ISSN No. 1606-7754                   Vol.13 No.2  August 2005

Post-necrotic left ventricular dysfunction in Diabetes Mellitus: Effects of trimetazidine
Federico Cacciapuoti,**Carmine Musto, *Raffaele Marfella, Eleonora Manfredi, Alessandro Arciello**, Angelo S Boccia, Fulvio Cacciapuoti, Luigi Petruzzelli
Cattedra di Medicina Interna and *Cardiac Research Center–Seconda Facoltà di Medicina-Università di Napoli, **U.T.I.C. “Vecchio Pellegrini”Hospital-Napoli

Abstract

The Index of Myocardial Performance (IMP) in 149 non-diabetic (group I) and 151 diabetic (group II) subjects who were treated for acute myocardial infarction was evaluated using two-dimensional Doppler echocardiography. Isovolumetric Contraction Time (ICT), Isovolumetric Relaxation Time (IRT) and Ejection Time (ET) were also measured. All patients in both groups received conventional, anti-ischaemic therapy (nitrates, ACE-inhibitors, and antiplatelet drug). In addition, 74 patients in group II (subgroup IIa) received an oral dose of 20 mg of trimetazidine, three times daily. The remaining 77 diabetics in group II were treated with conventional drugs alone (subgroup IIb). All diabetic patients (group II) also received an anti-diabetic (oral drug or insulin) treatment to keep their diabetes under control. Twelve months after the experiment, IMP was significantly (p<0.001) higher in diabetic patients (0.55±0.05) compared to non-diabetic controls (0.49±0.04). IRT was similar in both groups (81±15 ms vs 83±12 ms) and ET (275±27 ms vs 295±29 ms) was decreased in diabetics compared to the control group. The one-year follow-up showed a significant decrease in IMP in patients treated with trimetazidine (subgroup IIa) compared to those treated with conventional drugs (subgroup IIb alone). IRT values were lower in sub-group IIa compared to that of subgroup IIb. ICT returned towards the normal limits in both subgroups. Finally, ET decreased in subgroup IIa but increased in subgroup IIb compared to values obtained at the onset of treatment. In conclusion, trimetazidine when added to the conventional, anti-ischaemic therapy, seems to induce a more evident attenuation of post-AMI left ventricular dysfunction compared to those not given the drug.

Key words: AMI, coronary heart disease, diabetes, echography, haemodynamics, trimetazidine

Introduction

Diabetes Mellitus (DM) is an independent risk factor for coronary artery disease (CAD).1,2 Some findings indicate that CAD is more severe in diabetics than in the general population.3,4 In DM, CAD is associated with abnormal coagulation resulting in the dysfunction of the coagulation processes, including increased platelet activation and aggregation, fibrinogen concentration, and circulating von Willebrand factor. In addition, DM induces alterations in myocardial fatty acid and in glucose metabolism. These factors increase the post-necrotic left ventricular dysfunction.5 With respect to the metabolic derangement, Lopaschuk et al6 have described the relationship between impaired myocardial carbohydrate/lipid metabolism and mechanical function during and after ischaemia in normal and diabetic heart. On the other hand, it is known that almost all patients with acute myocardial infarction (AMI) have impaired left ventricular function often evolving into heart failure.7,8 Jaffe et al9 reported an increased incidence in congestive heart failure after myocardial infarction of modest extent in diabetics compared to non-diabetic patients.

Some drugs act on cardiac metabolism in both normal and diabetic subjects.10 Trimetazidine is the first known metabolically active agent, acting at mitochondrial levels, that improves cardiac energy production by a metabolic switch, via inhibition of fatty acids oxidation towards activation of glucose oxidation, which protects the ischaemic heart.11-13 TRIMPOL (TRIMetazidine in POLand) studies,14,15 showed a decrease in the mean number of angina attacks, an improvement in exercise tolerance and a reduction in nitrate consumption during treatment with trimetazidine in combination with conventional drugs, for diabetics with CAD. Ranolazine is a similar drug used in the treatment of patients with severe chronic angina.16 Contrary to the haemodynamic drugs, these substances act directly on heart metabolism and are the most promising therapeutic agents for the treatment of angina pectoris without coronary obstruction.17,18

Impaired ventricular function can be evaluated by Doppler echocardiography to calculate the Index of Myocardial Performance (IMP). This method was first employed by Tei et al. 19-21 The aim of this study was to compare the degree of left ventricular dysfunction in diabetics with AMI to non diabetic controls. The effects of trimetazidine when added to the conventional anti-ischaemic and antidiabetic drugs on IMP and other time intervals of the cardiac cycle were also evaluated.

Subjects and Methods

One hundred and forty nine non-diabetic patients (98 M and 51 F) aged between 48 and 72 years with their first episode of AMI, but without signs of previous cardiovascular and/or respiratory diseases were enrolled (group I). One hundred and fifty one diabetics (102 M and 49 F), with ages ranged from 49 to 73 years with recent, first AMI and without other cardiac disease were included in the study (group II). For admission to study, both non-diabetic controls and diabetic patients needed to satisfy the following criteria: typical acute chest pain; acute ischaemic changes of ST-T tract in at least two continuous electrocardiographic leads; transient rise of troponine or creatinine-kinase that is significant for myocardial necrosis. Exclusion criteria were: atrial fibrillation; sinus tachycardia >100 beats/min; arterial pressure >130/80 mmHg and valvular diseases.

At hospital discharge, both controls and diabetics received an anti-thrombotic drug (Aspirin-100 mg or Clopidogrel-75 mg), an ACE-inhibitor (Lisinopril-5 mg), a nitroderivative drug and an oral hypoglycaemic agent or insulin-therapy if diabetic. The time-interval between AMI and the enrolment in the study was 10±3 days. All patients in the two groups underwent Doppler two-dimensional echocardiography, using a commercially available ultrasound machine (ATL 5000, HDI). LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) were estimated from standard apical 4-chamber views. Ejection Fraction (EF) was measured according to Simpson’s biplane disk method.22 WMSI was calculated using criteria from the American Society of Echocardiography.22 Three to five consecutive beats were measured and averaged. IMP was obtained from the inflow tract and outflow tract of left ventricle. The distance between the cessation of mitral flow to the onset of following mitral flow is the sum of Isovolumetric Contraction Time (ICT), Isovolumetric Relaxation Time (IRT) and Ejection Time (ET) and was defined as a. The distance between the onset and the end of aortic flow is ET and was defined as b. IMP was obtained according to the  formula: (a - b) / b

ICT and IRT were also separately measured. After the baseline echocardiographic studies, group II patients were randomly assigned to trimetazidine therapy (subgroup IIa) or placebo (subgroup IIb) groups. The randomization criteria were: the clinical status, the ECG-AMI-extension, EF, WMSI, age, sex blood glucose-levels. The same Doppler evaluations were also performed in two subgroups of diabetics after 12 months. All of the echocardiographic examinations were repeated by the same sonographers, without the knowledge of subgroup assignment.

Statistical analysis
The means ± SD of IMP, ICT, IRT, and ET were calculated after AMI, in both the control group (group I) and diabetics (group II). These were compared using the Student-t-test for unpaired data. A p value < 0.05 was considered significant. The same evaluations were performed twelve months later in subgroups Ia and IIb patients.

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