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(Circulation Research. 2004;94:1249.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Role of Cardiac Myosin Binding Protein C in Sustaining Left Ventricular Systolic Stiffening

Bradley M. Palmer, Dimitrios Georgakopoulos, Paul M. Janssen, Yuan Wang, Norman R. Alpert, Diego F. Belardi, Samantha P. Harris, Richard L. Moss, Patrick G. Burgon, Christine E. Seidman, J.G. Seidman, David W. Maughan, David A. Kass

From the Department of Molecular Physiology and Biophysics (B.M.P., Y.W., N.R.A., D.W.M.), University of Vermont, Burlington, Vt; Departments of Medicine and Biomedical Engineering (D.G., D.F.B., D.A.K.), Johns Hopkins Medical Institutions, Baltimore, Md; The Institute of Molecular Cardiobiology (P.M.J.), Johns Hopkins University School of Medicine, Baltimore, Md; Department of Physiology (S.P.H., R.L.M.), University of Wisconsin Medical School, Madison, Wis; and the Department of Genetics (P.G.B., C.E.S., J.G.S.), Howard Hughes Medical Institute and Harvard Medical School, Boston, Mass.

Correspondence to Bradley M. Palmer, PhD, 127 HSRF Beaumont Ave, Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405. E-mail palmer{at}physiology.med.uvm.edu

Despite advances in the molecular biology of cardiac myosin binding protein-C (cMyBP-C), little is understood about its precise role in muscle contraction, particularly in the intact heart. We tested the hypothesis that cMyBP-C is central to the time course and magnitude of left ventricular systolic elastance (chamber stiffening), and assessed mechanisms for this influence in intact hearts, trabeculae, and skinned fibers from wild-type (+/+) and homozygous truncated cMyBP-C (t/t) male mice. cMyBP-C protein was not detected by gel electrophoresis or Western blot in t/t myocardium. cMyBP-C t/t ventricles displayed reduced peak elastance, but more strikingly a marked abbreviation of the systolic elastance time course, which peaked earlier (27.6±2.1 ms) than in +/+ controls (47.8±1.6 ms). Control hearts reached only 42±4% of maximum elastance at the onset of ejection, with substantial further stiffening during ejection. This contrasted to t/t mutants, which reached 77±3% of peak elastance before ejection of peak. These unusual findings were not observed in alternative models involving severe cardiomyopathy, but were recapitulated in a cMyBP-C null mouse. The abbreviated elastance time course and lower peak were consistent with earlier time-to-peak trabecular tension, increased unloaded shortening velocity in t/t skinned muscle strips, and dramatically reduced myofilament stiffness at diastolic calcium concentrations. These results provide novel insights into the role of cMyBP-C in myocardial systolic mechanics. Abnormal sarcomere shortening velocity and abbreviated muscle stiffening may underlie development of cardiac dysfunction associated with deficient incorporation of cMyBP-C.

Key Words: C-protein • ventricular mechanics • time-varying elastance • cardiomyopathy • myocardium

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