Heart failure patients are classified by ejection fraction (EF) into distinct groups: heart failure with preserved EF (HFpEF) or heart failure with reduced EF (HFrEF). Although patients with heart failure commonly have multiple comorbidities that complicate management and may adversely affect outcomes, their role in the HFpEF and HFrEF groups is not well-characterized. This review summarizes the role of noncardiac comorbidities in patients with HFpEF versus HFrEF, emphasizing prevalence, underlying pathophysiologic mechanisms, and outcomes. Pulmonary disease, diabetes mellitus, anemia, and obesity tend to be more prevalent in HFpEF patients, but renal disease and sleep-disordered breathing burdens are similar. These comorbidities similarly increase morbidity and mortality risk in HFpEF and HFrEF patients. Common pathophysiologic mechanisms include systemic and endomyocardial inflammation with fibrosis. We also discuss implications for clinical care and future HF clinical trial design. The basis for this review was discussions between scientists, clinical trialists, and regulatory representatives at the 10th Global CardioVascular Clinical Trialists Forum.

Objectives Heart failure (HF) is characterized by perturbations in energy homeostasis and metabolism. The reversibility and prognostic value of circulating markers reporting on these changes remain unclear. We sought to describe the metabolomic profiles of patients along the spectrum of systolic HF, determine their association with adverse outcomes in a clinical trial of HF, and evaluate whether identified metabolites change with treatment for end-stage systolic HF. Methods To assess association of metabolites with clinical outcomes, a population of 453 chronic systolic HF patients who participated in the HF-ACTION trial, which randomized ambulatory, stable patients to exercise training versus usual care, were included. To assess change in metabolites with mechanical circulatory support, 41 patients with end-stage HF who underwent left ventricular assist device (LVAD) placement were studied. Targeted, quantitative profiling of 60 metabolites using tandem flow injection mass spectrometry was performed on frozen plasma samples obtained prior to randomization in the HF-ACTION group, as well as, prior to and ≥90 days post placement in the LVAD group. Principal components analysis (PCA) was used for data reduction; linear regression and Cox-proportional hazards regression modeling were used to assess the relation between the PCA-derived metabolite factor levels and clinical outcomes among patients from the HF-ACTION study. Differences between metabolite factors associated with outcomes in the HF-ACTION and LVAD groups were assessed using Wilcoxon rank sum tests. Results Five PCA-derived factors were significantly associated with peak VO2 levels at baseline in fully adjusted models. Of these, Factor 5 (composed of long-chain acylcarnitines) was associated with increased risk of all 3 pre-specified HF-ACTION clinical outcomes: all-cause mortality/all-cause hospitalization (HR: 1.24; 95% CI 1.09–1.42), all cause-hospitalization (HR: 1.42; 95% CI 1.16–1.74), and cardiovascular death or cardiovascular hospitalization (HR: 1.22; CI 1.06–1.39). Individual components of Factor 5 (C16, C18:1, and C18:2 acylcarnitine metabolites) were significantly higher in patients with end-stage HF prior to LVAD placement and decreased significantly after LVAD therapy. Conclusions In chronic HF patients, circulating long chain acylcarnitine metabolite levels were independently associated with clinical outcomes and decreased after long-term mechanical circulatory support. These metabolites, which report on mitochondrial fatty acid β-oxidation, highlight pathways that may serve as potential targets for new diagnostics or therapeutic interventions.

BackgroundMetabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF).Methods and ResultsWe identified HFpEF cases, HFrEF controls, and no‐HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ≥45%, diastolic dysfunction grade ≥1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No‐HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long‐chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no‐HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance.ConclusionsWe identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.