title: Age-related changes in familial hypertrophic cardiomyopathy phenotype in transgenic mice and humans.
abstract: 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. Herein we compare morphologic and functional characteristics, and disease evolution, in a transgenic mouse and a single family with a MHC mutation. Ten male αMHC(403) transgenic mice (at t-5 weeks, -12 weeks, and -24 weeks) and 10 HCM patients from the same family with a β-myosin heavy chain mutation were enrolled. Morphometric, conventional echocardiographic, tissue Doppler and strain analytic characteristics of transgenic mice and HCM patients were assessed. Ten male transgenic mice (αMHC(403)) were examined at ages -5 weeks, -12 weeks, and -24 weeks. In the transgenic mice, aging was associated with a significant increase in septal (0.59±0.06 vs. 0.64±0.05 vs. 0.69±0.11 mm, P<0.01) and anterior wall thickness (0.58±0.1 vs. 0.62±0.07 vs. 0.80±0.16 mm, P<0.001), which was coincident with a significant decrease in circumferential strain (-22%±4% vs. -20%±3% vs. -19%±3%, P=0.03), global longitudinal strain (-19%±3% vs. -17%±2% vs. -16%±3%, P=0.001) and E/A ratio (1.9±0.3 vs. 1.7±0.3 vs. 1.4±0.3, P=0.01). The HCM patients were classified into 1st generation (n=6; mean age 53±6 years), and 2nd generation (n=4; mean age 32±8 years). Septal thickness (2.2±0.9 vs. 1.4±0.1 cm, P<0.05), left atrial (LA) volume (62±16 vs. 41±5 mL, P=0.03), E/A ratio (0.77±0.21 vs. 1.1±0.1, P=0.01), E/e' ratio (25±10 vs. 12±2, P=0.03), global left ventricular (LV) strain (-14%±3% vs. -20%±3%, P=0.01) and global LV early diastolic strain rate (0.76±0.17 s(-1) vs. 1.3±0.2 s-1, P=0.01) were significantly worse in the older generation. In β-myosin heavy chain mutations, transgenic mice and humans have similar progression in morphologic and functional abnormalities. The αMHC(403) transgenic mouse model closely recapitulates human disease.
authors.affiliation: Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, 410-516-8000, USA.|Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Hong-Chang
authors.initials: HC
authors.lastname: Luo
authors.affiliation: Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, 410-516-8000, USA.
authors.forename: Iraklis
authors.initials: I
authors.lastname: Pozios
authors.affiliation: Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, 410-516-8000, USA.
authors.forename: Styliani
authors.initials: S
authors.lastname: Vakrou
authors.affiliation: Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, 410-516-8000, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Sorensen
authors.affiliation: Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, 410-516-8000, USA.
authors.forename: Roselle M
authors.initials: RM
authors.lastname: Abraham
authors.affiliation: Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, 410-516-8000, USA. tabraha3@jhmi.edu.
authors.forename: Theodore
authors.initials: T
authors.lastname: Abraham
mesh_terms: D000328:Adult; D000367:Age Factors; D000375:Aging; D000818:Animals; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics* / Q000503:physiopathology*; D003430:Cross-Sectional Studies; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D005260:Female; D006321:Heart / Q000503:physiopathology; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics*; D010641:Phenotype; D013045:Species Specificity; D055815:Young Adult
chemical_list: C584019:Myh6 protein, mouse; D018995:Myosin Heavy Chains