Article

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

ABSTRACT

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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    ABSTRACT: Sudden cardiac death accounts for 100,000 victims in Germany per year. Predominantly, patients with structural heart disease such as coronary artery disease or dilated cardiomyopathy are affected. However, approximately 5-10% of sudden deaths hit patients without structural disease of the heart. The proportion of young patients (< 40 years of age) in this group is even higher (10-20%). In younger patients significantly more diseases like hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia and primary electrical diseases of the heart could be observed such as long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. The primary electrical diseases are different concerning their electrocardiographical pattern, clinical triggers of arrhythmias, results of invasive diagnostics and therapy. Meanwhile, molecular genetic screening can reveal specific mutations of ion channels and can identify consecutive functional defects. The significance of programmed ventricular stimulation is at present unclear concerning risk stratification in patients with Brugada syndrome and short QT syndrome and of no significance in long QT syndrome and catecholaminergic polymorphic ventricular tachycardias. The implantable cardioverter defibrillator is the therapy of choice in most symptomatic patients. With increasing knowledge as a result of sophisticated molecular genetic screening, identification of underlying ion channel defects and new details of the mechanisms of arrhythmogenesis, a potential genotype-guided therapy will gain more importance in the future.
    No preview · Article · Jan 2006 · Herzschrittmachertherapie & Elektrophysiologie
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