February 2025 Issue
L-carnitine and CVD
By Carrie Dennett, MPH, RDN, CD
Today’s Dietitian
Vol. 27 No. 2 P. 18
Teasing Out the Potential Benefits and Potential Harms
Despite being a conditionally essential nutrient, carnitine is a topic of uncertainty, even controversy, because it’s like a coin with two sides, and those sides can appear to be in direct conflict with each other. On one side, evidence from randomized controlled trials suggests that circulating levels of carnitine may increase the risk of atherosclerosis and CVD. On the other side, evidence from randomized controlled trials also suggests that L-carnitine may be a beneficial adjunct to standard medical treatment for CVD. Both narratives are complicated and nuanced.
Carnitine is a generic term for several compounds, including L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine. Humans can synthesize carnitine from the amino acids lysine and methionine, which is why it’s a conditionally essential nutrient. This synthesis happens primarily in the liver, with some in the kidneys, before being transported to other tissues. Carnitine is abundant in animal food sources, especially red meat. Carnitine is most concentrated in tissues that use fatty acids as their primary fuel, such as skeletal and cardiac muscle because it’s required for mitochondrial beta-oxidation of long-chain fatty acids for energy production.1
Carnitine Deficiency and Dietary Sources
The human body needs about 15 mg of carnitine per day from a combination of endogenous and dietary sources, and a typical omnivore diet provides up to 10 times that amount.2 Healthy individuals generally synthesize enough carnitine to prevent deficiency. However, pregnancy and certain health conditions may cause increased excretion of carnitine, which could increase risk of deficiency.
Oral or intravenous L-carnitine supplementation is used for treatment of both primary and secondary carnitine deficiencies.1 Primary systemic carnitine deficiency is a rare condition caused by mutations in the gene that codes for the carnitine transporter, OCTN2. This causes poor intestinal absorption of dietary carnitine, increased urinary loss of carnitine due to poor reabsorption, and defective carnitine uptake by muscles.3 Secondary carnitine deficiencies are typically caused by inherited genetic defects in the metabolism of amino acids, cholesterol, and fatty acids and are also found in patients with end-stage renal disease undergoing hemodialysis, which impairs the reabsorption of carnitine.1
Looking at dietary sources, 3 oz of beef steak provides 42 to 122 mg of L-carnitine, 3 oz of cooked ground beef provides 64 to 74 mg, 1 cup of whole milk provides 8 mg, and 3 oz of cooked chicken breast provides 2 to 4 mg.1 Many energy drinks also contain L-carnitine, according to a 2022 study, but the amounts were not available.4 The bioavailability of dietary carnitine can vary depending on the amount in a meal and whether someone typically eats a plant-based diet or a diet that’s higher in meat. Overall, bioavailability from food is 54% to 87%, significantly higher than the 14% to 18% bioavailability of L-carnitine in oral supplement form. Regardless of the source, unabsorbed L-carnitine is degraded by colonic bacteria,5 which research suggests is a key step in the potential risks of elevated L-carnitine intake.
L-carnitine, TMAO, and CVD
While research has found associations between increased circulating levels of L-carnitine and increased risk of atherosclerosis and CVD, the real concern may be how carnitine is metabolized. The gut microbiota converts L-carnitine into trimethylamine (TMA), which may then be oxidized by enzymes in the liver to form trimethylamine N-oxide (TMAO). TMAO, which can also be formed from choline as a precursor, is itself associated with an increased risk of CVD despite being naturally found in some species of fish and seafood. While elevated plasma concentrations of L-carnitine are associated with increased risk of cardiovascular incidents—such as heart attack, stroke, and death—independent of traditional CVD risk factors, this appears to only be true when TMAO is also elevated.6 Proposed mechanisms include effects on cholesterol, the hormone angiotensin II—which can raise blood pressure, and increased platelet clumping, possibly leading to blood clots.7.8
A 2020 cross-sectional study using data from 1,653 participants in the Multiethnic Cohort Study identified several associations of plasma levels of TMAO and its precursors, including carnitine, with inflammatory and cardiometabolic biomarkers. Higher concentrations of carnitine were seen in the upper quartiles of TMAO.9 A 2017 systemic review and meta-analysis found that high TMAO levels were a much stronger predictor of cardiovascular events than were elevated levels of its nutrient precursors, including carnitine, regardless of conventional CVD risk factors.10
To investigate whether circulating L-carnitine is related to the risk of incident coronary heart disease (CHD) in apparently healthy people at normal risk, A 2022 prospective nested case-control study looked at associations between CVD risk and 10-year changes in plasma L-carnitine levels in 772 women enrolled in the Nurses’ Health Study. Women who remained free from nonfatal myocardial infarction or fatal CHD at the 10-year mark were followed for about 16 more years, during which time researchers identified 386 incident cases of CHD and randomly selected one matched control for each.11
Overall, a greater increase in L-carnitine over the initial 10 years was related to a 36% higher risk of CHD in the subsequent follow-up, regardless of the initial L-carnitine levels. The 10-year changes in L-carnitine were positively associated with red meat consumption over time, and women who had greater increases in L-carnitine and red meat intake of 36 g/day or more, had an 86% greater risk of CHD, as compared with those with lower red meat intake and lesser increases in L-carnitine. There was also a significant correlation between TMAO changes and L-carnitine changes in the women with CHD.
