Background: 

Heart failure patients have an increased risk of ventricular arrhythmias. This is partly because ventricular myocytes are more prone to developing arrhythmias because of altered Ca²⁺ homeostasis. One proposed mechanism for this Ca²⁺ dependent arrythmogenicity is reduced abundance of the cardiac sarcoplasmic reticulum Ca²⁺ ATPase (SERCA2) combined with increased adrenergic stimulation. However, the individual contributions of these factors remain to be clearified.

Methods: 

Whole cell voltage clamp technique combined with Ca²⁺ imaging was used to study spontaneous Ca²⁺ release in isolated ventricular cardiomyocytes from mice with inducible disruption of the Serca2 gene (SERCA2 KO) with Serca2flox/flox mice serving as controls. In vivo arrhythmias were recorded with telemetric ECG surveillance after i.p. injections of isoproterenol and caffeine.

Results: 

Six days after induction of Serca2 gene disruption, SERCA2 protein abundance in the left ventricles of SERCA2 KO mice was 47% compared to controls. Ventricular extrasystoles occurred with lower frequency in SERCA2 KO mice, while ventricular tachycardia and ventricular fibrillation could be elicited in both groups. Arrhythmogenic Ca²⁺ release in isolated cardiomyocytes, seen as Ca²⁺ waves, occurred less often in SERCA2 KO than control myocytes, but isoproterenol increased the propensity for waves in both groups.

Conclusions: 

Reduced SERCA2 protein abundance and increased b adrenergic stimulation have opposite effects on the propensity for arrhythmogenic Ca²⁺ release in ventricular cardiomyocytes: Even though reduced SERCA2 abundance decreases the propensity for developing arrhythmias, b adrenergic stimulation can still elicit Ca²⁺ waves and ventricular arrhythmias. Further studies are needed to determine the arrhythmogenic potential of b adrenergic stimulation in SERCA2 KO hearts, reflecting the situation in heart failure patients.