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(Circulation Research. 2002;90:66.)
© 2002 American Heart Association, Inc.

Cellular Biology

Alterations of Myocardial Dynamic Stiffness Implicating Abnormal Crossbridge Function in Human Mitral Regurgitation Heart Failure

L.A. Mulieri, W. Barnes, B.J. Leavitt, F.P. Ittleman, M.M. LeWinter, N.R. Alpert, D.W. Maughan

From the Departments of Molecular Physiology & Biophysics (L.A.M., W.B., N.R.A., D.W.M.) and Surgery (B.J.L., F.P.I.) and the Cardiology Unit (M.M.L.W.), University of Vermont, Burlington Vt.

Correspondence to Louis A. Mulieri, PhD, Dept of Molecular Physiology and Biophysics, Given Building, University of Vermont, Burlington, VT 05405-0068. E-mail mulieri{at}physiology.med.uvm.edu

Mitral regurgitation (MR) causes ventricular dilation, a blunted myocardial force-frequency relation, and increased crossbridge force-time integral (FTI). The mechanism of FTI increase was investigated using sinusoidal length perturbation analysis to compare crossbridge function in skinned left ventricular (LV) epicardial muscle strips from 5 MR and 5 nonfailing (NF) control hearts. Myocardial dynamic stiffness was modeled as 3 parallel viscoelastic processes. Two processes characterize intermediate crossbridge cycle transitions, B (work producing) and C (work absorbing) with Q₁₀s of 4 to 5. No significant differences in moduli or kinetic constants of these processes were observed between MR and NF. The third process, A, characterizes a nonenzymatic (Q₁₀=0.9) work-absorbing viscoelasticity, whose modulus increases sigmoidally with [Ca²⁺]. Effects of temperature, crossbridge inhibition, or variation in [MgATP] support associating the calcium-dependent portion of A with the structural "backbone" of the myosin crossbridge. Extension of the conventional sinusoidal length perturbation analysis allowed using the A modulus to index the lifetime of the prerigor, AMADP crossbridge. This index was 75% greater in MR than in NF (P=0.02), suggesting a mechanism for the previously observed increase in crossbridge FTI. Notably, the A-process modulus was inversely correlated (r²=0.84, P=0.03) with in vivo LV ejection fraction in MR patients. The longer prerigor dwell time in MR may be clinically relevant not only for its potential role as a compensatory mechanism (increased economy of tension maintenance and increased resistance to ventricular dilation) but also for a potentially deleterious effect (reduced elastance and ejection fraction).

Key Words: mitral regurgitation • heart failure • myocardial stiffness • crossbridge function • prerigor dwell time

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