Prognostic Implications of Long-Chain Acylcarnitines in Heart Failure and Reversibility With Mechanical Circulatory Support

Abstract

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.

Targeted Metabolomic Profiling of Plasma and Survival in Heart Failure Patients

“…Despite taking a very different statistical approach, two factors of our PMP (Arg, C18.1 AC) were also contributing factors in the most predictive principle component identified from the Ahmad study. (18) This consistency of our findings with those of previous investigators strongly supports external validity. (7,18,26– 29) Moreover, although the primary aim here was to validate the importance of circulating metabolites in HF and not define a biomarker, the PMP did statistically add to current optimal prognosticators; a high hurdle that few markers (such as troponin and neutral endopeptidase) have achieved (30,31)…”

“…Similarly, there is growing data derived from the setting of HF, in which specific plasma metabolite levels were reported to be associated with incident disease or risk of death (11–15). More recently, a few systematic evaluations of the metabolites in HF were published which further support the overall hypothesis that circulating metabolites may be deranged in the setting of HF and indeed may reflect the underlying disease state (16–18). Larger scale validation of the plasma metabolome regarding prognostic value, or as way to stratify HF phenotypes, is still urgently needed.…”

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

“…Similarly, our group recently found that patients with end‐stage HF had significantly higher plasma LCAC levels than those with chronic, stable HFrEF 51. Furthermore, we demonstrated that greater plasma LCAC levels were independently associated with worse functional status and mortality in chronic stable HFrEF 51. Altogether, the plasma LCAC elevations in HFpEF and HFrEF observed in our study and previous investigations may highlight a shared metabolic impairment characteristic of the HF state.…”

“…Interestingly, they also found that Stage A HF patients had plasma LCAC levels higher than normal controls, but lower than Stage C HF patients. Similarly, our group recently found that patients with end‐stage HF had significantly higher plasma LCAC levels than those with chronic, stable HFrEF 51. Furthermore, we demonstrated that greater plasma LCAC levels were independently associated with worse functional status and mortality in chronic stable HFrEF 51.…”

Metabolomic Analysis in Heart Failure

“…21 Circulating levels of long-chain acylcarnitines are also increased in patients with end-stage HF compared with those who have chronic HF with systolic cardiac dysfunction, and this increase predicts the risk of hospitalization or death. 22 Interestingly, in contrast to the increased level of circulating acylcarnitine, acylcarnitines are reported to be reduced in the failing heart itself, possibly caused by increased utilization, altered carnitine metabolism, or decreased acylcarnitine synthesis. 23, 24 Phospholipids are molecules that generally have 2 hydrophobic fatty acid tails and a hydrophilic head, and form the major component of cell membranes.…”