Metabolite signatures of heart failure, sleep apnoea, their interaction, and outcomes in the community

Abstract

Aims: Sleep apnoea and congestive heart failure (CHF) commonly co-exist, but their interaction is unclear. Metabolomics may clarify their interaction and relationships to outcome.

Methods and results: We assayed 372 circulating metabolites and lipids in 1919 and 1524 participants of the Framingham Heart Study (FHS) (mean age 54 ± 10 years, 53% women) and Women's Health Initiative (WHI) (mean age 67 ± 7 years), respectively. We used linear and Cox regression to relate plasma concentrations of metabolites and lipids to echocardiographic parameters; CHF and its subtypes heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF); and sleep indices. Adenine dinucleotide phosphate (ADP) associated with left ventricular (LV) fractional shortening; phosphocreatine with LV wall thickness; lysosomal storage molecule sphingomyelin 18:2 with LV mass; and nicotine metabolite cotinine with time spent with an oxygen saturation less than 90% (β = 2.3 min, P = 2.3 × 10^-5 ). Pro-hypertrophic metabolite hydroxyglutarate partly mediated the association between LV wall thickness and HFpEF. Central sleep apnoea was significantly associated with HFpEF (P = 0.03) but not HFrEF (P = 0.5). There were three significant metabolite canonical variates, one of which conferred protection from cardiovascular death [hazard ratio = 0.3 (0.11, 0.81), P = 0.02].

Conclusions: Energetic metabolites were associated with cardiac function; energy- and lipid-storage metabolites with LV wall thickness and mass; plasma levels of nicotine metabolite cotinine were associated with increased time spent with a sleep oxygen saturation less than 90%, a clinically significant marker of outcome, indicating a significant hazard for smokers who have sleep apnoea.

Keywords: Biomarker; Framingham; Heart failure; Lipid; Metabolite; Mortality; Sleep apnoea.

Figure 1

Summary of cardiac and sleep metabolite associations. Cotinine was associated with decreased SpO₂ concentrations on sleep studies, increased heart rates, and decreased LV ejection fraction. Inositol was associated with increased aortic dimension. Sphingomyelins are stored in cardiac lysosomes and were associated with LV mass. Phosphocreatine is the main storage form of high‐energy phosphates and was associated with mean LV diastolic wall thickness, posterior wall thickness, and interventricular wall thickness. Tricarboxylic acid cycle intermediate α‐ketoglutarate was associated with mean LV wall thickness. Energetic metabolite ADP was associated with ejection fraction. Triacylglycerols were associated with mean left atrial dimension. Nicotinamide adenine dinucleotide precursor niacinamide and cardiac fuel substrates BCAAs were associated with LV internal dimensions. ADP, adenine dinucleotide phosphate; BCAAs, branched chain amino acids; HFpEF, heart failure with preserved ejection fraction; LV, left ventricular; TAG, triacylglycerols.

Figure 2

(A) Of the 10 identified canonical variates (dimensions), three were significant. (B) Metabolite Variate 1 was inversely associated with HFrEF and HFpEF; Metabolite Variate 2 was inversely associated with HFrEF; and Metabolite Variate 3 was most positively associated with HFpEF. (C) Metabolite Variate 1 was significantly protective for cardiovascular death. Av O₂ sat, average oxygen saturation; cAHI, apnoea–hypopnoea index, central sleep apnoea; CI, confidence interval; CV, cardiovascular; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; Min O₂ sat, minimum oxygen saturation; obAHI, apnoea–hypopnoea index, obstructive sleep apnoea; T < 90, time spent with oxygen saturation less than 90%.