In the studies discussed below it is important to note that treatment with L -carnitine or propionyl- L -carnitine was used as an adjunct (in addition) to appropriate medical therapy, not in place of it. Myocardial Infarction (Heart Attack).
Angina pectoris is chest pain that occurs when the coronary blood supply is insufficient to meet the metabolic needs of the heart muscle ( ischemia ). The addition of oral L -carnitine or propionyl- L -carnitine to pharmacologic therapy for chronic stable angina has been found to modestly improve exercise tolerance and decrease electrocardiographic signs of ischemia during exercise testing in a limited number of angina patients. One randomized, placebo -controlled study in 200 patients with exercise-induced stable angina found that supplementing conventional medical therapy with 2 grams/day of L -carnitine for six months significantly reduced the incidence of premature ventricular contractions at rest and also improved exercise tolerance (52). In addition, a randomized, placebo-controlled cross-over trial in 44 men with chronic stable angina found that administering 2 grams/day of L -carnitine for four weeks significantly increased the exercise workload tolerated prior to the onset of angina and decreased ST segment depression (electrocardiographic evidence of ischemia) during exercise compared to placebo (53). In a more recent randomized, placebo-controlled trial in 47 men and women with chronic stable angina, the addition of 2 grams/day of L -carnitine for three months significantly improved exercise duration and decreased the time required for exercise-induced ST segment changes to return to baseline compared to placebo (54). One study examined the effect of propionyl-L-carnitine on ischemia in men with myocardial dysfunction and angina pectoris by measuring hemodynamic and angiographic variables before, during, and after administering intravenous propionyl- L -carnitine (15 mg/kg body weight). In this study, propionyl- L -carnitine decreased myocardial ischemia, evidenced by significant reductions in ST-segment depression and left ventricular end-diastolic pressure (55). Although these results are promising, large-scale studies are needed to determine whether L -carnitine or propionyl- L -carnitine is a beneficial therapy for angina pectoris.
Secondary carnitine deficiency or depletion may result from either genetic or acquired conditions. Hereditary causes include genetic defects in amino acid degradation (e.g., propionic aciduria) and lipid metabolism (e.g., medium chain acyl-CoA dehydrogenase deficiency) (19). Such inherited disorders can lead to a build-up of organic acids, which are subsequently removed from the body via urinary excretion of acylcarnitine esters. Increased urinary losses of carnitine can lead to a systemic depletion of carnitine (1). Systemic carnitine depletion can also occur in disorders of impaired renal reabsorption. For instance, Fanconi's syndrome is a hereditary or acquired condition in which the proximal tubular reabsorption function of the kidneys is impaired (20). Malfunction of the kidney consequently results in increased urinary losses of carnitine. One example of an exclusively acquired carnitine deficiency involves chronic use of pivalate-conjugated antibiotics. Pivalate is a branched-chain fatty acid that is metabolized to form an acylCoA ester that is transesterified to carnitine and subsequently excreted in the urine as pivaloyl carnitine. Urinary losses of carnitine via this route can be 10-fold greater than the sum of daily carnitine intake and biosynthesis (see Safety ); thus, systemic carnitine depletion can result (17). Further, patients with renal disease who undergo hemodialysis are at risk for secondary carnitine deficiency because hemodialysis removes carnitine from the blood (see Hemodialysis ) (21).
Regardless of etiology, a secondary carnitine deficiency is characterized clinically by low plasma concentrations of free carnitine (less than 20 micromol/L) and increased acylcarnitine/free carnitine ratios (greater than 0.4) (19, 22). Secondary deficiencies are more common than the rare, primary carnitine disorders. Nutrient Interactions.
L -carnitine is a derivative of the amino acid, lysine. Its name is derived from the fact that it was first isolated from meat ( carnis ) in 1905. Only the L - isomer of carnitine ( Figure 1 ) is biologically active (1). L -carnitine appeared to act as a vitamin in the mealworm ( Tenebrio molitor ) and was therefore termed vitamin B T (2). Vitamin B T, however, is actually a misnomer because humans and other higher organisms can synthesize L -carnitine (see Metabolism and Bioavailability ). Under certain conditions, the demand for L -carnitine may exceed an individual's capacity to synthesize it, making it a conditionally essential micronutrient (3, 4). Metabolism and Bioavailability.
For more information about aging and oxidative stress, see the article, Aging with Dr. Tory Hagen, in the Fall/Winter 2000 Linus Pauling Institute Newsletter. Disease Treatment Cardiovascular Disease.
