Reduced Stretch-Induced Force Response in Failing Human Myocardium Caused by Impaired Na+-Contraction Coupling

Background-Stretch elicits an immediate, followed by a delayed, inotropic response in various animal models and failing human myocardium. This study aimed to characterize functional differences in the stretch response between failing and nonfailing human myocardium. Methods and Results-Experiments were performed in muscle tissue from 86 failing and 16 nonfailing human hearts. Muscles were stretched from 88% to 98% of optimal length. Resulting immediate (Frank-Starling mechanism [FSM]) and delayed (slow-force response [SFR]) increases in twitch force were assessed before and after blockade of nitric oxide synthase, phosphatidylinositol-3-kinase, or reverse-mode Na+/Ca2+ exchange. Stretch-induced changes in [Na+](i) were measured using fluorescent indicator sodium-binding benzofuran isophthalate-AM. Nitric oxide synthase isoform expression was quantified by Western blot analysis. FSM was comparable between nonfailing (227 +/- 8%) and failing (222 +/- 9%) myocardium, whereas the additional increase during SFR (approximate to 5 minutes) was larger in nonfailing myocardium (to 126 +/- 3% versus 119 +/- 2% of force of FSM, respectively; P<0.05). Basal [Na+](i) and stretch-induced increase in [Na+](i) were lower in nonfailing myocardium. Inhibition of the Na+/H+ exchange largely reduced the increase in [Na+](i) and significantly blocked the SFR. In both groups, SFR was almost completely prevented by reverse-mode Na+/Ca+-exchanger inhibition. Although neuronal and inducible nitric oxide synthase expression were significantly upregulated in failing myocardium, inhibition of nitric oxide synthase and phosphatidylinositol-3-kinase had no effect on FSM or SFR. Conclusions-These data demonstrate a Na+-independent FSM and a Na+-dependent SFR in both nonfailing and failing human myocardium. The larger stretch-dependent increase in [Na+](i) in failing myocardium was associated with a blunted functional response, indicating impaired Na+-contraction coupling in the failing human heart. (Circ Heart Fail. 2009;2:47-55.)