The cardiac ryanodine receptor (RyR2) and its role in heart disease.

The cardiac ryanodine receptor has become a subject of increasing interest as its role in the etiology of cardiac disease is becoming more apparent. In this article, we review the current knowledge of the structure and function of the cardiac ryanodine receptor and its implications in cardiac pathophysiology. Cardiac ryanodine receptors function by regulating calcium release from the sarcoplasmic reticulum in cardiomyocytes, thereby playing an integral role in excitation-contraction coupling. In heart failure, the myocardium remains in a chronic hyperadrenergic state. This leads to protein kinase A hyperphosphorylation of ryanodine receptors within cardiomyocytes, ultimately leading to calcium leakage from the sarcoplasmic reticulum into the cytosol and thus impairing excitation-contraction coupling. These mechanisms could partially explain the pathophysiology underlying the reduced cardiac output seen in heart failure. Beta-adrenergic blockade appears to correct the abnormality and reestablishes normal ryanodine receptor function. These calcium leaks can also generate delayed afterdepolarizations, which can lead to fatal arrhythmias. Two genetic diseases have been linked to mutations in the cardiac ryanodine receptor: arrhythmogenic right ventricular dysplasia type 2 and catecholaminergic polymorphic ventricular tachycardia or familial polymorphic ventricular tachycardia. As our understanding of this receptor and its modulators deepens, the possibility of clinical application draws near.