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Original Articles

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

Dirk von Lewinski, MD; Jens Kockskämper, PhD; Danan Zhu, MD; Heiner Post, MD; Andreas Elgner, MD and Burkert Pieske, MD

From the Department of Cardiology (D.v.L., J.K., H.P., B.P.), Medical University Graz, Graz, Austria; Department for Cardiology, Pulmonology, and Vascular Medicine (D.Z.), University Hospital RWTH Aachen, Aachen, Germany; and Department of Cardiology and Pneumology (A.E.), Georg-August-University, Göttingen, Germany.

Correspondence to Dirk von Lewinski, MD, Abteilung Kardiologie, Medizinische Universität Graz, Auenbruggerplatz 15, 8036 Graz, Austria. E-mail dirk.von-lewinski{at}meduni-graz.at

Received May 27, 2008; accepted November 18, 2008.

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 (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.

Key Words: contractility • heart failure • myocardial contraction • physiology

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CLINICAL PERSPECTIVE

Related Article

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

Dirk von Lewinski, Jens Kockskämper, Danan Zhu, Heiner Post, Andreas Elgner, and Burkert Pieske
Circ Heart Fail 2009 2: 47-55. [Abstract] [Full Text] [PDF]