Selective upregulation of cardiac endothelin system in patients with ischemic but not idiopathic dilated cardiomyopathy - Endothelin-1 system in the human failing heart

Only scarce information is available on the activity and modifications of t he cardiac endothelin (ET)-1 system in heart failure due to ischemic (ICM) or idiopathic dilated (DCM) cardiomyopathy, The activity of the ET-1 system was investigated by measuring cardiac ET-1 and big ET-1 formation and quan tifying cardiac mRNA for prepro-ET-l (ppET-1), ET-converting enzyme-1, and ETA and ETB receptors both in myocardium and in isolated myocytes using Nor thern blot, reverse transcription-polymerase chain reaction, and in situ hy bridization in 22 patients with DCM and 20 with ICM who underwent cardiac t ransplantation and in 7 potential heart transplant donors (nonfailing heart s). Notwithstanding a similar increase of plasma ET-1 in the 2 groups, card iac ET formation, mRNA levels for ppET-1, and ET, and ET, receptors were hi gher on both the myocardium and isolated myocytes from ICM than on those fr om DCM hearts (P<0.001 for all), ppET-1 and ET-converting enzyme-1 mRNAs we re expressed on myocytes and endothelial and interstitial cells in ICM, whe reas in DCM and nonfailing hearts they were mainly expressed on nonmyocyte cells. In both ICM and DCM, the ETA mRNA signal was expressed on both myocy tes and nonmyocyte cells, whereas ETB mRNA was almost exclusively localized on nonmyocyte cells. ETA- and ETB-specific receptor binding was increased on both myocytes and cardiac membranes, showing a positive correlation with left ventricular ejection fraction in ICM (r=0.78 and 0.70) but not in DCM patients. The present results show that human ventricular myocytes express all of the components of the ET-1 system, which is selectively upregulated in ICM patients and appears to be functionally important in the maintenanc e of cardiac function.