The sarcoplasmic reticulum (SR) calcium ATPase 2 (SERCA2) recycles Ca2+ back into the SR following the release of Ca2+ that triggers contraction. This intracellular cycling of Ca2+ accounts for 95% of the Ca2+ transient in rodents. Surprisingly, cardiac function was well maintained 4 weeks following gene deletion in adult mice (KO) in spite of less than 5% detectable SERCA2 protein. However, KO mice die suddenly between 8 and 10 weeks after gene deletion. Thus the compensation responsible for maintained cardiac function at 4 weeks was gradually lost. At 7 weeks echocardiography revealed reduced systolic and diastolic tissue velocities and SERCA2 protein was undetectable. Na⁺/ Ca2+-exchanger protein (NCX) had increased to 255% of control. Also the 1C unit of the L-type Ca2+ channel (LTCC) was increased to 176% compared to control. Patch clamp experiments revealed increased cycling of Ca2+ across the cell membrane that partly compensated for the loss of SR function. In face of the increase in NCX protein, rate of decay of the Ca2+-transient was significantly slowed compared to 4 weeks. This was due to an elevation of intracellular [Na⁺] probably linked to downregulation of the Na⁺/K⁺ pump. Also, the action potential was prolonged contributing to attenuated forward mode operation of NCX. Interestingly, the compensation included formation of new t-tubules in the longitudinal direction containing NCX protein, but no LTCCs. Thus, cardiac function in mice can be well maintained in the almost complete absence of SERCA2 by increased Ca2+ cycling across the sarcolemma, but eventually attenuation of Ca2+ extrusion by NCX due to Na⁺ accumulation and prolongation of the action potenitial leads to progressive heart failure with a strong diastolic dysfunction.