Kevin Klatt, PhD, RD, an assistant research scientist and instructor in the Department of Nutrition Sciences and Toxicology at University of California, Berkeley, cautions that epidemiological studies using circulating levels of nutrients or metabolites as proxies for dietary exposure often don’t correlate with randomized controlled trials that aim to increase levels of those nutrients or metabolites. “This is often because circulating levels are subject to varying levels of homeostatic regulation, reflecting not only intake but also absorption, distribution across tissues, metabolism to other compounds, and excretion,” he says.”
Johanna Lampe, PhD, RD, research professor in the Department of Epidemiology at the University of Washington School of Public Health and associate director of the Public Health Services Division at Fred Hutchinson Cancer Research Center in Seattle, says about 95% of TMA is converted to TMAO in the liver. “From that standpoint, it’s probably more the variation in what’s happening at the microbiome level as far as exposure to these compounds.”
That’s why the TMAO synthesis pathway has become one of the first gut microbiota targets for pharmaceutical interventions to prevent CVD,12 even though that pathway is quite complex.
Genetic Influences and Complex Pathways
The gut microbiota’s first step in converting unabsorbed carnitine into TMA is generation of the intermediate gamma-butyrobetaine (GBB), which has been shown to be atherogenic in mice, although research in humans is inconclusive. 6 Multiple microbes in both the small and large intestines can convert dietary L-carnitine into GBB, but relatively few can transform GBB into TMA.13 The GBB-to-TMA conversion is much higher in omnivores than in vegans and vegetarians, likely because of differences in the gut microbiota, although this aspect of the L-carnitine-to-TMAO pathway is not fully understood. Interestingly, in a group of seven vegans/vegetarians given 500 mg/day of supplemental L-carnitine for two to three months, only three demonstrated increased GBB-to-TMA conversion.6
There could be a genetic explanation. Exposure to GBB results in the upregulation of a specific microbial gene cluster, gbu (GBB utilizing), which is responsible for the conversion of GBB to TMA—and more abundant in people who eat red meat. In many vegans, expression of the necessary genes appears toeither be absent or suppressed to nearly undetectable levels. This elimination of the gbu gene cluster from the gut microbiome may be a mechanism that helps explain why plant-based diets are associated with reduced risk of CVD and other metabolic disorders associated with elevated TMAO.14
Researchers have questioned whether GBB levels themselves could play a role in CVD risk. In a clinical cohort of 2,918 participants, fasting levels of GBB were dose-dependently associated with prevalence of CVD, coronary artery disease (CAD), and peripheral artery disease (PAD), even after adjusting for traditional risk factors. Higher GBB levels were also associated with increased risk of—and poorer survival from—major cardiovascular events (death, myocardial infarction, or stroke), but only when TMAO levels were also elevated.14
Continuing along the carnitine metabolism pathway to the liver, individual genetic variation may play a role in elevated TMAO levels by increasing conversion of TMA to TMAO by the enzyme flavin-containing monooxygenase 3 (FMO3). Increased expression of the FMO3 gene could be a culprit in atherosclerosis and CVD.8 FMO3 may have adverse effects on blood lipids and glucose independently of TMAO formation, although more research is needed.15
Also, in the liver, trimethyllysine (TML), a modified amino acid, can be converted to GBB and then to carnitine and potentially to TMA and TMAO. A 2016 study found that patients with carotid atherosclerosis had elevated blood levels of GBB and carnitine but not TML or TMAO, compared with healthy controls. However, higher serum levels of GBB and TML, but not TMAO or carnitine, were independently associated with cardiovascular death after adjustment for estimated glomerular filtration rate.16
L-carnitine in CVD Treatment
Despite research on potential cardiovascular risks of elevated levels of carnitine or its metabolites, L-carnitine is emerging as a target for CVD prevention and treatment due to its important role in the oxidation of fatty acids and cardiac energy metabolism. L-carnitine facilitates transport of long-chain fatty acids into the mitochondrial matrix, where it can reduce oxidative stress and may reduce markers of inflammation.17-19 During ischemic events that block blood flow to the heart, carnitine prevents the fatty acid ester accumulation that can lead to fatal ventricular arrhythmias.18 However, results of clinical trials of the effects of carnitine supplements on CVD have been mixed.