Myopathic Carnitine Deficiency Primary myopathic carnitine deficiency is a rare genetic disorder in which the carnitine deficiency is limited to skeletal and cardiac muscle. Symptoms, including muscle pain and progressive muscle weakness, begin in childhood or adolescence (4). Serum carnitine levels, however, are usually normal (18). In general, the myopathic form of primary carnitine deficiency is less severe than the systemic form (4). Secondary Carnitine Deficiency or Depletion.
Age-related declines in mitochondrial function and increases in mitochondrial oxidant production are thought to be important contributors to the adverse effects of aging. Tissue L -carnitine levels have been found to decline with age in humans and animals (24). One study found that feeding aged rats acetyl- L -carnitine (ALCAR) reversed the age-related declines in tissue L -carnitine levels and also reversed a number of age-related changes in liver mitochondrial function; however, high doses of ALCAR increased liver mitochondrial oxidant production (25). ALCAR supplementation in rats has also been shown to improve or reverse age-related mitochondrial declines in skeletal and cardiac muscle (26, 27). Studies have found that supplementing aged rats with either ALCAR or alpha-lipoic acid, a mitochondrial cofactor and antioxidant, improved mitochondrial energy metabolism, decreased oxidative stress, and improved memory (28, 29). Interestingly, co-supplementation of ALCAR and alpha-lipoic acid resulted in even greater improvements than either compound administered alone. Likewise, several studies have reported that supplementing rats with both L -carnitine and alpha-lipoic acid blunts the age-related increases in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and DNA strand breaks in a variety of tissues (heart, skeletal muscle, and brain). Improvements in mitochondrial enzyme and respiratory chain activities and decreased apoptosis have also been observed (30-39). While these findings are very exciting, it is important to realize that these studies used relatively high doses of the compounds and only for a short time. Co-supplementation of aged rats with ALCAR and alpha-lipoic acid for a longer time period (three months) improved both the number of total and intact mitochondria and mitochondrial ultrastructure of neurons in the hippocampus (39). It is not yet known whether taking relatively high doses of these two naturally occurring substances will have similar effects in humans. Clinical trials in humans are planned, but it will be several years before the results are available.
Heart failure is described as the heart's inability to pump enough blood for all of the body's needs. In coronary artery disease, accumulation of atherosclerotic plaque in the coronary arteries may prevent heart regions from getting adequate circulation, ultimay resulting in cardiac damage and impaired pumping ability. Myocardial infarction (MI) may also damage the heart muscle, which could potentially lead to heart failure. Because physical exercise increases the demand on the weakened heart, measures of exercise tolerance are frequently used to monitor the severity of heart failure. Echocardiography is also used to determine the left ventricular ejection fraction (LVEF), an objective measure of the heart's pumping ability. A LVEF of less than 40% is indicative of systolic heart failure (47).
Endogenous biosynthesis of L -carnitine is catalyzed by the concerted action of five different enzymes. This process requires two essential amino acids (lysine and methionine ), iron (Fe2+), vitamin B 6, niacin in the form of nicotinamide adenine dinucleotide (NAD), and may also require vitamin C (4). One of the earliest symptoms of vitamin C deficiency is fatigue, thought to be related to decreased synthesis of L -carnitine (23). Disease Prevention Aging.
Nutritional carnitine deficiencies have not been identified in healthy people without metabolic disorders, suggesting that most people can synthesize enough L -carnitine (1). Even strict vegetarians (vegans) show no signs of carnitine deficiency, despite the fact that most dietary carnitine is derived from animal sources (8). Infants, particularly premature infants, are born with low stores of L -carnitine, which could put them at risk of deficiency given their rapid rate of growth. One study reported that infants fed carnitine-free, soy-based formulas grew normally and showed no signs of a clinically relevant carnitine deficiency; however, some biochemical measures related to lipid metabolism differed significantly from infants fed the same formula supplemented with L -carnitine (14). Soy-based infant formulas are now fortified with the amount of L -carnitine normally found in human milk (15).
L -carnitine and short-chain acylcarnitines (esters of L -carnitine), such as acetyl- L -carnitine, are excreted by the kidneys. Renal reabsorption of L -carnitine is normally very efficient; in fact, an estimated 95% is thought to be reabsorbed by the kidneys (1). Therefore, carnitine excretion by the kidney is normally very low. However, several conditions can decrease carnitine reabsorption efficiency and, correspondingly, increase carnitine excretion. Such conditions include high-fat (low-carbohydrate) diets, high-protein diets, pregnancy, and certain disease states (see Primary Systemic Carnitine Deficiency) (11). In addition, when circulating L -carnitine levels increase, as in the case of oral supplementation, renal reabsorption of L -carnitine becomes saturated, resulting in increased urinary excretion of L -carnitine (5). Dietary or supplemental L -carnitine that is not absorbed by enterocytes is degraded by colonic bacteria to form two principal products, trimethylamine and gamma-butyrobetaine. Gamma-butyrobetaine is eliminated in the feces; trimethylamine is efficiently absorbed and metabolized to trimethylamine-N-oxide, which is excreted in the urine (9). Biological Activities.
