Role of Nutriceutical Agents in Cardiovascular Diseases
In the July issue of CVR&R, part I of this review discussed the nutriceuticals L-arginine, taurine, and coenzyme Q10 in the context of the treatment and prevention of cardiovascular disease. Part II continues with a review of the clinical data regarding the use of the nutriceuticals carnitine, N-acetylcysteine, creatine, glutathione, selenium, resveratrol, beta-sitosterol, and flavonoids. The authors conclude with the presentation and critique of a template for the assessment and integration of information, from clinical studies on complementary and alternative therapies into responsible medical practice.

Carnitine is an amino acid derivative that is found in all cells of the body, especially striated muscles. It is synthesized in the liver, kidneys, and brain from the amino acids lysine and methionine. Two analogs of carnitine, acetyl-L-carnitine and propionyl-L-carnitine, have been used clinically. It plays an important role in the transport of free fatty acids across the inner mitochondrial membranes for energy production. It is a cofactor in carbohydrate metabolism and has been noted to reduce the buildup of toxic metabolites in an ischemic condition. Although its approved indications are primary/secondary carnitine deficiencies, it is widely utilized by patients with a variety of cardiovascular conditions.

L-carnitine has been reported to beneficially affect cardiac function and it has been postulated to be cardioprotective due to its antioxidant effects. Studies have suggested that it will lower, to a variable extent, plasma triglycerides and elevate high-density lipoprotein cholesterol levels.

Both free and total myocardial carnitine levels are reduced in the ischemic and peri-ischemic zone during periods of prolonged acute ischemia. This is associated with significant elevation of free fatty acid levels and toxic ester levels with a reduction in adenosine triphosphate and creatine phosphate. These intracellular changes in the ischemic myocardium can result in a poor outcome following acute myocardial infarction (MI). It has been suggested that supplementation of carnitine may mitigate ischemic injury. Benefits have been postulated that include enhanced glucose oxidation, preservation of myocardial carnitine, reduction in loss of high-energy phosphates, and reduction in the accumulation of toxic esters.

There are few trials suggesting the beneficial role of carnitine in patients with acute MI. Rebuzzi et al. found that L-carnitine reduced the extent of MI in a study, if given within 8 hours of onset of symptoms. The L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial studied patients after first anterior wall MI. In this double-blind, randomized control trial, 472 patients were treated with either L-carnitine (intravenously for 5 days, followed by orally) or placebo for 12 months. Although there was no change in overall ejection fraction (EF), there were significant reductions in left ventricular diastolic and systolic dimensions in the active group, and there was a non-significant reduction in rate of death or congestive heart failure (CHF) (6% with carnitine vs. 9.6% with placebo [p =NS]). Corbucci et al. demonstrated the absence of ischemic changes in the carnitine group vs. controls in 120 patients undergoing extracorporeal circulation during aortopulmonary bypass surgery. Levels of lactate, pyruvate, and succinate/fumarate ratio, reflective of glycolytic cellular metabolism, were measured before and after extracorporeal circulation. These levels remained within normal range in patients with supplemental carnitine when compared with the placebo group.

A number of small, uncontrolled studies have noted a lower systemic vascular resistance, an augmented inotropic state, and enhanced lactate extraction as a consequence of carnitine treatment. These reported hemodynamic effects, if confirmed, would suggest a role in the treatment of CHF. Deficiency of carnitine has been well documented to cause dilated cardiomyopathy along with skeletal myopathy. Mancini et al. studied 60 patients with CHF (EF <50% New York Heart Association class II or III) for 180 days. Patients received 500 mg three times a day of propionyl-L-carnitine or placebo. The only other medications used in these patients were digoxin and diuretics. There was significant improvement in exercise times (increased by 26%) and EFs (increased by 14%). In another large study of 574 patients with heart failure and EF <40% exercise tolerance was significantly improved in the carnitine group when compared with placebo. However, the carnitine group demonstrated a slightly higher mortality (3.0% vs. 1.9%) and a higher admission rate (6.3% vs. 5.3%). Romagnoli et al. studied the effects of L-carnitine in dialysis patients. Their observational study showed that the addition of L-carnitine to conventional therapy resulted in overall improved clinical status with increased mean EF from 32% to 41.8% (p<0.05) and reduction in erythropoietin dosage.

Lower carnitine levels have been found in the muscle biopsies of patients undergoing revascularization procedure for peripheral arterial occlusive disease. Brevetti et al., in a double-blind, placebo-controlled, dose-titration, multicenter trial, have shown that active treatment with propionyl-L-carnitine for a period of 24 weeks significantly improved maximum walking distance and time of onset of symptoms with minimal adverse side effects in 245 patients with peripheral arterial occlusive disease.

Palazzuoli et al. noted that L-carnitine reduced myocardial arrhythmic activity in 30 patients with ischemic heart disease. Patients were divided into three groups (carnitine group, propafenone group, and carnitine + propafenone group). The carnitine group showed significant reduction in arrhythmic activity, measured as extrasystolic ventricular multifocal beats. This response was further substantiated in the combination group.

The results of the clinical studies of carnitine and its derivatives in the therapy of ischemic heart disease and peripheral arterial occlusive disease should be the subject of a large, randomized, controlled clinical trial. The role in CHF is equivocal and the report of an increased mortality and admission rate associated with an improved EF should limit its use pending further studies.

The dose reported in clinical trials ranged from 20 mg/d to 2 g/d. Possible adverse reactions include nausea, vomiting, abdominal cramps, diarrhea, myasthenia, and seizure activity. There is no known contraindication.