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Abstract: Abnormal Ca2+ cycling in the failing heart might be corrected by enhancing the activity of the cardiac Ca2+ pump, the sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a) isoform. This can be obtained by increasing the pump''s affinity for Ca2+ by suppressing phospholamban (PLB) activity, the in vivo inhibitor of SERCA2a. In SKO mice, gene-targeted replacement of SERCA2a by SERCA2b, a pump with a higher Ca2+ affinity, results in cardiac hypertrophy and dysfunction. The stronger PLB inhibition on cardiac morphology and performance observed in SKO was investigated here in DKO mice, which were obtained by crossing SKO with PLB−/− mice. The affinity for Ca2+ of SERCA2 was found to be further increased in these DKO mice. Relative to wild-type and SKO mice, DKO mice were much less spontaneously active and showed a reduced life span. The DKO mice also displayed a severe cardiac phenotype characterized by a more pronounced concentric hypertrophy, diastolic dysfunction and increased ventricular stiffness. Strikingly, beta-adrenergic or forced exercise stress induced acute heart failure and death in DKO mice. Therefore, the increased PLB inhibition represents a compensation for the imposed high Ca2+-affinity of SERCA2b in the SKO heart. Limiting SERCA2''s affinity for Ca2+ is physiologically important for normal cardiac function. An improved Ca2+ transport in the sarcoplasmic reticulum may correct Ca2+ mishandling in heart failure, but a SERCA pump with a much higher Ca2+ affinity may be detrimental. [Copyright &y& Elsevier]