Men have worse mortality in heart failure with reduced ejection fraction (HFrEF), even after accounting for traditional risk factors.
A metabolomics risk score, capturing the end-effect of sex-dependent karyotypic, genetic, hormonal and environmental influences, will attenuate the increased residual risk of mortality observed in males.
Metabolome-wide association study was performed in 187 HFrEF (EF <50%) patients in the Metabolomics, Oxidative Stress and Vascular Function in HF (MOV) study (Discovery Cohort (DC), mean age 54.0 ± 13.0 yrs, 49.2% male, 62.0% black) to determine unique endogenous metabolites associated with all-cause mortality (n=19). Metabolites that were significantly different between sexes, or had a significant metabolite*sex interaction (n=11) were further selected. Of these metabolites, those that attenuated the association of male sex with mortality were included in the metabolomics risk score (MS) (n=7). Association of male sex with mortality was determined in Cox proportional hazards models with and without inclusion of MS. Results were validated in an external validation cohort of 240 HFrEF patients in the The Atlanta Cardiomyopathy Consortium (TACC) study (Validation Cohort (VC), mean age 56.6 ± 12.0 yrs, 66.3% male, 45.4% black).
There were 24 deaths (12.8%) during a median follow up of 782 [IQR 453, 1069] days in the DC. Males had a higher risk of mortality than females (adjusted HR: 3.84, 95% CI: 1.43-10.27; p=0.01). Metabolites that met aforementioned criteria for inclusion in the MS were: Bilirubin, Uric Acid, Hypoxanthine, L-Tyrosine, Phenylpyruvate, Oleoylcarnitine and Linoelaidyl carnitine (Table 1A). MS was higher in men than in women (0.90 ± 4.76 vs -0.66 ± 4.97, p=0.03) and associated with mortality in men (adjusted HR: 1.73, 95% CI: 1.20-2.29, p<0.001) but not in women (p=0.32) (p<0.001 for MS*sex interaction). Addition of MS to Cox models attenuated the association of male sex with mortality by 22.16%. The VC confirmed these findings: MS attenuated the association of male sex with mortality by 33.59% (Table 1B). The MS remained significantly associated with mortality (p≤0.01) in all models.
A metabolomics risk score representing the cardio-hepatic axis, purine metabolism, phenylalanine metabolism and the carnitine shuttle contributes to the increased residual risk of mortality in males with HFrEF.
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