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

Female HCM carriers of the MCT1 rs1049434 T-allele exhibited significantly greater interventricular septal thickness compared with AA homozygotes.

• Female T-allele carriers (TT/TA) had a mean septal thickness of 23.2 mm versus 14.2 mm in AA homozygotes (p = 0.037).
• The study included 10 women among the 26 patients with established HCM.
• All participants carried pathogenic or likely pathogenic sarcomeric variants identified through a familial HCM program.
• Septal wall thickness was the primary structural endpoint assessed via standardized echocardiography and cardiac magnetic resonance imaging.

In male HCM patients, septal thickness did not differ significantly by MCT1 rs1049434 genotype.

• There were 16 men among the 26 patients with established HCM.
• No statistically significant genotype-dependent difference in septal thickness was observed in men.
• The absence of a genotype effect in men contrasts with the significant finding in women, indicating a sex-specific modulation of hypertrophic remodeling.

Male HCM patients engaged in vigorous physical activity showed a consistently milder structural phenotype compared to less active male patients.

• Male patients engaged in vigorous physical activity had lower mean septal thickness (18.3 mm vs. 19.9 mm), though this difference was not statistically significant (p = 0.585).
• The exercise-active group also showed directionally favorable markers of mechanical severity.
• The findings suggest exercise-related metabolic conditioning may attenuate disease severity in men.

The predominant phenotypic morphology was asymmetric septal hypertrophy in both sexes, without genotype-dependent differences in phenotypic distribution.

• Phenotypic distribution was assessed among the 26 individuals who fulfilled diagnostic criteria for HCM (10 women, 16 men).
• No genotype-dependent differences in phenotypic morphology were observed in either sex.
• Clinical phenotyping included electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging.

The study population consisted of 56 carriers of pathogenic or likely pathogenic sarcomeric variants, of whom 26 fulfilled diagnostic criteria for HCM.

• All 56 participants were examined in a familial HCM program and underwent standardized clinical phenotyping.
• Genotyping of MCT1 rs1049434 (T1470A; Asp490Glu) was performed on genomic DNA.
• Analyses focused on sex-stratified genotype distribution and phenotypic expression among the 26 HCM-positive individuals.
• The functional rs1049434 polymorphism affects MCT1-mediated lactate transport and substrate utilization.

MCT1 rs1049434 modulates hypertrophic remodeling in HCM through a genotype-sex-environment interaction.

• Impaired monocarboxylate handling (T-allele) is associated with greater hypertrophic remodeling in women.
• In men, exercise-related metabolic conditioning appears to attenuate disease severity regardless of genotype.
• The authors conclude these findings are relevant to precision medicine approaches in HCM.
• MCT1 plays a central role in myocardial lactate handling and metabolic adaptation.