Introduction to L-Carinine
History of L-CarnitineThe compound carnitine was isolated from meat extracts and identified during the first decade of this century. It was a compound with no known function until the 1950s, when it was shown to be a required growth factor for the mealworm Tenebrio molitor. Since it was a small water soluble compound required in the diet of Tenebrio molitor, it was given the name vitamin BT. Although carnitine is clearly a vitamin for the mealworm, there is no data to suggest that carnitine is a vitamin for the healthy human adult. There is some data indicating that carnitine is a conditionally essential nutrient for some segments of the population who would be under the care of a physician. Table I lists the types of pathophysiology that might result in a patient's requiring carnitine in the diet. However, certain businesses are marketing carnitine to the public as vitamin BT or vitamin B7 in such a manner that the customer would assume that it is a vitamin for humans. There has been an enormous increase in the basic science research and clinical research interest in carnitine during the sixth, seventh, and eighth decades of this century. In 1964, a symposium entitled "Recent Research On Carnitine, Its Relation To Lipid Metabolism," a symposium in 1979 entitled "Carnitine Biosynthesis, Metabolism and Functions," and a symposium in 1985 entitled "Clinical Aspects of Human Carnitine Deficiency" were convened, and the proceedings published Carnitine has been the subject of several recent review articles.
Function of L-CarnitineCarnitine plays an essential role in the regulation of long- chain fatty acid metabolism in skeletal and cardiac muscle, a process that is mediated by well-characterized enzymatic mechanisms. Here, Irving Fritz and Edoardo Arrigoni-Martelli review the evidence that carnitine and its O-acyl derivatives also influence membrane fluidity, ion channel functions, smooth muscle contractility, membrane stability and cardiac functions. The authors present the view that direct interactions of carnitine derivatives with cell membranes are independent of reactions catalysed by carnitine acyltransferases. They propose that the novel actions discussed are implicated in the mechanisms by which carnitine and its derivatives protect perfused hearts subjected to ischaemia or to oxidative stress, and help people suffering from certain types of myocardial ischaemia or peripheral arterial disease.
L-Carnitine and CardiomyopathyPrimary carnitine deficiency often presents as progressive cardiomyopathy. It is due to a defect in the plasma membrane carnitine transport system that is normally present in heart, muscle and kidney. This system serves to maintain intracellular carnitine levels 20-50 times higher than plasma concentrations. Patients with this defect cannot maintain adequate carnitine levels in muscle tissue for fatty acid oxidation. One case of primary carnitine deficiency is described. Two siblings had died earlier probably due to the same disease. The eight month old boy presented with a common cold and cardiomyopathy. He was treated with digoxin and diuretics until the diagnosis was confirmed. The patient's uptake of carnitine in fibroblasts was extremely low, about 5% of the normal range. The father had about 50% reduction of carnitine uptake in fibroblasts, the mother showed no sign of impaired uptake. The boy was treated with oral carnitine, 100 mg/kg/day. There was a normal level of carnitine in serum after two months of treatment and the cardiomyopathy disappeared completely in one year. Primary carnitine deficiency is a treatable disorder and therefore skeletal muscle biopsy and blood chemistry should be performed in all children with undiagnosed cardiomyopathy. Treatment with oral carnitine must be initiated quickly to avoid sudden death.
Treatment mitochondrial dysfunction with L-Carnitine, scientific review
Carnitine--from cellular mechanisms to potential clinical applications in heart diseaseA-4845 Atar D; Spiess M; Mandinova A; Cierpka H; Noll G; Luscher TF [Review] [24 refs]: European Journal of Clinical Investigation: 27:12:973-6 (1997)
This review deals with the cellular metabolic actions of carnitine and its potential role as a drug investigated in a number of clinical settings. It is not the aim of the present work to provide a comprehensive overview over the details of cellular metabolism or of all potential clinical applications, but rather to highlight the involvement in major metabolic pathways potentially relevant to clinical benefit.
Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over studyG Brevetti, M Chiariello, G Ferulano, A Policicchio, E Nevola, A Rossini, T Attisano, G Ambrosio, N Siliprandi and C Angelini Department of Medicine, Second Medical School, University of Naples, Italy.
