Selective enhancement of cardiomyocyte efficiency results in a pernicious heart condition

Transgenic mice with selective induction of calreticulin transgene expression in cardiomyocytes (Cardiac(CRT+)) were analyzed. Cardiac(CRT+) cardiomyocytes showed increased contractility and Ca(2+) transients. Yet, in vivo assessment of cardiac performance, and ischemic tolerance of Cardiac(CRT+) mice demonstrated right ventricle dilation and reduced cardiac output, increased QT interval and decreased P amplitude. Paradoxically, ex vivo working hearts from Cardiac(CRT+) mice showed enhanced ischemic cardio-protection and cardiac efficiency. Under aerobic conditions, Cardiac(CRT+) hearts showed less efficient cardiac function than sham control hearts due to an increased ATP production from glycolysis relative to glucose oxidation. During reperfusion, this inefficiency was reversed, with Cardiac(CRT+) hearts exhibiting better functional recovery and increased cardiac efficiency compared to sham control hearts. On the other hand, mechanical stretching of isolated cardiac fibroblasts activated the IRE1α branch of the unfolded protein response pathway as well as induction of Col1A2 and TGFβ gene expression ex vivo, which were all suppressed by tauroursodeoxycholic acid.