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Original Articles

Effects of Cardiac Myosin Isoform Variation on Myofilament Function and Crossbridge Kinetics in Transgenic Rabbits

Takeki Suzuki, MD; Bradley M. Palmer, PhD; Jeanne James, MD; Yuan Wang, MS; Zengyi Chen, MD; Peter VanBuren, MD; David W. Maughan, PhD; Jeffrey Robbins, PhD and Martin M. LeWinter, MD

From the Department of Medicine (T.S., Z.C., P.V.B., M.M.L.W.), Cardiology Unit, Fletcher Allen Health Care, Burlington, Vt; Department of Molecular Physiology and Biophysics (B.M.P., Y.W., D.W.M.), University of Vermont, Burlington, Vt; and Division of Molecular Cardiovascular Biology (J.J., J.R.), Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio.

Correspondence to Martin M. LeWinter, MD, Cardiology Unit, Fletcher Allen Health Care, 111 Colchester Ave, Burlington, VT 05401. E-mail martin.lewinter{at}vtmednet.org

Received June 30, 2008; accepted February 20, 2009.

Background— The left ventricles of both rabbits and humans express predominantly β-myosin heavy chain (MHC). Transgenic (TG) rabbits expressing 40% -MHC are protected against tachycardia-induced cardiomyopathy, but the normal amount of -MHC expressed in humans is only 5% to 7% and its functional importance is questionable. This study was undertaken to identify a myofilament-based mechanism underlying tachycardia-induced cardiomyopathy protection and to extrapolate the impact of MHC isoform variation on myofilament function in human hearts.

Methods and Results— Papillary muscle strips from TG rabbits expressing 40% (TG40) and 15% -MHC (TG15) and from nontransgenic (NTG) controls expressing 100% β-MHC (NTG40 and NTG15) were demembranated and calcium activated. Myofilament tension and calcium sensitivity were similar in TGs and respective NTGs. Force-clamp measurements revealed 50% higher power production in TG40 versus NTG40 (P<0.001) and 20% higher power in TG15 versus NTG15 (P<0.05). A characteristic of acto-myosin crossbridge kinetics, the "dip" frequency, was significantly higher in TG40 versus NTG40 (0.70±0.04 versus 0.39±0.09 Hz, P<0.01) but not in TG15 versus NTG15. The calculated crossbridge time-on was also significantly shorter in TG40 (102.3±14.2 ms) versus NTG40 (175.7±19.7 ms) but not in TG15 versus NTG15.

Conclusions— The incorporation of 40% -MHC leads to greater myofilament power production and more rapid crossbridge cycling, which facilitate ejection and relengthening during short cycle intervals, and thus protect against tachycardia-induced cardiomyopathy. Our results suggest, however, that, even when compared with the virtual absence of -MHC in the failing heart, the 5% to 7% -MHC content of the normal human heart has little if any functional significance.

Key Words: diastole • myosin isoforms • myofilament • heart failure • transgenic rabbits

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