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Circulation: Heart Failure
Year: 2009  |  Volume: 2  |  Issue: 4  |  Page No.: 334 - 341

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

T Suzuki, B. M Palmer, J James, Y Wang, Z Chen, P VanBuren, D. W Maughan, J Robbins and M. M. LeWinter    

Abstract:

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.

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