Cardiac angiotensin II formation in the clinical course of heart failure and its relationship with left ventricular function

In 76 patients with heart failure (HF) (New York Heart Association [NYHA] c lasses I through TV) and in 15 control subjects, cardiac angiotensin II (An g II) generation and its relationship with left ventricular function were i nvestigated by measuring aorta-coronary sinus concentration gradients of en dogenous angiotensins and in a part of patients by studying I-125-labeled A ng I kinetics. Gene expression and cellular localization of the cardiac ren in-angiotensin system components, the density of AT(1) and AT(2) on membran es and isolated myocytes, and the capacity of isolated myocytes for synthes izing the hypertrophying growth factors insulin-like growth factor-I (IGF-I ) and endothelin (ET)-1 were also investigated on 22 HF explanted hearts (N YHA classes m and IV) and 7 nonfailing (NF) donor hearts. Ang II generation increased with progression of HF, and end-systolic wall stress was the onl y independent predictor of Ang II formation. Angiotensinogen and angiotensi n-converting enzyme mRNA levels were elevated in HF hearts, whereas chymase levels were not, and mRNAs were almost exclusively expressed on nonmyocyte cells. Ang II was immunohistochemically detectable both on myocytes and in terstitial cells. Binding studies showed that AT(1) density on failing myoc ytes did not differ from that of NF myocytes, with preserved AT(1)/AT(2) ra tio, Conversely AT(1) density was lower in failing membranes than in NF one s. Ang II induced IGF-I and ET-I synthesis by isolated NF myocytes, whereas failing myocytes were unable to respond to Ang II stimulation. This study demonstrates that (1) the clinical course of HF is associated with progress ive increase in cardiac Ang II formation, (2) AT(1) density does not change on failing myocytes, and (3) failing myocytes are unable to synthesize IGF -I and ET-1 in response to Ang II stimulation.