Published online before print June 14, 2004, doi: 10.1161/01.CIR.0000132472.98675.EC
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(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
This article has been cited by other articles:
 |
|
 |
|
  T. Yamamoto, M. Yano, X. Xu, H. Uchinoumi, H. Tateishi, M. Mochizuki, T. Oda, S. Kobayashi, N. Ikemoto, and M. Matsuzaki Identification of Target Domains of the Cardiac Ryanodine Receptor to Correct Channel Disorder in Failing Hearts Circulation, February 12, 2008; 117(6): 762 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Liu and S. G. Priori Disruption of calcium homeostasis and arrhythmogenesis induced by mutations in the cardiac ryanodine receptor and calsequestrin Cardiovasc Res, January 15, 2008; 77(2): 293 - 301. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Chen, M. L. Marquardt, D. J. Tester, K. J. Sampson, M. J. Ackerman, and R. S. Kass Mutation of an A-kinase-anchoring protein causes long-QT syndrome PNAS, December 26, 2007; 104(52): 20990 - 20995. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Lehnart, M. J. Ackerman, D. W. Benson Jr, R. Brugada, C. E. Clancy, J. K. Donahue, A. L. George Jr, A. O. Grant, S. C. Groft, C. T. January, et al. Inherited Arrhythmias: A National Heart, Lung, and Blood Institute and Office of Rare Diseases Workshop Consensus Report About the Diagnosis, Phenotyping, Molecular Mechanisms, and Therapeutic Approaches for Primary Cardiomyopathies of Gene Mutations Affecting Ion Channel Function Circulation, November 13, 2007; 116(20): 2325 - 2345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Smith Matters of the heart: the physiology of cardiac function and failure Exp Physiol, November 1, 2007; 92(6): 973 - 986. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. F. James Inhibition of SR Ca2+ uptake: A novel action of the RyR2-FKBP12.6 antagonist K201 Cardiovasc Res, November 1, 2007; 76(2): 199 - 201. [Full Text] [PDF]
|
|
|
|
 |
|
 X. Meng, B. Xiao, S. Cai, X. Huang, F. Li, J. Bolstad, R. Trujillo, J. Airey, S. R. W. Chen, T. Wagenknecht, et al. Three-Dimensional Localization of Serine 2808, a Phosphorylation Site in Cardiac Ryanodine Receptor J. Biol. Chem., August 31, 2007; 282(35): 25929 - 25939. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Paavola, M. Viitasalo, P. J. Laitinen-Forsblom, M. Pasternack, H. Swan, I. Tikkanen, L. Toivonen, K. Kontula, and M. Laine Mutant ryanodine receptors in catecholaminergic polymorphic ventricular tachycardia generate delayed afterdepolarizations due to increased propensity to Ca2+ waves Eur. Heart J., May 1, 2007; 28(9): 1135 - 1142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. H.T. Wehrens Leaky ryanodine receptors cause delayed afterdepolarizations and ventricular arrhythmias Eur. Heart J., May 1, 2007; 28(9): 1054 - 1056. [Full Text] [PDF]
|
|
|
|
 |
|
 R. P. Katra, T. Oya, G. S. Hoeker, and K. R. Laurita Ryanodine receptor dysfunction and triggered activity in the heart Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2144 - H2151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E. D. J. ter Keurs and P. A. Boyden Calcium and Arrhythmogenesis Physiol Rev, April 1, 2007; 87(2): 457 - 506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Keller, J. P.Y. Kao, M. Egger, and E. Niggli Calcium waves driven by "sensitization" wave-fronts Cardiovasc Res, April 1, 2007; 74(1): 39 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Lucats, L. Vinet, A. Bize, X. Monnet, D. Morin, J. B. Su, P. Rouet-Benzineb, O. Cazorla, J.