The Heart Is Just a Muscle

McGarrah, Robert W.; Ahmad, Tariq; Koeberl, Dwight D.; Patel, Chetan B.

doi:10.1161/circulationaha.114.011647

Cited by 1 publication

(1 citation statement)

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“…This pattern of metabolite abnormalities suggests impaired mitochondrial fatty acid oxidation, a finding previously described in HF, and also noted in rare mitochondrial disorders of lipid metabolism: Carnitine palmitoyltransferase 2 (CPT2) deficiency and Carnitine-acylcarnitine translocase (CACT) deficiency, both of which are associated with skeletal and cardiac myopathy (16). This further confirms that HF is characterized by dysfunction in a central pathway of energy utilization by the heart and peripheral musculature, that the measured abnormalities have prognostic importance, and that use of mitochondrial-based therapeutics might hold promise in the treatment of chronic systolic HF (4,17). …”

Section: Discussionsupporting

confidence: 63%

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

Ahmad

Kelly

McGarrah

et al. 2016

Journal of the American College of Cardiology

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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.

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Section: Discussionsupporting

confidence: 63%