By Richard S. Liebowitz, MD
L-carnitine is a compound whose use has been proposed both for the prevention and treatment of a wide variety of disease states. Although similar in structure to amino acids, L-carnitine is in fact a quaternary amine that is naturally found in skeletal and heart muscle. It is not an essential compound; under normal circumstances the human body can synthesize L-carnitine from the amino acids methionine and lysine, with several vitamins and iron serving as co-factors in this synthesis. L-carnitine also is present in the diet, found in large quantities in foods of animal origin.1 Vegans, therefore, may be at risk for developing low levels of L-carnitine.
Acetyl-L-carnitine is available as a supplement. Due to the highly charged nature of L-carnitine, it does not cross the blood-brain barrier. However, acetyl-L-carnitine readily crosses the brain barrier and has been employed when investigating central nervous system effects of L-carnitine. Peripherally, this compound is converted to L-carnitine and, as expected, raises blood levels of L-carnitine.2
Mechanism of Action
L-carnitine serves an important role in mitochondrial energy production and waste removal. It is responsible for transporting free fatty acids as an energy source for oxidative metabolism into the mitochondria, as well as removing toxic fatty acid esters.3 This is particularly important in cardiac muscle, because these esters accumulate during times of ischemia. Inborn errors of metabolism do occur related to L-carnitine metabolism, and the Food and Drug Administration (FDA) has approved L-carnitine for treatment of these conditions.4 Secondary L-carnitine deficiency has been described in patients undergoing hemodialysis, and the FDA also has approved L-carnitine for this indication.
Recognizing the high concentration of L-carnitine in cardiac muscle, as well as the ability of L-carnitine to clear toxic intermediates during ischemia, has led to the investigation of L-carnitine as a potential treatment for cardiac ischemia and congestive heart failure.
Clinical Trials
There is a significant body of literature (72 Medline citations since 1966) examining the potential role of L-carnitine, as a single agent as well as in combination with other natural products, in the treatment of congestive heart failure.
In a Greek study published in the American Heart Journal in 2000, 80 patients with a mean age of less than 50 years who were suffering from New York Heart Association Class III-IV heart failure due to idiopathic dilated cardiomyopathy were randomized to receive either 2 g/d of L-carnitine or placebo.5 Blinded treatment occurred for three months followed by a three-year period of un-blinded follow-up. The Kaplan-Meier survival curve revealed a statistically significant (P < 0.04) survival advantage at three years in favor of the L-carnitine-treated cohort, with a mortality of 18% in the control group and 3% in the L-carnitine group. Another interesting finding was that seven subjects (21%) of the control group experienced atrial fibrillation while only one patient on L-carnitine failed to maintain sinus rhythm.
Another study looked at the combination of L-carnitine with coenzyme Q10 and taurine (MyoVive) vs. placebo in patients with an ejection fraction of less than 40% who were scheduled to undergo cardiac bypass surgery.6 Subjects underwent radionuclide ventriculography both at randomization and just prior to surgery, with a mean treatment period of nearly 30 days. Myocardial biopsies were performed during surgery, and left ventricular end diastolic volume, a factor that, when elevated, is related to the risk of death in surgical revascularization, was compared between the two groups. Increased stores of the components of MyoVive were noted in the myocardial biopsies of treated patients, and significantly decreased end diastolic volume (P = 0.037) also favored the MyoVive-treated subjects.
In an Italian study designed to assess L-carnitine’s ability to limit left ventricular dilatation after an acute myocardial infarction (MI), 472 patients were randomized to receive either L-carnitine or placebo within 24 hours of presentation.7 All these patients were younger than 80 years of age with no prior history of MI, valvular heart disease, or a left bundle branch block. The L-carnitine group received 9 g/d of intravenous L-carnitine for five days followed by 2 g three times per day for the next year. Both groups were well-matched demographically, and approximately 80% of both groups received thrombolytics. Importantly, the study was initiated in 1991, before the clear benefit of ACE inhibitors was established, and a small percentage (8%) received an ACE inhibitor. The findings revealed lower end diastolic and systolic volumes in the treatment groups that was evident echocardiographically by the time of hospital discharge and maintained for 12 months. A trend toward a lower incidence of major adverse events was noted, but the study was not sufficiently powered for this finding or the decreased mortality noted to be statistically significant. A second trial by the same group plans to enroll 4,000 patients and investigate the combination of L-carnitine with ACE inhibitors and early reperfusion.