A double-blind, cross-over study was designed to evaluate the effects of L-carnitine in patients with peripheral vascular disease. After drug washout, 20 patients were randomly assigned to receive placebo or L- carnitine (2 g bid, orally) for a period of 3 weeks and were then crossed over to the other treatment for an additional 3 weeks. The effect on walking distance at the end of each treatment period was measured by treadmill test. Absolute walking distance rose from 174 +/- 63 m with placebo to 306 +/- 122 m (p less than .01) with carnitine. Biopsy of the ischemic muscle, carried out before and after 15 days of L-carnitine administration in four additional patients, showed that treatment significantly increased total carnitine levels. An additional goal of this study was to ascertain the effects of L-carnitine on the metabolic changes induced by exercise in the affected limb. In six patients under control conditions, arterial and popliteal venous lactate and pyruvate concentrations were determined at rest, when the maximal walking distance was reached, and 5 min after the walking test. Twenty-four hours later, L-carnitine was administered intravenously (3 g as a bolus followed by an infusion of 2 mg/kg/min for 30 min) and metabolic assessments were repeated. Five minutes after the walking test, popliteal venous lactate concentration increased by 107 +/- 16% before treatment and by only 54 +/- 32% (p less than .01) after carnitine. Furthermore, carnitine induced a more rapid recovery to the resting value of the lactate/pyruvate ratio.
Primary systemic carnitine deficiency presenting as recurrent Reye-like syndrome and dilated cardiomyopathyHou JW. Division of Medical Genetics, Department of Pediatrics, Chang Gung Children's Hospital, Taoyuan, Taiwan, ROC.
Carnitine deficiency syndrome is a rare and potentially fatal but treatable metabolic disorder. I present a 6-year-old girl with primary systemic carnitine deficiency (SCD) proved by very low plasma carnitine level. Her major clinical features included neonatal metabolic acidosis, epilepsy, recurrent infections, acute encephalopathy, and dilated cardiomyopathy with heart failure before 4 years of age. Other features such as hepatomegaly, hypoglycemia, or hyperammonemia were noted around 5 years of age. Her health improved with resolving cardiomyopathy after the use of L-carnitine (50-100 mg/kg/day). Patients with SCD have high morbidity and mortality. If SCD is suggested as a cause of Reye-like syndrome or dilated cardiomyopathy, L-carnitine therapy should be initiated as a diagnostic test immediately, until the definite diagnosis is confirmed.
L-Carnitine: a potential treatment for blocking apoptosis and preventing skeletal muscle myopathy in heart failureVescovo G, Ravara B, Gobbo V, Sandri M, Angelini A, Della Barbera M, Dona M, Peluso G, Calvani M, Mosconi L, Dalla Libera L. Internal Medicine, City Hospital, 45011 Adria, Italy.
Skeletal muscle in congestive heart failure is responsible for increased fatigability and decreased exercise capacity. A specific myopathy with increased expression of fast-type myosins, myocyte atrophy, secondary to myocyte apoptosis triggered by high levels of circulating tumor necrosis factor-alpha (TNF-alpha) has been described. In an animal model of heart failure, the monocrotaline-treated rat, we have observed an increase of apoptotic skeletal muscle nuclei. Proapoptotic agents, caspase-3 and -9, were increased, as well as serum levels of TNF-alpha and its second messenger sphingosine. Treatment of rats with L-carnitine, known for its protective effect on muscle metabolism injuries, was found to inhibit caspases and to decrease the levels of TNF-alpha and sphingosine, as well as the number of apoptotic myonuclei. Staurosporine was used in in vitro experiments to induce apoptosis in skeletal muscle cells in culture. When L-carnitine was applied to skeletal muscle cells, before staurosporine treatment, we observed a reduction in apoptosis. These findings show that L-carnitine can prevent apoptosis of skeletal muscles cells and has a role in the treatment of congestive heart failure-associated myopathy.
