Carnitine for Cardiovascular Diseases
By Dónal P. O'Mathùna, PhD, Senior Lecturer in Ethics, Decision-Making & Evidence, School of Nursing, Dublin City University, Ireland. Dr. O'Mathùna reports no financial relationships relevant to this field of study.
L-carnitine is both an amino acid and a conditionally essential nutrient, defined as an organic compound which is usually produced in sufficient quantities by the body. However, such a compound can become essential under specific circumstances when biosynthesis is less than optimal, and where dietary sources necessarily assume primacy.1 Carnitine can be synthesized from the essential amino acids lysine and methionine, or is available from the diet.2 Biosynthesis occurs primarily in the liver, with 10-20 mg produced daily by the average adult.1 More than 90% of the carnitine in the body is stored in cardiac and skeletal muscle. Dietary intake of carnitine is typically 100-300 mg daily, although it is much lower among strict vegetarians. The primary sources of carnitine are meat, fish, avocados, and some soy products, with lower amounts available in dairy products.1
Carnitine is available as a dietary supplement and has become popularly recommended for a number of uses in recent years. These have ranged from use as a weight loss supplement and performance enhancing agent for athletes, to being recommended as part of the management of several cardiovascular disorders. This article will examine the evidence available for the use of carnitine in people with cardiovascular disease.
Pharmacology
In the body, L-carnitine is converted into various esters to constitute an endogenous carnitine pool. The most prevalent forms are acetyl-L-carnitine (ALC) and propionyl-L-carnitine (PLC), with PLC believed to possess particular therapeutic advantages over the other derivatives.3 ALC crosses the blood-brain barrier better than L-carnitine and is believed to hold potential in protecting people against neurodegenerative diseases.3 However, much more research has been conducted on carnitine and heart disease, particularly using PLC. This derivative has a high affinity for cardiac and skeletal muscle, and its pharmacokinetics are better than the other derivatives.3
Mechanism of Action
L-carnitine plays a particularly important role in regulating the supply of energy in cardiac tissues.2 It is an essential cofactor in fatty acid metabolism. The primary function of L-carnitine is to transport long-chain fatty acids across the inner membrane of mitochondria.4 Once across this membrane, the fatty acids are broken down to acetyl-CoA via beta-oxidation, thereby allowing the release of their metabolic energy. This process is particularly important in cardiac tissue.2
Carnitine supplementation has been promoted as a way to increase fat metabolism for athletes and those seeking to lose weight. The claim is that additional carnitine in skeletal muscle would permit additional metabolism of fatty acids and energy production. However, oral carnitine supplementation has been shown to not increase muscle carnitine concentration, making claims that carnitine promotes weight loss "not only unfounded but theoretically impossible."4
Cardiovascular diseases like heart failure and ischemic heart disease often are accompanied by reduced cellular energy production and lower work efficiency.2 Carnitine is believed to have a beneficial effect in counteracting these changes. Oxidative damage is also involved in some cardiac diseases, and carnitine has been shown to have antioxidant actions, reducing the production of oxidative compounds and stimulating the gene expression of other antioxidants.3
In addition to transporting fatty acids into mitochondria for beta-oxidation, carnitine plays a role in transporting intermediate beta-oxidation products out of the mitochondria. Accumulation of these intermediates has been implicated in the development of insulin resistance, heart failure, and ischemia.2 There is developing interest in the possibility that carnitine and its derivatives may play a role in preventing type 2 diabetes and its associated increased risk for heart disease.
Clinical Studies
The potential therapeutic effects of carnitine and its derivatives have been investigated in clinical trials since the 1980s.3 During periods of ischemia myocardial carnitine levels decrease, and this reduction may exacerbate ischemia as energy production is compromised.5 A few small studies in the early 1990s found some benefits from administering L-carnitine to acute myocardial infarction (MI) patients. The largest trial in this area to date, the Italian CEDIM-2 trial, randomly assigned 2330 acute anterior MI patients to either L-carnitine or placebo.6 The trial was designed to enroll 4000 patients, but this sample size was not achieved due to unexpectedly slow enrollment. Those assigned to treatment with L-carnitine received 9 g/day by continuous IV for 5 days, followed by 4 g/day orally for 6 months. The primary endpoint was a composite incidence of death and heart failure after 6 months, which ultimately did not differ significantly between the groups (P = 0.27). The secondary endpoint was mortality after 5 days, which was lower in the L-carnitine group (2.3% vs 3.8%; P = 0.041).
The earlier CEDIM trial enrolled 472 patients with a first acute MI diagnosed within 24 hours of the onset of chest pain.7 The same protocol and doses were used in CEDIM-2, except the trial continued for 12 months. At the end of that time, the composite incidence of death and heart failure did not differ significantly between the carnitine and placebo groups (6.0% vs 9.6%, respectively; P > 0.05).
While clinical research with L-carnitine did not produce the beneficial effects anticipated, animal research suggested PLC would be more promising. PLC is highly specific for cardiac and skeletal muscle.8 A number of small studies in people with chronic heart failure (CHF) showed that 1 month of PLC improved maximum exercise duration and peak VO2 levels.8 Fifty patients with mild CHF (New York Heart Association class II) were randomized to receive either 1.5 g/day PLC or placebo for 6 months.9 The PLC group had significantly greater improvements in maximal exercise time (P < 0.01), left ventricular shortening fraction (P < 0.01), and left ventricular ejection fraction (P < 0.0001).
