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

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% (beta = 2.3 min, P = 2.3 x 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.

Automated summary

The study found that metabolites were associated with cardiac function, energy- and lipid-storage metabolites were related to left ventricular wall thickness and mass, and plasma levels of nicotine metabolite cotinine were linked to increased time spent with a sleep oxygen saturation less than 90%. Smokers with sleep apnoea had a significantly higher risk for adverse outcomes. Central sleep apnoea was significantly associated with heart failure with preserved ejection fraction (HFpEF) but not heart failure with reduced ejection fraction.