Arrhythmogenesis in Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract

Abstract-Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by life threatening arrhythmias and mutations in the gene encoding the ryanodine receptor (RyR2). Disagreement exists on whether (1) RyR2 mutations induce abnormal calcium transients in the absence of adrenergic stimulation; (2) decreased affinity of mutant RyR2 for FKBP12.6 causes CPVT; (3) K201 prevent arrhythmias by normalizing the FKBP12.6-RyR2 binding. We studied ventricular myocytes isolated from wild-type (WT) and knock-in mice harboring the R4496C mutation (RyR2 R4496Cϩ/Ϫ ). Pacing protocols did not elicit delayed afterdepolarizations (DADs) (nϭ20) in WT but induced DADs in 21 of 33 (63%) RyR2R4496Cϩ/Ϫ myocytes (Pϭ0.001). Superfusion with isoproterenol (30 nmol/L) induced small DADs (45%) and no triggered activity in WT myocytes, whereas it elicited DADs in 87% and triggered activity in 60% of RyR2R4496Cϩ/Ϫ myocytes (Pϭ0.001). DADs and triggered activity were abolished by ryanodine (10 mol/L) but not by K201 (1 mol/L or 10 mol/L). In vivo administration of K201 failed to prevent induction of polymorphic ventricular tachycardia (VT) in RyR2R4496Cϩ/Ϫ mice. Measurement of the FKBP12.6/RyR2 ratio in the heavy sarcoplasmic reticulum membrane showed normal RyR2-FKBP12.6 interaction both in WT and RyR2R4496Cϩ/Ϫ either before and after treatment with caffeine and epinephrine. We suggest that (1) triggered activity is the likely arrhythmogenic mechanism of CPVT; (2) K201 fails to prevent DADs in RyR2R4496Cϩ/Ϫ myocytes and ventricular arrhythmias in RyR2R4496Cϩ/Ϫ mice; and (3) RyR2-FKBP12.6 interaction in RyR2 R4496Cϩ/Ϫ is identical to that of WT both before and after epinephrine and caffeine, thus suggesting that it is unlikely that the R4496C mutation interferes with the RyR2/FKBP12.6 complex. Key Words: cardiac electrophysiology Ⅲ ryanodine receptor Ⅲ sudden death Ⅲ transgenic mice Ⅲ ventricular tachycardia C atecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by adrenergically mediated bidirectional or polymorphic ventricular tachycardia leading to syncope and/or sudden cardiac death in individuals without structural heart disease. 1,2 In 2001, we reported that the autosomal dominant form of CPVT is caused by mutations in the ryanodine receptor gene (RyR2). 3 Based on the evidence that the morphology of ventricular tachycardia observed in CPVT resembles that of digitalis induced ventricular tachycardia (VT), it had been suggested that arrhythmogenesis in CPVT could be mediated by delayed afterdepolarizations (DADs) and triggered activity. Although the discovery that CPVT is caused by mutations in the ryanodine receptor has substantiated this hypothesis, up to now no conclusive demonstration that DADs cause CPVT is available.Furthermore, although several authors have characterized in vitro the functional consequences of RyR2 mutations, 4 -6 the molecular and electrophysiological derangements leading to arrhythmias in CPVT patients are still uncl...

Prenatal exposure to carbon monoxide delays postnatal cardiac maturation

“…38 The explanation is not obvious, but it is important to underline that a latent 'arrhythmogenic propensity', such as reduction of repolarization reserve or destabilization of diastolic potential, often results in arrhythmias only in the presence of physiological triggering factors, such as adrenergic overactivation or stress conditions. 39,40 Moreover, at variance with channelopathies because of mutations, the alterations that we observed in hearts from CO-exposed rats are not permanent, but rather spontaneously normalize toward control during cardiac maturation. To explore the occurrence and/or the susceptibility to develop arrhythmias, further investigation is warranted to assess the effect of stressors on ECG and/or mortality within the 'period of vulnerability'.…”

Increasing Ryanodine Receptor Open Probability Alone Does Not Produce Arrhythmogenic Calcium Waves

“…The first would be to use an agent that reduces RyR P o and increases SR threshold for Ca 2ϩ waves. Mixed results have been obtained in cellular studies using JTV 519, 40,41 and no clinical study has at present been performed. We have recently shown in cellular studies that decreasing RyR opening with tetracaine can abolish Ca 2ϩ waves and have argued that a more selective version of tetracaine could be clinically useful.…”

“…8 This is thought to be responsible for the arrhythmogenic diastolic Ca 2ϩ release in conditions such as digitalis intoxication 6,7,9 and reperfusion following ischemia; 10 and (2) changes in the properties of the RyR. Mutations in the human RyR [11][12][13] or accessory proteins such as calsequestrin 14 increase susceptibility to lethal arrhythmias such as catecholaminergic polymorphic ventricular tachycardia. It has also been suggested that in heart failure, the open probability (P o ) of the normal RyR may be increased by protein kinase A-dependent phosphorylation and that this may be arrhythmogenic.…”

Cellular mechanisms of arrhythmogenic cardiac alternans

“…Traditionally, calcium mediated arrhythmogenesis is associated with delayed after depolarizations and abnormal impulse formation. (Katra et al, 2007;Liu et al, 2006;Rosen, 1985;Ter Keurs et al, 2006;Wehrens et al, 2003) However, in this manuscript we focus on how cardiac alternans, a mechanisms of reentrant excitation, is another significant way mechanical dysfunction and arrhythmogenesis are causally related.Cardiac alternans can refer to either mechanical (contractile) or electrical (repolarization) oscillations that occur on an every other beat basis. Cardiac alternans has been recognized for more than 100 years.…”