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The role of hypertrophy and growth factors in heart failure
Insights
Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) show promise in treating heart failure after myocardial infarction (MI) in rats. These factors improve cardiac function and reduce negative remodeling, offering a potential new therapeutic avenue.
Area of Science:
- Cardiology
- Endocrinology
- Pharmacology
Background:
- Physiologic trophic factors, growth hormone (GH) and insulin-like growth factor 1 (IGF-1), influence body weight and cardiac mass.
- Studies suggest GH and IGF-1 promote vasodilation and enhance myocardial contractility.
- ACE inhibitors offer benefits in heart failure partly by inhibiting hypertrophy and reducing afterload.
Purpose of the Study:
- To investigate the potential of IGF-1 and GH as an alternative therapeutic approach for heart failure post-myocardial infarction (MI).
- To evaluate the effects of IGF-1 and GH on cardiac remodeling, function, and systemic hemodynamics in a rat MI model.
Main Methods:
- Administration of IGF-1 early post-MI (2 days) or combined IGF-1 and GH later post-MI (4 weeks) in a rat MI model.
- Assessment of body weight (BW), left-ventricular (LV) weight, LV end-diastolic volume (EDV), stroke volume, LV ejection fraction, cardiac output (CO), systemic vascular resistance (SVR), and cardiac index (CI).
- Comparison of treated rats with control groups and examination of effects in conjunction with ACE inhibitors or angiotensin II receptor blockade.
Main Results:
- Early IGF-1 administration increased BW and LV ejection fraction in rats with large infarctions, with unchanged LV weight/BW.
- Later IGF-1/GH treatment led to increased BW, reduced LV dilation (lower LVEDV/BW), increased CO (by 46%), decreased SVR, and elevated CI.
- Independent studies showed GH or IGF/GH administration post-MI, alone or with ACE inhibitors, increased BW, CI, and LV dP/dtmax, while decreasing SVR.
Conclusions:
- Growth factor therapy (GH and IGF-1) demonstrates favorable effects in mitigating heart failure early and late after MI in rats.
- Beneficial effects appear to stem from systemic vasodilation, improved cardiac output, and enhanced myocardial contractility, rather than solely compensatory hypertrophy.
- Growth factors represent a promising therapeutic strategy for post-MI heart failure, potentially improving cardiac performance and reducing adverse remodeling.
Abstract:
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.