Prolyl-hydroxylase domain proteins (PHD) are cellular oxygen sensing molecules, which regulate the stability of the a-subunit of the transcription factor Hypoxia inducible factor (HIF)-1. HIF-1 affects cardiac development as well as adaptation of the heart towards increased pressure overload or myocardial infarction. We have knocked out PHD2 in cardiomyocytes (cPhd2^-/-) using Phd2^flox/flox mice in combination with MLCvCre mice, which resulted in HIF-1a stabilization and activation of HIF target genes in the heart. Whereas cPhd2^-/- mice showed no gross abnormalities in cardiac filament structure or function, we observed a significantly increased cardiac capillary density in those mice. Furthermore the cardiac metabolism in cPhd2-/- mice was shifted toward glycolysis with a net increase in glucose uptake and a net decrease in fatty acid uptake. cPhd2^-/- mice did not respond differently to increased mechanical load by transverse aortic constriction compared to their wild type littermates. After ligation of the left anterior descending artery, however, the area at risk and area of necrosis were significantly smaller in the cPhd2^-/-mice compared to Phd2 wt mice in line with the described pivotal role HIF-1a for tissue protection in case of myocardial infarction. This correlated with a decreased number of apoptotic cells in the infarcted myocardium in the cPhd2^-/- mice. Interestingly, cPHD2^-/- mice exhibit at late onset of cadiomyopathy with increased posterior wall thickness, septum thickness and fibrosis, indicating that the chronic activation of HIF-1a has negative effects on heart function. This should be taken into account when considering PHDs as targets for therapeutic manipulations.