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(Circulation. 2004;110:982-987.)
© 2004 American Heart Association, Inc.

Original Articles

Thin Filament-Based Modulation of Contractile Performance in Human Heart Failure

Teruo Noguchi, MD^*; Mark Hünlich, MD^*; Phillip C. Camp, MD; Kelly J. Begin, BS; Mohamed El-Zaru, MD; Richard Patten, MD; Bruce J. Leavitt, MD; Frank P. Ittleman, MD; Norman R. Alpert, PhD; Martin M. LeWinter, MD; Peter VanBuren, MD

From the Cardiovascular Research Center (T.N., M.H., K.J.B., M.E., B.J.L., F.P.I., N.R.A., M.M.L., P.V.), University of Vermont, College of Medicine, Burlington; Cardiology Unit (T.N.), Internal Medicine, National Cardiovascular Center Osaka, Japan; Department of Cardiology and Pneumology (M.H.), University of Göttingen, Göttingen, Germany; Cardiothoracic Surgery (P.C.C.), University of Kentucky, College of Medicine, Lexington; and Molecular Cardiology Research Institute (R.P.), New England Medical Center, Boston, Mass.

Correspondence to Peter VanBuren, MD, University of Vermont, College of Medicine, 126C HSRF Bldg, 149 Beaumont Ave, Burlington, VT 05405. E-mail vanburen{at}physiology.med.uvm.edu

Received March 23, 2004; revision received May 13, 2004; accepted May 21, 2004.

Background— The contribution of the sarcomere’s thin filament to the contractile dysfunction of human cardiomyopathy is not well understood.

Methods and Results— We have developed techniques to isolate and functionally characterize intact (native) thin filaments obtained from failing and nonfailing human ventricular tissue. By use of in vitro motility and force assays, native thin filaments from failing ventricular tissue exhibited a 19% increase in maximal velocity but a 27% decrease in maximal contractile force compared with nonfailing myocardium. Native thin filaments isolated from human myocardium after left ventricular assist device support demonstrated a 37% increase in contractile force. Dephosphorylation of failing native thin filaments resulted in a near-normalization of thin-filament function, implying a phosphorylation-mediated mechanism. Tissue expression of the protein kinase C isoforms , ß₁, and ß₂ was increased in failing human myocardium and reduced after left ventricular assist device support.

Conclusions— These novel findings demonstrate that (1) the thin filament is a key modulator of contractile performance in the failing human heart, (2) thin-filament function is restored to near normal levels after LVAD support, and (3) the alteration of thin-filament function in failing human myocardium is mediated through phosphorylation, most likely through activation of protein kinase C.

Key Words: heart failure • filaments • heart-assist device • kinases • phosphorylation

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