Cell-intrinsic functional effects of the α-cardiac myosin arg-403-gln mutation in familial hypertrophic cardiomyopathy

Peiying Chuan, Sivaraj Sivaramakrishnan, Euan A. Ashley, James A. Spudich

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13 Scopus citations


Human familial hypertrophic cardiomyopathy is the most common Mendelian cardiovascular disease worldwide. Among the most severe presentations of the disease are those in families heterozygous for the mutation R403Q in β-cardiac myosin. Mice heterozygous for this mutation in the α-cardiac myosin isoform display typical familial hypertrophic cardiomyopathy pathology. Here, we study cardiomyocytes from heterozygous 403/+ mice. The effects of the R403Q mutation on force-generating capabilities and dynamics of cardiomyocytes were investigated using a dual carbon nanofiber technique to measure single-cell parameters. We demonstrate the Frank-Starling effect at the single cardiomyocyte level by showing that cell stretch causes an increase in amplitude of contraction. Mutant 403/+ cardiomyocytes exhibit higher end-diastolic and end-systolic stiffness than +/+ cardiomyocytes, whereas active force generation capabilities remain unchanged. Additionally, 403/+ cardiomyocytes show slowed relaxation dynamics. These phenotypes are consistent with increased end-diastolic and end-systolic chamber elastance, as well as diastolic dysfunction seen at the level of the whole heart. Our results show that these functional effects of the R403Q mutation are cell-intrinsic, a property that may be a general phenomenon in familial hypertrophic cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)2782-2790
Number of pages9
JournalBiophysical journal
Issue number12
StatePublished - Jun 20 2012

Bibliographical note

Funding Information:
P.C. is supported by the Agency for Science, Technology and Research, Singapore, S.S., E.A.A., and J.A.S. are supported by a Stanford Cardiovascular Institute seed grant, E.A.A. is supported by National Institutes of Health Director's New Innovator Award OD004613, and J.A.S is supported by National Institutes of Health grant GM33289.


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