Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 20, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm075
Troponin T and ß-Myosin mutations have distinct cardiac functional effects in hypertrophic cardiomyopathy patients without hypertrophy
1 Dept Cardiology, IRCCS San Matteo Hospital, Pavia, Italy
2 Biostatistics Unit, Medical Research Council of South Africa, Tygerberg, South Africa
3 Dept Medicine, University of Stellenbosch Health Sciences Faculty, Tygerberg, South Africa
4 MRC/US Centre for Molecular and Cellular Biology, Dept Biomedical Sciences, University of Stellenbosch Health Sciences Faculty Tygerberg, South Africa
5 The Hatter Institute, Dept Medicine, University of Cape Town, Cape Town, South Africa
Address for Correspondence and Reprints JC Moolman-Smook MRC/US Centre for Molecular and Cellular Biology, Room 4036, University of Stellenbosch Health Sciences Faculty, Francie van Zijl Drive, PO Box 19063, Tygerberg 7505, South Africa Tel: +27-21-9389693; Fax: +27-21-9389476, email: HM{at}sun.ac.za
Aims: The validity of genotype:phenotype correlation studies in human hypertrophic cardiomyopathy (HCM) has recently been questioned, yet animal models and in vitro studies suggest distinct effects for different mutations. The aims of this study were to investigate whether distinct hypertrophic cardiomyopathy (HCM) have different consequences for cardiac structure and function in the absence of the confounding effects of hypertrophy.
Methods: Individuals aged 20-65years belonging to 21 R92WTNNT2, R403WMYH7, or A797TMYH7 mutation-bearing families were investigated with 2D, M-mode and Doppler echocardiography. Cardiac structural and functional parameters were compared between prehypertrophic mutation-carriers and their non-carrier family members, with concomitant adjustment for appropriate covariates. Findings were evaluated against existing animal and in vitro functional data.
Results: The distinct functional effect of the R92WTNNT mutation was a relative increase in systolic functional parameters, that of the A797TMYH7 mutation was reduced diastolic function, while the R403WMYH7 mutation reduced both systolic and diastolic function. The observed early effects of the R92WTNNT2 mutation mechanistically fit with prolonged force-transients precipitated by increased Ca2+ sensitivity of the thin filament, and that of the MYH7 mutations with local ATP depletion.
Conclusions: Evaluation of the impact of the mutations on cardiac structure and function in prehypertrophic mutation carriers, relative to the baseline norm provided by their non-carrier family members, best recapitulated existing animal and in vitro functional data, while inclusion of mutation carriers with hypertrophy obscured such findings. The results prompt speculation that timely treatment aimed at ameliorating Ca2+ sensitivity for R92WTNNT2 carriers, and energy depletion for MYH7 mutation carriers, may offer a plausible approach for preventing progression from a preclinical into a decompensated state.
Time for primary review: 20
HCM mutations and prehypertrophic cardiac function
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