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Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 14, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn094
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
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The molecular phenotype of human cardiac myosin associated with hypertrophic obstructive cardiomyopathy

Adam M. Jacques1, Natalia Briceno1, Andrew E. Messer1, Clare E. Gallon1, Shapour Jalizadeh2, Edwin Garcia1, Gaele Kikonda-Kanda1, Jenifer Goddard2, Sian Harding1, Hugh Watkins2, Victor Tsang3, William J. Mckenna3 and Steven B. Marston1

1 Cardiac Medicine, NHLI, Imperial College London, London, U.K
2 Dept of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX3 9DU
3 The Heart Hospital, London, UK

Address for correspondence: Steven Marston National Heart and Lung Institute Imperial College London Guy Scadding Building Dovehouse street London SW3 6LY Tel: +44 (0)20 7351 8147 Fax: +44 (0) 20 7823 3392 Mobile: 07941 135583 s.marston{at}imperial.ac.uk

Aim: The aim of the study was to compare the functional and structural properties of the motor protein, myosin, and isolated myocyte contractility in heart muscle excised from hypertrophic cardiomyopathy patients by surgical myectomy with explanted failing heart and non-failing donor heart muscle.

Methods: Myosin was isolated and studied using an in vitro motility assay. The distribution of myosin light chain 1 isoforms was measured by 2D electrophoresis. Myosin light chain 2 phosphorylation was measured in SDS-PAGE using Pro-Q Diamond phosphoprotein stain

Results: The fraction of actin filaments moving when powered by myectomy myosin was 21% less than with donor myosin (p=0.006), whilst the sliding speed was not different (0.310±0.034 for myectomy myosin vs 0.305±0.019 µm/sec for donor myosin in 6 paired experiments). Failing heart myosin showed 18% reduced motility. One myectomy myosin sample produced a consistently higher sliding speed than donor heart myosin and was identified with a disease-causing heavy chain mutation (V606M). In myectomy myosin the level of atrial light chain 1 relative to ventricular light chain 1 was 20±5% compared with 11±5% in donor heart myosin and the level of myosin light chain 2 phosphorylation was decreased by 30-45%. Isolated cardiomyocytes showed reduced contraction amplitude (1.61±0.25% vs 3.58±0.40%) and reduced relaxation rates compared to donor myocytes (TT50%= 0.32±0.09 sec vs 0.17±0.02).

Conclusions: Contractility in myectomy samples resembles the hypocontractile phenotype found in end-stage failing heart muscle irrespective of the primary stimulus, and this phenotype is not a direct effect of the hypertrophy-inducing mutation. The presence of a myosin heavy chain mutation causing hypertrophic cardiomyopathy can be predicted from a simple functional assay.

KEYWORDS Contractile apparatus; contractile function; hypertrophy; protein phosphorylation

Time for primary review: 37


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