A 2020 systemic review and meta-analysis of 44 randomized controlled trials that included both healthy adults and those with certain health conditions found that L-carnitine supplementation significantly lowered the inflammatory markers C-reactive protein, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), and malondialdehyde; and significantly increased levels of the endogenous antioxidant superoxide dismutase. IL-6 and TNF-alpha levels showed a greater decrease with higher dosages of L-carnitine. Ten studies used a dosage of less than 500 mg, seven trials used 500 to 1,000 mg, 12 used 1,000 to 2,000 mg, and 13 used 2,000 or more mg.20
A 2019 systematic review and meta-analysis of 13 randomized clinical trials found that L-carnitine supplementation was significantly associated with lower levels of C-reactive protein in comparison to controls. Also, a slight but statistically significant decrease was observed in IL-6 and TNF-alpha levels. The results were stronger in studies longer than 12 weeks, and doses higher than 2,000mg/day more effectively reduced TNF-alpha.17
Results of a 2023 umbrella meta-analysis on 13 interventional meta-analyses suggest that supplemental doses of L-carnitine of more than 2 g/day can decrease total and LDL-cholesterol and triglycerides, and increase HDL-cholesterol levels. However, the authors noted that the results were heterogeneous, and except for LDL-cholesterol, the results, while statistically significant, were not clinically significant.21 A 2016 study found that in patients with elevated LDL, triglyceride, and lipoprotein (a) levels who received 2 g of L-carnitine plus 20 mg/day of simvastatin had a statistically significant but modest reduction in lipoprotein (a) compared with patients who received the simvastatin plus placebo.22
A meta-analysis of 17 clinical trials that included 1,625 adults with chronic heart failure found that supplementing with 1 to 6 g/day of L-carnitine for seven days to three years improved clinical symptoms and cardiac function compared with conventional treatment, and the benefits did not vary by supplement dose or study duration.23 A 2022 systemic review and dose-response meta-analysis of 22 randomized controlled human trials found that L-carnitine supplementation did not have a significant effect on blood pressure.24
A 2022 study that used Mendelian randomization found that genetically predicted higher endogenous L-carnitine levels were nominally associated with higher risk of CAD and heart failure in men and women, although the association did not hold for CAD in women from some data sources. Genetically predicted higher L-carnitine levels were also associated with higher triglyceride levels and lower HDL levels in men. The authors concluded that these results suggest no benefit of L-carnitine for CVD or its risk factors, with the caveat that the role of endogenous L-carnitine may not correspond to exogenous carnitine from food or supplements.25
A 2022 randomized clinical trial gave 1 g supplemental L-carnitine or placebo twice a day for six months to 157 individuals aged 58 to 75 years with metabolic syndrome. Total and LDL cholesterol levels increased in the L-carnitine group, and L-carnitine supplementation was also associated with 9.3% greater carotid arterial plaque stenosis in males who ate less red meat and had lower baseline stenosis and total plaque volume than other participants.26
A 2018 study including participants on a nonvegetarian diet found that 24 weeks of supplementation with 1,500 mg of L-carnitine increased fasting blood levels of carnitine and increased levels of TMAO tenfold but did not increase lipids, inflammatory markers, or other markers of atherosclerosis in healthy, omnivore, nonsmoking, physically active women ages 65 to 70 when compared with placebo. The authors noted that the length of the study was a limitation, as atherosclerosis develops over many years.27
Recommendations for RDs
How should dietitians make sense of the unclear role of carnitine in CVD—and how should they advise patients and consumers?
“Carnitine is like many areas of nutrition where we lack large, well-conducted placebo-controlled randomized trials assessing disease endpoints. It is exceedingly easy to look at a compound like carnitine and come up with bioplausible reasons it should be ‘good’ or ‘bad’ for cardiovascular diseases,” he says. “The impact on TMAO levels and whether this causally increases CVD risk is still uncertain. Dietitians should be thinking about carnitine and how to communicate what we know and don’t know in populations where users may be pursuing carnitine supplementation.”
Those populations include both recreational and elite athletes, who may use L-carnitine supplements for performance enhancement. A 2020 systematic review found that short-term use may have benefits, but long-term use can elevate fasting TMAO.28
“From a prevention standpoint in relation to a number of chronic diseases, we are already encouraging people to decrease intake of red meat,” Lampe says. “These foods are typically our sources of carnitine.”
A 2018 crossover study with 113 participants found that chronic consumption—defined as daily intake with around 258 mg/d of carnitine— of red meat increased levels of TMAO produced from carnitine and decreased TMAO excretion, but these levels decreased within four weeks of stopping eating red meat.29
“Given the uncertainty on this topic, relative to the overall body of evidence we have for CVD prevention, I tend to encourage folks not to focus on it too much,” Klatt says, adding that other than current recommendations to focus on cardioprotective foods and limit red meat, making carnitine less of a concern, there are currently no evidence-based practice guidelines encouraging the planning of diets based around TMAO lowering.30 “Focusing on the issue too much runs the risk of folks paying for expensive lab testing with limited known clinical utility.”
— Carrie Dennett, MPH, RDN, CD, is the nutrition columnist for The Seattle Times, owner of Nutrition By Carrie, and author of Healthy for Your Life: A Non-Diet Approach to Optimal Well-Being.
References
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