Catecholaminergic Polymorphic Ventricular Tachycardia

Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function

“…The classical mechanism of RyR2-triggered arrhythmias in CPVT requires the participation of mutation-destabilized RyR2 channels eager to release Ca 2+ during diastole and ignite cellular processes that lead to DADs (6)(7)(8)(9). This scheme, therefore, necessarily rests on intrinsically hyperactive RyR2 channels that are primed for activation by any of a number of adrenergically induced exacerbating factors (e.g., increased I CaL , RyR2 phosphorylation, increased SR load).…”

“…However, RyR2 channels operate within a limited margin of safety because conditions that demand higher RyR2 activity (such as sympathetic stimulation) also increase the vulnerability of the heart to life-threatening arrhythmias (4), and this risk is higher in hearts harboring mutant RyR2 channels. Indeed, point mutations in RYR2, the gene encoding for the cardiac RyR channel, are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) (5), a highly arrhythmogenic syndrome triggered by sympathetic stimulation that may lead to sudden cardiac death, especially in children and young adults (6).…”

“…In this scheme, RyR2 channels destabilized by gain-of-function mutations release Ca 2+ during diastole, generating a depolarizing transient inward current (I ti ) as the sarcolemmal Na + -Ca 2+ exchanger (NCX) extrudes the released Ca 2+ . This electrogenic inward current then causes DADs, which, if sufficiently large, reach the threshold to initiate untimely action potentials (APs) and generate triggered activity (6)(7)(8). Hence, hyperactive RyR2 channels eager to release Ca 2+ on their own appear as essential components of this arrhythmogenic scheme.…”

Guidelines for Risks and Prevention of Sudden Cardiac Death (JCS 2010) - Digest Version -

“…[124][125][126][127] CPVT is not associated with organic heart diseases, and there is no sex difference in incidence. In patients with CPVT, exercise and intravenous isoproterenol induce a gradual increase in PVC, which further lead to polymorphic or bidirectional VT, very fast polymorphic VT (350 to 400/min), and finally to VF.…”

Unveiling Specific Triggers and Precipitating Factors for Fatal Cardiac Events in Inherited Arrhythmia Syndromes

“…25,29,30 CPVT CPVT is a hereditable disorder characterized by adrenergicinduced bidirectional and polymorphic VT without structural heart diseases, leading to syncope and SCD. 31,32 RYR2 (encoding the cardiac ryanodine receptor), CAQS2 (encoding cardiac calsequestrin), KCNJ2 (encoding IK1: inwardly rectifying potassium currents), TRDN (encoding the junctional protein triadine) have been identified as causative genes for CPVT ( Table 1). 5,32,33 Recently, mutations in 2 (CALM1 and CALM2) of 3 genes (CALM1-3) encoding identical peptide sequences for the essential Ca 2+ -signaling protein calmodulin were reported to be associated with malignant forms of LQTS, CPVT and idiopathic VF.…”