Comparison of two murine models of familial hypertrophic cardiomyopathy.
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.
McConnell
B K
BK
Cardiovascular Division and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Fatkin
D
D
Semsarian
C
C
Jones
K A
KA
Georgakopoulos
D
D
Maguire
C T
CT
Healey
M J
MJ
Mudd
J O
JO
Moskowitz
I P
IP
Conner
D A
DA
Giewat
M
M
Wakimoto
H
H
Berul
C I
CI
Schoen
F J
FJ
Kass
D A
DA
Seidman
C E
CE
Seidman
J G
JG
D000199:Actins / Q000235:genetics; D000483:Alleles; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D015152:Blotting, Northern; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D004195:Disease Models, Animal; D004452:Echocardiography; D004594:Electrophysiology; D005192:Family Health; D008297:Male; D051379:Mice; D009154:Mutation; D020125:Mutation, Missense; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D012518:Sarcomeres / Q000737:chemistry; D013997:Time Factors; D019076:Transgenes; D018487:Ventricular Dysfunction, Left; D000099163:Myosin Binding Protein C
D000199:Actins; D009320:Atrial Natriuretic Factor; D002352:Carrier Proteins; D012333:RNA, Messenger; D000099163:Myosin Binding Protein C