movie S7). This correlative light and electron microscopy (CLEM) revealed that mEmerald-Chmp4b expressed in the target cell was specifically recruited to the target plasma membrane opposite the secreted IM (Fig. 3, B and C). The topography of the plasma membrane at the site of ESCRT recruitment was markedly convoluted, exhibiting many bud-like projections (movie S7, TS 0:37 to 0:40). mEmerald-Chmp4b fluorescence also overlapped with some vesicular structures in the intercellular synaptic space (Fig. 3C). Together, the live-cell imaging and the 3D cryo-SIM and FIB-SEM CLEM demonstrate the localization of ESCRT proteins at the synapse that was the definitive site of CTL killing and was thus spatially and temporally correlated to perforin secretion. These data implicate the ESCRT complex in the repair of perforin pores.

FIG. 3. Correlative 3D cryo-SIM and FIB-SEM reveal localization of target-derived ESCRT within the cytolytic IS.

(A) Three example datasets showing correlative 3D cryo-SIM and FIB-SEM imaging of OT-I CTLs (red) captured moments after secretion of lytic granules toward peptide-pulsed ID8 cancer cells (blue) expressing mEmerald-Chmp4b (green fluorescence). (B and C) Single FIB-SEM slices corresponding to the orange boxes in (A), overlaid with CTL and cancer cell segmentation (B) or correlative cryo-SIM fluorescence of mEmerald-Chmp4b derived from the target cell (C).

Function of ESCRT proteins in repair of perforin pores

We next investigated whether ESCRT inhibition could enhance the susceptibility of target cells to CTL-mediated killing. Prolonged inactivation of the ESCRT pathway is itself cytotoxic (9). We thus developed strategies to ablate ESCRT function that would allow us a window of time to assess CTL killing (fig. S4). We used two approaches to block ESCRT function: CRISPR knockout of the Chmp4b gene or overexpression of VPS4a^E228Q (E228Q, Glu²²⁸ → Gln), a dominant-negative kinase allele that impairs ESCRT function (fig. S4, A to C) (10). We took care to complete our assessment of target killing well in advance of spontaneous target cell death (fig. S4D).

We tested the capacity of OT-I CTLs to kill targets presenting one of four previously characterized peptides that demonstrate a range of potencies at stimulating the OT-I TCR: SIINFEKL (N4), the cognate peptide, and three separate variants (in order of highest to lowest affinity), SIITFEKL (T4), SIIQFEHL (Q4H7), and SIIGFEKL (G4) (18, 19). Target cells were pulsed with peptide, washed, transferred to 96-well plates, and allowed to adhere before the addition of OT-I CTLs. Killing was assessed by monitoring the uptake of a fluorogenic caspase 3/7 indicator (Fig. 4, A to D, and fig. S5A). Killing was significantly more efficient in ESCRT-inhibited target cells for both CRISPR depletion of Chmp4b (Fig. 4, A to C) and expression of the dominant-negative VPS4a^E228Q (Fig. 4D). The difference in killing between the ESCRT-inhibited and control cells was greater when the lower-potency T4, Q4H7, and G4 peptides were used. Nevertheless, ESCRT inhibition moderately improved killing efficiency even in the case of the high-potency SIINFEKL peptide. ESCRT inhibition had no effect on MHC class I expression on the surface of target cells (fig. S5B). Thus, ESCRT inhibition could sensitize target cells to perforin- and granzyme-mediated killing, especially at physiologically relevant TCR-peptide MHC affinities.

FIG. 4. ESCRT inhibition enhances susceptibility of cancer cells to CTL killing and recombinant lytic proteins.

(A) Representative time-lapse data of killing of peptide-pulsed Chmp4b knockout (KO) or control B16-F10 cells by OT-I CTLs. Affinity of the pulsed peptide to OT-I TCR decreases from left to right. Error bars indicate SDs. (B) Images extracted from T4 medium-affinity peptide condition show software-detected caspase 3/7+ events in control and Chmp4b KO conditions. (C and D) Data representing the 4-hour time point of assays measuring OT-I T cells killing either Chmp4b KO (C) or VPS4 dominant-negative (D) target cells with matched controls. Error bars indicate SDs of data. Data are representative of at least three independent experimental replicates. pMHC, peptide-MHC; HA, hemagglutinin. (E and F) Determination of sublytic dose of Prf. B16-F10 cells expressing VPS4a (WT or E228Q) were exposed to increasing concentrations of Prf. Cell viability was determined by morphological gating (E). FSC, forward scatter; SSC, side scatter. (G and H) B16-F10 cells expressing VPS4a (WT or E228Q) were exposed to a sublytic dose of Prf in combination with increasing concentrations of recombinant GZMB (rGZMB). Cell death was determined by Annexin V–allophycocyanin (APC) staining (G). Controls include a condition with no perforin and 5000 ng/ml rGZMB and sublytic perforin with no rGZMB. Graphs in (F) and (H) represent the means of three experiments, and error bars indicate SDs. Statistical significance was determined by multiple unpaired t tests with alpha = 0.05. ns, not significant; *P < 0.05; **P < 0.01; ***P < 0.001.

We next directly tested the effects of ESCRT inhibition when target cells were exposed to both recombinant perforin (Prf) and granzyme B (GZMB), the most potently proapoptotic granzyme in humans and mice (20). Prf alone at high concentrations can lyse cells (4), so we first determined a sublytic Prf concentration that would temporarily permeabilize the plasma membrane but permit the cells to recover. B16-F10 cells expressing either VPS4a^WT (WT, wild-type) or VPS4a^E228Q were exposed to a range of Prf concentrations in the presence of PI, and cell viability and PI uptake were assessed using flow cytometry. Cells that expressed dominant-negative VPS4a^E228Q were more sensitive to Prf alone than ESCRT-competent cells (Fig. 4, E and F). At 160 ng/ml Prf, there was no significant difference in cell viability for either condition. Cells in the live gate that were PI+ had been permeabilized by Prf but recovered. Although the percentage of PI+ live cells was similar under both sets of conditions, the mean fluorescence intensity of PI was higher in live ESCRT-inhibited cells (fig. S6). A delay in plasma membrane resealing could account for this difference.

We reasoned that delaying perforin pore repair might also enhance GZMB uptake into the target. ESCRT-inhibited cells were more sensitive to combined perforin-GZMB when cell death was measured by Annexin V staining (Fig. 4, G and H). Similar results were observed when these experiments were repeated with a murine lymphoma cancer cell line (fig. S7). The observation that ESCRT-inhibited target cells are more sensitive to both CTL-secreted and Prf-GZMB supports the hypothesis that the ESCRT pathway contributes to membrane repair after Prf exposure.

Escaping cell death is one of the hallmarks of cancer. Our findings suggest that ESCRT-mediated membrane repair of perforin pores may restrict accessibility of the target cytosol to CTL-secreted granzyme, thus promoting survival of cancer-derived cells under cytolytic attack. Although other factors may contribute to setting the threshold for target susceptibility to killing, the role of active repair of perforin pores must now be considered as a clear contributing factor.

Acknowledgments

We thank members of the Mellman laboratory for advice, discussion, and reagents; B. Haley for assistance with plasmid construct design; the Genentech FACS Core Facility for technical assistance; S. Van Engelenburg of Denver University for invaluable discussions and guidance; A. Wanner, S. Spaar, and the Ariande AI AG (https://ariadne.ai/) for assistance with FIB-SEM segmentation, CLEM coregistration, data presentation, and rendering; D. Bennett of the Janelia Research Campus for assisting with data upload to https://openorganelle.janelia.org; and the Genentech Postdoctoral Program for support.

