Sudden Death in Familial Polymorphic Ventricular Tachycardia Associated With Calcium Release Channel (Ryanodine Receptor) Leak

Abstract

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 Ca 2ϩ 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 Ϸ33% 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 Ca 2ϩ release channels and a significant rightward shift in the half-maximal inhibitory Mg 2ϩ concentration (IC 50 ). 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.

Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy

“…An alternative mechanism of arrhythmogenesis may result from catecholamine-induced hyperphosphorylation of RyR2 at Ser-2809, which dissociates FKBP12.6 from the channel, causing a diastolic calcium leak (19,20). To determine whether this leak underlies the abnormal calcium release in RyR2 R176Q/ϩ cardiomyocytes, we measured RyR2 Ser-2809 phosphorylation in hearts from RyR2 R176Q/ϩ and WT mice and also after isoproterenol treatment (100 g i.p.).…”

A mechanism for sudden infant death syndrome (SIDS): Stress-induced leak via ryanodine receptors

“…30 CPVT-associated RyR2 mutations lead to defective channel gating characterized by gain-of-function phenotype with increased open probability of the channels after PKA phosphorylation when measured under conditions that simulated diastole (low cytosolic [Ca 2+ ]), the resting phase of the heart cycle. 31 These RyR2 mutations confer a leaky phenotype on the channel that leads to aberrant diastolic Ca 2+ release from the sarcoplasmic reticulum (SR) that can initiate delayed afterdepolarizations, triggering ventricular arrhythmias and SCD.…”

Electrical heart disease: Genetic and molecular basis of cardiac arrhythmias in normal structural hearts

“…The knowledge of the genetic cause and specific proteins responsible for these conditions has now allowed a more in-depth understanding of the molecular mechanisms involved in disease susceptibility, enabling researchers to target specific molecular pathways in drug development, such as the proposed use of the novel compound JTV519 in the treatment of CPVT (9) or the use of mexiletine to prevent arrhythmia in patients with the LQTS type 3 (LQT3) (10). In addition, genotype-phenotype correlations demonstrated in clinical observation studies have enabled clinicians to risk stratify patients (11,12) and to offer the most appropriate treatment options.…”