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Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release.

Nature medicine | Jul 10, 2011

Carvedilol is one of the most effective beta blockers for preventing ventricular tachyarrhythmias in heart failure, but the mechanisms underlying its favorable antiarrhythmic benefits remain unclear. Spontaneous Ca(2+) waves, also called store overload-induced Ca(2+) release (SOICR), evoke ventricular tachyarrhythmias in individuals with heart failure. Here we show that carvedilol is the only beta blocker tested that effectively suppresses SOICR by directly reducing the open duration of the cardiac ryanodine receptor (RyR2). This unique anti-SOICR activity of carvedilol, combined with its beta-blocking activity, probably contributes to its favorable antiarrhythmic effect. To enable optimal titration of carvedilol's actions as a beta blocker and as a suppressor of SOICR separately, we developed a new SOICR-inhibiting, minimally beta-blocking carvedilol analog, VK-II-86. VK-II-86 prevented stress-induced ventricular tachyarrhythmias in RyR2-mutant mice and did so more effectively when combined with either of the selective beta blockers metoprolol or bisoprolol. Combining SOICR inhibition with optimal beta blockade has the potential to provide antiarrhythmic therapy that can be tailored to individual patients.

Pubmed ID: 21743453 RIS Download

Mesh terms: Action Potentials | Animals | Anti-Arrhythmia Agents | Arrhythmias, Cardiac | Bisoprolol | Calcium | Calcium Channel Blockers | Carbazoles | Cell Line | Drug Therapy, Combination | Electrocardiography | Gene Knock-In Techniques | Humans | Metoprolol | Mice | Mice, Mutant Strains | Microscopy, Confocal | Mutation, Missense | Propanolamines | Ryanodine Receptor Calcium Release Channel

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Associated grants

  • Agency: NIGMS NIH HHS, Id: R01 GM111397
  • Agency: NIAMS NIH HHS, Id: R01 AR054098
  • Agency: NHLBI NIH HHS, Id: R01 HL075210
  • Agency: NHLBI NIH HHS, Id: R01 HL057832-15
  • Agency: NIAMS NIH HHS, Id: R01 AR054098-04
  • Agency: Intramural NIH HHS, Id: R01 HL075210-08
  • Agency: Canadian Institutes of Health Research, Id: R01 HL090905
  • Agency: NHLBI NIH HHS, Id: R01 HL057832
  • Agency: NHLBI NIH HHS, Id:
  • Agency: NHLBI NIH HHS, Id:

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