Abstract: Series 101, Lecture 3
The Harvey Lectures Series 101 (2005—2006)
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Lecture #3: Thursday, January 19, 2006 — Time and Location
Heart Failure and Sudden Cardiac Death: Causes and Cures
Andrew R Marks, MD
Professor and Chair of Physiology and Cellular Biophysics
Clyde and Helen Wu Professor of Molecular Cardiology in Medicine
Director of the Center for Molecular Cardiology
College of Physicians and Surgeons, Columbia University
New York, New York
Heart failure and sudden cardiac death are leading causes of mortality. Developing effective therapy has been hampered due to a lack of understanding of the mechanisms that cause these disorders. We have shown that “leaky†ryanodine receptor/calcium release channels (RyR2) contribute to heart failure and sudden cardiac death in humans and relevant animal models. RyR2 is the major calcium release channel on the sarcoplasmic reticulum and is required for excitation-contraction coupling. RyR2 becomes leaky in failing hearts due to PKA hyperphosphorylation of the channel that results from chronic activation of the “fight or flight†stress response. PKA hyperphosphorylation decreases the binding affinity of calstabin2, a subunit of the channel, rendering the channels leaky. Treatment with a 1,4 benzothiazepine derivative that enhances the affinity of calstabin2 for RyR2 improves cardiac function and prevents sudden cardiac death in animal models.
Lecture Sponsor: GE Global Research and Development
