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Familial hypertrophic cardiomyopathy mice display gender differences in electrophysiological abnormalities
C I Berul1, M E Christe, M J Aronovitz
1Department of Cardiology, Children's Hospital, Boston, MA 02115, USA. berul@cardio.tch.harvard.edu
Insights
Familial hypertrophic cardiomyopathy (FHC) in alpha-myosin heavy chain mutant mice shows gender-specific electrophysiologic abnormalities. Male FHC mice exhibit significant cardiac conduction and rhythm disturbances, unlike females.
Area of Science:
- Cardiology
- Genetics
- Physiology
Background:
- Familial hypertrophic cardiomyopathy (FHC) is a genetic heart disease.
- A specific alpha-myosin heavy chain mutation (Arg403Gln) causes FHC.
- Gender differences in FHC presentation are increasingly recognized.
Purpose of the Study:
- To investigate gender-specific cardiac electrophysiologic differences in mice with an alpha-myosin heavy chain mutation.
- To compare in vivo electrophysiology between male and female heterozygous alpha-MHC403/+ mice and wild-type controls.
Main Methods:
- Utilized surface electrocardiogram (ECG) and in vivo cardiac electrophysiology studies (EPS).
- Evaluated heterozygous alpha-MHC403/+ mice and litter-mate controls (30 +/- 8 weeks old).
- Assessed intracardiac electrophysiology, ECG intervals, conduction times, and inducibility of ventricular tachycardia.
Main Results:
- Male alpha-MHC403/+ mice showed significant ECG abnormalities (right axis deviation) and prolonged electrophysiologic parameters (ventricular repolarization, sinus node recovery).
- Ventricular tachycardia was inducible in 62% of male and 28% of female alpha-MHC403/+ mice.
- Female alpha-MHC403/+ mice displayed electrophysiologic characteristics similar to female wild-type controls.
Conclusions:
- Identified distinct, gender-specific electrophysiologic abnormalities in alpha-MHC403/+ FHC mice.
- Findings in male FHC mice align with previously reported histological and hemodynamic derangements.
- Highlights the importance of considering gender in FHC pathophysiology and potential therapeutic strategies.
Abstract:
Genetically-manipulated mice harboring an alpha-myosin heavy chain Arg403Gln missense mutation (alpha-MHC403/+) display a phenotype characteristic of familial hypertrophic cardiomyopathy (FHC). Male and female (30 +/- 8 week old) heterozygous alpha-MHC403/+ mice and litter-mate controls were evaluated using a surface electrocardiogram (ECG) and an in vivo cardiac electrophysiology study (EPS). Wild type animals had normal intracardiac electrophysiology, with no significant differences between male and female control mice during EPS. The female wild-type mice did have slower heart rates and longer ECG intervals than their male wild-type counterparts. The female alpha-MHC403/+ mice had similar ECG's, cardiac conduction times, and refractory periods compared with female wild-type mice. In contrast, male FHC mice had distinctive ECG and electrophysiologic abnormalities including right axis deviation, prolonged ventricular repolarization and prolonged sinus node recovery times. During programmed ventricular stimulation, 62% of male alpha-MHC403/+ mice and 28% of female alpha-MHC403/+ mice had inducible ventricular tachycardia. These studies identify gender-specific electrophysiologic abnormalities in alpha-MHC403/+ FHC mice, concordant with the histological and hemodynamic derangements previously reported.