Metabolic modulation and optimization of energy consumption in heart failureFerrari R, Cicchitelli G, Merli E, Andreadou I, Guardigli G. Dipartimento di Cardiologia, Universita di Ferrara, Arcispedale Sant'Anna, Ferrara, Italy. firstname.lastname@example.org
Chronic heart failure (CHF) is a common and disabling syndrome with a poor prognosis. It is a major and increasing public health problem. Angiotensin-converting enzyme inhibitors, diuretics, and digitalis are the standards treatments for CHF. Other drugs, such as beta-blockers, spironolactone, calcium antagonists, vasodilators, and antiarrhythmic agents are used to counteract the progression of the syndrome or to improve the hemodynamic profile. Despite optimum treatment with neurohumoral antagonists, prognosis of CHF remains poor; the patients complain of persistent reductions in their exercise capacity and quality of life. Fatigue and shortness of breath, two common and disabling symptoms in patient with CHF, are relatively independent from hemodynamic and neuroendocrine changes, although they seem to be related to the impairment of peripheral muscle metabolism and energetic phosphate production. Therefore, CHF is a complex metabolic syndrome in which the metabolism of cardiac and peripheral muscles is impaired and novel therapeutic strategies have been aimed at positive modulation with compounds such as carnitine, trimetazidine, and ranolazine.
Carnitine and its role in cardiovascular diseaseRetter AS. Department of Medicine, Temple University Medical Center, Philadelphia, Pennsylvania 19140, USA.
L-carnitine and its derivative, propionyl-L-carnitine, are organic amines produced and metabolized endogenously. These compounds are essential in the process of fatty acid oxidation and have also been shown to reduce intracellular accumulation of toxic metabolites during ischemia. Currently, exogenous administration of carnitine is indicated only as therapy for primary and secondary carnitine deficiency. However, it has been hypothesized that because of its ability to enhance energy production and remove toxic metabolites during ischemia, carnitine therapy may be useful in the treatment of various cardiac diseases. In fact, there is increasing evidence that endogenous carnitine has beneficial effects in the treatment of congestive heart failure, arrhythmia, peripheral vascular disease, and acute ischemia.
Propionyl-L-carnitine as protector against adriamycin-induced cardiomyopathySayed-Ahmed MM, Salman TM, Gaballah HE, Abou El-Naga SA, Nicolai R, Calvani M. Pharmacology Unit, National Cancer Institute, Fum El-Khalig, Kasr El-Aini Street, Cairo, Egypt.
Propionyl- l -carnitine (PLC) is a naturally occurring compound that has been considered for the treatment of many forms of cardiomyopathies. In this study, the possible mechanisms whereby PLC could protect against adriamycin (ADR)-induced cardiomyopathy were carried out. Administration of ADR (3 mg kg(-1)i.p., every other day over a period of 2 weeks) resulted in a significant two-fold increase in serum levels of creatine phosphokinase, lactate dehydrogenase and glutamic oxaloacetic transaminase, whereas daily administration of PLC (250 mg kg(-1), i.p. for 2 weeks) induced non-significant change. Daily administration of PLC to ADR-treated rats resulted in complete reversal of ADR-induced increase in cardiac enzymes except lactate dehydrogenase which was only reversed by 66%. In cardiac tissue homogenate, ADR caused a significant 53% increase in malonedialdehyde (MDA) and a significant 50% decrease in reduced glutathione (GSH) levels, whereas PLC induced a significant 33% decrease in MDA and a significant 41% increase in GSH levels. Daily administration of PLC to ADR-treated rats completely reversed the increase in MDA and the decrease in GSH induced by ADR to the normal levels. In rat heart mitochondria isolated 24 h after the last dose, ADR induced a significant 48% and 42% decrease in(14)CO(2)released from the oxidation of [1-(14)C]palmitoyl-CoA and [1-(14)C]palmitoylcarnitine, respectively, whereas PLC resulted in a significant 66% and 54% increase in the oxidation of both substrates, respectively. Interestingly, administration of PLC to ADR-treated rats resulted in complete recovery of the ADR-induced decrease in the oxidation of both substrates. In addition, in rat heart mitochondria, the oxidation of [1-(14)C]pyruvate, [1-(14)C]pyruvate and [1-(14)C]octanoate were not affected by ADR and/or PLC treatment. Moreover, ADR caused severe histopathological lesions manifested as toxic myocarditis which is protected by PLC. Worth mentioning is that PLC had no effect on the antitumour activity of ADR in solid Ehrlich carcinoma. Results from this study suggest that: (1) in the heart, PLC therapy completely protects against ADR-induced inhibition of mitochondrial beta -oxidation of long-chain fatty acids; (2) PLC has and/or induces a powerful antioxidant defense mechanism against ADR-induced lipid peroxidation of cardiac membranes; and finally (3) PLC has no effect on the antitumour activity of ADR. Copyright 2001 Academic Press.
