In patients with chronic heart failure (HF), circulating long-chain acylcarnitine metabolite levels are independently associated with adverse outcomes, according to new research published in the Journal of the American College of Cardiology.

Researchers sought to evaluate metabolomic profiles of patients with systolic HF, determine the role of metabolomic profiles in adverse outcomes, and test to see if the identified metabolites changed with treatment for end-stage systolic HF.

Comorbidities, BMI, sex, and race were similarly distributed amongst the patients (median age 59 years in the chronic HF group; 68 years in the end-stage HF group), all of whom were chosen from an HF-ACTION biomarker substudy.


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In terms of cardiovascular fitness, however, the groups differed: peak V02 of 14.3 ml/kg/min in the chronic HF vs 12.5 ml/kg/min in end-stage HF; Ve-VCO2 slope of 32.3 in chronic HF vs 42.1 in end-stage HF; and N-terminal pro-B natriuretic peptide 823 ng/l in chronic HF and 3108 ng/l in end-stage HF. Left ventricle ejection fraction (LVEF) was not statistically significantly different between the 2 groups: 25% in chronic HF and 20% in end-stage HF.

Metabolomic factors 5 and 7 (long-chain and medium-chain acylcarnitines) were associated with an increased risk of the primary outcome of all-cause mortality or hospitalization (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.09-1.42 and HR: 1.16; 95% CI: 1.02-1.31, respectively) whereas factor 9 (amino acids) was associated with a decreased risk (HR: 0.88; 95% CI: 0.78-0.99).

Metabolomic factor 5 was associated with a greater risk of the secondary outcomes, including all-cause hospitalization (HR: 1.42; 95% CI: 1.16-1.74) and cardiovascular death or cardiovascular hospitalization (HR: 1.22; 95% CI: 1.06 to 1.39). Interestingly, factors 7 and 9 did not have associations with risk of hospitalization or cardiovascular death.

“Of the major components of this factor [factor 5], levels of C16, C18:1, and C18:2 acylcarnitines were significantly higher in patients with end-stage HF prior to LVAD [left ventricular assist device] implantation but decreased with circulatory support,” researchers noted. “We observed that elevated plasma levels of key long-chain acylcarnitines (C16 and C18) were independently associated with impaired cardio-respiratory capacity and also increased risk of all adverse clinical outcomes.”

These acylcarnitines are derivatives of dietary fatty acids, palmitate and oleate, respectively, and patients with end-stage HF had significantly higher levels of both which decreased with LVAD support. “These findings are consistent with the notion that the syndrome of HF be characterized by a general state of metabolic inflexibility and mitochondrial inefficiency that leads to accumulation of metabolic intermediates of FA [fatty acid] oxidation such as the long-chain acylcarnitines.”

Researchers concluded that the metabolic processes responsible for regulating blood levels of mitochondrial FA metabolites may provide a pathway to future therapies for patients with worsening HF.

Reference

Ahmad T, Kelly JP, McGarrah RW, et al. Prognostic implications of long-chain acylcarnitines in heart failure and reversibility with mechanical circulatory support. J Am Coll Cardiol. 2016;67(3):291-299. doi: j.jacc.2015.10.079.