Minoru Horie, M.D., Ph.D.,
Shiga University of Medical Sciences, Otsu, Japan
In cardiac Ca handling, ryanodine receptor (RyR) channel plays a key role. The channel is encoded by RYR2 gene, encompassing 105 exons on chromosome 1q43, and is expressed on sarcoplasmic reticulum (SR). It collaborates with voltage-dependent L-type Ca channel (LTCC) and releases substantial volume of Ca from the SR, which is a major Ca source for the myocardial excitation-contraction coupling. The channel opening is triggered by intracellular Ca increase through LTCC (Ca-induced Ca release). Since the first discovery of RYR2 mutations as the cause of catecholaminergic polymorphic ventricular tachycardia (CPVT1), several pathologic conditions were shown to be associated with RYR2 mutations.
CPVT is a familial arrhythmogenic disorder characterized by adrenergically-mediated polymorphic VT in the structurally intact heart with onset of manifestations in childhood and adolescence, leading to syncope and sudden cardiac death. Arrhythmias in CPVT are associated with gain-of-function RYR2 mutations and mediated by delayed afterdepolarizations (DADs), oscillations of the membrane potential associated with intracellular Ca-overload. RYR2 mutations are also found in some arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C type 2). More recently, RYR2-associated pathological entity was expanded to the non-compaction of the ventricular myocardium (LVNC), which is referred to as “spongy” myocardium. LVNC is characterized by numerous prominent trabeculations and deep inter-trabecular recesses in hypertrophied and hypokinetic segments of the left ventricle, detected by echocardiography or other imaging modalities. Functional RyR defects are thought to delay embryonic myocardial development with lack of compaction of the loose myocardial meshwork.
Finally, several RYR2 mutations are reported to be related with short-coupled variant of torsade de points (ScTdP), characterized by bizarre polymorphic VT triggered by an extremely short coupling interval in the structurally intact heart. Though precise mechanistic link remains unknown, contrary to CPVT, a loss-of-function type mutation was identified in a proband with typical ScTdP phenotypes.