L -carnitine is synthesized primarily in the liver but also in the kidneys and then transported to other tissues. It is most concentrated in tissues that use fatty acids as their primary fuel, such as skeletal and cardiac (heart) muscle. In this regard, L -carnitine plays an important role in energy production by conjugating fatty acids for transport into the mitochondria (1).
Absorption of Exogenous L -Carnitine Dietary L -Carnitine.
Primary Systemic Carnitine Deficiency.
In healthy people, carnitine homeostasis (balance) is maintained through endogenous biosynthesis of L -carnitine, absorption of carnitine from dietary sources, and elimination and reabsorption of carnitine by the kidneys (5). Endogenous Biosynthesis.
Humans can synthesize L -carnitine from the amino acids lysine and methionine in a multi-step process. Specifically, protein -bound lysine is enzymatically methylated to form episilon-N-trimethyllysine; three molecules of methionine provide the methyl groups for the reaction. Epsilon-N-trimethyllysine is released for carnitine synthesis by protein hydrolysis (5, 6). Several enzymes are involved in endogenous L -carnitine biosynthesis. The enzyme gamma-butyrobetaine hydroxylase, however, is absent from cardiac and skeletal muscle but highly expressed in human liver, testes, and kidney (7). The rate of L -carnitine biosynthesis in humans was studied in vegetarians and is estimated to be 1.2 micromol/kg of body weight/day (8). Changes in dietary carnitine intake or renal reabsorption do not appear to affect the rate of endogenous carnitine synthesis (1).
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While bioavailability of L -carnitine from the diet is quite high (see Dietary L -Carnitine ), absorption from oral L -carnitine supplements is considerably lower. According to one study, bioavailability of L -carnitine from oral supplements (0.5-6 gram dosage) ranges from 14%-18% of the total dose (5). Less is known regarding the metabolism of the acetylated form of L -carnitine, acetyl- L -carnitine (ALCAR); however, bioavailability of ALCAR is thought to be higher than L -carnitine. The results of in vitro experiments suggest that ALCAR is partially hydrolyzed upon intestinal absorption (10). In humans, administration of 2 grams of ALCAR per day for 50 days increased plasma ALCAR levels by 43%, suggesting that some acetyl- L -carnitine is absorbed without hydrolysis or that L -carnitine is reacetylated in the enterocyte (5). Elimination and Reabsorption.
The bioavailability of L -carnitine from food can vary depending on dietary composition. For instance, one study reported that bioavailability of L -carnitine in individuals adapted to low-carnitine diets (i.e., vegetarians; 66%-86%) is higher than those adapted to high-carnitine diets (i.e., regular red meat eaters; 54%-72%) (9). L -Carnitine Supplements.
Primary systemic carnitine deficiency is a rare, autosomal recessive disorder caused by mutations in the gene for the carnitine transporter protein OCTN2 (16, 17). Afflicted individuals have poor intestinal absorption of dietary L-carnitine and impaired L-carnitine reabsorption by the kidneys, i.e., increased urinary loss of L -carnitine (4). The disorder usually presents in early childhood and is characterized by low plasma carnitine, progressive cardiomyopathy, skeletal myopathy, hypoglycemia, and hypoammonemia (1, 4, 16). Without treatment, primary systemic carnitine deficiency is fatal. Treatment consists of pharmacological doses of L -carnitine; such therapy corrects the cardiomyopathy and muscle weakness (17).
