Carnitine Insufficiency Is Associated With Adverse Outcomes in Patients With Heart Failure With Preserved Ejection Fraction

Abstract

Background: L-carnitine is an essential nutrient that plays a vital role in fatty acid energy metabolism of the heart and skeletal muscles. Primary or secondary carnitine insufficiency contributes to progressive left ventricular systolic dysfunction and physical frailty. However, the clinical features of patients with heart failure with preserved ejection fraction (HFpEF) and carnitine insufficiency remain unclear. Objectives: The present study aimed to evaluate the clinical characteristics and outcomes of these patients. Design: A prospective cohort study. Setting: Tottori University hospital. Participants: 117 patients who were hospitalized with HFpEF (ejection fraction ≥45%). Measurement: All measurements were obtained at hospital discharge. Carnitine insufficiency was defined as the lowest quantile of free carnitine level (<56.3 μmol/L) or the highest quantile of acylcarnitine to free carnitine ratio (≥0.35). Nutritional status and physical activity were assessed by the Geriatric Nutritional Risk Index (GNRI) and Barthel index (BI). Left ventricular diastolic function was assessed by echocardiography. The composite endpoints were hospitalization for heart failure and death from cardiac causes. Results: Patients with carnitine insufficiency (44.4%) had lower values of GNRI and BI, higher B-type natriuretic peptide levels, and lower early diastolic mitral annular velocity in the subgroups with sinus rhythm compared with those with preserved carnitine (all p<0.05). During a mean follow-up of 472±249 days, composite endpoints occurred in 26.5% of patients. Multivariate Cox hazard analysis showed that carnitine insufficiency was an independent predictor of cardiac events (p<0.05). Conclusions: Carnitine insufficiency is associated with adverse outcomes in patients with HFpEF.

Trimethylamine N‐oxide and outcomes in patients hospitalized with acute heart failure and preserved ejection fraction

“…This may increase acylcarnitine but decrease free carnitine in the myocardium, resulting in an elevated acylcarnitine to free carnitine ratio that reflects relative carnitine deficiency. Our and other recent studies showed that an elevated acylcarnitine to free carnitine ratio was associated with a poorer prognosis in patients with HFpEF than in those with HFrEF 24,36 . The prognostic effect of TMAO may be partially explained by abnormal fatty acid metabolism and relative carnitine deficiency.…”

“…Carnitine is metabolized by some gut microbial taxa to form TMAO, 12 but the association between carnitine metabolism and TMAO levels has not been well investigated in patients with HF. Carnitine plays an important role in energy metabolism in the cardiac and skeletal muscles through transporting fatty acids into the mitochondria 24 . Incomplete fatty acid metabolism results in the accumulation of highly toxic acyl CoA 32,33 .…”

“…Carnitine plays an important role in energy metabolism in the cardiac and skeletal muscles through transporting fatty acids into the mitochondria. 24 Incomplete fatty acid metabolism results in the accumulation of highly toxic acyl CoA. 32,33 Free carnitine is consumed and reduced owing to detoxification of acyl CoA, and its metabolite, acylcarnitine, increases.…”

“…High TMAO levels were defined as those greater than the median value of the patients (20.37 μmol/L). Serum l ‐carnitine levels were measured by enzymatic cycling methods (carnitine assay kit; Kainos Laboratories Co., Tokyo, Japan) as previously described 24,25 …”

“…Serum L-carnitine levels were measured by enzymatic cycling methods (carnitine assay kit; Kainos Laboratories Co., Tokyo, Japan) as previously described. 24,25 Geriatric Nutritional Risk Index…”