Development and pathomechanisms of cardiomyopathy in very long-chain acyl-CoA dehydrogenase deficient (VLCAD(-/-))...

Area of Science:

• Biochemistry
• Cardiology
• Genetics

Background:

• Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a common inherited metabolic disorder.
• Cardiac dysfunction, including hypertrophic cardiomyopathy, is a known manifestation of VLCADD.
• The role of medium-chain triglycerides (MCT) in managing VLCADD-related cardiomyopathy requires further investigation.

Purpose of the Study:

• To characterize the long-term cardiac function in VLCAD-deficient (VLCAD(-/-)) mice.
• To investigate the effects of continuous medium-chain triglyceride (MCT) supplementation on cardiac phenotype in VLCAD(-/-) mice.
• To elucidate the mechanisms underlying cardiac energy deficiency and cardiomyopathy in VLCADD.

Main Methods:

• In vivo cardiac MRI for morphology and function assessment.
• (31)P-MRS for cardiac energetics and phosphocreatine-to-ATP ratio measurement.
• PET imaging for myocardial glucose uptake and real-time PCR for gene expression analysis.

Main Results:

• VLCAD(-/-) mice exhibited progressive cardiac dysfunction over 12 months, with reduced phosphocreatine-to-ATP ratios indicating chronic energy deficiency.
• Long-term MCT supplementation exacerbated cardiac issues, leading to dilated cardiomyopathy with diabetic heart disease-like features.
• Age-related decline in cardiac energy production and function was observed, with insufficient compensatory mechanisms.

Conclusions:

• Cardiac energy production and function decline with age in VLCAD deficiency.
• Impaired beta-oxidation and long-term MCT supplementation induce cardiomyopathy through distinct mechanisms.
• Cardiac MRI and MRS are valuable tools for monitoring cardiac function and energetics in patients with beta-oxidation defects for preventive therapy.