In severe heart failure, cardiomyocytes undergoing apoptotic cell death can be detected. Since detailed mechanisms contributing to this increased apoptosis sensitivity are unknown, cardiac expression of several pro- and anti-apoptotic members of the Bcl-2 family has been investigated. Anti-apoptotic proteins of the Bcl-2 family prevent the release of apoptosis-inducing molecules from the mitochondria and stabilize the mitochondrial transmembrane potential. Therefore, we analyzed the expression of several Bcl-2 family members in left ventricular specimens of the explanted terminally failing human myocardium compared with non-failing donor hearts. Furthermore, patients supported by a ventricular assist device (VAD) were included in this study. The implantation of a VAD is used for bridging the time until heart transplantation and results in a hemodynamic unloading of the failing heart and in an improvement of the peripheral perfusion. Within the group of Bcl-2-related proteins, mRNA of the anti-apoptotic Bcl-xL was especially decreased in terminal heart failure (see table). This diminished Bcl-xL mRNA expression could be partially renormalized by treatment with inhibitors of the angiotensin-converting enzyme (ACE) along with a positive correlation of mRNA and protein expression. Furthermore, Bcl-xL mRNA was increased by VAD support (see table), which was depending on the time on VAD. Donors Explants without VAD with VAD mRNA/RNA pre VAD post VAD Bak [amol/mg] 301 ± 105 170 ± 93* 158 ± 91* 138 ± 52 Bax [amol/mg] 2,1 ± 1,2 2,3 ± 2,3 1,6 ± 0,9 2,1 ± 1,4 Bcl-2 [amol/mg] 16,4 ± 9,5 18,1 ± 11,9 11,4 ± 9,0 9,3 ± 5,0 Bcl-x [amol/mg] 215 ± 92 134 ± 57* 144 ± 47* 176 ± 42† Mcl-1 [amol/mg] 3,2 ± 1,5 3,5 ± 1,6 3,5 ± 0,8 4,2 ± 1,1† n: 10 24 10 *pvs donors; †pvs pre VAD This Bcl-xL mRNA could be shown in situ in cardiomyocytes, but is also expressed in the human endothelium. As shown in an in vitro cell culture model, the endothelial Bcl-xL mRNA expression is maintained by influence of chronic laminar shear stress depending on the endothelial production of nitric oxide, which is physiologically induced by the flowing blood. In contrast to the myocardial overload in heart failure, cardiac Bcl-xL mRNA expression is neither influenced by hypoperfusion in the hibernating myocardium of a porcine animal model nor by subsequent reperfusion in the stunned myocardium. These data indicate the correction of a changed expression of Bcl-2-related proteins in terminal heart failure by ACE inhibition or VAD support along with an alteration of the expression balance on mitochondria towards a decreased apoptosis sensitivity.