Improved pacing tolerance of the ischemic human myocardium after administration of carnitine (original) (raw)
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Therapeutic Effects of l-Carnitine and Propionyl-l-carnitine on Cardiovascular Diseases: A Review
Annals of The New York Academy of Sciences, 2004
Abstract: 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.
The uses of L-Carnitine in cardiology
. International Journal of Biomed Research (ISSN: 2690-4861), 2021
L-carnitine is a non-protein amino acid synthesized from the essential amino acids lysine and methionine or obtained from dietary sources. Accumulating scientific research evidence suggests that L-carnitine has beneficial cardiovascular effects, and a potential in the management of a variety of cardiovascular disorders including congestive heart failure. The aim of this paper is to review the uses of L-Carnitine in cardiology. Conclusion: Chronic heart diseases remain an important cause of morbidity and mortality in Iraq and many other countries in the world suggesting a need for advancing their medical therapy, possibly through emphasis on impairment in substrate metabolism and heart energy and substrate utilization which contribute to contractile dysfunction, and not expected to improve with traditional therapies. Fat is the most important energy source for heart muscle , and carnitine is vital for normal fatty acid beta-oxidation, and inadequate carnitine can cause cardiac dysfunction. There is convincing evidence from experimental and clinical research that L-Carnitine has a beneficial effect when used in the treatment of a variety of heart diseases including congestive heart failure, myocardial infarction, and angina. The effect of L-Carnitine can be attributed to cardio-protective effects against ischemia and increasing the rate of fatty acid transport into mitochondria. It can improve exercise tolerance and oxygen consumption leading to symptomatic improvement and mortality reduction. As an anti-anginal agent, it can reduce ST segment depression and left ventricular end-diastolic pressure. L-Carnitine can also improve myocardial ischemia by relieving inhibition of mitochondrial adenine nucleotide translocase.
Effects of carnitine on the ischemic arrested heart
Basic Res Cardiol, 1982
We investigated the effect of L-carnitine on the recovery of cardiac function after ischemic arrest in the perfused rat heart. L-carnitine was added to a cardioplegie solution, both as a free base and hydrochloride. The addition of L-earnitine as a free base to the solution had no effect on recovery of cardiac function. When L-earnitine HC1 was added to the cardioplegic solution, it was necessary to adjust the pH of the solution to 7.4. The hearts arrested with this solution showed a greater incidence of reperfusion dysrhythmias than those in the control or the free base solution, but the overall recovery of cardiac function was the same as control. The hydrochloride of L-carnitine is strongly acidic, and these findings indicate that either the free base or a properly buffered solution must be used to study effects of carnitine upon cardiac function.
Molecular and Cellular Biochemistry, 2000
The metabolic and genic effects induced by a 20-fold lowering of carnitine content in the heart were studied in mildronatetreated rats. In the perfused heart, the proportion of palmitate taken up then oxidized was 5-10% lower, while the triacylglycerol (TAG) formation was 100% greater than in controls. The treatment was shown to increase the maximal capacity of heart homogenates to oxidize palmitate, the mRNA level of carnitine palmitoyltransferase I (CPT-I) isoforms, the specific activity of CPT-I in subsarcolemmal mitochondria and the total carnitine content of isolated mitochondria. Concomitantly, the increased mRNA expression of lipoprotein lipase, fatty acid translocase and enzymes of TAG synthesis was associated with a 5-and 2times increase in serum TAG and free fatty acid contents, respectively. The compartmentation of carnitine at its main functional location was expected to allow the increased CPT-I activity to ensure in vivo correct fatty acid oxidation rates. All the inductions related to fatty acid transport, oxidation and esterification most likely stem from the abundance of blood lipids providing cardiomyocytes with more fatty acids. (Mol Cell Biochem 258: [171][172][173][174][175][176][177][178][179][180][181][182] 2004) fatty acid supply and channelling of most of these fatty acids towards the mitochondrial β-oxidation pathway.
