L-carnitine treatment for congestive heart failure--experimental and clinical study.

To evaluate the therapeutic efficacy of l-carnitine in heart failure, the myocardial carnitine levels and the therapeutic efficacy of l-carnitine were studied in cardiomyopathic BIO 14.6 hamsters and in patients with chronic congestive heart failure and ischemic heart disease. BIO 14.6 hamsters and patients with heart failure were found to have reduced myocardial free carnitine levels (BIO 14.6 vs FI, 287 +/- 26.0 vs 384.8 +/- 83.8 nmol/g wet weight, p less than 0.05; patients with heart failure vs without heart failure, 412 +/- 142 vs 769 +/- 267 nmol/g p less than 0.01). On the other hand, long-chain acylcarnitine level was significantly higher in the patients with heart failure (532 +/- 169 vs 317 +/- 72 nmol/g, p less than 0.01). Significant myocardial damage in BIO 14.6 hamsters was prevented by the intraperitoneal administration of l-carnitine in the early stage of cardiomyopathy. Similarly, oral administration of l-carnitine for 12 weeks significantly improved the exercise tolerance of patients with effort angina. In 9 patients with chronic congestive heart failure, 5 patients (55%) moved to a lower NYHA class and the overall condition was improved in 6 patients (66%) after treatment with l-carnitine. L-carnitine is capable of reversing the inhibition of adenine nucleotide translocase and thus can restore the fatty acid oxidation mechanism which constitutes the main energy source for the myocardium. Therefore, these results indicate that l-carnitine is a useful therapeutic agent for the treatment of congestive heart failure in combination with traditional pharmacological therapy.

Myocardial free carnitine and fatty acylcarnitine levels in patients with chronic heart failure.

To study the tissue carnitine level in patients with chronic heart failure, we obtained biopsy specimens of the left ventricular papillary muscle from 8 patients with mitral valve disease undergoing valve replacement surgery. As a control group autopsy specimens from 7 patients without heart disease were obtained within 4 hours of death. The free carnitine level in the heart was significantly lower in patients with chronic heart failure than in the control group (412 +/- 142 nmol/g wet tissue vs 769 +/- 267; p less than 0.01, mean +/- SD). The long-chain acylcarnitine level was significantly higher in chronic heart failure than in the control group (532 +/- 169 nmol/g wet tissue vs 317 +/- 72; p less than 0.01). The total carnitine level in chronic heart failure was similar to that in the control group (1321 +/- 170 nmol/g wet tissue vs 1315 +/- 377). These results show that in failing myocardium the fatty acid metabolism may be impaired, and administration of carnitine may be worth trying to treat chronic heart failure.

Effects of L-carnitine on exercise tolerance in patients with stable angina pectoris.

The effects of L-carnitine (900 mg, p.o. daily) on exercise performance were studied in 12 patients with stable effort angina using a multistage treadmill exercise test. Exercise tests were performed at the end of the placebo period and after 4 and 12 weeks of carnitine therapy. While 12 patients experienced angina during treadmill tests in the placebo period, 2 patients were free of angina after treatment with carnitine. The mean exercise time was 11.4 +/- 0.7 min (mean +/- SE) in the placebo period. This increased significantly to 12.2 +/- 0.5 min (p less than 0.05) after 4 weeks and 12.8 +/- 0.5 min (p less than 0.01) after 12 weeks of treatment with carnitine. The time required for 1 mm ST depression to occur was 6.4 +/- 0.9 min in the placebo period. This increased significantly to 7.6 +/- 0.9 min (p less than 0.01) after 4 weeks and 8.8 +/- 1.0 min after 12 weeks of treatment with carnitine. There was significantly less ST segment depression during the same exercise load after 12 weeks of treatment as compared with that in the placebo period (p less than 0.05). The heart rate and the pressure rate product at the same work load showed no significant difference among the 3 testing periods. The results of this study suggest that L-carnitine may improve exercise tolerance in patients with effort angina.

Unstable angina in a patient with mucocutaneous lymph node syndrome.