Myocardial infarction (MI) occurs when an atherosclerotic plaque in a coronary artery ruptures. The resultant clot can obstruct the blood supply to the heart muscle, causing injury or damage to the heart. L -carnitine treatment has been found to reduce injury to heart muscle resulting from ischemia in several animal models (40). In humans, L -carnitine administration immediay after MI diagnosis has improved clinical outcomes in several, small clinical trials. In one trial, half of 160 men and women diagnosed with a recent MI were randomly assigned to receive 4 grams/day of oral L -carnitine in addition to standard pharmacological treatment. After one year of treatment, mortality was significantly lower in the L -carnitine supplemented group compared to the control group (1.2% vs. 12.5%), and angina attacks were less frequent (41). In a controlled clinical trial in 96 cardiac patients, treatment with intravenous L-carnitine (5 gram bolus followed by 10 g/day for three days) following a MI resulted in lower levels of creatine kinase-MB and troponin-I, two markers of cardiac injury (42). However, not all clinical trials have found L -carnitine supplementation to be beneficial after MI. In a randomized, double-blind, placebo -controlled trial, 60 men and women diagnosed with an acute MI were treated with either intravenous L -carnitine (6 grams/day) for seven days followed by oral L -carnitine (3 grams/day) for three months or placebo (43). After three months, mortality did not differ between the two groups, nor did echocardiographic measures of cardiac function. In a larger placebo-controlled trial, 472 patients treated in an intensive care unit within 24 hours of having their first MI were randomly assigned to either intravenous L -carnitine therapy (9 grams/day) for five days followed by oral L -carnitine (6 grams/day) for 12 months or a placebo; both groups also received standard medical therapy (44, 45). Although there were no significant differences in mortality or the incidence of congestive heart failure (CHF), left ventricular volumes were significantly lower in the L -carnitine treated group at the end of one year, suggesting that L -carnitine therapy may limit adverse effects of acute MI on the heart muscle. Based on these findings, a randomized placebo-controlled trial in 2,330 patients with acute MI was undertaken to determine the effect of L -carnitine therapy on the incidence of heart failure six months after MI. L -carnitine therapy (9 grams/day intravenously for five days, then 4 grams/day orally for six months) did not affect the incidence of heart failure and death in this study (46). Heart Failure.
Addition of L -carnitine to standard medical therapy for heart failure has been evaluated in several clinical trials. A randomized, placebo-controlled study in 70 heart failure patients found that three-year survival was significantly higher in the group receiving oral L -carnitine (2 grams/day) compared to the group receiving placebo (48). In a randomized, single-blind, placebo-controlled trial in 30 heart failure patients, oral administration of 1.5 grams/day of propionyl- L -carnitine for one month resulted in significantly improved measures of exercise tolerance and a slight but significant decrease in left ventricular size compared to placebo (49). A larger randomized, double-blind, placebo-controlled trial compared the addition of propionyl- L -carnitine (1.5 grams/day for six months) to the treatment regimen of 271 heart failure patients to a placebo group consisting of 266 patients (50). Overall, exercise tolerance was not different between the two groups. However, in patients with higher LVEF values (greater than 30%), exercise tolerance was significantly improved in the propionyl- L -carnitine versus placebo group, suggesting that propionyl-L-carnitine may help improve exercise tolerance in higher functioning heart failure patients. A recent study in 29 patients with mild diastolic heart failure (LVEF > 45%) found that 1.5 grams/day of oral L-carnitine for three months improved some measures of diastolic function compared to baseline (51). Angina Pectoris.
L-carnitine is required for mitochondrial beta-oxidation of long-chain fatty acids for energy production (1). Long-chain fatty acids must be in the form of esters of L -carnitine (acylcarnitines) in order to enter the mitochondrial matrix where beta-oxidation occurs ( Figure 2 ). Proteins of the carnitine-acyl transferase family transport acylcarnitines into the mitochondrial matrix. On the outer mitochondrial membrane, carnitine-palmitoyl transferase I (CPTI) catalyzes the transfer of long-chain fatty acids into the cytosol from coenzyme A (CoA) to L -carnitine, the rate-limiting step in fatty acid oxidation (12). A transport protein called carnitine:acylcarnitine translocase (CACT) facilitates the transport of acylcarnitine esters across the inner mitochondrial membrane. On the inner mitochondrial membrane, carnitine-palmitoyl transferase II (CPTII) catalyzes the transfer of fatty acids from L -carnitine to free CoA in the mitochondrial matrix, where they are metabolized through beta-oxidation, ultimay yielding propionyl-CoA and acetyl-CoA (1). Regulation of Energy Metabolism through Modulation of Acyl CoA:CoA Ratio.
Mitochondrial Oxidation of Long-Chain Fatty Acids.
CoA is required as a cofactor for numerous cellular reactions (1). Within the mitochondrial matrix, carnitine acetyl transferase (CAT) catalyzes the trans-esterification (transfer) of short- and medium-chain fatty acids from CoA to carnitine ( Figure 2 ). The acylcarnitine esters can then be exported from the mitochondria via CACT, and the resulting free CoA can participate in other reactions. For example, pyruvate dehydrogenase (PDH) catalyzes the formation of acetyl-CoA from pyruvate and free CoA (13). Acetyl-CoA, in turn, can be oxidized to produce energy (ATP) in the tricarboxylic acid (TCA) cycle. Carnitine facilitates the oxidation of glucose by removing acyl groups generated by fatty acid beta-oxidation and freeing CoA to participate in the PDH reaction (1). Deficiency.
Acetyl l carnitine adverse effects