Consequences of pressure overload on sarcomere protein mutation-induced hypertrophic cardiomyopathy

Joachim P SCHMITT; Christopher SEMSARIAN; Michael ARAD; Joseph GANNON; Ferhaan AHMAD; Catherine DUFFY; Richard T LEE; Christine E SEIDMAN; J. G SEIDMAN

doi:10.1161/01.CIR.0000086469.85750.48

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Consequences of pressure overload on sarcomere protein mutation-induced hypertrophic cardiomyopathy

Journal article

Open access

Peer reviewed

Consequences of pressure overload on sarcomere protein mutation-induced hypertrophic cardiomyopathy

Joachim P SCHMITT, Christopher SEMSARIAN, Michael ARAD, Joseph GANNON, Ferhaan AHMAD, Catherine DUFFY, Richard T LEE, Christine E SEIDMAN and J. G SEIDMAN

Circulation (New York, N.Y.), Vol.108(9), pp.1133-1138

2003

DOI: 10.1161/01.CIR.0000086469.85750.48

PMID: 12925456

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Abstract

Background: Whether ventricular remodeling from hypertrophic cardiomyopathy (HCM), systemic hypertension, or other pathologies arises through a common signaling pathway or through independent molecular mechanisms is unknown. To study this, we assessed cardiac hypertrophy in a mouse model of HCM subjected to increased left ventricular (LV) load. Methods and results: Transverse aortic banding of mice with or without an Arg403Gln cardiac myosin heavy chain mutation (alphaMHC403/+) produced similarly elevated LV pressures (120+/-30 versus 112+/-14 mm Hg; P=NS). No mice developed heart failure, and mortality (26% alphaMHC403/+, 35% wild-type) was comparable. Load-induced hypertrophy was identical in banded 129SvEv alphaMHC403/+ mice (LV anterior wall [LVAW]=1.28+/-0.11) and 129SvEv wild-type mice (LVAW=1.29+/-0.11 mm; P=NS). Genetically outbred Black Swiss (BS) alphaMHC403/+ mice showed only mildly exaggerated hypertrophy in response to aortic banding (BS alphaMHC403/+ LVAW=1.30+/-0.13 mm; BS wild-type LVAW=1.17+/-0.15 mm; P=0.03), suggesting some effect from a BS genetic locus that modifies hypertrophy induced by the cardiac MHC Arg403Gln mutation. Histopathology and molecular markers of hypertrophy were comparable in all banded 129SvEv or BS mice. Banded alphaMHC403/+ mice had potential for greater hypertrophy, because cyclosporin A treatment markedly augmented hypertrophy. Conclusions: The uniform hypertrophic response to increased ventricular load in wild-type and alphaMHC403/+ mice indicates independent cardiac remodeling pathways and predicts that coexistent hypertension and HCM should not profoundly exacerbate cardiac hypertrophy. In contrast, sarcomere mutation and cyclosporin A-mediated calcineurin inhibition stimulate a shared hypertrophic signaling pathway. Defining distinct signaling pathways that trigger myocyte growth should help to tailor therapies for cardiac hypertrophy.

Heart

Cardiology. Vascular system

Biological and medical sciences

Myocarditis. Cardiomyopathies

Medical sciences

Details

Title: Subtitle: Consequences of pressure overload on sarcomere protein mutation-induced hypertrophic cardiomyopathy
Creators: Joachim P SCHMITT - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Mass, United States
Christopher SEMSARIAN - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Mass, United States
Michael ARAD - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Mass, United States
Joseph GANNON - Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass, United States
Ferhaan AHMAD - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Mass, United States
Catherine DUFFY - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Mass, United States
Richard T LEE - Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass, United States
Christine E SEIDMAN - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Mass, United States
J. G SEIDMAN - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Mass, United States
Resource Type: Journal article
Publication Details: Circulation (New York, N.Y.), Vol.108(9), pp.1133-1138
DOI: 10.1161/01.CIR.0000086469.85750.48
PMID: 12925456
NLM abbreviation: Circulation
ISSN: 0009-7322
eISSN: 1524-4539
Publisher: Lippincott Williams & Wilkins; Hagerstown, MD
Language: English
Date published: 2003
Academic Unit: Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984025425002771

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