To describe the overall role of reduced sarcoplasmic reticulum Ca²⁺ ATPase (SERCA2) for Ca²⁺ wave development.

SERCA2 knockout [Serca2^flox/flox Tg(αMHC-MerCreMer); KO] mice allowing inducible cardiomyocyte-specific disruption of the Serca2 gene in adult mice were compared with Serca^flox/flox (FF) control mice. Six days after Serca2 gene disruption, SERCA2 protein abundance was reduced by 53% in KO compared with FF, whereas SERCA2 activity in field-stimulated, Fluo-5F AM-loaded cells was reduced by 42%. Baseline Ca²⁺ content of the sarcoplasmic reticulum (SR) and Ca²⁺ transient amplitude and rate constant of decay measured in whole-cell voltage-clamped cells were decreased in KO to 75, 81, and 69% of FF values. Ca²⁺ waves developed in only 31% of KO cardiomyocytes compared with 57% of FF when external Ca²⁺ was raised (10 mM), although SR Ca²⁺ content needed for waves to develop was 79% of FF values. In addition, waves propagated at a 15% lower velocity in KO cells. Ventricular extrasystoles (VES) occurred with lower frequency in SERCA2 KO mice (KO: 3 ± 1 VES/h vs. FF: 8 ± 1 VES/h) (P < 0.05 for all results).

Reduced SERCA2 abundance resulted in decreased amplitude and decay rate of Ca²⁺ transients, reduced SR Ca²⁺ content, and decreased propensity for Ca²⁺ wave development.