Pediatric Research, 2003
Adriamycin (ADR) inhibits the carnitine palmitoyl transferase (CPT) system and consequently the transport of longchain fatty acids across mitochondrial membranes. L-Carnitine (CARN) plays a major role in fatty acid oxidation by translocating activated long-chain fatty acids into the matrix of mitochondria. CARN has been shown to be of benefit in certain cardiac conditions including cardiomyopathy and myocardial infarction. This study was devised to investigate the effect of CARN on altered CPT I and CPT II activity in the cardiomyopathy associated with ADR therapy. We also assessed the effect of CARN on the plasma free, total, and acylcarnitine concentrations. Four groups, each consisting of four male Sprague-Dawley rats, were studied: group 1(n ϭ 4) was not given either ADR or CARN; group 2 (n ϭ 4) was given ADR (15 and 20 mg/kg, respectively, cumulative dose) by i.p. injections for 1 and 2 wk; group 3 (n ϭ 4) was given the same dose of ADR with CARN (200 mg/kg); and group 4 (n ϭ 4) was given CARN (200 mg/kg). The activities of CPT I and CPT II in heart were significantly decreased in the ADR-treated rats (p Ͻ 0.05) in a dose-dependent manner. The reduced activities of CPT I and CPT II, inhibited by ADR, were not normalized by supplementation with CARN (p Ͻ 0.05). In rats supplemented with CARN alone, the activities of CPT I and CPT II were elevated approximately 50% above those of the control rats (p Ͻ 0.05). ADR treatment resulted in elevation of plasma free and total CARN concentrations (p Ͻ 0.05). Supplementation with CARN did not effect the increased plasma CARN concentrations resulting from ADR treatment (p Ͻ 0.05). This study supports the concept that ADR toxicity results from the inhibition of both CPT I and CPT II activities and that one of the causes of ADR-induced cardiomyopathy is a result of globally impaired fatty acid oxidation.
Protection of the ischemic dog myocardium with carnitine
American Journal of Cardiology, 1978
In 25 open chest anesthesized dogs, left anterior descending coronary arterial blood flow was measured with an electromagnetic flowmeter while aortlc blood pressure and epicardial electrocardiograms were recorded. lschemia was produced in the left anterior descending arterial bed by decreasing mean flow to one third of control levels for a 5 minute period with a mlcrometer snare device. Thfs produced an Increase In S-T segment devlatlon greater than 4 mv in the ischemic bed. Control and ischemlc left anterlor descending arterial bed tissue samples were obtained by drill biopsy and were analyzed for adenosine triphosphate (ATP) and creatine phosphate levels and adenine nucleotide translocase activity. The ATP levels decreased from 5.6 f 1.2 to 3.6 f 1.4 pmoles/g, and creatlne phosphate decreased from 15.3 f 4.6 to 5.8 f 3.8 ~moles/llter. The adenine nucleotkte translocase activtty decreased from an average control value of 42,957 f 9,480 to 29,100 f 6,609 disintegrations per minute (dpm)/mg during the 5 minute period of ischemia. With the lschemia maintained, 100 mg/cc of L-carnltine was infused into the ischemic left anterior descending arterial bed at a rate of 1 cc/min for 5 minutes (17 dogs), and 80 mg/kg of D-L carnltine was given intravenously in 8 dogs. The epicardial S-T segment deviation decreased to approximately 2 mv after the carnltine infusion, with ischemia maintained. A third biopsy sample of the ischemlc bed showed that the ATP level had increased to 5.2 f 1.1 and the creatfne phosphate to 10.8 f 4.8 ~les/~ the adenine nucleotkte trar&case actfvfty had increased to 37,800 f 7,210 dpm/mg.
A Moderate Carnitine Deficiency Exacerbates Isoproterenol-Induced Myocardial Injury in Rats
Cardiovascular Drugs and Therapy, 2016
Purpose The myocardium is largely dependent upon oxidation of fatty acids for the production of ATP. Cardiac contractile abnormalities and failure have been reported after acute emotional stress and there is evidence that catecholamines are responsible for acute stress-induced heart injury. We hypothesized that carnitine deficiency increases the risk of stressinduced heart injury. Methods Carnitine deficiency was induced in Wistar rats by adding 20 mmol/L of sodium pivalate to drinking water (P). Controls (C) received equimolar sodium bicarbonate and a third group (P + Cn) received pivalate along with 40 mmol/L carnitine. After 15 days, 6 rats/group were used to evaluate function of isolated hearts under infusion of 0.1 μM isoproterenol and 20 rats/group were submitted to a single subcutaneous administration of 50 mg/kg isoproterenol. Results Isoproterenol infusion in C markedly increased the heart rate, left ventricular (LV) systolic pressure and coronary flow rate. In P rats, isoproterenol increased the heart rate and LV systolic pressure but these increases were not paralleled by a rise in the coronary flow rate and LV diastolic pressure progressively increased. Subcutaneous isoproterenol induced 15 % mortality rate in C and 50 % in P (p < 0.05). Hearts of surviving P rats examined 15 days later appeared clearly dilated, presented a marked impairment of LV function and a greater increase in tumor necrosis factor α (TNFα) levels. All these detrimental effects were negligible in P + Cn rats. Conclusions Our study suggests that carnitine deficiency exposes the heart to a greater risk of injury when sympathetic nerve activity is greatly stimulated, for example during emotional, mental or physical stress.