Funding: A.T.R. and I.M. are funded by Genentech/Roche. C.S.X., G.S., A.W., D.A., N.I., and H.F.H. are funded by the Howard Hughes Medical Institute (HHMI).

Please look for a Followup Post concerning “Developing a Pharmacovigilence Framework for Engineered T-Cell Therapies”

References

Ertl HC, Zaia J, Rosenberg SA, June CH, Dotti G, Kahn J, Cooper LJ, Corrigan-Curay J, Strome SE: Considerations for the clinical application of chimeric antigen receptor T cells: observations from a recombinant DNA Advisory Committee Symposium held June 15, 2010. Cancer research 2011, 71(9):3175-3181.
Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA: Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Molecular therapy : the journal of the American Society of Gene Therapy 2010, 18(4):843-851.
Kandalaft LE, Powell DJ, Jr., Coukos G: A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer. Journal of translational medicine 2012, 10:157.

Other posts on this site on Immunotherapy and Cancer include

Report on Cancer Immunotherapy Market & Clinical Pipeline Insight

New Immunotherapy Could Fight a Range of Cancers

Combined anti-CTLA4 and anti-PD1 immunotherapy shows promising results against advanced melanoma

Molecular Profiling in Cancer Immunotherapy: Debraj GuhaThakurta, PhD

Pancreatic Cancer: Genetics, Genomics and Immunotherapy

$20 million Novartis deal with ‘University of Pennsylvania’ to develop Ultra-Personalized Cancer Immunotherapy

Upcoming Meetings on Cancer Immunogenetics

Tang Prize for 2014: Immunity and Cancer

ipilimumab, a Drug that blocks CTLA-4 Freeing T cells to Attack Tumors @DM Anderson Cancer Center

Juno’s approach eradicated cancer cells in 10 of 12 leukemia patients, indicating potential to transform the standard of care in oncology

http://www.nature.com/focus/Lasker/2013/pdf/ES-Lasker13-Sudhof.pdf

Calcium-Channel Blocker, Calcium as Neurotransmitter Sensor and Calcium Release-related Contractile Dysfunction (Ryanopathy)

Posted in Calcium Signaling, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, tagged Aviva Lev-Ari, Bernard Katz, Calcium-Channel Blocker, gene therapy, Heart Failure, Larry H. Bernstein, Michael J Berridge, Smooth muscle tissue, Stanford University, Vascular smooth muscle on September 16, 2013| Leave a Comment »

Calcium-Channel Blocker, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

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

Image created by Adina Hazan 06/30/2021

Introduction

Author: Larry H Bernstein, MD, FACC

This Chapter is one of a series of articles on calcium activation, in this case, in the signaling of smooth muscle cells by the interacting neural innervation. The process occurs by calcium triggering neurotransmitter release by initiating synaptic vesicle fusion. The mechanism by which this occurs is addressed in detail, and involves the interaction of soluble N-acetylmaleimide-sensitive factor (SNARE) and SM proteins, and in addition, the discovery of a calcium-dependsent Syt1 (C) domain of protein- kinase C isoenzyme, which binds to phospholipids.

The 2013 Lasker Prize was awarded to Richard Schell (Genentech) and Thomas Sudolf (Stanford University) for their discoveries concerning the molecular machinery and regulatory mechanism that underlie the rapid release of neurotransmitters, a process that underlies all of the brain’s activities. They identified and isolated many of this reaction’s key elements, unraveled central aspects of its fundamental mechanism, and deciphered how cells govern it with extreme precision. These advances have provided a molecular framework for understanding some of the most devastating disorders that afflict humans as well as normal functions such as learning and memory, explaining unresolved hypotheses derived from the earlier work in the 1950sof the late Bernard Katz. We also see that the work clarifies the debates initiated by the Nobelist Santiago Ramon y Cajal (1891) concerning the development of neural networks. A biological relay system achieves these feats. Neurotransmission kicks off with an electrical pulse that runs down a nerve cell, or neuron. When that signal reaches the tip, calcium enters the cell. In response, the neuron liberates chemical messengers—neurotransmitters.

In the 1950s, the late Bernard Katz figured out that cells eject neurotransmitters in fixed amounts. Balloon-like containers—vesicles—each hold set quantities of the chemicals. Calcium incites these lipid-bound sacs to fuse with the membrane that encases the cell, and their contents spill out. The picture that emerges from the later work is that synaptic vesicle exocytosis operates by a general mechanism of membrane fusion that revealed itself to be a model for all membrane fusion, but that is uniquely regulated by a calcium-sensor protein called synaptotagmin. The general membrane-fusion mechanism thus identified is mediated by SNARE- (for soluble NSF-receptors) and SM-proteins (for Sec1/Munc18-like proteins), largely discovered at the synapse, with synaptotagmin acting together with a molecular assistant called complexin as a clamp and activator of the membrane fusion mediated by the SNARE- and SM-proteins. Strikingly, the biochemical properties of synaptotagmin were found to precisely correspond to the extraordinary calcium-triggering properties of release, and to account for a regulatory pathway that also applies to other types of calcium-triggered fusion, for example fusion observed in hormone secretion and fertilization. At the synapse, finally, these interdependent machines — the fusion apparatus and its synaptotagmin-dependent control mechanism — are embedded in a proteinaceous active zone that links them to calcium channels, and regulates the docking and priming of synaptic vesicles for subsequent calcium-triggered fusion. Thus, work on neurotransmitter release revealed a hierarchy of molecular machines that mediate the fusion of synaptic vesicles, the calcium-control of this fusion, and the embedding of calcium-controlled fusion in the context of the presynaptic terminal at the synapse.

This portion of the discussion deals with the interaction of the neuronal endings interwoven into smooth muscle. The calcium triggering of smooth muscle contractions is similar with respect to airways and arteries, urinary bladder, uterine contraction, and gastrointestinl tract.

The basic mechanism that underlie this MOTIF taken as variations of that described above are well described by Michael J. Berridge in ‘Smooth muscle cell calcium activation mechanisms’. (J Physiol. 2008 Nov 1;586(Pt 21):5047-61.
http://dx.doi.org/10.1113/jphysiol.2008.160440. Epub 2008 Sep 11.)

This is illustrated in his graphical examples.

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

Figure 1. The three main mechanisms responsible for generating the Ca2+ transients that trigger smooth muscle cell (SMC) contraction. From: Smooth muscle cell calcium activation mechanisms.

A, receptor-operated channels (ROCs) or a membrane oscillator induces the membrane depolarization (ΔV) that triggers Ca2+ entry and contraction.

B, a cytosolic Ca2+ oscillator induces the Ca2+ signal that drives contraction.

C, a cytosolic Ca2+ oscillator in interstitial cells of Cajal (ICCs) or atypical SMCs induces the membrane depolarization that spreads through the gap junctions to activate neighbouring SMCs. Reproduced from Berridge (2008), with permission.

Michael J Berridge. J Physiol. 2008 November 1;586(Pt 21):5047-5061. http://www.ncbi.nlm.nih.gov/pmc/articles/instance/2652144/bin/tjp0586-5047-f1.jpg

Figure 5. Vascular or airway SMCs are driven by a cytosolic oscillator that generates a periodic release of Ca2+ from the endoplasmic reticulum that usually appears as a propagating Ca2+ wave. From: Smooth muscle cell calcium activation mechanisms.

