Although sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), individuals bearing a mutant cardiac myosin binding protein C (MyBP-C) gene usually have a better prognosis than individuals bearing beta-cardiac myosin heavy chain (MHC) gene mutations. Heterozygous mice bearing a cardiac MHC missense mutation (alphaMHC(403/+) or a cardiac MyBP-C mutation (MyBP-C(t/+)) were constructed as murine FHC models using homologous recombination in embryonic stem cells. We have compared cardiac structure and function of these mouse strains by several methods to further define mechanisms that determine the severity of FHC. Both strains demonstrated progressive left ventricular (LV) hypertrophy; however, by age 30 weeks, alphaMHC(403/+) mice demonstrated considerably more LV hypertrophy than MyBP-C(t/+) mice. In older heterozygous mice, hypertrophy continued to be more severe in the alphaMHC(403/+) mice than in the MyBP-C(t/+) mice. Consistent with this finding, hearts from 50-week-old alphaMHC(403/+) mice demonstrated increased expression of molecular markers of cardiac hypertrophy, but MyBP-C(t/+) hearts did not demonstrate expression of these molecular markers until the mice were >125 weeks old. Electrophysiological evaluation indicated that MyBP-C(t/+) mice are not as likely to have inducible ventricular tachycardia as alphaMHC(403/+) mice. In addition, cardiac function of alphaMHC(403/+) mice is significantly impaired before the development of LV hypertrophy, whereas cardiac function of MyBP-C(t/+) mice is not impaired even after the development of cardiac hypertrophy. Because these murine FHC models mimic their human counterparts, we propose that similar murine models will be useful for predicting the clinical consequences of other FHC-causing mutations. These data suggest that both electrophysiological and cardiac function studies may enable more definitive risk stratification in FHC patients.
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http://dx.doi.org/10.1161/01.res.88.4.383 | DOI Listing |
J Mol Cell Cardiol
February 2017
Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110-1093, USA; Department of Medicine, Washington University Medical School, St. Louis, MO 63110-1093, USA. Electronic address:
Familial hypertrophic cardiomyopathy (HCM), linked to mutations in myosin, myosin-binding proteins and other sarcolemmal proteins, is associated with increased risk of life threatening ventricular arrhythmias, and a number of animal models have been developed to facilitate analysis of disease progression and mechanisms. In the experiments here, we use the αMHC mouse line in which one αMHC allele harbors a common HCM mutation (in βMHC, Arg403 Gln). Here, we demonstrate marked prolongation of QT intervals in young adult (10-12week) male αMHC mice, well in advance of the onset of measurable left ventricular hypertrophy.
View Article and Find Full Text PDFJACC Basic Transl Sci
February 2016
School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Australia.
Heterozygous mice ( ) expressing the human disease-causing mutation exhibit cardinal features of hypertrophic cardiomyopathy (HCM) including hypertrophy, myocyte disarray, and increased myocardial fibrosis. Treatment of mice with the L-type calcium channel (I) antagonist diltiazem has been shown to decrease left ventricular anterior wall thickness, cardiac myocyte hypertrophy, disarray, and fibrosis. However, the role of the I in the development of HCM is not known.
View Article and Find Full Text PDFJ Huazhong Univ Sci Technolog Med Sci
October 2014
Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, 410-516-8000, USA.
β-myosin heavy chain mutations are the most frequently identified basis for hypertrophic cardiomyopathy (HCM). A transgenic mouse model (αMHC(403)) has been extensively used to study various mechanistic aspects of HCM. There is general skepticism whether mouse and human disease features are similar.
View Article and Find Full Text PDFCirculation
September 2003
Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, Mass 02115, USA.
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).
J Clin Invest
April 2002
Department of Genetics, Howard Hughes Medical Institute and Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Dominant mutations in sarcomere protein genes cause hypertrophic cardiomyopathy, an inherited human disorder with increased ventricular wall thickness, myocyte hypertrophy, and disarray. To understand the early consequences of mutant sarcomere proteins, we have studied mice (designated alphaMHC(403/+)) bearing an Arg403Gln missense mutation in the alpha cardiac myosin heavy chain. We demonstrate that Ca(2+) is reduced in the sarcoplasmic reticulum of alphaMHC(403/+) mice, and levels of the sarcoplasmic reticulum Ca(2+)-binding protein calsequestrin are diminished in advance of changes in cardiac histology or morphology.
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