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Updated: Apr 28, 2026
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Diastolic dysfunction and altered energetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy
M Spindler1, K W Saupe, M E Christe
1NMR Laboratory for Physiological Chemistry, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Insights
Familial hypertrophic cardiomyopathy in alphaMHC403/+ mice shows impaired diastolic function and altered cardiac energetics. These findings in mouse models offer insights into human hypertrophic cardiomyopathy mechanisms.
Area of Science:
- Cardiology
- Molecular Biology
- Biophysics
Background:
- Familial hypertrophic cardiomyopathy (HCM) is often caused by mutations in cardiac myosin heavy chain genes.
- A specific missense mutation (arginine to glutamine at position 403) in beta-cardiac myosin heavy chain is linked to HCM.
Purpose of the Study:
- To investigate the physiological and bioenergetic consequences of the alphaMHC403/+ mutation in a mouse model.
- To understand the mechanisms underlying diastolic dysfunction in HCM.
Main Methods:
- Utilized an isolated, isovolumic heart preparation in alphaMHC403/+ mice.
- Measured cardiac performance and cardiac energetics simultaneously using 31P nuclear magnetic resonance spectroscopy.
- Assessed diastolic function, left ventricular relaxation, end-diastolic pressure, and high-energy phosphate content.
Main Results:
- Observed impaired diastolic function during inotropic stimulation, characterized by decreased relaxation rate and increased end-diastolic pressure.
- Found reduced phosphocreatine and increased inorganic phosphate levels, indicating decreased free energy from ATP hydrolysis.
- Demonstrated an exaggerated heart rate decrease in response to increased perfusate calcium in mutant hearts compared to wild types.
Conclusions:
- alphaMHC403/+ mouse hearts exhibit workload-dependent diastolic dysfunction, mirroring human familial hypertrophic cardiomyopathy.
- Alterations in high-energy phosphate content suggest an energy-dependent mechanism contributes to the observed diastolic dysfunction.
Abstract:
An arginine to glutamine missense mutation at position 403 of the beta-cardiac myosin heavy chain causes familial hypertrophic cardiomyopathy. Here we study mice which have this same missense mutation (alphaMHC403/+) using an isolated, isovolumic heart preparation where cardiac performance is measured simultaneously with cardiac energetics using 31P nuclear magnetic resonance spectroscopy. We observed three major alterations in the physiology and bioenergetics of the alphaMHC403/+ mouse hearts. First, while there was no evidence of systolic dysfunction, diastolic function was impaired during inotropic stimulation. Diastolic dysfunction was manifest as both a decreased rate of left ventricular relaxation and an increase in end-diastolic pressure. Second, under baseline conditions alphaMHC403/+ hearts had lower phosphocreatine and increased inorganic phosphate contents resulting in a decrease in the calculated value for the free energy released from ATP hydrolysis. Third, hearts from alphaMHC403/+ hearts that were studied unpaced responded to increased perfusate calcium by decreasing heart rate approximately twice as much as wild types. We conclude that hearts from alphaMHC403/+ mice demonstrate work load-dependent diastolic dysfunction resembling the human form of familial hypertrophic cardiomyopathy. Changes in high-energy phosphate content suggest that an energy-requiring process may contribute to the observed diastolic dysfunction.
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