The oscillator is induced/modulated by neurotransmitters such as acetylcholine (ACh), 5-hydroxytryptamine (5-HT), noradrenaline (NA) and endothelin-1 (ET-1), which act through inositol 1,4,5-trisphosphate (InsP3) that initiates the oscillatory mechanism. The sequence of steps 1–9 is described in the text. Reproduced from Berridge (2008), with permission.
Michael J Berridge. J Physiol. 2008 November 1;586(Pt 21):5047-5061. http://www.ncbi.nlm.nih.gov/pmc/articles/instance/2652144/bin/tjp0586-5047-f5.jpg

Figure 7. The cytosolic Ca2+ oscillator responsible for pacemaker activity in interstitial cells of Cajal releases periodic pulses of Ca2+ that form a Ca2+ wave. From: Smooth muscle cell calcium activation mechanisms.

tjp0586-5047-f7 The cytosolic Ca2+ oscillator responsible for pacemaker activity in interstitial cells of Cajal releases periodic pulses of Ca2+ that form a Ca2+ wave.

The increase in Ca2+ activates Cl− channels (CLCA) to give the spontaneous transient inward currents (STICs) that sum to form the spontaneous transient depolarizations (STD) resulting in the slow waves of membrane depolarization (see inset). Current flow through gap junctions allows these waves to spread into neighbouring smooth muscle cells to activate contraction. See text for a description of the oscillator that drives this activation process. Reproduced from Berridge (2008), with permission.
Michael J Berridge. J Physiol. 2008 November 1;586(Pt 21):5047-5061. http://www.ncbi.nlm.nih.gov/pmc/articles/instance/2652144/bin/tjp0586-5047-f7.gif

This article is the Part IX in a series of articles on Activation and Dysfunction of the Calcium Release Mechanisms in Cardiomyocytes and Vascular Smooth Muscle Cells.

The Series consists of the following articles:

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

Larry H Bernstein, MD, FCAP

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 Arrhythmiasand Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

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

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

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

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

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

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

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

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

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

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

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

Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP

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

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

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

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

This article has FIVE Sections:

Section One

Innovations in Combination Drug Therapy: Calcium-Channel Blocker – Amlodipine (Norvasc) in single-pill combinations (SPCs) of drugs

Section Two

Calcium-Channel Blockers: Drug Class and Indications

Section Three

Brand and Generic Calcium Channel Blocking Agents

Section Four

Dysfunction of the Calcium Release Mechanism

Section Five

The Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Section One

Innovations in Combination Drug Therapy:

Calcium-Channel Blocker, Amlodipine (Norvasc) in Single-Pill Combinations (SPCs) of Drugs

Latest development on Cardiovascular Pharmacotherapy relates to the development of a Duo Combination Therapy to include a leading Calcium-Channel Blocker, Amlodipine (Norvasc), as one of the two drug classes in one pill:The research investigated the therapeutic efficacy achieved via a comparison of a two single-pill combinations (SPCs) of drugs:

telmisartan/amlodipine (T/A) [ARB/CCB]

and

telmisartan/hydrochlorothiazide (T/H) [ARB/Diuterics]

Drug classes:

ARB – telmisartan
CCB – amlodipine
Diuretics – hydrochlorothiazide

A review of the benefits of early treatment initiation with single-pill combinations of telmisartan with amlodipine or hydrochlorothiazide

Authors: Segura J, Ruilope LM

Published Date September 2013 Volume 2013:9 Pages 521 – 528

http://www.dovepress.com/articles.php?article_id=14373

DOI: http://dx.doi.org/10.2147/VHRM.S48291


Published:	16 September 2013, Dovepress Journal: Vascular Health and Risk Management

Julian Segura, Luis Miguel Ruilope

Department of Nephrology, Hospital 12 de Octubre, Madrid, Spain

Abstract:

This review discusses the rationale for earlier use of single-pill combinations (SPCs) of antihypertensive drugs, with a focus on telmisartan/amlodipine (T/A) and telmisartan/hydrochlorothiazide (T/H) SPCs.

Compared with the respective monotherapies, the once-daily T/A and T/H SPCs have been shown to result in significantly higher blood pressure (BP) reductions, BP goal rates, and response rates in patients at all stages of hypertension.

As expected, BP reductions are highest with the highest dose (T80/A10 and T80/H25) SPCs. Subgroup analyses of the telmisartan trials have reported the efficacy of both SPCs to be consistent, regardless of the patients’ age, race, and coexisting diabetes, obesity, or renal impairment.

In patients with mild-to-moderate hypertension, the T/A combination provides superior 24-hour BP-lowering efficacy compared with either treatment administered as monotherapy.

Similarly, the T/H SPC treatment provides superior 24-hour BP-lowering efficacy, especially in the last 6 hours relative to other renin–angiotensin system inhibitor-based SPCs.

The T/A SPC is associated with a lower incidence of edema than amlodipine monotherapy, and

The T/H SPC with a lower incidence of hypokalemia than hydrochlorothiazide monotherapy

Existing evidence supports the use of the T/A SPC for the treatment of hypertensive patients with prediabetes, diabetes, or metabolic syndrome, due to the metabolic neutrality of both component drugs, and the use of the T/H SPC for those patients with edema or in need of volume reduction.

Keywords: angiotensin receptor blockers, or ARBs, calcium-channel blocker, or CCBs, essential hypertension, diuretic, , renin-angiotensin system inhibitor, or ACEI

http://www.dovepress.com/articles.php?article_id=14373
We reported on 5/29/2012

Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

Triple Combination Therapy: ARB and Calcium Channel Blocker and Diuretics

In July 2010, a triple combination drug for hypertension was approved by the US Food and Drug Administration. Tribenzor contains olmesartan medoxomil, amlodipine and hydrochlorothiazide, according to Monthly Prescribing Reference.

http://pharmaceuticalintelligence.com/2012/05/29/445/

TRIBENZOR is a Daiichi Sankyo’s product- ARB and Calcium Channel Blocker and Diuretic

How TRIBENZOR work

Tribenzor contains olmesartan medoxomil, amlodipine and hydrochlorothiazide. High blood pressure makes the heart work harder to pump blood through the body and causes damage to blood vessels. TRIBENZOR can help your blood vessels relax and reduce the amount of fluid in your blood. This can make your blood pressure lower. Medicines that lower blood pressure may lower your chance of having a stroke or a heart attack.

Some people may need more than 1—or even more than 2—medicines to help control their blood pressure. TRIBENZOR combines 3 effective medicines in 1 convenient pill. Read the following chart to learn how each medicine works in its own way to help lower blood pressure.

TRIBENZOR: 3 effective medicines in 1 pill

The medicine in TRIBENZOR	How it works	What it does
Angiotensin II receptor blocker	Blocks a natural chemical in your body that causes blood vessels to narrow.	Lowers Yours blood pressure
Calcium channel blocker	Blocks the narrowing effect of calcium on your blood vessels. This helps your blood vessels relax.
Diuretic (water pill)	Helps your kidneys flush extra fluid and salt from your body. This lowers the amount of fluid in your blood.

http://www.tribenzor.com/how_works.html

Effectively lower blood pressure. People taking the 3 medicines in TRIBENZOR had greater reductions in blood pressure than did people taking any 2 of the medicines combined

Start to work quickly. People taking TRIBENZOR saw results in as little as 2 weeks

AZOR is a Daiichi Sankyo’s product- ARB and Calcium Channel Blocker

How AZOR work

AZOR relaxes and widens blood vessels to help lower blood pressure.

You may have already tried another blood pressure medicine that works a certain way to lower blood pressure. But 1 blood pressure medicine may not be enough for you. You may find the help you need with the 2 effective medicines in AZOR.

AZOR combines 2 effective medicines in 1 convenient pill.

Learn how each medicine in AZOR works in its own way to help lower blood pressure.

The medicine in AZOR

How it works

What it does

Angiotensin II receptor blocker (ARB)

Blocks a natural chemical in your body that causes blood vessels to narrow. This helps your blood vessels relax and widen.

