Positive inotropic effect of insulin-like growth factor-1 on normal and failing cardiac myocytes

Objective: The acute administration of growth hormone (GH) or insulin- like growth factor-1 (IGF-1) improves cardiac performance, possibly contributing to the beneficial effects of GH therapy on heart failure (HF). GH can induce the production of IGF-1 and thus the actions of GH may be mediated through its IGF-1 induction. However, these effects have not yet been demonstrated in failing hearts and the cellular basis of GH or IGF-1- induced inotropic effects remains unknown. We examined the direct effects of GH and IGF-1 on the contractile function and intracellular calcium ([Ca²⁺](i)) homeostasis in normal and failing myocytes. Methods: To determine whether GH and IGF-1 have a direct effect on myocardial contractility and whether the GH/IGF-1-induced effect was the results of changes in Ca²⁺ activation, cell shortening and [Ca²⁺](i) transient were simultaneously measured in the left ventricular myocyte preparations, isolated from normal and rapid pacing-induced HF dogs. Results: Basal shortening of HF myocytes was reduced by 64% (p<0.01). In normal and HF myocytes, GH (0.4-40 x 10^-3 IU/ml) had no effect on either cell shortening or [Ca²⁺](i) transients. In normal myocytes, IGF-1 exerted a positive inotropic effect in a time- and dose-dependent manner (25-500 ng/ml), associated with a parallel increase of [Ca²⁺](i) transient amplitude. IGF- 1 increased the shortening magnitude in normal (121±5% increase from baseline, p<0.05) and HF (118±4% increase from baseline, p<0.05) myocytes. It also increased [Ca²⁺](i) transient amplitude in normal and HF cells by 124±4 and 125±7%, respectively. The percent increase of cell shortening and [Ca²⁺](i) transient amplitude was comparable between normal and HF myocytes. Furthermore, IGF-1 did not shift the trajectory of the relaxation phase in the phase-plane plots of cell length vs. [Ca²⁺](i), indicating that it did not change myofilament Ca²⁺ sensitivity. Conclusions: In both normal and HF conditions, IGF-1 exerted an acute direct positive inotropic effect in adult cardiac myocytes by increasing the availability of [Ca²⁺](i) to the myofilaments, possibly explaining the beneficial effect of GH on HF.