Metabolomic Profiles and Heart Failure Risk in Black Adults: Insights From the Jackson Heart Study

Abstract

Background: Heart failure (HF) is a heterogeneous disease characterized by significant metabolic disturbances; however, the breadth of metabolic dysfunction before the onset of overt disease is not well understood. The purpose of this study was to determine the association of circulating metabolites with incident HF to uncover novel metabolic pathways to disease.

Methods: We performed targeted plasma metabolomic profiling in a deeply phenotyped group of Black adults from the JHS (Jackson Heart Study; n=2199). We related metabolites associated with incident HF to established etiological mechanisms, including increased left ventricular mass index and incident coronary heart disease. Furthermore, we evaluated differential associations of metabolites with HF with preserved ejection fraction versus HF with reduced ejection fraction.

Results: Metabolites associated with incident HF included products of posttranscriptional modifications of RNA, as well as polyamine and nitric oxide metabolism. A subset of metabolite-HF associations was independent of well-established HF pathways such as increased left ventricular mass index and incident coronary heart disease and included homoarginine (per 1 SD increase in metabolite level, hazard ratio, 0.77; P=1.2×10^-3), diacetylspermine (hazard ratio, 1.34; P=3.4×10^-3), and uridine (hazard ratio, 0.79; P, 3×10^-4). Furthermore, metabolites involved in pyrimidine metabolism (orotic acid) and collagen turnover (N-methylproline) among others were part of a distinct metabolic signature that differentiated individuals with HF with preserved ejection fraction versus HF with reduced ejection fraction.

Conclusions: The integration of clinical phenotyping with plasma metabolomic profiling uncovered novel metabolic processes in nontraditional disease pathways underlying the heterogeneity of HF development in Black adults.

Keywords: heart diseases; heart failure; medicine; metabolomics; plasma.

Figure 1:

Analysis plan for metabolomic profiling of incident heart failure in the Jackson Heart Study LVMi: left ventricular mass index; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; CHD: coronary heart disease; HF: heart failure; JHS: Jackson Heart Study

Figure 2:

Effect Size Modification of Incident Coronary Heart Disease on the Association of Metabolites with Incident Heart Failure The percent reduction in effect size (hazard ratio) for metabolites in a cox proportional hazards regression for incident heart failure with the addition of incident coronary heart disease as a time dependent variable. Baseline model was adjusted for age, sex, body mass index, hypertension, systolic blood pressure, total cholesterol, high density lipoprotein, Diabetes mellitus, eGFR, smoking status and history of coronary heart disease. Incident coronary heart disease was added as a time dependent covariate to determine change in effect size.

Figure 3:

Risk discrimination for incident heart failure for metabolites vs. clinical risk factors. The C-statistic along with confidence intervals are displayed for each model in its association with incident heart failure. BNP: Brain natreutic peptide *Clinical risk factors: age, sex, body mass index, hypertension, systolic blood pressure, eGFR, diabetes, smoking status, total cholesterol, high density lipoprotein and history of coronary heart disease