Lowers

Your

Blood

pressure

Calcium channel blocker

Blocks the narrowing effect of calcium on your blood vessels. This helps your blood vessels relax.

http://www.AZOR.com/how_works.html

Section Two

Calcium-Channel Blockers: Drug Class and Indications

In Sudhof’s Lasker Award presentation he refers to the biochemical properties of synaptotagmin were found to precisely correspond to the extraordinary calcium-triggering properties of release, and to account for a regulatory pathway that also applies to other types of calcium-triggered fusion, for example fusion observed in hormone secretion. A CCB would have to block the calcium-triggering properties of release, and consequently, would block the release of neurohormones. This is because the fusion apparatus and its synaptotagmin-dependent control mechanism linked to the calcium channels, docking and priming synaptic vesicles, being blocked, disables the calcium-control of the vesicle fusion that is necessary for neurotransmitter release. Consequently, the end result would be increased vascular flow from the inhibition.

What are calcium channel blockers and how do they work?

In order to pump blood, the heart needs oxygen. The harder the heart works, the more oxygen it requires. Angina (heart pain) occurs when the supply of oxygen to the heart is inadequate for the amount of work the heart must do. By dilating the arteries, CCBs reduce the pressure in the arteries. This makes it easier for the heart to pump blood, and, as a result, the heart needs less oxygen. By reducing the heart’s need for oxygen, CCBs relieve or prevent angina. CCBs also are used for treating high blood pressure because of their blood pressure-lowering effects. CCBs also slow the rate at which the heart beats and are therefore used for treating certain types of abnormally rapid heart rhythms.

For what conditions are calcium channel blockers used?

CCBs are used for treating high blood pressure, angina, and abnormal heart rhythms (for example, atrial fibrillation, paroxysmal supraventricular tachycardia).

They also may be used after a heart attack, particularly among patients who cannot tolerate beta-blocking drugs, have atrial fibrillation, or require treatment for their angina.

Unlike beta blockers, CCBs have not been shown to reduce mortality or additional heart attacks after a heart attack.

CCBs are as effective as ACE inhibitors in reducing blood pressure, but they may not be as effective as ACE inhibitors in preventing the kidney failure caused by high blood pressure or diabetes.

They also are used for treating:

CCBs are also used in the prevention of migraine headaches.

Are there any differences among calcium channel blockers?

CCBs differ in their duration of action, the process by which they are eliminated from the body, and, most importantly, in their ability to affect heart rate and contraction. Some CCBs [for example, amlodipine (Norvasc)] have very little effect on heart rate and contraction so they are safer to use in individuals who have heart failure or bradycardia (a slow heart rate). Verapamil (Calan, Isoptin) and diltiazem (Cardizem) have the greatest effects on the heart and reduce the strength and rate of contraction. Therefore, they are used in reducing heart rate when the heart is beating too fast.

What are the side effects of calcium channel blockers?

The most common side effects of CCBs are constipation, nausea,headache, rash, edema (swelling of the legs with fluid), low blood pressure, drowsiness, and dizziness.
Liver dysfunction and over growth of gums may also occur. When diltiazem (Cardizem) or verapamil (Calan, Isoptin) are given to individuals with heart failure, symptoms of heart failure may worsen because these drugs reduce the ability of the heart to pump blood.
Like other blood pressure medications, CCBs are associated with sexual dysfunction.

http://www.medicinenet.com/calcium_channel_blockers/article.htm

Section Three

Brand and Generic Calcium Channel Blocking Agents

A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

Calcium channel blockers block voltage gated calcium channels and inhibits the influx of calcium ions into cardiac and smooth muscle cells. The decrease in intracellular calcium reduces the strength of heart muscle contraction, reduces conduction of impulses in the heart, and causes vasodilatation.

Decrease in intracellular calcium in the heart decreases cardiac contractility. Decreased calcium in the vascular smooth muscle reduces its contraction and therefore causes vasodilatation.

Decrease in cardiac contractility decreases cardiac output and vasodilatation decreases total peripheral resistance, both of which cause a drop in blood pressure.

Calcium channel blocking agents are used to treat hypertension.

Filter by: — all conditions –AnginaAngina Pectoris ProphylaxisArrhythmiaAtrial FibrillationAtrial FlutterBipolar DisorderCluster HeadachesCoronary Artery DiseaseHeart FailureHigh Blood PressureHypertensive EmergencyHypertrophic CardiomyopathyIdiopathic Hypertrophic Subaortic StenosisIschemic StrokeMigraine PreventionNocturnal Leg CrampsPremature LaborRaynaud’s SyndromeSubarachnoid HemorrhageSupraventricular Tachycardia

Drug Name ( View by: Brand | Generic )

Afeditab CR (Pro, More…)generic name: nifedipine

Diltia XT (Pro, More…)generic name: diltiazem

Diltiazem Hydrochloride SR (More…)generic name: diltiazem

Nimotop (Pro, More…)generic name: nimodipine

Verelan PM (Pro, More…)generic name: verapamil

Cartia XT (Pro, More…)generic name: diltiazem

Adalat (More…)generic name: nifedipine

Calan SR (Pro, More…)generic name: verapamil

Cardizem (Pro, More…)generic name: diltiazem

Diltiazem Hydrochloride CD (More…)generic name: diltiazem

Isoptin SR (Pro, More…)generic name: verapamil

Nifediac CC (Pro, More…)generic name: nifedipine

Tiazac (Pro, More…)generic name: diltiazem

Procardia (Pro, More…)generic name: nifedipine

Adalat CC (Pro, More…)generic name: nifedipine

Cardizem LA (Pro, More…)generic name: diltiazem

Calan (Pro, More…)generic name: verapamil

Procardia XL (Pro, More…)generic name: nifedipine

Isoptin (More…)generic name: verapamil

Nifedical XL (Pro, More…)generic name: nifedipine

Plendil (Pro, More…)generic name: felodipine

Taztia XT (Pro, More…)generic name: diltiazem

Cardizem CD (Pro, More…)generic name: diltiazem

Norvasc (Pro, More…)generic name: amlodipine

Verelan (Pro, More…)generic name: verapamil

Cardene SR (Pro, More…)generic name: nicardipine

DynaCirc CR (Pro, More…)generic name: isradipine

Sular (Pro, More…)generic name: nisoldipine

Cardene (Pro, More…)generic name: nicardipine

Cardene IV (Pro, More…)generic name: nicardipine

Cleviprex (Pro, More…)generic name: clevidipine

Covera-HS (Pro, More…)generic name: verapamil

Dilacor XR (Pro, More…)generic name: diltiazem

Dilt-XR (Pro, More…)generic name: diltiazem

Diltiazem Hydrochloride XR (More…)generic name: diltiazem

Diltiazem Hydrochloride XT (More…)generic name: diltiazem

Diltzac (Pro, More…)generic name: diltiazem

Dynacirc (Pro, More…)generic name: isradipine

Matzim LA (Pro, More…)generic name: diltiazem

Nymalize (Pro, More…)generic name: nimodipine

Vascor (More…)generic name: bepridil

Section Four

Dysfunction of the Calcium Release Mechanism

For Disruption of Calcium Homeostasis in Vascular Smooth Muscle Cells, see

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

Part V: Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

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

http://pharmaceuticalintelligence.com/2013/08/26/heart-smooth-muscle-excitation-contraction-coupling-cytoskeleton-cellular-dynamics-and-ca2-signaling/

For Disruption of Calcium Homeostasis in Cardiomyocyte Cells, see

Aviva Lev-Ari, PhD, RN

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

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/

Section Five

The Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

This topic is covered in

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 V: Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

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

http://pharmaceuticalintelligence.com/2013/08/26/heart-smooth-muscle-excitation-contraction-coupling-cytoskeleton-cellular-dynamics-and-ca2-signaling/

