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

Abstract

Background: Heart failure (HF) is characterized by perturbations in energy homeostasis and metabolism. The reversibility and prognostic value of circulating markers associated with these changes remain unclear.

Objectives: This study 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, we evaluated a population of 453 chronic systolic HF patients who had been randomized to exercise training versus usual care. 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, as well as prior to and ≥90 days post-placement in the LVAD group. Principal components analysis was used for data reduction.

Results: Five principal components analysis-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 clinical trial outcomes: all-cause mortality/all-cause hospitalization, all cause-hospitalization, and cardiovascular death or cardiovascular hospitalization. Individual components of factor 5 were significantly higher in patients with end-stage HF prior to LVAD placement and decreased significantly post-implantation.

Conclusions: In chronic HF patients, circulating long-chain acylcarnitine metabolite levels were independently associated with adverse clinical outcomes and decreased after long-term mechanical circulatory support. These metabolites may serve as potential targets for new diagnostics or therapeutic interventions. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437).

Keywords: metabolomics; phenotypes; prognosis.

Figure 1. Kaplan-Meier Curves for the relationship between tertiles of the long-chain acylcarnitine factor (Factor 5) and time-to-event for the primary outcome of all-cause mortality and hospitalization

Adverse events showing adjusted Kaplan-Meier curve of relations between tertiles of metabolite factors 5 and risk of primary outcome.

Figure 2. Levels of Metabolites in the long-chain acylcarnitine factor (Factor 5) in Patients with Chronic Heart Failure and End-Stage Heart Failure before and after LVAD placement

Metabolite levels that were significantly different before and after LVAD placement are marked by *, whereas those that were significantly different between chronic HF and pre-LVAD are marked by ┼. C16, C18:1 and C18:2 were significantly higher at baseline in patients with end-stage HF prior to LVAD placement, and decreased after support. The other major components of Factor 5—Arginine, C18, and C20:4—did not change significantly with LVAD support.

Central Figure

The primary energy source for the normally functioning human heart is free fatty acids, which are broken down by β-oxidation and entered into the Krebs cycle for eventual conversion into ATP. Long chain fatty acids are converted to their respective acyl-coenzyme A (CoA) ester by the ATP-dependent acyl-CoA synthetases. These acyl-CoA esters are then converted into acylcarnitine and free CoA by CPT-I at the outer mitochondrial membrane. The resulting acylcarnitine is then transported across the inner mitochondrial membrane by the carnitine:acylcarnitine translocase in exchange for free carnitine. Once inside the mitochondrial matrix, the acyl-CoA ester is reformed by CPT-II, and carnitine is released for further exchange by the carnitine:acylcarnitine translocase. In the failing heart, dysfunction in these key enzymes may lead to inadequate substrate utilization, which would be hypothesized to be reflected in serum elevations of long chain fatty acid intermediate metabolites such as long-chain acylcarnitines. Targeting these pathways might lead to novel therapeutics for heart failure.