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Cardiovascular Research Advance Access originally published online on November 20, 2007
Cardiovascular Research 2008 77(4):687-694; doi:10.1093/cvr/cvm075
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Troponin T and β-myosin mutations have distinct cardiac functional effects in hypertrophic cardiomyopathy patients without hypertrophy

Miriam Revera1, Lize van der Merwe2, Marshall Heradien3, Althea Goosen3, Valerie A. Corfield4, Paul A. Brink3 and Johanna C. Moolman-Smook4,5,*

1 Department of Cardiology, IRCCS San Matteo Hospital, Pavia, Italy
2 Biostatistics Unit, Medical Research Council of South Africa, Tygerberg, South Africa
3 Department of Medicine, University of Stellenbosch Health Sciences Faculty, Tygerberg, South Africa
4 MRC/US Centre for Molecular and Cellular Biology, Department of Biomedical Sciences, Room 4036, University of Stellenbosch Health Sciences Faculty, Francie van Zijl Drive, PO Box 19063, Tygerberg 7505, South Africa
5 The Hatter Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa

* Corresponding author. Tel: +27 21 9389693; fax: +27 21 9389476. E-mail address: 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 HCM-mutations have different consequences for cardiac structure and function in the absence of the confounding effects of hypertrophy.

Methods and results: Individuals aged 20–65 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. 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.

Conclusion: 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.

KEYWORDS Hypertrophic cardiomyopathy; Contractile function; Troponin T; β-myosin; Mutation

Time for primary review: 20 days


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