Summary

Work on neurotransmitter release revealed a hierarchy of molecular machines that mediate the fusion of synaptic vesicles, the calcium-control of this fusion, and the embedding of calcium-controlled fusion in the context of the presynaptic terminal at the synapse. The neural transmission is described as a biological relay system. Neurotransmission kicks off with an electrical pulse that runs down a nerve cell, or neuron. When that signal reaches the tip, calcium enters the cell. In response, the neuron liberates chemical messengers—neurotransmitters. When the calcium-controlled fusion at the presynaptic junction is blocked, as with a CCB, neurotransmitters are not released. The activity of the neurotransmitters would be to cause smaooth muscle contraction of the vessel. The CCB would cause relaxation and flow.

http://www.nature.com/focus/Lasker/2013/pdf/ES-Lasker13-Sudhof.pdf

Part IX of this series of articles discussed the mechanism of the signaling of smooth muscle cells by the interacting parasympathetic neural innervation that occurs by calcium triggering neurotransmitter release by initiating synaptic vesicle fusion. It involves the interaction of soluble N-acetylmaleimide-sensitive factor (SNARE) and SM proteins, and in addition, the discovery of a calcium-dependent Syt1 (C) domain of protein- kinase C isoenzyme, which binds to phospholipids. It is reasonable to consider that it differs from motor neuron activation of skeletal muscles, mainly because the innervation is in the involuntary domain. The cranial nerve rooted innervation has evolved comes from the spinal ganglia at the corresponding level of the spinal cord. It is in this specific neural function that we find a mechanistic interaction with adrenergic hormonal function, a concept intimated by the late Richard Bing. Only recently has there been a plausible concept that brings this into serious consideration. Moreover, the review of therapeutic drugs that are used in blocking adrenergic receptors are closely related to the calcium-channels. Interesting too is the participation of a phospholipid bound protein-kinase isoenzyme C calcium-dependent domain Syt1. The neurohormonal connection lies in the observation by Katz in the 1950’s that the vesicles of the neurons hold and eject fixed amounts of neurotransmitters. The mechanism of this action will be futher discussed in Part X.

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

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

Posted in Calcium Signaling, Cell Biology, Signaling & Cell Circuits, Cytoskeleton, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Origins of Cardiovascular Disease, tagged ATP, Aviva Lev-Ari, Calcium, Calcium in biology, Calcium-Channel Blocker, gene therapy, Heart Failure, Justin Pearlman, Larry H. Bernstein, Smooth muscle tissue on September 12, 2013| Leave a Comment »

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

Author, Introduction: Larry H Bernstein, MD, FCAP

Author, Summary: Justin Pearlman, MD, PhD, FACC

and

Article Curator: Aviva Lev-Ari, PhD, RN

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

Image created by Adina Hazan 06/30/2021

This article is the Part VIII in a series of articles on Activation and Dysfunction of the Calcium Release Mechanisms in Cardiomyocytes and Vascular Smooth Muscle Cells. Calcium has a storage and release cycle that flags activation of important cellular activities that include in particular the cycle activation of muscle contraction both to circulate blood and control its pressure and distribution. Homeostasis – the maintenance of status – requires controlled release of calcium from storage and return of calcium to storage. Such controls are critical both within cells, and for the entire biologic system. Thus the role of kidneys in maintaining the correct total body load of available calcium is just as vital as the subcellular systems of calcium handling in heart muscle and in the muscles that line arteries to control blood flow. The practical side to this knowledge includes not only identifying abnormalities at the cellular as well as system levels, but also identifying better opportunities to characterize disease and to intervene.

The Series consists of the following articles:

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

Larry H Bernstein, MD, FCAP

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

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

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

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

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

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

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

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

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

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

Aviva Lev-Ari, PhD, RN

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

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

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

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

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

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

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

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

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

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

Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP

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

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

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

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

This article has three Sections:

Section One:

Vascular Smooth Muscle Cells: The Cardiovascular Calcium Signaling Mechanism

Section Two:

Cardiomyocytes Cells: The Cardiac Calcium Signaling Mechanism

Section Three:

The Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Introduction

by Larry H Bernstein, MD, FACC

Introduction

This discussion in two Sections brings to a conclusion the two main aspects of calcium signaling and transient current induction in the cardiovascular system – involving vascular smooth muscle and cardiomyocyte. In this first Section, it extends the view of smooth muscle beyond the vascular smooth muscle to contraction events in gastrointestinal tract, urinary bladder, and uterus, but by inference, to ductal structures (gallbladder, parotid gland, etc.). This discussion also reinforces the ECONOMY of the evolutionary development of these functional MOTIFS, as a common thread is used again, and again, in specific contexts. The main elements of this mechanistic framework are:

the endoplasmic (sarcoplasmic) reticulum as a strorage depot for calcium needed in E-C coupling
the release of Ca(2+) into the cytoplasm
the generation of a voltage and current with contraction of the muscle cell unit
the coordination of smooth muscle cell contractions (in waves)
- this appears to be related to the Rho/Rho kinase pathway
there is also a membrane depolarization inherent in the activation mechanism
whether there is an ordered relationship between the calcium release and the membrane polarization, and why this would be so, in not clear
three different models of calcium release are shown from the MJ Berridge classification article below in Figure 1.
Model C is of special interest because of the focus on cytosolic (Ca+) ion transfers involving the interstitial cells of Cajal (Ramin e’ Cajal) through gap junctions

Santiago Ramón y Cajal (Spanish: [sanˈtjaɣo raˈmon i kaˈxal]; 1 May 1852 – 18 October 1934) was a Spanish pathologist, histologist and neuroscientist. He was awarded the Nobel Prize in Physiology or Medicine in 1906 together with Italian Camillo Golgi “in recognition of their work on the structure of the nervous system”. Relevant to this discussion, he discovered a new type of cell, to be named after him: the interstitial cell of Cajal (ICC). This cell is found interleaved among neurons embedded within the smooth muscles lining the gut, serving as the generator and pacemaker of the slow waves of contraction that move material along the gastrointestine, vitally mediating neurotransmission from motor nerves to smooth muscle cells . Cajal also described in 1891 slender horizontal bipolar cells in the developing marginal zone of lagomorphs.(See the Cajal’s original drawing of the cells) , considered by Retzius as homologues to the cells he found in humans and in other mammals (Retzius, 1893, 1894). The term Cajal–Retzius cell is applied to reelin-producing neurons of the human embryonic marginal zone.

Section One

Vascular Smooth Muscle Cells: The Cardiovascular Calcium Signaling Mechanism

Smooth Muscle Cell Calcium Activation Mechanisms

Michael J. Berridge

J Physiol 586.21 (2008) pp 5047–5061

Classification of Smooth Muscle Ca2+ Activation Mechanisms

Excitation–contraction coupling in SMCs occurs through two main mechanisms. Many SMCs are activated by Ca2+ signalling cascades (Haddock & Hill, 2005; Wray et al. 2005). In addition, there is a Rho/Rho kinase signaling pathway that acts by altering the Ca2+ sensitivity of the contractile system (Somlyo & Somlyo, 2003). Since the latter appears to have more of a modulatory function,most attention will focus on how Ca2+ signalling is activated. Since membrane depolarization is a key element for the activation of many SMCs,much attention will focus on the mechanisms responsible for depolarizing the membrane. However, there are other SMCs where activation depends on the periodic release of Ca2+ from internal stores. These different Ca2+ activation mechanisms fall into the following three main groups (Fig. 1).

Figure 1. The three main mechanisms responsible for generating the Ca2+ transients that trigger smooth

muscle cell (SMC) contraction

A, receptor-operated channels (ROCs) or a membrane oscillator induces the membrane depolarization (_V) that

triggers Ca2+ entry and contraction.

