l-carnitine, a friend or foe for cardiovascular disease? A Mendelian randomization study

Abstract

Background l-carnitine is emerging as an item of interest for cardiovascular disease (CVD) prevention and treatment, but controversy exists. To examine the effectiveness and safety of l-carnitine, we assessed how genetically different levels of l-carnitine are associated with CVD risk and its risk factors. Given higher CVD incidence and l-carnitine in men, we also examined sex-specific associations. Methods We used Mendelian randomization to obtain unconfounded estimates. Specifically, we used genetic variants to predict l-carnitine, and obtained their associations with coronary artery disease (CAD), ischemic stroke, heart failure, and atrial fibrillation, as well as CVD risk factors (type 2 diabetes, glucose, HbA1c, insulin, lipid profile, blood pressure and body mass index) in large consortia and established cohorts, as well as sex-specific association in the UK Biobank. We obtained the Wald estimates (genetic association with CVD and its risk factors divided by the genetic association with l-carnitine) and combined them using inverse variance weighting. In sensitivity analysis, we used different analysis methods robust to pleiotropy and replicated using an l-carnitine isoform, acetyl-carnitine. Results Genetically predicted l-carnitine was nominally associated with higher risk of CAD overall (OR 1.07 per standard deviation (SD) increase in l-carnitine, 95% CI 1.02 to 1.11) and in men (OR 1.09, 95% CI 1.02 to 1.16) but had a null association in women (OR 1.00, 95% CI 0.92 to 1.09). These associations were also robust to different methods and evident for acetyl-carnitine. Conclusions Our findings do not support a beneficial association of l-carnitine with CVD and its risk factors but suggest potential harm. l-carnitine may also exert a sex-specific role in CAD. Consideration of the possible sex disparity and exploration of the underlying pathways would be worthwhile.

L‐carnitine alleviates cardiac microvascular dysfunction in diabetic cardiomyopathy by enhancing PINK1‐Parkin‐dependent mitophagy through the CPT1a‐PHB2‐PARL pathways

“…A Mendelian randomization study did not suggest a beneficial association between L‐carnitine and CVD and its risk factors. In contrast, L‐carnitine increased the risk of coronary artery disease in men 57 . In addition, several studies have revealed that L‐carnitine supplementation elevates plasma levels of trimethylamine‐N‐oxide (TMAO), a compound that is considered proatherogenic 38 .…”

“…Several recent studies have reported that L-carnitine may be unbeneficial and even harmful to cardiovascular disease (CVD). [55][56][57] A Mendelian randomization study did not suggest a beneficial association between L-carnitine and CVD and its risk factors. In contrast, L-carnitine increased the risk of coronary artery disease in men.…”

“…In contrast, L-carnitine increased the risk of coronary artery disease in men. 57 In addition, several studies have revealed that L-carnitine supplementation elevates plasma levels of trimethylamine-N-oxide (TMAO), a compound that is considered proatherogenic. 38 Furthermore, orally administered L-carnitine increased TMAO levels in mice via intestinal microbiota metabolism and promoted atherosclerosis.…”

Total meat (flesh) supply may be a significant risk factor for cardiovascular diseases worldwide

“…Similarly, l-carnitine, the active form of dietary carnitine and a driver of TMAO production in red meat, has been targeted by researchers for exploring CVD prevention and treatment (Wang et al, 2022;Zhao et al, 2022).…”

“…In the past years, red meat‐associated metabolites, such as trimethylamine‐ N ‐oxide (TMAO), have gained attention in their relationship between red meat eating and CVDs (Wang et al, 2022 ). Similarly, l ‐carnitine, the active form of dietary carnitine and a driver of TMAO production in red meat, has been targeted by researchers for exploring CVD prevention and treatment (Wang et al, 2022 ; Zhao et al, 2022 ).…”