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The cardiac SERCA2 Ca 2+  pump is critical for maintaining normal Ca 2+  handling in the heart. Reduced SERCA2a content and blunted Ca 2+  reuptake are frequently observed in failing hearts and evidence implicates poor cardiac Ca 2+  handling in the progression of heart failure. To gain insight into mechanism we investigated a novel genetic mouse model of inducible severe and progressive SERCA2 deficiency (inducible  Serca2  knockout, SERCA2 KO). These mice eventually die from overt heart failure 7-10 weeks after knockout but as yet there have been no reports on intrinsic mechanical performance at the isolated whole heart organ level. Thus we studied whole-organ  ex vivo  function of hearts isolated from SERCA2 KO mice at one and four weeks post-knockout in adult animals. We found that isolated KO heart function was only modestly impaired one week post-knockout, when SERCA2a protein was 32% of normal. At four weeks post-knockout, function was severely impaired with near non-detectable levels of SERCA2. During perfusion with 10 mM caffeine, LV developed pressures were similar between 4-week KO and control hearts, and end-diastolic pressures were lower in KO. When hearts were subjected to ischemia-reperfusion injury, recovery was not different between control and KO hearts at either one or four weeks post-knockout. Our findings indicate that  ex vivo  function of isolated SERCA2 KO hearts is severely impaired long before symptoms appear  in vivo , suggesting that physiologically relevant heart function  in vivo  can be sustained for weeks in the absence of robust SR Ca 2+  flux.

Prominent Heart Organ-Level Performance Deficits in a Genetic Model of Targeted Severe and Progressive SERCA2 Deficiency