B, a cytosolic Ca2+ oscillator induces the Ca2+ signal that drives contraction.

C, a cytosolic Ca2+ oscillator in interstitial cells of Cajal (ICCs) or atypical SMCs induces the membrane depolarization

that spreads through the gap junctions to activate neighbouring SMCs. Reproduced from Berridge (2008), with permission

SOURCE for Figure 1: J Physiol 586.21 M. J. Berridge Smooth muscle cell calcium activation mechanisms 5048

Mechanism A.

Many SMCs are activated by membrane depolarization (_V) that opens L-type voltage-operated channels (VOCs) allowing external Ca2+ to flood into the cell to trigger contraction. This depolarization is induced either by ionotropic receptors (vas deferens) or a membrane oscillator (bladder and uterus). Themembrane oscillator, which resides in the plasma membrane, generates the periodic pacemaker depolarizations responsible for the action potentials that drive contraction. The depolarizing signal that activates gastrointestinal, urethral and ureter SMCs is described in mechanism C.

Mechanism B.

The rhythmical contractions of vascular, lymphatic, airway and corpus cavernosum SMCs depend on an endogenous pacemaker driven by a cytosolic Ca2+ oscillator that is responsible for the periodic release of Ca2+ from the endoplasmic reticulum. The periodic pulses of Ca2+ often cause membrane depolarization, but this is not part of the primary activation mechanism but has a secondary role to synchronize and amplify the oscillatory mechanism. Neurotransmitters and hormones act by modulating the frequency of the cytosolic oscillator.

Mechanism C.

A number of SMCs are activated by pacemaker cells such as the interstitial cells of Cajal (ICCs) (gastrointestinal and urethral SMCs) or atypical SMCs (ureter). These pacemaker cells have a cytosolic oscillator that generates the repetitive Ca2+ transients that activate inward currents that spread through the gap junctions to provide the depolarizing signal (_V) that triggers contraction through mechanism A. In the following sections, some selected SMC types will illustrate how these signalling mechanisms have been adapted to control different contractile functions with particular emphasis on how Ca2+ signals are activated.

Vascular, Lymphatic and Airway Smooth Muscle Cells

Vascular, lymphatic and airway smooth muscle, which generate rhythmical contractions over an extended period of time, have an endogenous pacemaker mechanism driven by a cytosolic Ca2+ oscillator. In addition, these SMCs also respond to neurotransmitters released from the neural innervation. In the case of mesenteric arteries, the perivascular nerves release both ATP and noradrenaline (NA). The ATP acts first to produce a small initial contraction that is then followed by a much larger contraction when NA initiates a series of Ca2+ transients (Lamont et al. 2003). Such agonist-induced Ca2+ oscillations are a characteristic feature of the activation mechanisms of vascular (Iino et al. 1994; Lee et al. 2001; Peng et al. 2001; Perez & Sanderson, 2005b; Shaw et al. 2004) and airway SMCs (Kuo et al. 2003; Perez & Sanderson, 2005a; Sanderson et al. 2008). In some blood vessels, a specific tone is maintained by the spatial averaging of asynchronous oscillations. However, there are some vessels where the oscillations in groups of cells are synchronized resulting in the pulsatile contractions known as vasomotion (Mauban et al. 2001; Peng et al. 2001; Lamboley et al. 2003; Haddock & Hill, 2005). Such vasomotion is also a feature of lymphatic vessels (Imtiaz et al. 2007). Another feature of this oscillatory activity is that variations in transmitter concentration are translated into a change in contractile tone through a mechanism of frequency modulation (Iino et al. 1994; Kuo et al. 2003; Perez & Sanderson, 2005a,b). Frequency modulation is one of the mechanisms used for encoding and decoding signalling information through Ca2+ oscillations (Berridge, 2007).

The periodic pulses of Ca2+ that drive these rhythmical SMCs are derived from the internal stores through the operation of a cytosolic Ca2+ oscillator (Haddock & Hill, 2005; Imtiaz et al. 2007; Sanderson et al. 2008). The following general model, which applies to vascular, lymphatic, airway and perhaps also to corpus cavernosum SMCs, attempts to describe the nature of this oscillator and how it can be induced or modulated by neurotransmitters. A luminal loading Ca2+ oscillation mechanism (Berridge & Dupont, 1994; Berridge, 2007) forms the basis of this cytosolic oscillator model that depends upon the following sequential series of events (Fig. 5).

Figure 5. Vascular or airway SMCs are driven by a cytosolic oscillator that generates a periodic release

of Ca2+ from the endoplasmic reticulum that usually appears as a propagating Ca2+ wave

The oscillator is induced/modulated by neurotransmitters such as acetylcholine (ACh), 5-hydroxytryptamine (5-HT),

noradrenaline (NA) and endothelin-1 (ET-1), which act through inositol 1,4,5-trisphosphate (InsP3) that initiates

the oscillatory mechanism. The sequence of steps 1–9 is described in the text. Reproduced from Berridge (2008),

with permission.

SOURCE for Figure 5: J Physiol 586.21 M. J. Berridge Smooth muscle cell calcium activation mechanisms 5053

http://pharmaceuticalintelligence.com/2013/08/26/heart-smooth-muscle-excitation-contraction-coupling-cytoskeleton-cellular-dynamics-and-ca2-signaling/

For Disruption of Calcium Homeostasis in Vascular Smooth Muscle Cells, see

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

Part V: Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

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

Section Two

Cardiomyocytes Cells: The Cardiac Calcium Signaling Mechanism

Cardiomyocytes and Ca2+ Channels

Published August 8, 2011 // JCB vol. 194 no. 3 355-365
The Rockefeller University Press, doi: 10.1083/jcb.201101100

Cellular mechanisms of cardiomyopathy

Pamela A. Harvey and
Leslie A. Leinwand

+Author Affiliations

Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, Boulder, CO 80309

Correspondence to Leslie Leinwand: leslie.leinwand@colorado.edu

Abbreviations

DCM dilated cardiomyopathy

HCM hypertrophic cardiomyopathy

MyH Cmyosin heavy chain

RCM restrictive cardiomyopathy

Introduction

The heart relies on a complex network of cells to maintain appropriate function. Cardiomyocytes, the contracting cells in the heart, exist in a three-dimensional network of endothelial cells, vascular smooth muscle, and an abundance of fibroblasts as well as transient populations of immune cells. Gap junctions electrochemically coordinate the contraction of individual cardiomyocytes, and their connection to the extracellular matrix (ECM) transduces force and coordinates the overall contraction of the heart. Intracellularly, repeating units of actin and myosin form the backbone of sarcomere structure, the basic functional unit of the cardiomyocyte (Fig. 1). The sarcomere itself consists of ∼20 proteins; however, more than 20 other proteins form connections between the myocytes and the ECM and regulate muscle contraction (Fig. 1 B). Given the complexity of the coordinated efforts of the many proteins that exist in multimeric complexes, dysfunction occurs when these interactions are disrupted.

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Figure 1. Anatomy of the cardiac sarcomere(A) Diagram of the basic organization of the sarcomere. The sarcomere forms the basic contractile unit in the cardiomyocytes of the heart. Thin filaments composed of actin are anchored at the Z line and form transient sliding interactions with thick filaments composed of myosin molecules. The M Line, I Band, and A Band are anatomical features defined by their components (actin, myosin, and cytoskeletal proteins) and appearance in polarized light. Titin connects the Z line with the M line and contributes to the elastic properties and force production of the sarcomere through its extensible region in the I Band. Coordinated shortening of the sarcomere creates contraction of the cardiomyocyte. (B) Representation of the major proteins of the cardiac sarcomere. Attachment to the ECM is mediated by costameres composed of the dystroglycan–glycoprotein complex and the integrin complex. Force transduction and intracellular signaling are coordinated through the costamere. The unique roles of each of these proteins are critical to appropriate function of the heart. T-cap, titin cap; MyBP-C, myosin-binding protein C; NOS, nitric oxide synthase.

