Little is known about the long-term impact of cardiac transplantation on activity and modifications of endothelin (ET)-1 system, vascular endothelial growth factor (VEGF), and mitochondrial metabolism and morphology in patients with ischemic cardiomyopathy (ICM) versus dilated cardiomyopathy (DCM). Messenger RNA (mRNA) expression levels of ET-1, endothelin converting enzyme (ECE)-1, VEGF-C, carnitine palmitoyltransferase (CPT)-1, and carnitine acetyltransferase (CARAT), as well as the number of normal, edematous, and degenerated mitochondria were assessed in left ventricular biopsies of 21 patients with DCM and 20 with ICM (New York Heart Association class III-IV) before and up to 3 months after cardiac transplantation. Cardiac samples of donated, nonfailing hearts served as controls (n=10). In cardiac biopsies of both ICM and DCM patients, ET-1, VEGF-C, CPT-1, and CARAT mRNA were up-regulated, whereas ECE-1 mRNA was down-regulated (P<0.05). Degenerated mitochondria had the highest number in both groups, followed by normal and edematous mitochondria. After cardiac transplantation, in ICM patients impaired gene expression levels decreased to, or below, normal levels, and the number of normal mitochondria increased (P<0.05). In implanted hearts of DCM patients, however, up-regulated ET-1 transcript levels persisted and the number of normal mitochondria decreased, whereas the number of degenerated mitochondria increased (P<0.05), and edematous mitochondria remained unchanged in number. These results show that cardiac transplantation corrects the impaired hemodynamic and echocardiographic parameters in both groups, whereas in DCM, the molecular pathology of ET-1 system and mitochondria persists. Therefore, it is more likely that these changes are the cause rather than a consequence of DCM.