Dyadic CaV1.2 channels are essential components of cardiac EC-coupling, this is demonstrated during heart failure when the architecture of cardiomyocytes is remodeled, and t-tubules become fractured, displaced, disorganized, and separated from the jSR [72] creating orphaned RYR2 [91], and resulting in reduced Ca2+ transient amplitude, contractile dysfunction, and promotion of arrhythmia promoting dyssynchronous Ca2+ release events [92,93,94,95]. The gene discussed is CACNA1C; the disease is heart failure.