Sex- and Exercise-Dependent Modulation of Hypertrophic Remodeling by the MCT1 rs1049434 Polymorphism

Area of Science:

• Cardiovascular Genetics
• Metabolic Physiology
• Cardiomyopathy Research

Background:

• Monocarboxylate transporter 1 (MCT1) is crucial for heart lactate metabolism.
• The MCT1 rs1049434 polymorphism (T1470A) influences lactate transport but its role in sarcomere-related hypertrophic cardiomyopathy (HCM) is unclear.

Purpose of the Study:

• To investigate the clinical relevance of the MCT1 rs1049434 polymorphism in familial HCM.
• To explore genotype-sex-environment interactions in HCM pathogenesis.

Main Methods:

• Studied 56 carriers of sarcomeric variants in a familial HCM program.
• Performed genotyping for MCT1 rs1049434 and standardized clinical phenotyping.
• Analyzed sex-stratified genotype distribution and phenotypic expression, focusing on septal wall thickness.

Main Results:

• In female HCM patients, T-allele carriers (TT/TA) had significantly greater septal thickness than AA homozygotes (23.2 vs. 14.2 mm; p=0.037).
• Septal thickness did not differ by genotype in male HCM patients.
• Male patients with vigorous exercise showed a milder structural phenotype and favorable mechanical markers.

Conclusions:

• The MCT1 rs1049434 polymorphism's effect on HCM is context-dependent.
• Impaired monocarboxylate handling in women correlates with increased hypertrophic remodeling.
• In men, exercise may attenuate HCM severity, suggesting a genotype-sex-environment interaction for precision medicine.