Although the heart may functionally tolerate a variety of pathological insults, adaptive responses that aim to maintain function eventually fail, resulting in a wide range of functional deficits or cardiomyopathy. Although a multitude of intrinsic and extrinsic stimuli promote cardiomyopathies, the best described causes are the >900 mutations in genes expressed in the cardiomyocyte (Fig. 1 B; Wang et al., 2010). Mutations in most of these genes cause a diverse range of cardiomyopathies, many with overlapping clinical phenotypes. Mutations in sarcomeric genes are usually inherited in an autosomal-dominant manner and are missense mutations that are incorporated into sarcomeres (Seidman and Seidman, 2001). Thus far >400 mutations in 13 sarcomeric proteins including β-myosin heavy chain (β-MyHC), α-cardiac actin, tropomyosin, and troponin have been associated with cardiomyopathy (www.cardiogenomics.med.harvard.edu). Table I summarizes these mutated proteins.

Ca²⁺ regulation and calcineurin signaling

Ca²⁺ concentrations inside the cardiomyocyte are critically important to actin–myosin interactions. Ca²⁺ is sequestered within the sarcoplasmic reticulum and the sarcomere itself, which serves as an intracellular reserve that is released in response to electrical stimulation of the cardiomyocyte. After contraction, sarco/endoplasmic reticulum Ca²⁺-ATPase sequesters the Ca²⁺ back into the sarcoplasmic reticulum to restore Ca²⁺balance. There is a clear correlation between force production and perturbation of Ca²⁺regulation, alterations of which might directly induce pathological, anatomical, and functional alterations that lead to heart failure via activation of GPCRs (Minamisawa et al., 1999).

Ca²⁺ in the cytosol can be increased to modulate sarcomere contractility by signaling through Gα_q recruitment and activation of PLCβ. Ca²⁺ released from the sarcoplasmic reticulum activates calmodulin, which phosphorylates calcineurin, a serine/threonine phosphatase. Upon activation, calcineurin interacts with and dephosphorylates nuclear factor of activated T cells (NFAT), which then translocates into the nucleus. Calcineurin activation exacerbates hypertrophic signals and expedites the transition to a decompensatory state. Indeed, cardiac-specific overexpression of calcineurin or NFAT leads to significant cardiac hypertrophy that progresses rapidly to heart failure (Molkentin et al., 1998). Administration of antagonists of calcineurin attenuates the hypertrophic response of neonatal rat ventricular myocytes to stimuli such as phenylephrine (PE) and angiotensin II (Taigen et al., 2000).

Mechanotransduction and signaling in the cardiomyocyte

The responses of cardiomyocytes to systemic stress or genetic abnormalities are modulated by mechanosensitive mechanisms within the cardiomyocyte (Molkentin and Dorn, 2001; Seidman and Seidman, 2001; Frey and Olson, 2003). A complex network of proteins that connects the sarcomere to the ECM forms the basis of the mechanotransduction apparatus. For example, components of the costamere complex, which form the connection between the sarcomere and the ECM via integrins, initiate intracellular signaling and subsequently alter contractile properties and transcriptional regulation in response to membrane distortion. Mechanosensitive ion channels are also implicated in signal initiation in response to systemic stress (Le Guennec et al., 1990;Zhang et al., 2000; de Jonge et al., 2002). These channels are likely responsible for acute changes that might initiate other longer-term responses in the heart but are nonetheless important to consider when examining possible transducers of systemic and tissue alterations to the cardiomyocyte.

Changes in wall stress induce signaling pathways that are associated with the development of cardiac pathology. The many intracellular signaling pathways that mediate responses to increased demand on the heart have been extensively reviewed elsewhere (Force et al., 1999; Molkentin and Dorn, 2001; Heineke and Molkentin, 2006). Here, we focus on pathways that are intimately involved in pathogenesis (Fig. 4). Although their effects in compensatory responses early in pathology initially increase function by promoting growth and contractility, persistent responses eventually compromise function.

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Figure 4. Signaling pathways associated with cardiac hypertrophy.

Although many pathways are associated with cardiomyopathy, up-regulation of transcription and induction of apoptosis are major mediators of pathogenic responses in the heart. The GPCR-associated pathway (dark red) can be activated by ET-1 and AngII, which are released in response to reduced contractility, and mediates contractile adaptation through increased calcium release from the sarcoplasmic reticulum. Increased intracellular calcium activates calmodulin and induces activation of the transcription factor MEF2. Incorporation into the sarcomere of mutant proteins that exhibit reduced ATP efficiency inhibits the sequestration of calcium from the cytosol and further enhances increases in intracellular calcium concentration. GPCR signaling is also associated with activation of the Akt signaling pathway (light green) that induces fetal gene expression and the cardiac hypertrophic response through inhibition of GSK3β. Apoptotic pathways (light blue) are induced by cytochrome c (CytC) release from mitochondria and activation of death receptors (like FasR) by cytokines such as TNF. Calcium overload and myocyte loss significantly contribute to reduced contractility in many forms of cardiomyopathy. ET-1, endothelin-1; HDAC, histone deacetylase; NFAT, nuclear factor of activated T cells; MEF-2, myocyte enhancer factor 2; SERCA, sarco/endoplasmic reticulum calcium-ATPase; cFLIP, cellular FLICE-inhibitory protein; AngII, angiotensin II; FasR, Fas receptor.

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/

For Disruption of Calcium Homeostasis in Cardiomyocyte Cells, see

Aviva Lev-Ari, PhD, RN

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

Section Three

The Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

This topic is covered in

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

Summary

Justin D Pearlman, MD, PhD, FACC PENDING

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

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

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

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

Author and Curator: Larry H Bernstein, MD, FCAP

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

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

Image created by Adina Hazan 06/30/2021

Voice of Justin Pearlman, MD, PhD, FACC

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

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

The Series consists of the following articles:

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

Larry H Bernstein, MD, FCAP

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

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

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

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

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

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

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

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

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

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

Aviva Lev-Ari, PhD, RN

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

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

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

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

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

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

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

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

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

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

Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP

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

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

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

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

and

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

Larry H Bernstein, MD, FCAP

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

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

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

doi: 10.1016/j.pharmthera.2009.03.006

PMCID: PMC2704947

Ryanodine receptor-mediated arrhythmias and sudden cardiac death

Lynda M. Blayney and F. Anthony Lai

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

This article has the following sections:

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

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

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

Author: Justin D Pearlman, MD, PhD, FACC

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

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

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

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

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

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

Aviva Lev-Ari, PhD, RN

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

Anderson Publications (2006-2013)

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

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

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

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

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

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

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

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

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

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

Therapeutic Implications of these physiological research discoveries

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

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

Curator: Aviva Lev-Ari, PhD, RN

Summary

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

Author: Larry H Bernstein, MD, FCAP

PENDING

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

Curator: Aviva Lev-Ari, PhD, RN

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

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

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

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

Author: Justin D Pearlman, MD, PhD, FACC

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

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

Calcium and Myosin in Muscle Contraction

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

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

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

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

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

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

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

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

Treatment Selection

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

Positive inotropic agents

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

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

Negative inotropic agents

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

Class IA antiarrhythmics such as

Class IC antiarrhythmics such as

Flecainide

and

Pressors

Therapeutic Implications

1. Arrhythmias

2. Heart Failure

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

Therapeutic Implications

Author: Larry H Bernstein, MD, FCAP

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

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

Curator: Aviva Lev-Ari, PhD, RN

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

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

Follath F.

