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(+)/Ca(2+) 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 (approximately 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.