AIMS Angiotensin-converting enzyme inhibitors (ACE-Is) prevent the rise in myocardial angiotensin II that occurs after left ventricular assist device (LVAD) implantation, but do not fully normalize cardiac function. Here, we determined the effect of LVAD implantation, with or without ACE-Is, on cardiac renin, aldosterone, and norepinephrine, since these hormones, like angiotensin II, are likely determinants of myocardial recovery during LVAD support. METHODS AND RESULTS Biochemical measurements were made in paired LV myocardial samples obtained from 20 patients before and after LVAD support in patients with and without ACE-I therapy. Pre-LVAD renin levels were 100x normal and resulted in almost complete cardiac angiotensinogen depletion. In non-ACE-I users, LVAD support, by normalizing blood pressure, reversed this situation. Cardiac aldosterone decreased in parallel with cardiac renin, in agreement with the concept that cardiac aldosterone is blood-derived. Cardiac norepinephrine increased seven-fold, possibly due to the rise in angiotensin II. Angiotensin-converting enzyme inhibitor therapy prevented these changes: renin and aldosterone remained high, and no increase in norepinephrine occurred. CONCLUSION Although LV unloading lowers renin and aldosterone, it allows cardiac angiotensin generation to increase and thus to activate the sympathetic nervous system. Angiotensin-converting enzyme inhibitors prevent the latter, but do not affect aldosterone. Thus, mineralocorticoid receptor antagonist therapy during LVAD support may play a role in further promoting recovery.