The pathogenesis of familial hypertrophic cardiomyopathy: early and evolving effects from an alpha-cardiac myosin...

Area of Science:

• Cardiovascular Biology
• Genetic Medicine
• Molecular Cardiology

Background:

• Familial hypertrophic cardiomyopathy (FHC) is a genetic disorder caused by sarcomeric protein mutations.
• FHC leads to impaired relaxation, fibrosis, and increased chamber stiffness.
• Distinguishing early abnormalities from disease progression is crucial for understanding FHC pathogenesis.

Purpose of the Study:

• To investigate the temporal evolution of cardiac abnormalities in a mouse model of FHC.
• To differentiate primary genetic defects from secondary responses in FHC development.
• To provide insights into the progression of FHC for therapeutic development.

Main Methods:

• In vivo analysis of a mouse model with an Arg403Gln alpha-cardiac myosin heavy chain mutation.
• Assessment of in situ pressure-volume relations using newly developed methods.
• Comparison of cardiac function and histology in young (6 weeks) and older (20 weeks) mutant mice.

Main Results:

• Young FHC mice exhibited delayed pressure relaxation, impaired filling, and accelerated systolic pressure rise without overt morphological changes.
• Older FHC mice showed similar or less pronounced kinetic changes but developed hyperdynamic contraction, increased end-systolic stiffness, and outflow tract gradients.
• Older mutant mice displayed reduced cardiac index due to diminished chamber filling, mirroring human FHC hallmarks.

Conclusions:

• The study reveals a distinct temporal progression of cardiac dysfunction in FHC, starting with kinetic alterations and evolving to characteristic human disease features.
• Early kinetic changes precede the development of hyperdynamic contraction and chamber stiffness in FHC.
• Understanding the chronological development of FHC pathology can guide the timing and focus of therapeutic interventions.