Source

Department of Medicine, University Hospital Zurich, Switzerland.

Abstract

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

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

+Author Affiliations

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

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

Abstract

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

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

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

Key Words:

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

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

+Author Affiliations

Cardiology Division, Stanford University School of Medicine, CA.

Abstract

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

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

Ryanopathy: causes and manifestations of RyR2 dysfunction in heart failure

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

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

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

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

Source

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

Abstract

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

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

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

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

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

Mark E. Anderson

+Author Affiliations

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

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

Key Words:

See related article, pages 1314–1322

CaMKII Is a Pluripotent Signaling Molecule in Heart

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

Ryanodine Receptors Are Central

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

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

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

Kinases Facilitate Communication Between LTCCs and RyRs

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

Heart Failure Is a Disease of Disordered Ca²⁺_i Homeostasis

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

Is Heart Failure a Disease of Enzymatic Over-Activity?

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

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

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

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

What We Learned and What We Need to Know

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

Acknowledgments

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

Footnotes

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

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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.

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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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Zhang R, Khoo MS, Wu Y, Yang Y, Grueter CE, Ni G, Price EE, Thiel W, Guatimosim S, Song LS, Madu EC, Shah AN, Vishnivetskaya TA, Atkinson JB, Gurevich VV, Salama G, Lederer WJ, Colbran RJ, Anderson ME. Calmodulin kinase II inhibition protects against structural heart disease. Nature Med. 2005; 11:409–417.

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Dzhura I, Wu Y, Colbran RJ, Corbin JD, Balser JR, Anderson ME. Cytoskeletal disrupting agents prevent calmodulin kinase, IQ domain and voltage-dependent facilitation of L-type Ca2+ channels. J Physiol. 2002; 545: 399–406.

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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

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

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

Other tightly related articles by Prof. Anderson, ME

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

Summary

Author: Justin D Pearlman, MD, PhD, FACC

PENDING

Author: Larry H Bernstein, MD, FCAP

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

Curator: Aviva Lev-Ari, PhD, RN

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

Anderson ME, General Hospital Iowa City and University of Iowa

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

Mark E. Anderson, MD, PhD

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

Contact Information

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

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

Results: 1 to 20 of 419

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

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

PMID:

17038644 [PubMed – indexed for MEDLINE] Free Article

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

Select item 186900392.

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

PMID:

18690039 [PubMed – indexed for MEDLINE] Free Article

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

Select item 122088073.

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

PMID:

12208807 [PubMed – indexed for MEDLINE] Free Article

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

Select item 164135754.

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

PMID:

16413575 [PubMed – indexed for MEDLINE]

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

Select item 159222735.

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

PMID:

15922273 [PubMed – indexed for MEDLINE]

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

Select item 169829376.

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

PMID:

16982937 [PubMed – indexed for MEDLINE] Free Article

RGS6, a modulator of parasympathetic activation in heart.

Select item 208646737.

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

PMID:

20864673 [PubMed – indexed for MEDLINE] Free PMC Article

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

Select item 180480558.

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

PMID:

18048055 [PubMed – indexed for MEDLINE] Free PMC Article

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

Select item 192739099.

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

PMID:

19273909 [PubMed – indexed for MEDLINE] Free PMC Article

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

Select item 2279626010.

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

PMID:

22796260 [PubMed – indexed for MEDLINE]

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

Select item 1280798611.

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

PMID:

12807986 [PubMed – indexed for MEDLINE] Free PMC Article

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

Select item 2061038012.

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

PMID:

20610380 [PubMed – indexed for MEDLINE] Free PMC Article

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

Select item 2087700913.

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

PMID:

20877009 [PubMed – indexed for MEDLINE] Free PMC Article

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

Select item 1686169714.

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

PMID:

16861697 [PubMed – indexed for MEDLINE] Free Article

CaMKII determines mitochondrial stress responses in heart.

Select item 2305174615.

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

PMID:

23051746 [PubMed – indexed for MEDLINE] Free PMC Article

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

Select item 2267914016.

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

PMID:

22679140 [PubMed – indexed for MEDLINE] Free Article

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

Select item 1729239117.

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

PMID:

17292391 [PubMed – indexed for MEDLINE]

Calmodulin kinase II inhibition protects against structural heart disease.

Select item 1579358218.

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

PMID:

15793582 [PubMed – indexed for MEDLINE]

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

Select item 1835989319.

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

PMID:

18359893 [PubMed – indexed for MEDLINE] Free Article

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

Select item 2233802020.

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

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

Wilson S. Colucci, MD

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

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

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

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

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

3.	Calamaras TD, Lee C, Lan F, Ido Y, Siwik DA, Colucci WS. Post-translational Modification of Serine/Threonine Kinase LKB1 via Adduction of the Reactive Lipid Species 4-Hydroxy-trans-2-nonenal (HNE) at Lysine Residue 97 Directly Inhibits Kinase Activity. J Biol Chem. 2012 Dec 7; 287(50):42400-6.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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45.	Bianchi P, Kunduzova O, Masini E, Cambon C, Bani D, Raimondi L, Seguelas MH, Nistri S, Colucci W, Leducq N, Parini A. Oxidative stress by monoamine oxidase mediates receptor-independent cardiomyocyte apoptosis by serotonin and postischemic myocardial injury. Circulation. 2005 Nov 22; 112(21):3297-305.
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46.	Maytin M, Colucci WS. Cardioprotection: a new paradigm in the management of acute heart failure syndromes. Am J Cardiol. 2005 Sep 19; 96(6A):26G-31G.
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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.
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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.
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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.
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50.	Pfister O, Mouquet F, Jain M, Summer R, Helmes M, Fine A, Colucci WS, Liao R. CD31- but Not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res. 2005 Jul 8; 97(1):52-61.
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51.	Communal C, Colucci WS. The control of cardiomyocyte apoptosis via the beta-adrenergic signaling pathways. Arch Mal Coeur Vaiss. 2005 Mar; 98(3):236-41.
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52.	Kuster GM, Pimentel DR, Adachi T, Ido Y, Brenner DA, Cohen RA, Liao R, Siwik DA, Colucci WS. Alpha-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes is mediated via thioredoxin-1-sensitive oxidative modification of thiols on Ras. Circulation. 2005 Mar 8; 111(9):1192-8.
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53.	McMurray J, Køber L, Robertson M, Dargie H, Colucci W, Lopez-Sendon J, Remme W, Sharpe DN, Ford I. Antiarrhythmic effect of carvedilol after acute myocardial infarction: results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial. J Am Coll Cardiol. 2005 Feb 15; 45(4):525-30.
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54.	Bianchi P, Pimentel DR, Murphy MP, Colucci WS, Parini A. A new hypertrophic mechanism of serotonin in cardiac myocytes: receptor-independent ROS generation. FASEB J. 2005 Apr; 19(6):641-3.
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55.	Kuster GM, Kotlyar E, Rude MK, Siwik DA, Liao R, Colucci WS, Sam F. Mineralocorticoid receptor inhibition ameliorates the transition to myocardial failure and decreases oxidative stress and inflammation in mice with chronic pressure overload. Circulation. 2005 Feb 1; 111(4):420-7.
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56.	Taniyama Y, Ito M, Sato K, Kuester C, Veit K, Tremp G, Liao R, Colucci WS, Ivashchenko Y, Walsh K, Shiojima I. Akt3 overexpression in the heart results in progression from adaptive to maladaptive hypertrophy. J Mol Cell Cardiol. 2005 Feb; 38(2):375-85.
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57.	Colucci WS (Editor): Atlas of Heart Failure – Cardiac Function and Dysfunction, Fourth Edition, Braunwald E (Series Editor). Current Medicine. 2005.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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