Introduction
Men have worse mortality in heart failure with reduced ejection fraction (HFrEF),
even after accounting for traditional risk factors.
Hypothesis
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.
Methods
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).
Results
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.
Conclusions
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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Copyright
© 2020 Published by Elsevier Inc.
