Published online before print June 14, 2004, doi: 10.1161/01.CIR.0000132472.98675.EC
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(Circulation. 2004;109:3208-3214.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Sudden Death in Familial Polymorphic Ventricular Tachycardia Associated With Calcium Release Channel (Ryanodine Receptor) Leak
From the Center for Molecular Cardiology, Department of Physiology and Cellular Biophysics (S.E.L., X.H.T.W., S.R.R., A.R.M.) and Department of Medicine (S.-X.D., Z.C., D.W.L.), Columbia University College of Physicians and Surgeons, New York, NY, and Department of Medicine (P.J.L., K.K., H.S.), University of Helsinki, Finland.
Correspondence to Andrew R. Marks, MD, Center for Molecular Cardiology, Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, 630 W. 168th St, P&S 9-401, Box 65, New York, NY 10032. E-mail arm42{at}columbia.edu
Received February 26, 2004; revision received April 8, 2004; accepted May 3, 2004.
Background— Familial polymorphic ventricular tachycardia (FPVT) is characterized by exercise-induced arrhythmias and sudden cardiac death due to missense mutations in the cardiac ryanodine receptor (RyR2), an intracellular Ca2+ release channel required for excitation-contraction coupling in the heart.
Methods and Results— Three RyR2 missense mutations, P2328S, Q4201R, and V4653F, which occur in Finnish families, result in similar mortality rates of 
33% by age 35 years and a threshold heart rate of 130 bpm, above which exercise induces ventricular arrhythmias. Exercise activates the sympathetic nervous system, increasing cardiac performance as part of the fight-or-flight stress response. We simulated the effects of exercise on mutant RyR2 channels using protein kinase A (PKA) phosphorylation. All 3 RyR2 mutations exhibited decreased binding of calstabin2 (FKBP12.6), a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, FPVT-mutant RyR2 channels showed a significant gain-of-function defect consistent with leaky Ca2+ release channels and a significant rightward shift in the half-maximal inhibitory Mg2+ concentration (IC50). Treatment with the experimental drug JTV519 enhanced binding of calstabin2 to RyR2 and normalized channel function.
Conclusions— Sympathetic activation during exercise induces ventricular arrhythmias above a threshold heart rate in RyR2 mutation carriers. Simulating the downstream effects of the sympathetic activation by PKA phosphorylation of RyR2 channels containing these FPVT missense mutations produced a consistent gain-of-function defect. RyR2 function and calstabin2 depletion were rescued by JTV519, suggesting stabilization of the RyR2 channel complex may represent a molecular target for the treatment and prevention of exercise-induced arrhythmias and sudden death in these patients. (Circulation. 2004;109:3208-3214.)
Key Words: calcium • death, sudden • arrhythmia • sarcoplasmic reticulum • drugs
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