Persistent increases in Ca2+ influx through Cav1.2 shortens action potential and causes Ca2+ overload-induced afterdepolarizations and arrhythmias

Persistent elevation of Ca2+ influx due to prolongation of the action potential (AP), chronic activation of the beta-adrenergic system and molecular remodeling occurs in stressed and diseased hearts. Increases in Ca2+ influx are usually linked to prolonged myocyte action potentials and arrhythmias. However, the contribution of chronic enhancement of Cav1.2 activity on cardiac electrical remodeling and arrhythmogenicity has not been completely defined and is the subject of this study. Chronically increased Cav1.2 activity was produced with a cardiac specific, inducible double transgenic (DTG) mouse system overexpressing the beta 2a subunit of Cav (Cav beta 2a). DTG myocytes had increased L-type Ca2+ current (ICa-L), myocyte shortening, and Ca2+ transients. DTG mice had enhanced cardiac performance, but died suddenly and prematurely. Telemetric electrocardiograms revealed shortened QT intervals in DTG mice. The action potential duration (APD) was shortened in DTG myocytes due to significant increases of potassium currents and channel abundance. However, shortened AP in DTG myocytes did not fully limit excess Ca2+ influx and increased the peak and tail ICa-L. Enhanced I-Ca promoted sarcoplasmic reticulum (SR) Ca2+ overload, diastolic Ca2+ sparks and waves, and increased NCX activity, causing increased occurrence of early and delayed afterdepolarizations (EADs and DADs) that may contribute to premature ventricular beats and ventricular tachycardia. AV blocks that could be related to fibrosis of the AV node were also observed. Our study suggests that increasing ICa-L does not necessarily result in AP prolongation but causes SR Ca2+ overload and fibrosis of AV node and myocardium to induce cellular arrhythmogenicity, arrhythmias, and conduction abnormalities.