An 11-year-old boy with mucocutaneous lymph node syndrome, who later developed an acute anteroseptal infarction and unstable angina, is presented. Anginal attacks were shown by 24-hour long-term ambulatory electrocardiographic recording. He was shown to have multiple coronary aneurysms with thrombi, and underwent a successful aorto-coronary bypass.

Effects of l-carnitine on action potential of canine papillary muscle during hypoxic perfusion.

Under hypoxic (95% N2 + 5% CO2) perfusion, electrophysiological effects of L-carnitine on canine papillary muscles were studied using standard microelectrode techniques. During hypoxic perfusion for 60 min, resting membrane potential (RMP), action potential amplitude (APA) and maximum upstroke velocity of phase 0 were decreased, and action potential duration (APD) and effective refractory period (ERP) were shortened. Application of L-carnitine 25 mM under hypoxic perfusion increased RMP and APA and prolonged APD and ERP significantly. As effects of L-carnitine during hypoxic perfusion might be that of hypertonicity, effects of sucrose of the same tonicity as L-carnitine were studied under hypoxia. Sucrose did not cause significant changes on various parameters of action potential compared with hypoxic perfusion. It was suggested that the increase in RMP, and the prolongation of APD and ERP might be caused by an increase in intracellular ATP content. The findings in this study could be an explanation of possible antiarrhythmic effects of L-carnitine.

Effects of L-carnitine on ventricular arrhythmias after coronary reperfusion.

Effects of L-carnitine on ventricular arrhythmias and myocardial metabolism in a reperfused ischemic myocardium were studied in 35 anesthetized mongrel dogs. The left anterior descending coronary artery was ligated for 40 min and then reperfused for 15 min. L-carnitine (100 mg/kg) was administered intravenously 5 min before the coronary ligation and infused continuously at a rate of 20 mg/kg/min from 5 min before the reperfusion to the end of the experiment. Electrocardiograms were recorded continuously throughout the experiment. Transmural myocardial samples were obtained from both the ischemic and the nonischemic areas after 15 min of reperfusion and used for the determination of ATP, free carnitine, long chain acyl carnitine and long chain acyl CoA. L-carnitine significantly reduced the incidence rate of ventricular fibrillation after reperfusion (from 29% in the controls to 5%, p less than 0.05). ATP in the ischemic myocardium in the L-carnitine group was significantly higher than that in the control group (p less than 0.05). Free carnitine in the control group significantly decreased in the ischemic area as compared with the nonischemic area (p less than 0.01). In L-carnitine group, on the other hand, no difference was observed between them. Long chain acyl CoA in the control group significantly increased in the ischemic area as compared with the non-ischemic area (p less than 0.01). In L-carnitine group, on the other hand, no difference was observed between them. Thus, the accumulation of long chain acyl CoA in the ischemic myocardium was reduced by the L-carnitine treatment. These data suggest that L-carnitine has protective effects on ventricular arrhythmias and on metabolic changes after coronary artery reperfusion following coronary artery occlusion.

Effects of L-carnitine on action potential or canine papillary muscle impaired by long chain acyl carnitine.

It has been reported that long chain acyl carnitine accumulates in ischemic myocardium, and L-carnitine prevents ventricular arrhythmias as well as the accumulation of long chain acyl carnitine in ischemic and free fatty acid supplemented hearts. The purpose of this study was to observe the electrophysiological effects of long chain acyl carnitine, and to evaluate the protective effect of L-carnitine on the transmembrane action potential impaired by long chain acyl carnitine. Using standard microelectrode techniques, transmembrane action potentials were recorded from isolated canine papillary muscle. Palmitoyl carnitine (0.3 mM and 0.6 mM) decreased the resting membrane potential, action potential amplitude and maximum upstroke velocity of phase 0, and shortened action potential duration and effective refractory period in a concentration-dependent manner. Application of L-carnitine (25 mM) prevented the effect of palmitoyl carnitine (0.3 mM) on the transmembrane action potential. These results suggest that long chain acyl carnitine plays an important role in arrhythmogenesis, and that the effect is prevented by L-carnitine.