Reduced sarcoplasmic reticulum Ca pump activity is antiarrhythmic in ischemic cardiomyopathy.

BACKGROUND

We have described an arrhythmic mechanism seen only in cardiomyopathy that involves increased mitochondrial Ca handling and selective transfer of Ca to the sarcoplasmic reticulum (SR). Modeling suggested that mitochondrial Ca transfer to the SR via type 2a sarco/endoplasmic reticulum Ca-ATPase (SERCA2a) is a crucial element of this arrhythmic mechanism.

OBJECTIVE

We tested the role of SERCA2a in arrhythmias during ischemic cardiomyopathy.

METHODS

Myocardial infarction (MI) was induced in wild-type (Wt) and SERCA2a heterozygous knockdown (SERCA) mice.

RESULTS

Compared with Wt MI mice, SERCA2a heterozygous knockdown (SERCA) MI mice had a substantially lower mortality after 3 weeks of MI without a significant change in MI area. Aside from a significant delay of the cytoplasmic Ca transient decay existed in SERCA compared with Wt, SERCA did not affect cardiac systolic and diastolic function at the whole organ or single cell levels either before or after MI. After MI, SERCA mice had reduced SERCA2a expression in the MI border zone compared with Wt MI mice. SERCA mice had significantly decreased corrected QT intervals and less ventricular tachycardia compared with Wt MI mice. SERCA cardiomyocytes from MI mice showed a reduced action potential duration and reduced triggered activity compared with Wt MI cardiomyocytes. Reduction in arrhythmic risk was accompanied by reduced diastolic SR Ca sparks, reduced SR Ca content, reduced oxidized ryanodine receptor, and increased calsequestrin 2 in SERCA MI mice.

CONCLUSION

SERCA2a knockdown was antiarrhythmic after MI without affecting overall systolic performance. Possible antiarrhythmic mechanisms included reduced SR free Ca and reduced diastolic SR Ca release.