Plasma acylcarnitines and risk of cardiovascular disease: effect of Mediterranean diet interventions

Abstract

Background: Previous studies have suggested that metabolite profiles of elevated acylcarnitines were associated with increased risk of cardiovascular disease (CVD) in populations with established coronary disease. However, to our knowledge, this association has not been evaluated in the context of primary cardiovascular prevention.

Objectives: We evaluated the association between 28 plasma acylcarnitine species and risk of incident CVD and the potential modifying effect of Mediterranean diet (MedDiet) interventions.

Design: We measured plasma acylcarnitines with the use of high-throughput liquid chromatography-tandem mass spectrometry at baseline and after 1 y of follow-up, both individually and classified into short-, medium-, or long-chain scores, in a case-cohort study within the Prevención con Dieta Mediterránea (PREDIMED) study, which is a randomized Mediterranean dietary intervention for primary cardiovascular prevention. A randomly selected subcohort (n = 751) and all available incident CVD cases (n = 229) after 4.8 y of follow-up were included in the current study.

Results: After adjustment for age, sex, body mass index, and other CVD risk factors, participants in the highest quartile of baseline short- and medium-chain acylcarnitines had a higher risk of CVD than did participants in the lowest quartile [HRs: 1.80 (95% CI: 1.11, 2.91; P-trend 0.01) and 1.55 (95% CI: 1.01, 2.48; P-trend = 0.04), respectively]. Increased short-chain acylcarnitines after 1 y were associated with higher risks of total CVD and stroke. Participants with higher baseline concentrations of short-, medium-, and long-chain acylcarnitines who were randomly assigned to the control group had a higher risk of CVD than did subjects with lower concentrations of acylcarnitines who were assigned to the MedDiet group.

Conclusions: Our data support the conclusion that metabolite profiles characterized by elevated concentrations of acylcarnitines are independently associated with risks of total CVD and stroke alone in participants at high risk of CVD. MedDiet interventions may mitigate the adverse associations shown between higher concentrations of acylcarnitines and CVD. This trial was registered at www.controlled-trials.com as ISRCTN35739639.

Keywords: Mediterranean diet; PREDIMED; acylcarnitines; cardiovascular disease; metabolomics.

FIGURE 1

Multivariate adjusted HRs (95% CIs) of incident CVD and Qs of baseline acylcarnitine scores stratified by intervention group (Mediterranean interventions compared with a control group). An inverse normal transformation was applied to raw baseline values, and a weighted sum of these values was computed to calculate the scores. (A) Short-chain acylcarnitines (C2carnitine, C3DCCH3carnitine, C3carnitine, C4carnitine, C4OHcarnitine, C5carnitine, C5:1carnitine, C5:DCcarnitine, C6carnitine, and C7carnitine). (B) Medium-chain acylcarnitines (C8carnitine, C9carnitine, C10carnitine, C10:2carnitine, C12carnitine, C12:1carnitine, C14carnitine, C14:1carnitine, and C14:2carnitine). (C) Long-chain acylcarnitines (C16carnitine, C18carnitine, C18:1carnitine, C18:1OHcarnitine, C18:2carnitine, C20carnitine, C20:4carnitine, and C26carnitine). n = 980 for the 3 carnitine scores. Analyses were adjusted for age, sex, BMI, physical activity (metabolic equivalent tasks in min/d), family history of premature heart disease, and smoking. The P values for the interactions between each MedDiet intervention group (extra-virgin olive oil and nuts) (as binary; yes or no) and acylcarnitine scores (continuous) with 2 product terms (extra-virgin olive oil × acylcarnitine score and nuts × acylcarnitine score) and 2 df were 0.04, 0.09, and 0.48 for short-, medium-, and long-chain acylcarnitine scores, respectively. CVD, cardiovascular disease; MedDiet, Mediterranean diet; Q, quartile; ref, reference.