Reduced sarcoplasmic reticulum Ca²⁺ pump activity is antiarrhythmic in ischemic cardiomyopathy

We have described an arrhythmic mechanism seen only in cardiomyopathy that involves increased mitochondrial Ca²⁺ handling and selective transfer of Ca²⁺ to the sarcoplasmic reticulum (SR). Modeling suggested that mitochondrial Ca²⁺ transfer to the SR via type 2a sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA2a) is a crucial element of this arrhythmic mechanism.

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

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

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 Ca²⁺ 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 Ca²⁺ sparks, reduced SR Ca²⁺ content, reduced oxidized ryanodine receptor, and increased calsequestrin 2 in SERCA^+/- MI mice.

SERCA2a knockdown was antiarrhythmic after MI without affecting overall systolic performance. Possible antiarrhythmic mechanisms included reduced SR free Ca²⁺ and reduced diastolic SR Ca²⁺ release.