-J. Mercadier, L. Hittinger, et al. The inotropic adaptation during late preconditioning against myocardial stunning is associated with an increase in FKBP12.6 Cardiovasc Res, February 1, 2007; 73(3): 560 - 567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Hove-Madsen, C. Prat-Vidal, A. Llach, F. Ciruela, V. Casado, C. Lluis, A. Bayes-Genis, J. Cinca, and R. Franco Adenosine A2A receptors are expressed in human atrial myocytes and modulate spontaneous sarcoplasmic reticulum calcium release Cardiovasc Res, November 1, 2006; 72(2): 292 - 302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Kannankeril, B. M. Mitchell, S. A. Goonasekera, M. G. Chelu, W. Zhang, S. Sood, D. L. Kearney, C. I. Danila, M. De Biasi, X. H. T. Wehrens, et al. Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy PNAS, August 8, 2006; 103(32): 12179 - 12184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Liu, B. Colombi, M. Memmi, S. Zissimopoulos, N. Rizzi, S. Negri, M. Imbriani, C. Napolitano, F. A. Lai, and S. G. Priori Arrhythmogenesis in Catecholaminergic Polymorphic Ventricular Tachycardia: Insights From a RyR2 R4496C Knock-In Mouse Model Circ. Res., August 4, 2006; 99(3): 292 - 298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Jona and P. P. Nanasi Cardiomyopathies and sudden cardiac death caused by RyR2 mutations: Are the channels the beginning and the end? Cardiovasc Res, August 1, 2006; 71(3): 416 - 418. [Full Text] [PDF]
|
|
|
|
|
|
S. E. Lehnart, C. Terrenoire, S. Reiken, X. H. T. Wehrens, L.-S. Song, E. J. Tillman, S. Mancarella, J. Coromilas, W. J. Lederer, R. S. Kass, et al. Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias PNAS, May 16, 2006; 103(20): 7906 - 7910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. George, H. Jundi, N. Walters, N. L. Thomas, R. R. West, and F. A. Lai Arrhythmogenic Mutation-Linked Defects in Ryanodine Receptor Autoregulation Reveal a Novel Mechanism of Ca2+ Release Channel Dysfunction Circ. Res., January 6, 2006; 98(1): 88 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Ai, J. W. Curran, T. R. Shannon, D. M. Bers, and S. M. Pogwizd Ca2+/Calmodulin-Dependent Protein Kinase Modulates Cardiac Ryanodine Receptor Phosphorylation and Sarcoplasmic Reticulum Ca2+ Leak in Heart Failure Circ. Res., December 9, 2005; 97(12): 1314 - 1322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Jiang, R. Wang, B. Xiao, H. Kong, D. J. Hunt, P. Choi, L. Zhang, and S. R. W. Chen Enhanced Store Overload-Induced Ca2+ Release and Channel Sensitivity to Luminal Ca2+ Activation Are Common Defects of RyR2 Mutations Linked to Ventricular Tachycardia and Sudden Death Circ. Res., November 25, 2005; 97(11): 1173 - 1181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Brunet, T. Scheuer, R. Klevit, and W. A. Catterall Modulation of CaV1.2 Channels by Mg2+ Acting at an EF-hand Motif in the COOH-terminal Domain J. Gen. Physiol., September 26, 2005; 126(4): 311 - 323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kontula, P. J. Laitinen, A. Lehtonen, L. Toivonen, M. Viitasalo, and H. Swan Catecholaminergic polymorphic ventricular tachycardia: Recent mechanistic insights Cardiovasc Res, August 15, 2005; 67(3): 379 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Lehnart, X. H.T. Wehrens, and A. R. Marks Defective Ryanodine Receptor Interdomain Interactions May Contribute to Intracellular Ca2+ Leak: A Novel Therapeutic Target in Heart Failure Circulation, June 28, 2005; 111(25): 3342 - 3346. [Full Text] [PDF]
|
|
|
|
 |
|
 X. H.T. WEHRENS, S. E. LEHNART, and A. R. MARKS Ryanodine Receptor-Targeted Anti-Arrhythmic Therapy Ann. N.Y. Acad. Sci., June 1, 2005; 1047(1): 366 - 375. [Abstract] [Full Text] [PDF]
|
|