Adverse Effects
The side effect profile of L-carnitine appears to be very benign, with rare gastrointestinal complaints (nausea and vomiting) occurring most frequently.
Drug interactions have been reported with L-carnitine. Coumadin activity may be enhanced and thyroid hormone activity may be affected as well.8 It has been noted that replacement requirements for thyroid hormone have been increased with patients previously on a therapeutic dose. Caution should be exercised using this product in individuals who have a history of seizures, as an increased frequency of seizures has been reported.9 Patients with liver disease should be cautioned, as well as those on hemodialysis, as both of these situations may alter carnitine’s pharmacokinetics.10,11 There also have been reports of paradoxical effects when L-carnitine has been administered when cirrhosis is present.12
Dosage
Dose recommendations for oral use of L-carnitine range from 1.5 g/d to 4 g/d.13 Children in one study were safely dosed at 50 mg/kg twice a day,14 with a maximum dose of 4 g/d. Higher doses (up to 100 mg/kg twice daily) have been used intravenously in patients with acute myocardial ischemia.
Conclusion
Clinical studies in patients with both congestive heart failure and acute myocardial infarction suggest a potential therapeutic role for L-carnitine. Methodo- logical problems, including small sample sizes and lack of blinding, necessitate more definitive studies, but the apparent lack of significant adverse effects is encouraging. Although the potential for drug interactions appears to be small, further evaluation of L-carnitine in combination with other cardio-active drugs is warranted.
Recommendation
Clinicians caring for patients with heart failure and acute ischemia should consider adding L-carnitine to the standard treatment of these conditions. Further studies will help determine both the ideal dose and timing of supplementation.
Dr. Liebowitz, Medical Director, Duke Center for Integrative Health, Durham, NC, is on the Editorial Advisory Board for Alternative Medicine Alert.
References
1. Bieber LL. Carnitine. Annu Rev Biochem 1988;57: 261-283.
2. Burlina AP, et al. Uptake of acetyl-L-carnitine in the brain. Neurochem Res 1989;14:489-493.
3. Walter JH. L-carnitine. Arch Dis Child 1996;74:475-478.
4. Scaglia F, et al. Functional characterization of carnitine transporter defective in primary carnitine deficiency. Arch Biochem Biophys 1999;364:99-106.
5. Rizos I. Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administration. Am Heart J 2000;139:S120-S123.
6. Jeejeebhoy F, et al. Nutritional supplementation with MyoVive repletes essential cardiac myocyte nutrients and reduces left ventricular size in patients with left ventricular dysfunction. Am Heart J 2002;143: 1092-1100.
7. Colonna P, Iliceto S. Myocardial infarction and left ventricular remodeling: Results of the CEDIM trial. Carnitine Ecocardiografia Digitalizzata Infarto Miocardico. Am Heart J 2000;139:S124-S130.
8. Benvenga S, et al. Carnitine is a naturally occurring inhibitor of thyroid hormone nuclear uptake. Thyroid 2000;10:1043-1050.
9. Fariello RG, et al. Transient seizure activity induced by acetylcarnitine. Neuropharmacology 1984;23: 585-587.
10. Martindale W. Martindale the Extra Pharmacopoeia. London, England: Pharmaceutical Press; 1999.
11. Krahenbuhl S. Carnitine metabolism in chronic liver disease. Life Sci 1996;59:1579-1599.
12. Pugliese D, et al. Acute systemic and splanchnic haemodynamic effects of L-carnitine in patients with cirrhosis. Drugs Under Experimental Clin Res 1992; 18:147-153.
13. Jellin JM, et al. Pharmacist’s Letter/Prescriber’s Letter Natural Medicine Comprehensive Database. 5th ed. Stockton, CA: Therapeutic Research Faculty; 2003: 805-808.
14. Van Oudheusden LJ, Scholte HR. Efficacy of carnitine in the treatment of children with attention-deficit hyperactivity disorder. Prostaglandins Leukot Essent Fatty Acids 2002;67:33-38.
Liebowitz RS. L-carnitine and Heart Disease. Altern Med Alert 2003;6(8):88-90.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.