L-Carnitine for Treatment of Ischemic Heart Disease, Congestive Heart Failure, a
L-Carnitine for Treatment of Ischemic Heart Disease, Congestive Heart Failure, and Peripheral Vascular Disease
July 1999; Volume 2: 76-78
By Ernie-Paul Barrette, MD
Dietary supplements include a large group of amino acids, cofactors, and biochemical intermediates. L-carnitine, an essential cofactor, has been studied for 20 years as a treatment for cardiovascular diseases. Preliminary evidence suggests it may be beneficial.
Myocardial carnitine levels in patients with ischemic heart disease, congestive heart failure (CHF), and cardiomyopathy are reduced compared to normal patients.1
Origins
L-carnitine is found in meats and dairy products. Endogenous synthesis in the liver and kidney from lysine and methionine provide adequate amounts in vegetarians. Skeletal and cardiac muscle contain 98% of the body stores.
Biochemistry
L-carnitine plays a critical role in fatty acid oxidation as a cytosol mitochondria shuttle. Carnitine combines with long-chain acyl coenzyme A (CoA) yielding CoA and acyl-carnitine. The acyl-carnitine is transferred into the mitochondria by carnitine translocase where acyl CoA and carnitine are regenerated.
Mechanism of Action
During ischemia, long-chain acyl carnitine rapidly accumulates in the cytosol and acyl CoA levels rise in the mitochondria, while carnitine and ATP levels fall. High levels of long-chain acyl carnitine disrupt multiple membrane-bound enzymes (e.g., sodium potassium ATPase), damage lipid membranes, and uncouple oxidation-phosphorylation. In multiple animal systems, L-carnitine will decrease levels of long-chain esters and reduce injury during ischemia.2 In addition, carnitine will react with acetyl CoA in the mitochondria and shuttle acetyl carnitine to the cytosol, thus reducing the acetyl CoA/CoA ratio. Since high ratios will inhibit pyruvate dehydrogenase, the rate limiting step in glucose oxidation, carnitine appears to support glucose oxidation and limit lactic acid production.
History
Primary myopathic carnitine deficiency was first described 25 years ago. A progressive painless proximal weakness is seen. Cardiomyopathy may also be present. A systemic form presents with weakness and hepatic encephalopathy. These very rare disorders are seen in infants and children. In 1986 the FDA approved L-carnitine for use in primary carnitine deficiency. By 1980 interest in carnitine therapy for cardiovascular diseases had begun. Much has been published since, although almost all research has been in Europe, and primarily in Italy.
Secondary carnitine deficiencies occur with chronic TPN, dialysis, and valproic acid use. Carnitine supplements have been studied in these conditions as well as for chronic fatigue syndrome, hypercholesterolemia, AIDS, and enhancement of athletic performance. Some studies have used the free radical scavenger propionyl-L-carnitine (PLC). With the exception of studies of dialysis patients, however, data are very limited.
Clinical Studies
Ischemic Heart Disease. Ten trials have reported carnitine to benefit patients with angina pectoris. All of these trials have severe limitations. Sample size was 12 to 44 in all but one trial. A placebo arm was used in six, subjects were randomized in six, and only three were double-blind, randomized, controlled trials (DBRCT).
In the largest DBRCT, Cherchi studied 44 men with chronic stable angina in a crossover trial. Subjects received L-carnitine (1 g/d) or placebo for four weeks. Subjects taking carnitine showed significant improvements in mean exercise work load, watts to onset of angina, and ST segment depression.3
The only large trial randomized 200 patients with chronic stable angina to L-carnitine (2 g/d) or usual care for six months.4 Carnitine significantly improved exercise tolerance measured during cycle ergometric testing. More treated patients entered NYHA class I and were able to discontinue cardiac medications. However, lack of blinding and placebo may have biased the results.
L-carnitine has been studied in post-infarction patients. In an open trial, Davini et al followed 160 post-infarction patients for one year.5 Subjects were randomized to L-carnitine (2 g bid) or usual care. A remarkable decrease in mortality was seen with carnitine (1.2% vs. 12.5%, P < 0.005). However, this study has several problems. Lack of blinding may have influenced patient care. More patients with hypertension were in the control arm (27.8% vs. 17.6%) which may have contributed to their poorer outcome. Also, no information is provided regarding how many subjects received specific therapies (e.g., aspirin, beta-blockers, or ACE inhibitors).
The CEDIM trial also studied patients after a first anterior myocardial infarction.6 This multicenter DBRCT treated 472 subjects with either L-carnitine (9 g IV daily for five days then 6 g/d) or placebo for 12 months. Carnitine significantly attenuated left ventricular dilation. The increases in end-systolic and end-diastolic volumes were significantly lessened by carnitine. The incidence of death or CHF was 6% with carnitine vs. 9.6% with placebo (P = NS). However, only 8% received an ACE inhibitor and 35% a beta-blocker.
