Ryanodine Receptor-Targeted Anti-Arrhythmic Therapy

Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 07/2005; 1047(1):366-75. DOI: 10.1196/annals.1341.032
Source: PubMed


Cardiac arrhythmia is an important cause of death in patients with heart failure (HF) and inherited arrhythmia syndromes, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). Alterations in intracellular calcium handling play a prominent role in the generation of arrhythmias in the failing heart. Diastolic calcium leak from the sarcoplasmic reticulum (SR) via cardiac ryanodine receptors (RyR2) may initiate delayed afterdepolarizations and triggered activity leading to arrhythmias. Similarly, SR Ca(2+) leak through mutant RyR2 channels may cause triggered activity during exercise in patients with CPVT. Novel therapeutic approaches, based on recent advances in the understanding of the cellular mechanisms underlying arrhythmias in HF and CPVT, are currently being evaluated to specifically correct defective Ca(2+) release in these lethal syndromes.

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    • "Key factors in the development of DADs include increased SR Ca2+ load, and abnormal SR Ca2+ release (i.e., SR Ca2+ leak). In particular, aberrant RyR opening and diastolic SR leak have been shown to be a central factor in the development of DADs and lethal ventricular arrhythmias under disease conditions such as heart failure [25], [26]. Consistent with the mechanism of DAD development, we found that in female rat myocytes, rapid exposure to BPA or E2 markedly increased SR Ca2+ reuptake, SR load, and the fraction of SR Ca2+ release on a beat-to-beat basis. "
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