Altered force–frequency response in non-failing hearts with decreased SERCA pump-level

OBJECTIVE: Decreased SERCA2 activity is considered to significantly contribute to the contractile dysfunction of failing hearts. However, it is now known how decreases in SERCA activity affect cardiac function in detail and also if a decrease alone is sufficient to cause heart failure. METHODS: SERCA2 (+/-) gene-targeted mice (HET) were generated and heart function was analyzed using the isolated work-performing heart technique. Plasma and cardiac catecholamine levels were determined at three, six and nine months of age and heart sections from twelve months old mice subjected to standard histological analysis. RESULTS: We demonstrate that reduced expression of SERCA does not lead to cardiac hypertrophy or fibrosis and does not increase resting plasma-norepinephrine levels in HET mice. However, isolated perfused HET hearts exhibited decreased maximal rates of contraction and relaxation and prolonged time-parameters. The ability of the HET hearts to respond to increases in load (Starling) was not affected and they responded appropriately to beta-adrenergic stimulation. In contrast, the positive force-frequency response found in control hearts was not observed in the HET hearts. The response was flat and three out of five HET hearts failed to maintain work at 550 beats/min. CONCLUSIONS: We conclude that the SERCA2 pump level is a critical positive determinant of cardiac contractility and force-frequency relation.