The role of hypertrophy and growth factors in heart failure.
The physiologic trophic factors growth hormone (GH) and insulin-like growth factor 1 (IGF-1) generally increase body weight and cardiac mass proportionately, and several studies suggest that both growth factors cause vasodilation and increased myocardial contractility. Established clinical benefits of ACE inhibitors can be explained, at least in part, by inhibition of cell hypertrophy, lowered systemic vascular resistance (SVR) and afterload, leading to reduction of progressive left-ventricular (LV) enlargement. An alternative approach would be to administer IGF-1 or GH to stimulate compensatory hypertrophy and reduce afterload by their vasodilator action, as well as through potential favorable effects on myocardial contractility. In our initial study in the rat myocardial infarction (MI) model, when IGF-1 was administered early (at 2 days) post-MI and continued for 2 weeks, body weight (BW) increased and LV weight/BW remained unchanged, the LV end-diastolic volume (EDV) and stroke volume increased (but not when normalized to BW), and the LV ejection fraction increased in rats with large infarctions. These findings suggested a beneficial rather than detrimental effect of such treatment, and we then studied the action of combined IGF-1 and GH starting after infarct healing at 4-weeks' post-MI. BW increased substantially and LVEDV/BW was lower in treated rats than in control rats, suggesting relatively less LV dilation with little remodeling in this setting; IGF-1/GH increased the cardiac output by 46%, systemic vascular resistance (SVR) fell and the cardiac index (CI) was significantly elevated in treated rats with a large MI. Recently, others have used the rat MI model to study the effects of 2-weeks' of GH started at 4-weeks' post-MI, as well as IGF/GH for 2-weeks in rats treated with an ACE inhibitor for 3-month's post-MI. In both studies, in conscious treated rats the BW increased, LV/BW was not different compared to the control rats, but the CI increased, SVR fell, and estimated LV dP/dtmax was significantly augmented. Preliminary data in our laboratory suggest that beneficial effects may also occur with GH administration in the setting of chronic angiotensin II receptor blockade (losartan) after MI in the rat. Thus, growth factor therapy appears to have favorable effects in heart failure early and late after MI in the rat. Additional cardiac hypertrophy occurs early after MI, but the later beneficial effects appear to relate primarily to systemic vasodilation, improved cardiac output, and enhanced myocardial contractility.
Ross
J
J
Department of Medicine, University of California, San Diego, USA.
Hongo
M
M
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D006332:Cardiomegaly / Q000503:physiopathology*; D013006:Growth Hormone / Q000494:pharmacology / Q000502:physiology*; D006333:Heart Failure / Q000503:physiopathology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D009203:Myocardial Infarction / Q000503:physiopathology; D051381:Rats; D014655:Vascular Resistance / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone