Does left ventricular function improve with L-carnitine after acute myocardial infarction?R Iyer, A Gupta, A Khan, S Hiremath, Y Lokhandwala
Department of Cardiology, Seth G.S. Medical College and K.E.M. Hospital, Parel, Mumbai, India., India
A double blind randomized placebo controlled clinical trial was carried out to assess the efficacy and safety of L-carnitine in patients suffering from acute anterior wall myocardial infarction with respect to left ventricular function. Sixty patients (34 men, 26 women, mean age 56+11 yr.) with acute anterior wall myocardial infarction were randomized to placebo and L-carnitine. All the patients were given intravenous L-carnitine / placebo in the dose of 6gm/day for the first seven days followed by oral L-carnitine / placebo 3 gm/day in three divided doses for a period of three months. Echocardiography was performed for regional wall motion abnormality, left ventricular end systolic volume (ESV), end diastolic volume (EDV) and ejection fraction (EF) on admission, after seven days and after three months of the infarction. Forty-four patients completed the study. There were three deaths, two in the placebo and one in the L-carnitine group (p>0.05). Thirteen patients were lost to follow up. Echo parameters in both groups were comparable (p>0.05). The duration of chest pain prior to initiation of the I.V. L-carnitine was 7.5 + 5.2 hrs in the L-carnitine group and 7 + 4 hrs in the placebo group (p>0.05). There was no statistical difference in the EF, ESV and EDV on admission, at discharge and after three months in the L-carnitine and the placebo groups (p>0.05). No significant adverse effects were noted. L-carnitine, though a safe drug, does not affect the left ventricular function in patients with myocardial infarction.
Keywords: Aged, Carnitine, pharmacology,Double-Blind Method, Female, Human, Male, Middle Age, Myocardial Infarction, physiopathology,Ventricular Function, Left, drug effects,
Grants: Elder Pharmaceuticals
L-carnitine is a natural compound present in high concentrations in skeletal muscles and in myocardial tissues. Here it plays an important role in the fatty acid metabolism as a carrier of the acyl radicals from the cytoplasm to the intra-mitochondrial sites for beta-oxidation,. During the hypoxic conditions there is a rapid inhibition of the oxidative processes and a reduction in the tissue levels of free L-carnitine with an increase in the free fatty acids and their intermediate metabolites, mainly acyl-CoA in the cytoplasm. These have a detergent action and exert a disintegrating effect on the cellular membranes and inhibit some enzymatic activities essential to myocardial energy metabolism. Clinical studies in patients with angina, who underwent atrial pacing, showed that L-carnitine improved myocardial energy metabolism by increasing the use of free fatty acids and reducing the lactic acid flux in the coronary sinus. There have also been reports of patients with acute myocardial infarction treated with L-carnitine showing reduction in the area of necrosis, a lower mortality in the first 28 days after hospitalization, an improvement in general condition and of the functional status.
Acute myocardial infarction often results in regional left ventricular dysfunction thus leading to progressive left ventricular dilatation. Patients with dilated ventricles after myocardial infarction are at a higher risk of cardiac failure and death,. It has also been shown that limitation of the dilatation process after acute myocardial infarction exerts a significant benefit. Exogenous administration of L-carnitine has been shown to restore the intramitochondrial levels of L- carnitine and thus exert beneficial effects on the myocardial function,,. We carried out a double blind randomized placebo controlled study of intravenous L-carnitine followed by oral L-carnitine in patients suffering from acute myocardial infarction to test this hypothesis.
Sixty patients with acute anterior wall myocardial infarction were randomized to placebo and L-carnitine. There were 34 men and 26 women, aged 56 + 11 years. The diagnosis of infarction was based on the typical clinical presentation, ECG changes and the changes in the elevation of the cardiac enzymes, (CPK MB, and Troponin T).
* Acute anterior wall myocardial infarction
* Admission to the intensive care unit within 24 hrs of the chest pain
* Satisfactory echocardiographic imaging of the left ventricle allowing delineation of the left ventricular contours in both end-diastole and end systole.
* Age less than 80 years.
* History of previous myocardial infarction
* Presence of valvular or congenital heart disease or cardiomyopathy
* Absence of sinus rhythm
* Presence of bundle branch block
* Presence of concomitant diseases that can affect follow up.
Clearance for the study was taken from the hospital ethics committee and informed consent was taken from the patients. The patients had a right to opt out of the trial during the course of the study. L-carnitine or placebo was administered to the patients in the dose of 6 gm daily for a period of seven days and later 3 gm daily in three divided doses for a period of three months. The standard therapy for myocardial infarction was given irrespective of the treatment with L-carnitine. The patients received thrombolysis, aspirin, nitrates, ACE inhibitors and beta-blockers, as and when indicated. All the patients underwent 2D Echo evaluation on admission, at seven days and after three months. Echo assessment was done for end systolic volume (ESV), end diastolic volume (EDV) and ejection fraction (EF). The left ventricular volume measurements were obtained by averaging four consecutive cardiac cycles by the same observer. All the readings were taken in the apical 4 chamber and 2 chamber views and the average of the two was calculated. All the patients were monitored on a central monitor for 24 hours in cases of uncomplicated infarcts and more that 24 hours when the course was stormy.
There were 30 patients each in the L-carnitine and the placebo groups. There were 34 men and 26 women. The baseline parameters with regards to age, sex, history of hypertension, smoking, hypercholesterolemia and diabetes were comparable in both groups [Table - 1]. The CPK and the CPK-MB in the placebo and the L-carnitine groups were 526 + 380 vs 436 + 248 (p value NS) and 114 + 78 vs 84 + 52 (p value NS) respectively. Treatment was administered 6 + 3.5 hrs and 5.4 + 2.5 hrs after the onset of chest pain in the L-carnitine and the placebo groups respectively (p value NS). The duration of the chest pain prior to the initiation of the intravenous drug was 7.5 + 5.2 hrs in the L-carnitine group and 7 + 4 hrs in the placebo group (p value NS). The drugs prescribed during the course of the hospital stay are given in [Table - 2].
Thirteen patients were lost to follow up. There were three deaths, two in the placebo group and one in the L-carnitine group. There was no significant difference in the presence of arrhythmias in the L-carnitine and the placebo groups noted in the first 24 hours. None of the patients noted any adverse reactions to the drug in either group. The echocardiographic results are presented in the [Table - 3]. The echocardiographic parameters in both the groups were comparable. There was no statistical difference in the ESV, EDV and the EF on admission, at discharge and after three months in the L-carnitine and the placebo groups respectively.
Acute myocardial infarction is associated with left ventricular dysfunction. The process of left ventricular remodelling leads to left ventricular dilatation, which has been shown to be associated with increased morbidity and mortality. Prevention of the LV remodelling has been the major goal of the various drug strategies so far. Angiotensin converting enzyme inhibitors have been shown to limit and prevent remodelling after myocardial infarction in several randomised trials,. In the trials so far, the therapy with angiotensin converting enzyme inhibitors had to be discontinued in some patients due to presence of adverse events such as symptomatic hypotension, cough, diarrhoea etc. Hence there has always been a search for an alternative drug that can help in the same way as ACE inhibitors. In a rat model of acute myocardial infarction, administration of a derivative of carnitine (propionyl carnitine) significantly decreased the magnitude of left ventricular dilation after myocardial infarction. Similar results were shown in the multicentric CEDIM trial. This study was performed to evaluate the effects of L-carnitine administration on long term left ventricular dilation in 472 patients with acute myocardial infarction. Here the L-carnitine was administered in the dose of 9 gm/day intravenously for the first five days and then 6 gm/day orally for the next 12 months. The results of this trial demonstrated that early and long-term administration of carnitine in patients with acute myocardial infarction was effective in attenuating progressive left ventricular dilatation. Patients treated with L-carnitine fared significantly better (p<0.05) in this respect than the control group at three months (EDV increase 18+2.5 VS 11+2.2%; ESV increase 22.5+3.2% vs 12.6+3.1%) and at 12 months (EDV increase 28.5 +3.1%. vs 19.1+2.7%; ESV increase 39.9+4.2% vs 28.9+3.9%) after the emergent event.
The pattern of coronary artery disease is markedly different in Indians as compared to the Western population,. Ours was a pilot study performed on a similar basis to evaluate L-Carnitine in Indian patients, though less in number and a much shorter duration of follow up. We noticed that there was no significant statistical difference in the in the EF, ESV, EDV on admission at discharge and at 3 months of treatment in both the L-carnitine and the placebo groups respectively. This was in contradiction to the findings of the CEDIM trial. The dose of L-carnitine administered in our patients, were less than that in the CEDIM trial. This could probably be considered as one of the factors for the lack of advantage seen with administration of L-carnitine in our study. Another significant limitation of our study is the small number of patients studied. A larger number of patients need to be recruited to make a final conclusion regarding the efficacy of L-carnitine as regards left ventricular function in this subgroup of patients.
L-carnitine though a safe drug does not affect the left ventricular function and left ventricular remodeling in patients with acute myocardial infarction. However studies with a bigger sample size needs to be done to corroborate this finding.
[Table - 1], [Table - 2], [Table - 3]