Non-β-blocking R-carvedilol enantiomer suppresses Ca2+ waves and stress-induced ventricular tachyarrhythmia without lowering heart rate or blood pressure

Abstract

Carvedilol is the current β-blocker of choice for suppressing ventricular tachyarrhythmia (VT). However, carvedilol’s benefits are dose-limited, attributable to its potent β-blocking activity that can lead to bradycardia and hypotension. The clinically used carvedilol is a racemic mixture of β-blocking S-carvedilol and non-β-blocking R-carvedilol. We recently reported that novel non-β-blocking carvedilol analogues are effective in suppressing arrhythmogenic Ca2+ waves and stress-induced VT without causing bradycardia. Thus, the non-β-blocking R-carvedilol enantiomer may also possess this favourable anti-arrhythmic property. To test this possibility, we synthesized R-carvedilol and assessed its effect on Ca2+ release and VT. Like racemic carvedilol, R-carvedilol directly reduces the open duration of the cardiac ryanodine receptor (RyR2), suppresses spontaneous Ca2+ oscillations in human embryonic kidney (HEK) 293 cells, Ca2+ waves in cardiomyocytes in intact hearts and stress-induced VT in mice harbouring a catecholaminergic polymorphic ventricular tachycardia (CPVT)-causing RyR2 mutation. Importantly, R-carvedilol did not significantly alter heart rate or blood pressure. Therefore, the non-β-blocking R-carvedilol enantiomer represents a very promising prophylactic treatment for Ca2+-triggered arrhythmia without the bradycardia and hypotension often associated with racemic carvedilol. Systematic clinical assessments of R-carvedilol as a new anti-arrhythmic agent may be warranted.

Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

“…36 Interestingly, both JTV-519 and carvedilol displayed marked SOICR suppression. Other β-blockers (propranolol and labetalol) did not affect SOICR in the CPVT2-hiPSC-CMs, supporting the notion 36,37 that the SR-stabilizing property may be unique to carvedilol. Moreover, flecainide (1 µmol/L) or riluzole, despite possessing important antiarrhythmic actions, failed to significantly suppress SOICR, suggesting that their main antiarrhythmic action may not be related to SR stabilization.…”

“…For instance, carvedilol was suggested to stabilize RyR2 beyond its β-blocking action. 36,37 Similarly, many recent in vivo and clinical studies suggested a potential role for flecainide in CPVT. Two main mechanisms were suggested (1) flecainide may increase triggered-activity threshold by directly blocking Na + channels 39,44,46 or (2) flecainide may stabilize SR thereby decreasing diastolic Ca 2+ leak.…”

Enhanced Cytosolic Ca2+ Activation Underlies a Common Defect of Central Domain Cardiac Ryanodine Receptor Mutations Linked to Arrhythmias

“…We have previously shown that carvedilol, a beta-blocker, is able to reduce the duration of openings of single RyR2 channels and suppress RyR2-mediated spontaneous Ca 2ϩ release and stressinduced ventricular tachycardias in a mouse model harboring a CPVT-causing RyR2 mutation (11). We also showed that the non-beta-blocking carvedilol enantiomer, (R)-carvedilol, is also able to suppress spontaneous Ca 2ϩ waves and wave-evoked CPVT without the bradycardia associated with racemic carvedilol (15). Here we demonstrated that racemic carvedilol and the non-beta-blocking (R)-carvedilol enantiomer also suppressed spontaneous Ca 2ϩ oscillations in HEK293 cells expressing the CPVT-and AF-associated RyR2 mutations.…”

“…Mutations Associated with Atrial Fibrillation-We have previously shown that racemic carvedilol, a clinically used betablocker, and the non-beta-blocking (R)-carvedilol enantiomer suppress spontaneous Ca 2ϩ oscillations (SOICR) in HEK293 cells expressing a RyR2 mutation R4496C that is associated with CPVT (11,15). Interestingly, some of the RyR2 mutations located in the central domain, G3946A, M3978I, and Q4159P, have been associated with AF (16,19,23).…”

Treatment of catecholaminergic polymorphic ventricular tachycardia in mice using novel RyR2-modifying drugs

“…Finally, non-β-blocking carvedilol analogues were shown to be effective in suppressing arrhythmogenic Ca 2+ waves and β-adrenergic stress-induced VT in mice with CPVT. [31] Unlike S-carvedilol, which possessing β-blocking activity, the R-carvedilol enantiomer was shown to normalize RyR2 activity without causing bradycardia and hypotension.…”