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(Circulation Research. 2004;94:1392.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Functional Relevance of the Stretch-Dependent Slow Force Response in Failing Human Myocardium

Dirk von Lewinski, Burkhard Stumme, Florian Fialka, Claus Luers, Burkert Pieske

From the Department of Cardiology and Pneumology, Georg-August-University, Göttingen, Germany.

Correspondence to Prof Dr Burkert Pieske, Abteilung Kardiologie und Pneumologie, Georg-August Universität Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany. E-mail pieske{at}med.uni-goettingen.de

Stretch induces immediate and delayed inotropic effects in mammalian myocardium via distinct mechanosensitive pathways, but these effects are poorly characterized in human cardiac muscle. We tested the effects of stretch on immediate and delayed force response in failing human myocardium. Experiments were performed in muscle strips from 52 failing human hearts (37°C, 1 Hz, bicarbonate buffer). Muscles were stretched from 88% of optimal length to 98% of optimal length. The resulting immediate and delayed (ie, slow force response [SFR]) increases in twitch force were assessed without and after blockade of the sarcoplasmic reticulum (SR; cyclopiazonic acid and ryanodine), stretch-activated ion channels (SACs; gadolinium, streptomycin), L-type Ca²⁺-channels (diltiazem), angiotensin II type-1 (AT₁) receptors (candesartan), endothelin (ET) receptors (PD145065 or BQ123), Na⁺/H⁺ exchange (NHE1; HOE642), or reverse-mode Na⁺/Ca⁺ exchange (NCX; KB-R7493). We also tested the effects of stretch on SR Ca²⁺ load (rapid cooling contractures [RCCs]) and intracellular pH (in BCECF-loaded trabeculae). Stretch induced an immediate (<10 beats), followed by a slow (5 to 10 minutes), force response. Twitch force increased to 232±6% of prestretch value during the immediate phase, followed by a further increase to 279±8% during the SFR. RCC amplitude significantly increased, but pHi did not change during SFR. Inhibition of SACs, L-type Ca²⁺ channels, AT₁ receptors, or ET receptors did not affect the stretch-dependent immediate or SFR. In contrast, the SFR was reduced by NHE1 inhibition and almost completely abolished by reverse-mode NCX inhibition or blockade of sarcoplasmic reticulum function. The data demonstrate the existence of a functionally relevant, SR-Ca²⁺–dependent SFR in failing human myocardium, which partly depends on NHE1 and reverse-mode NCX activation.

Key Words: stretch • human myocardium • contractile function • sodium • calcium

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