Therapeutic Effects of l‐Carnitine and Propionyl‐l‐carnitine on Cardiovascular Diseases: A Review

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...

Protective effect of L-carnitine against cisplatin-induced liver and kidney oxidant injury in rats

“…This was probably due to less damage having occurred from oxygen-free radicals. In previous studies, CDDP has been found to have an antiperoxidative effect on several tissues, such as the liver, kidney, and lens [35][36][37]. GSH is the most important molecule for maintaining cell integrity and participation in cell metabolism [38].…”

Pharmacological manipulation of L-carnitine transport into L6 cells with stable overexpression of human OCTN2

“…Besides the well known roles of carnitine, several studies suggest that carnitine is involved in a multitude of other processes, for instance sperm quality assurance, immune responses or myocardial integrity and function, explaining the large interest for carnitine and OCTN2 [20][21][22].…”

Metabolic Modulators to Treat Cardiac Arrhythmias Induced by Ischemia and Reperfusion

“…Studies involving about 2500 patients with coronary artery disease (CAD) treated with L-Car for a year also showed a reduced incidence of angina, a decreased need of cardiac drugs and a greater effort tolerance (Naguib, 2005). Placebo-controlled studies performed in patients with stable chronic effort angina suggest that L-Car given acutely (40 mg/kg, iv) or chronically (1-3 g daily for a month) improves exercise capacity and the electrocardiographic manifestations of ischemia (Ferrari et al, 2004). L-Car does not have hemodynamic effects in healthy volunteers or patients with CAD.…”

“…L-Car does not have hemodynamic effects in healthy volunteers or patients with CAD. However, an improvement of individual maximal aerobic power is demonstrated in healthy subjects and athletes after chronic treatment with L-Car (4 g daily over a period of 2 weeks) (Ferrari et al, 2004). In a randomized, double-blind, placebo controlled, multicenter study called the Levocarnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial was performed to evaluate the effects of L-Car administration on long-term left ventricular dilatation in patients with AMI.…”