Congestive Heart Failure. Urinary carnitine excretion is increased in CHF.7 A DBRCT studied 60 patients with CHF (ejection fraction < 50%, NYHA class II or III) for 180 days.8 Subjects received either PLC (50 mg tid) or placebo. During the study only digoxin and diuretics were allowed. Significant improvements in maximum exercise times and ejection fractions were reported (e.g., ejection fraction 41% to 47%). Two other small trials reported similar results. However, a recently completed, unpublished large-scale trial of PLC in CHF failed to show an improvement in exercise capacity.9
Peripheral Vascular Disease. Muscle biopsies in patients undergoing revascularization for peripheral vascular disease (PVD) demonstrated lower carnitine levels compared to controls.10 A double-blind crossover trial with 20 men compared carnitine (2 g bid) and placebo for three weeks in random order.11 Carnitine significantly increased treadmill walking distances to claudication compared to placebo (306+/-122 m vs. 174+/-63 m, P < 0.01).
The same group reported a DBRCT of PLC vs. placebo for six months (n = 245).12 After two months, if the maximum walking distance had not improved more than 30%, then the PLC dose or placebo was increased. In a double-blind protocol, the PLC and placebo doses were titrated up every two months from 1 g/d to 3 g/d based on treadmill results. Maximum walking distance was significantly improved with PLC (PLC: from 214.6 m to 354 m vs. placebo: from 207.8 m to 298.1 m, P = 0.03). A non-significant improvement in initial claudication distance, a more reliable outcome than maximum walking distance, was seen with PLC.
Adverse Effects
Carnitine infrequently causes nausea, pyrosis, dyspepsia, and diarrhea. High doses have resulted in a body odor like rotting fish. A myasthenia gravis-like syndrome was seen in dialysis treated patients receiving dl-carnitine but not with L-carnitine. No drug interactions were reported.
Formulation and Dosage
L-carnitine is readily available. Prices vary dramatically, although 60 capsules of 500 mg L-carnitine is available via mail-order catalogs for less than $15. Most marketers suggest 1-2 g/d, which was the dose used in most studies. The CEDIM study used 6 g/d, which would be quite expensive even with the least expensive brand (approximately $45 per month). In primary carnitine deficiency, the recommended dose is three 330 mg tablets two to three times a day. The FDA licensed product, Carnitor® (Sigma Tau) is expensive; the average wholesale price for ninety 330 mg capsules is $75.30. Consequently, prescribing Carnitor instead of another supplement brand of carnitine increases the monthly cost of 1-2 g/d from $15-30 to $75-150.
Conclusion
Several preliminary reports suggest L-carnitine and PLC improve exercise tolerance in patients with chronic angina, CHF, and PVD. L-carnitine may also limit post-infarction left ventricular dilation. Reports of adverse reaction and drug interaction are absent. Unfortunately, there are no definitive trials. The best evidence, the CEDIM trial, did not look at a clinical end point. It is also unclear whether L-carnitine provides any benefit beyond well-established therapies, i.e., aspirin and beta-blockers in ischemic heart disease and ACE inhibitors in CHF.
Recommendation
L-carnitine should not replace well-established anti-anginals, aspirin, ACE inhibitors, and beta-blockers until further data are available. However, physicians may wish to consider its use in patients who are clinically failing while on these medications or in patients who are unable to take them due to contraindications or intolerance.
References
1. Regitz V, et al. Defective myocardial carnitine metabolism in congestive heart failure secondary to dilated cardiomyopathy and to coronary, hypertensive and valvular heart diseases. Am J Cardiol 1990;65: 755-760.
2. Arsenian MA. Carnitine and its derivatives in cardiovascular disease. Prog Cardiovasc Dis 1997;40: 265-286.
3. Cherchi A, et al. Effects of L-carnitine on exercise tolerance in chronic stable angina: A multicenter, double-blind, randomized, placebo controlled crossover study. Int J Clin Pharmacol Ther Toxicol 1985;23:569-572.
4. Cacciatore L, et al. The therapeutic effect of L-carnitine in patients with exercise-induced stable angina: A controlled study. Drugs Exp Clin Res 1991;17:225-235.
5. Davini P, et al. Controlled study on L-carnitine therapeutic efficacy in post-infarction. Drugs Exp Clin Res 1992;18:355-365.
6. 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.
7. Matsui S, et al. Urinary carnitine excretion in patients with heart failure. Clin Cardiol 1994;17:301-305.
8. Mancini M, et al. Controlled study on the therapeutic efficacy of propionyl-L-carnitine in patients with congestive heart failure. Arzneimittelforschung 1992;42:1101-1104.
9. Ferrari R, De Giuli F. The propionyl-L-carnitine hypothesis: An alternative approach to treating heart failure. J Card Fail 1997;3:217-224.
10. Brevetti G, et al. Muscle carnitine deficiency in patients with severe peripheral vascular disease. Circulation 1991;84:1490-1495.
11. Brevetti G, et al. Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: A double-blind, cross-over study. Circulation 1988;77:767-773.
12. Brevetti G, et al. Propionyl-L-carnitine in intermittent claudication: Double-blind, placebo-controlled, dose titration, multicenter study. J Am Coll Cardiol 1995;26:1411-1416.
A 70-year-old man suffered an anterior myocardial infarction one month ago. He has severe COPD and developed wheezing after a beta-blocker trial. He refuses to consider cardiac catheterization or surgery. He has had no angina since discharge. For which of the following medications is there no consistent evidence for benefit in the post-infarction patient?
a. Aspirin
b. L-carnitine
c. Calcium channel blockers
d. ACE inhibitors
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