Key result
The R403Q mutation in the alpha-myosin heavy chain reduced maximal oscillatory power (0.53±0.25 vs 1.03±0.18 mW/mm3) and altered crossbridge kinetics in a mouse model of FHC.
Absolute Event Rate: 0.53% vs 1.03%
The R403Q mutation alters crossbridge kinetics by increasing tension at submaximal calcium but blunting maximal tension and oscillatory power, providing a mechanistic basis for the pathophysiology of familial hypertrophic cardiomyopathy.
No clinical implications for FHC; leaves open whether murine crossbridge changes translate to human disease.
A mutation in the cardiac beta-myosin heavy chain, Arg403Gln (R403Q), causes a severe form of familial hypertrophic cardiomyopathy (FHC) in humans. We used small-amplitude (0.25%) length-perturbation analysis to examine the mechanical properties of skinned left ventricular papillary muscle strips from mouse hearts bearing the R403Q mutation in the alpha-myosin heavy chain (alphaMHC403/+). Myofibrillar disarray with variable penetrance occurred in the left ventricular free wall of the alphaMHC403/+ hearts. In resting strips (pCa 8), dynamic stiffness was approximately 40% greater than in wild-type strips, consistent with elevated diastolic stiffness reported for murine hearts with FHC. At pCa 6 (submaximal activation), strip isometric tension was approximately 3 times higher than for wild-type strips, whereas at pCa 5 (maximal activation), tension was marginally lower. At submaximal calcium activation the characteristic frequencies of the work-producing (b) and work-absorbing (c) steps of the crossbridge were less in alphaMHC403/+ strips than in wild-type strips (b=11+/-1 versus 15+/-1 Hz; c= 58+/-3 versus 66+/-3 Hz; 27 degrees C). At maximal calcium activation, strip oscillatory power was reduced (0. 53+/-0.25 versus 1.03+/-0.18 mW/mm3; 27 degrees C), which is partly attributable to the reduced frequency b, at which crossbridge work is maximum. The results are consistent with the hypothesis that the R403Q mutation reduces the strong binding affinity of myosin for actin. Myosin heads may accumulate in a preforce state that promotes cooperative activation of the thin filament at submaximal calcium but blunts maximal tension and oscillatory power output at maximal calcium. The calcium-dependent effect of the mutation (whether facilitating or debilitating), together with a variable degree of fibrosis and myofibrillar disorder, may contribute to the diversity of clinical symptoms observed in murine FHC.
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Blanchard et al. (1999) studied Familial hypertrophic cardiomyopathy. R403Q mutation in alpha-myosin heavy chain (alphaMHC403/+) vs. Wild-type was evaluated on Strip oscillatory power at maximal calcium activation (mW/mm3). The R403Q mutation in the alpha-myosin heavy chain reduced maximal oscillatory power (0.53±0.25 vs 1.03±0.18 mW/mm3) and altered crossbridge kinetics in a mouse model of FHC.
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