These results led to a multicenter, international study of exercise duration involving 537 CHF patients stabilized on various ACE inhibitors and diuretics.10 Participants were randomly assigned to receive either 2 g/day PLC or placebo. The primary endpoint was maximal exercise duration evaluated on an exercise bike. No statistically significant differences were found for either primary (P = 0.092) or secondary endpoints (evaluations of PLC's safety and tolerability, and quality of life assessments), or for adverse events (P = 0.289). Some subgroup analyses showed benefits in the PLC group, but the researchers stated that since the subgroups were not determined before the study was conducted these findings require further evaluation.
Several studies have examined L-carnitine and PLC in patients with peripheral arterial disease (PAD). This condition results from decreased blood flow and resultant lack of oxygen and nutrients to the legs. Walking becomes very difficult and painful, even at slow speeds.11 Metabolic factors are also involved, leading to interest in carnitine as an adjunctive treatment in PAD. A recent review identified 12 clinical trials of PLC for PAD.3 Most of these found that PLC significantly improved maximal walking distance and walking distance before onset of claudication. PLC has been found to be more effective than L-carnitine.2 However, the results were somewhat variable depending on the severity of PAD, route of administration of PLC, and duration of treatment. The latest Inter- Society Consensus for the Management of PAD guidelines concluded that PLC may help improve PAD symptoms when combined with physical exercise.12
Adverse Effects
Carnitine and its derivatives are well tolerated and generally safe.13 One of the larger randomized controlled trials found no significant differences in adverse effects, deaths, or cardiovascular hospitalizations between those taking 2 g/day PLC and placebo.10 At doses of 3 g/day and higher, carnitine may give people a "fishy" body odor.13 Some evidence indicates that carnitine may interfere with peripheral thyroid hormone utilization.14 Theoretically, at least, those with hypothyroidism should be cautious about taking carnitine supplements.
Formulation
L-carnitine is an FDA-approved prescription drug for the treatment of primary and secondary carnitine deficiencies in adults.13 The usual dose in these cases is 1-2 g/day oral tablets, or intravenous treatments at 50 mg/kg every 3-4 hours for the first 24 hours followed by 50 mg/kg/day. L-carnitine is also available as a dietary supplement. Doses of 2-6 g/day are usually suggested to support cardiac health. A number of clinical trials used IV solutions of L-carnitine. PLC is approved for use in Europe, but not in the United States. It is available in the United States as a dietary supplement.15
Conclusion
Carnitine is an important nutrient in the body, particularly in cardiac tissue. It plays an important role in cardiac health, and its metabolism is negatively impacted by various cardiovascular diseases. While early, small clinical trials suggested beneficial effects for patients after MI and with chronic heart failure, these have not been supported consistently by subsequent and larger clinical trials. Clinical trials involving patients with PAD have shown more consistent promise.
Recommendation
A significant body of evidence supports the importance of carnitine in fatty acid metabolism and cellular energy production. Carnitine is known to be beneficial in patients with diagnosed carnitine deficiency syndromes. However, many of the studies of carnitine and its derivatives have been conducted without evaluating patients' tissue carnitine levels. The inconsistent nature of research results to date may arise because patients have sufficient dietary carnitine. Greater attention needs to be paid to pre- and post-treatment tissue carnitine levels in future research to determine if certain patients are more likely to benefit from L-carnitine or PLC supplementation. Meanwhile, L-carnitine (2 g twice daily) may be of benefit along with exercise for those with claudication. However, the evidence does not generally support the use of carnitine supplements in patients with other cardiovascular diseases. n
References
1. Kendler BS. Supplemental conditionally essential nutrients in cardiovascular disease therapy. J Cardiovasc Nurs 2006;21:9-16.
2. Mingorance C, et al. Critical update for the clinical use of L-carnitine analogs in cardiometabolic disorders. Vasc Health Risk Manag 2011;7:169-176.
3. Mingorance C, et al. Pharmacological effects and clinical applications of propionyl-L-(carnitine). Nutr Rev 2011;69:279-290.
4. Jeukendrup AE, Randell R. Fat burners: Nutrition supplements that increase fat metabolism. Obes Rev 2011;12:841-851.
5. Gaby AR. Nutritional treatments for acute myocardial infarction. Altern Med Rev 2010;15:113-123.
6. Tarantini G, et al. Metabolic treatment with L-carnitine in acute anterior ST segment elevation myocardial infarction. A randomized controlled trial. Cardiology 2006;106:215-223.
7. Iliceto S, et al. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: The L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) Trial. J Am Coll Cardiol 1995;26:380-387.
8. Ferrari R, et al. Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: A review. Ann N Y Acad Sci 2004;1033:79-91.
9. Caponnetto S, et al. Efficacy of L-propionylcarnitine treatment in patients with left ventricular dysfunction. Eur Heart J 1994;15:1167-1173.
10. Investigators of the Study on Propionyl-L-Carnitine in Chronic Heart Failure. Study on propionyl-L-carnitine in chronic heart failure. Eur Heart J 1999;20:70-76.
11. Hiatt WR. Carnitine and peripheral arterial disease. Ann N Y Acad Sci 2004;1033:79-91.
12. Norgren L, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg 2007;33(Suppl 1):S1-S75.
13. Editors. Carnitine: Lessons from one hundred years of research. Ann N Y Acad Sci 2004 Nov;1033:79-91.
14. Benvenga S, et al. Effects of carnitine on thyroid hormone action. Ann N Y Acad Sci 2004;1033:158-167.
15. Office of Dietary Supplements. Carnitine. Available at: http://ods.od.nih.gov/factsheets/Carnitine-HealthProfessional. Accessed March 12, 2012.
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