Abstract 2733: Enhanced Cav1.2 Influx Induces Cardiac Conduction Disturbances and SR Ca2+ Overload to Induce Cardiac Arrhythmia but With Shortened QT and Action Potentials
Adrenergic overstimulation, abnormal regulation (e.g., hyperphosphorylation) and gene expression alterations (e.g., increased Cav1.2β2a expression) of Cav1.2 increase ICa-L in CVD, which has been proposed to contribute to the prolongation of cardiomyocyte (CM)action potentials (APs) of and QT intervals, and eventually to provide a substrate for arrhythmias.
Methods: To mimic the enhanced Cav1.2 activities in CVD, we established a transgenic mouse model overexpressing Cav1.2 β2a specifically in CMs. In-vivo ECG recordings and in-vitro ion currents and intracellular Ca2+ measurements were measured in transgenic (TG) and control (CTR) CMs.
Results: TG CMs had greater ICaL (13.8+/−1.6pA/pF vs. CTR 23.9+/− 2.5pA/pF, p < 0.01), CM fractional shortening and Ca2+ transients. TG mice had enhanced cardiac performance (by ECHO) up to 1 year but 50% TG mice died suddenly at the age of 6 months with no sign of heart failure, suggesting cardiac arrhythmias. Telemetrical ECG showed that there was no difference in heart rate in conscious CTR (571+/−29bpm, n = 8) and TG (561+/−24bpm, n = 8) mice but the QT interval was significantly shorter in TG (44.0+/−5.5ms) vs CTR (58.2+/−3.4ms) mice. Second degree AV block and ectopic premature ventricular beats were observed in all 8 TG mice but in 0 of the 8 CTR mice. A significantly greater % of TG CMs (28.5%) had early (EADs) and delayed (DADs) afterdepolarizations than CTR (0.0%). AP duration (APD) was significantly shorter in TG CMs (APD90%: 40.0+/−5.7ms, n = 13 vs. CTR: 95.6+/−15.2ms, n = 10). The shorter APD in TG CMs was associated with a significant increase of Ito (TG vs. CTR: 60.2±0.8pA/pF vs. 18.7±3.0pA/pF at +50mV). EADs and DADs in TG CMs could be due to enhanced Ca2+ handling (SR load (caffeine spritz and Fluo-4): F/F0 in TG 4.7+/−0.4 vs. CTR 3.2+/−0.3) and INCX (TG 2.15+/−0.6pA/pF vs CTR 1.12+/−0.3pA/pF at +60mV) in TG myocytes.
Conclusion: Increasing Cav1.2 activities shortens, rather than prolongs, QT intervals and CM APs because of concomitant augment of hyperpolarizing K+ currents in TG mice. However, there are conduction disturbances and arrhythmias possibly due to EADs and DADs brought about by enhanced Cav1.2 activities, SR Ca2+ load and NCX activities, indicating the dissociation of prolonged APs and QT from arrhythmias.
This research has received full or partial funding support from the American Heart Association, National Center.