SERCA2a is Critical for Arrhythmic Risk in Nonischemic Cardiomyopathy

Introduction: We have described previously an arrhythmic mechanism in nonischemic heart failure (NI-HF) that involves mitochondrial Ca2+ oscillations. Modeling suggested mitochondrial Ca2+ transfer to the sarcoplasmic reticulum via the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) was a crucial element of this arrhythmic mechanism. Hypothesis: Here, we tested whether altering SERCA2a could affect arrhythmias in NI-HF. Methods: NI-HF was induced by hypertension in Wt (FVB/NJ) and SERCA2a+/- heterozygous knockout mice by unilateral nephrectomy, deoxycorticosterone acetate (DOCA) treatment and substituting drinking water with 1% saline for six weeks. Results: Heterzygous KO of SERCA2a did not result in significant baseline changes in cardiac diastolic or systolic function (Resting sarcomere length: from 1.79 ± 0.04 μm in Wt to 1.77 ± 0.04 μm in SERCA2a+/- mice. Fractional shortening: 13.6 ± 3.0% in Wt to 11.3 ± 2.9% in SERCA2a+/- mice). As previously seen, Wt NI-HF cardiomyocytes had frequent early afterdepolarizations (EADs). Consistent with our previous modeling, SERCA2a+/- NI-HF cardiomyocytes showed reduced EADs. While SERCA2a+/- mice and SERCA2a+/- NI-HF mice both showed significantly delayed decay of the cytoplasmic Ca2+ transients compared to Wt and NI-HF cardiomyocytes, respectively, SERCA2a reduction ameliorated the reduction in resting sarcomere length and fractional shortening seen in the WT NI-HF mice. I Conclusion: These results suggests that SERCA2a plays an important role in arrhythmic risk during NI-HF, and these results may have important implications for SERCA2a overexpression as a HF therapy.