TY - JOUR
T1 - Comparison of two murine models of familial hypertrophic cardiomyopathy
AU - McConnell, Bradley K.
AU - Fatkin, Diane
AU - Semsarian, Christopher
AU - Jones, Karen A.
AU - Georgakopoulos, Dimitrios
AU - Maguire, Colin T.
AU - Healey, Michael J.
AU - Mudd, James O.
AU - Moskowitz, Ivan P.G.
AU - Conner, David A.
AU - Giewat, Michael
AU - Wakimoto, Hiroko
AU - Berul, Charles I.
AU - Schoen, Frederick J.
AU - Kass, David A.
AU - Seidman, Christine E.
AU - Seidman, Jonathan G.
PY - 2001/3/2
Y1 - 2001/3/2
N2 - 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 β-cardiac myosin heavy chain (MHC) gene mutations. Heterozygous mice bearing a cardiac MHC missense mutation (αMHC403/+ or a cardiac MyBP-C mutation (MyBP-C1/+) 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, αMHC403/+ mice demonstrated considerably more LV hypertrophy than MyBP-C1/+ mice. In older heterozygous mice, hypertrophy continued to be more severe in the αMHC403/+ mice than in the MyBP-C1/+ mice. Consistent with this finding, hearts from 50-week-old αMHC403/+ mice demonstrated increased expression of molecular markers of cardiac hypertrophy, but MyBP-C1/+ hearts did not demonstrate expression of these molecular markers until the mice were >125 weeks old. Electrophysiological evaluation indicated that MyBP-C1/+ mice are not as likely to have inducible ventricular tachycardia as αMHC403/+ mice. In addition, cardiac function of αMHC403/+ mice is significantly impaired before the development of LV hypertrophy, whereas cardiac function of MyBP-C1/+ 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.
AB - 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 β-cardiac myosin heavy chain (MHC) gene mutations. Heterozygous mice bearing a cardiac MHC missense mutation (αMHC403/+ or a cardiac MyBP-C mutation (MyBP-C1/+) 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, αMHC403/+ mice demonstrated considerably more LV hypertrophy than MyBP-C1/+ mice. In older heterozygous mice, hypertrophy continued to be more severe in the αMHC403/+ mice than in the MyBP-C1/+ mice. Consistent with this finding, hearts from 50-week-old αMHC403/+ mice demonstrated increased expression of molecular markers of cardiac hypertrophy, but MyBP-C1/+ hearts did not demonstrate expression of these molecular markers until the mice were >125 weeks old. Electrophysiological evaluation indicated that MyBP-C1/+ mice are not as likely to have inducible ventricular tachycardia as αMHC403/+ mice. In addition, cardiac function of αMHC403/+ mice is significantly impaired before the development of LV hypertrophy, whereas cardiac function of MyBP-C1/+ 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.
KW - Cardiac myosin binding protein C
KW - Cardiomyopathy
KW - Genetics
KW - Hypertrophy
KW - Myosin
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U2 - 10.1161/01.RES.88.4.383
DO - 10.1161/01.RES.88.4.383
M3 - Article
C2 - 11230104
AN - SCOPUS:0035793919
SN - 0009-7330
VL - 88
SP - 383
EP - 389
JO - Circulation research
JF - Circulation research
IS - 4
ER -