Defective myocardial carnitine metabolism in congestive heart failure secondary to dilated cardiomyopathy and to coronary, hypertensive and valvular heart diseasesRegitz V, Shug AL, Fleck E. German Heart Institute, Berlin.
Reduced myocardial carnitine concentrations in the explanted heart and elevated plasma levels have been found in patients undergoing heart transplant for end-stage congestive heart failure (CHF). To evaluate a possible loss of myocardial carnitine in less severe stages of CHF, total myocardial carnitine levels were compared in right ventricular endomyocardial biopsies from 28 patients with mild, moderate and severe dilated cardiomyopathy, 8 patients with CHF of different origin and 13 normal control subjects. If possible, free myocardial carnitine and free and total plasma carnitine were also determined. For the first time, myocardial carnitine levels have been measured in endomyocardial biopsies from 13 normal human hearts (control values: 9.9 +/- 0.8 nmol/mg noncollagen protein). In comparison with these control values, total myocardial carnitine was significantly reduced in patients with dilated cardiomyopathy (6.1 +/- 0.5 nmol/mg noncollagen protein, p less than 0.0001), and CHF of other origins (6.6 +/- 1.1 nmol/mg noncollagen protein, p less than 0.02). Free myocardial carnitine concentrations in dilated cardiomyopathy (4.6 +/- 0.4 nmol/mg noncollagen protein) and CHF of different origin (4.4 +/- 0.5 nmol/mg noncollagen protein) were also significantly different from control values (control values: 9.7 +/- 0.7 nmol/mg noncollagen protein, p less than 0.0001 and p less than 0.005 for both groups). The loss of free and total myocardial carnitine was comparable in dilated cardiomyopathy and CHF due to other diseases. In contrast, plasma free and total carnitine levels in the CHF patients were significantly elevated (67 +/- 5.5 mumol/liter, control values 41 +/- 3.7 mumol/liter, p less than 0.005). Alterations in myocardial carnitine metabolism represent nonspecific biochemical markers in CHF with yet unknown consequences for myocardial function.
Carnitine transport: pathophysiology and metabolism of known molecular defectsTein I. Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Canada. email@example.com
Early-onset dilatative and/or hypertrophic cardiomyopathy with episodic hypoglycaemic coma and very low serum and tissue concentrations of carnitine should alert the clinician to the probability of the plasmalemmal high-affinity carnitine transporter defect. The diagnosis can be established by demonstration of impaired carnitine uptake in cultured skin fibroblasts or lymphoblasts and confirmed by mutation analysis of the human OCTN2 gene in the affected child and obligate heterozygote parents. The institution of high-dose oral carnitine supplementation reverses the pathology in this otherwise lethal autosomal recessive disease of childhood, and carnitine therapy from birth in prospectively screened siblings may altogether prevent the development of the clinical phenotype. Heterozygotes may be at risk for cardiomyopathy in later adult life, particularly in the presence of additional risk factors such as hypertension and competitive pharmacological agents. OCTN2 belongs to a family of organic cation/carnitine transporters that function primarily in the elimination of cationic drugs and other xenobiotics in kidney, intestine, liver and placenta. The high- and low-affinity human carnitine transporters, OCTN2 and OCTN1, are multifunctional polyspecific organic cation transporters; therefore, defects in these transporters may have widespread implications for the absorption and/or elimination of a number of key pharmacological agents such as cephalosporins, verapamil, quinidine and valproic acid. A third organic/cation carnitine transporter with high specificity for carnitine, Octn3, has been cloned in mice. The juvenile visceral steatosis (jvs) mouse serves as an excellent clinical, biochemical and molecular model for the high-affinity carnitine transporter OCTN2 defect and is due to a spontaneous point mutation in the murine Octn2 gene on mouse chromosome 11, which is syntenic to the human locus at 5q31 that harbours the human OCTN2 gene.
