title: Alterations of myocardial dynamic stiffness implicating abnormal crossbridge function in human mitral regurgitation heart failure.
abstract: 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 Q(10)s 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 (Q(10)=0.9) work-absorbing viscoelasticity, whose modulus increases sigmoidally with [Ca(2+)]. 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 (r(2)=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).
authors.affiliation: Department of Molecular Physiology & Biophysics, University of Vermont, Burlington 05405-0068, USA. mulieri@physiology.med.uvm.edu
authors.forename: L A
authors.initials: LA
authors.lastname: Mulieri
authors.forename: W
authors.initials: W
authors.lastname: Barnes
authors.forename: B J
authors.initials: BJ
authors.lastname: Leavitt
authors.forename: F P
authors.initials: FP
authors.lastname: Ittleman
authors.forename: M M
authors.initials: MM
authors.lastname: LeWinter
authors.forename: N R
authors.initials: NR
authors.lastname: Alpert
authors.forename: D W
authors.initials: DW
authors.lastname: Maughan
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000368:Aged; D002118:Calcium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D008944:Mitral Valve Insufficiency / Q000503:physiopathology*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology
chemical_list: D000255:Adenosine Triphosphate; D002118:Calcium