Heart metabolic disturbances in cardiovascular diseasesCarvajal K, Moreno-Sanchez R. Departament de Bioquimica, Instituto Nacional de Cardiologia, Mexico City, Mexico. firstname.lastname@example.org
Myocardial function depends on adenosine triphosphate (ATP) supplied by oxidation of several substrates. In the adult heart, this energy is obtained primarily from fatty acid oxidation through oxidative phosphorylation. However, the energy source may change depending on several factors such as substrate availability, energy demands, oxygen supply, and metabolic condition of the individual. Surprisingly, the role of energy metabolism in development of cardiac diseases has not been extensively studied. For instance, alterations in glucose oxidation and transport developed in diabetic heart may compromise myocardial performance under conditions in which ATP provided by glycolysis is relevant, such as in ischemia and reperfusion. In some cardiac diseases such as ischemic cardiomyopathy, heart failure, hypertrophy, and dilated cardiomyopathy, ATP generation is diminished by derangement of fatty acid delivery to mitochondria and by alteration of certain key enzymes of energy metabolism. Shortage of some co-factors such as L-carnitine and creatine also leads to energy depletion. Creatine kinase system and other mitochondrial enzymes are also affected. Initial attempts to modulate cardiac energy metabolism by use of drugs or supplements as a therapeutic approach to heart disease are described.
Effects of L-propionyl-carnitine on ischemia-induced myocardial dysfunction in men with angina pectorisBartels GL; Remme WJ; Pillay M; Schönfeld DH; Kruijssen DA Am J Cardiol: 74:2:125-30 (1994)
To identify the effect of L-propionylcarnitine (LPC) on ischemia, 31 fasting, untreated male patients with left coronary artery disease were studied during 2 identical pacing stress tests 45 minutes before (atrial pacing test I:APST I:) and 15 minutes after (APST II) administration of 15 mg/kg of LPC or placebo. Hemodynamic, metabolic, and nuclear angiographic variables were studied before, during, and for 10 minutes after pacing. After LPC administration, arterial total carnitine levels increased from 47 +/- 1.7 mumol/liter (control) to 730 +/- 30 mumol/liter. Hemodynamic and metabolic variables were comparable in LPC and placebo during APSI I, and reproducible in placebo during both tests. Although LPC did not affect myocardial oxygen demand and supply, it diminished myocardial ischemia, indicated by a significant 12% and 50% reduction in ST-segment depression and left ventricular end-diastolic pressure, respectively, during APST II. Moreover, during APST II, left ventricular ejection fraction increased by 18% (p < 0.05 vs APST I). Furthermore, LPC improved recovery of myocardial function after pacing, with a reduction in the time to peak filling and a 21% increase in both peak ejection and filling rates 10 minutes after pacing (all p < 0.05). Thus, LPC prevents ischemia-induced ventricular dysfunction, not by affecting the myocardial oxygen supply-demand ratio but as a result of its intrinsic metabolic actions, increasing pyruvate dehydrogenase activity and flux through the citric acid cycle. Because it is well tolerated, it may be a valuable alternative or addition to available antiischemic therapy.
Carnitine metabolism and deficit--when supplementation is necessary?Evangeliou A, Vlassopoulos D. Neurology Dept., Creta's Medical School, A. Fleming Hospital, Athens, Greece.
Carnitine is an ammo acid derivative found in high energy demanding tissues (skeletal muscles, myocardium, the liver and the suprarenal glands). It is essential for the intermediary metabolism of fatty acids. Carnitine is indispensable for beta-oxidation of long-chain fatty acids in the mitochondria but also regulates CoA concentration and removal of the produced acyl groups. AcylCoAs act as restraining factor for several enzymes participating in intermediary metabolism. Transformation of AcylCoA into acylcarnitine is an important system for removing the toxic acyl groups. Although primary deficiency is unusual, depletion due to secondary causes, such as a disease or a medication side effect, can occur. Primary carnitine deficiency is caused by a defect in plasma membrane carnitine transporter in muscle and kidneys. Secondary carnitine deficiency is associated with several inborn errors of metabolism and acquired medical or iatrogenic conditions, for example in patients under valproate and zidovuline treatment. In cirrhosis and chronic renal failure, carnitine biosynthesis is impaired or carnitine is lost during hemodialysis. Other chronic conditions like diabetes mellitus, heart failure, Alzheimer disease may cause carnitine deficiency also observed in conditions with increased catabolism as in critical illness. Preterm neonates develop carnitine deficiency due to impaired proximal renal tubule carnitine re-absorption and immature carnitine biosynthesis. Carnitine stabilizes the cellular membrane and raises red blood cell osmotic resistance but has no metabolic influence on lipids in dialysis patients. L-Carnitine has been administered in senile dementia, metabolic nerve diseases, in HIV infection, tuberculosis, myopathies, cardiomyopathies, renal failure anemia and included in baby foods and milk.
Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathyLamhonwah AM, Olpin SE, Pollitt RJ, Vianey-Saban C, Divry P, Guffon N, Besley GT, Onizuka R, De Meirleir LJ, Cvitanovic-Sojat L, Baric I, Dionisi-Vici C, Fumic K, Maradin M, Tein I. Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Primary systemic carnitine deficiency or carnitine uptake defect (OMIM 212140) is a potentially lethal, autosomal recessive disorder characterized by progressive infantile-onset cardiomyopathy, weakness, and recurrent hypoglycemic hypoketotic encephalopathy, which is highly responsive to L-carnitine therapy. Molecular analysis of the SLC22A5 (OCTN2) gene, encoding the high-affinity carnitine transporter, was done in 11 affected individuals by direct nucleotide sequencing of polymerase chain reaction products from all 10 exons. Carnitine uptake (at Km of 5 microM) in cultured skin fibroblasts ranged from 1% to 20% of normal controls. Eleven mutations (delF23, N32S, and one 11-bp duplication in exon 1; R169W in exon 3; a donor splice mutation [IVS3+1 G > A] in intron 3; frameshift mutations in exons 5 and 6; Y401X in exon 7; T440M, T468R and S470F in exon 8 ) are described. There was no correlation between residual uptake and severity of clinical presentation, suggesting that the wide phenotypic variability is likely related to exogenous stressors exacerbating carnitine deficiency. Most importantly, strict compliance with carnitine from birth appears to prevent the phenotype. Copyright 2002 Wiley-Liss, Inc.
Therapeutic Effects of l-Carnitine and Propionyl-l-carnitine on Cardiovascular Diseases: A ReviewROBERTO FERRARI, E MERLI, G CICCHITELLI, D MELE, A FUCILI AND C CECONI Department of Cardiology, University Hospital of Ferrara, Cardiovascular Research Center, Salvatore Maugeri Foundation, IRCCS, Gussago (Brescia), Italy
Several experimental studies have shown that levocarnitine reduces myocardial injury after ischemia and reperfusion by counteracting the toxic effect of high levels of free fatty acids, which occur in ischemia, and by improving carbohydrate metabolism. In addition to increasing the rate of fatty acid transport into mitochondria, levocarnitine reduces the intramitochondrial ratio of acetyl-CoA to free CoA, thus stimulating the activity of pyruvate dehydrogenase and increasing the oxidation of pyruvate. Supplementation of the myocardium with levocarnitine results in an increased tissue carnitine content, a prevention of the loss of high-energy phosphate stores, ischemic injury, and improved heart recovery on reperfusion. Clinically, levocarnitine has been shown to have anti-ischemic properties. In small short-term studies, levocarnitine acts as an antianginal agent that reduces ST segment depression and left ventricular end-diastolic pressure. These short-term studies also show that levocarnitine releases the lactate of coronary artery disease patients subjected to either exercise testing or atrial pacing. These cardioprotective effects have been confirmed during aortocoronary bypass grafting and acute myocardial infarction. In a randomized multicenter trial performed on 472 patients, levocarnitine treatment (9 g/day by intravenous infusion for 5 initial days and 6 g/day orally for the next 12 months), when initiated early after acute myocardial infarction, attenuated left ventricular dilatation and prevented ventricular remodeling. In treated patients, there was a trend towards a reduction in the combined incidence of death and CHF after discharge. Levocarnitine could improve ischemia and reperfusion by (1) preventing the accumulation of long-chain acyl-CoA, which facilitates the production of free radicals by damaged mitochondria; (2) improving repair mechanisms for oxidative-induced damage to membrane phospholipids; (3) inhibiting malignancy arrhythmias because of accumulation within the myocardium of long-chain acyl-CoA; and (4) reducing the ischemia-induced apoptosis and the consequent remodeling of the left ventricle. Propionyl-l-carnitine is a carnitine derivative that has a high affinity for muscular carnitine transferase, and it increases cellular carnitine content, thereby allowing free fatty acid transport into the mitochondria. Moreover, propionyl-l-carnitine stimulates a better efficiency of the Krebs cycle during hypoxia by providing it with a very easily usable substrate, propionate, which is rapidly transformed into succinate without energy consumption (anaplerotic pathway). Alone, propionate cannot be administered to patients in view of its toxicity. The results of phase-2 studies in chronic heart failure patients showed that long-term oral treatment with propionyl-l-carnitine improves maximum exercise duration and maximum oxygen consumption over placebo and indicated a specific propionyl-l-carnitine effect on peripheral muscle metabolism. A multicenter trial on 537 patients showed that propionyl-l-carnitine improves exercise capacity in patients with heart failure, but preserved cardiac function.
Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administrationRizos I. University of Athens Medical School, Greece
We examined the efficacy of long-term L-carnitine administration for the treatment of heart failure caused by dilated cardiomyopathy in adult patients. To accomplish this, we studied 80 patients with moderate to severe heart failure (New York Heart Association classification III to IV) caused by dilated cardiomyopathy. This article reports on the nearly 3 years of follow-up data on patient mortality. Primary results will be published in the future. After a period of stable cardiac function up to 3 months, patients were randomly assigned to receive either L-carnitine (2 g/d orally) or placebo. There were no statistical differences between the 2 groups at baseline examination in clinical and hemodynamic parameters, such as ejection fraction, Weber classification, maximal time of cardiopulmonary exercise test, peak VO(2) consumption, arterial and pulmonary blood pressure, and cardiac output. After a mean of 33.7 +/- 11.8 months of follow-up (range 10 to 54 months), 70 patients were in the study: 33 in the placebo group and 37 in the L-carnitine group. At the time of analysis, 63 patients were alive. There were 6 deaths in the placebo group and 1 death in the L-carnitine group. Survival analysis with the Kaplan-Meier method showed that patients' survival was statistically significant (P <.04) in favor of the L-carnitine group. L-carnitine appears to possess considerable potential for the long-term treatment of patients with heart failure attributable to dilated cardiomyopathy.
Conditioned nutritional requirements: therapeutic relevance to heart failureSole MJ, Jeejeebhoy KN. University of Toronto, Toronto, Canada. email@example.com
BACKGROUND: The advent of disease, genetic predisposition or certain drug therapies may significantly alter the nutritional demands of specific organs. Several specific metabolic deficiencies have been found in the failing myocardium: (1) a reduction in L-carnitine, coenzyme Q10, creatine, and thiamine--nutrient cofactors important for myocardial energy production; (2) a relative deficiency of taurine, an amino acid integral to intracellular calcium homeostasis; (3) increased myocardial oxidative stress and a reduction of antioxidant defenses. Deficiencies of carnitine or taurine alone are well documented to result in dilated cardiomyopathy in animals and humans. Each of these deficiencies is amenable to restoration through dietary supplementation. A variety of nutrients have been investigated as single therapeutic agents in pharmacologic fashion, but there has been no broad-based approach to nutritional supplementation in congestive heart failure to correct this complex of metabolic abnormalities. METHOD AND RESULTS: We have demonstrated deficiencies in carnitine, taurine and coenzyme Q10 in cardiomyopathic hamster hearts during the late stage of the cardiomyopathy. In another study, we randomized placebo diet against a supplement containing taurine, coenzyme Q10, carnitine, thiamine, creatine, vitamin E, vitamin C, and selenium to cardiomyopathic hamsters during the late stages of the disease. Supplementation for 3 months markedly improved myocyte sarcomeric structure, developed pressure, +dp/dt, and -dp/dt. We also documented carnitine, taurine and coenzyme Q10 in biopsies taken from human failing hearts, the levels correlating with ventricular function. A double-blind, randomized, placebo-controlled trial of a supplement containing these nutrients, given for 30 days, restored myocardial levels and resulted in a significant decrease in left ventricular end-diastolic volume. CONCLUSION: These experiments suggest that a comprehensive restoration of adequate myocyte nutrition may be important to any therapeutic strategy designed to benefit patients suffering from congestie heart failure. Future studies in this area are of clinical importance.
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