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CLINICAL STUDY: CORONARY ARTERY DISEASE

Acute effects of heparin administration on the ischemic threshold of patients with coronary artery disease

Evaluation of the protective role of the metabolic modulator trimetazidine

Gabriele Fragasso, MD^*,*, Pier Marco Piatti, MD, Lucilla Monti, MD, Altin Palloshi, MD^*, Chunzeng Lu, MD^*, Gianpietro Valsecchi, PhD, Emanuela Setola, MD, Giliola Calori, MD, Guido Pozza, MD, Alberto Margonato, MD, FESC^* and Sergio Chierchia, MD, FESC, FACC^*

^* Dipartimento di Cardiologia e Scienze Cardiovascolari-Unità di Cardiologia Clinica, Università degli Studi di Milano, Istituto Scientifico/Università San Raffaele, Milan, Italy
Cattedra di Clinica Medica, Università degli Studi di Milano, Istituto Scientifico/Università San Raffaele, Milan, Italy
Epidemiologia e Biostatistica, Università degli Studi di Milano, Istituto Scientifico/Università San Raffaele, Milan, Italy

Manuscript received December 27, 2000; revised manuscript received October 10, 2001, accepted October 31, 2001.

^* Reprint requests and correspondence: Dr. Gabriele Fragasso, Dipartimento di Cardiologia e Scienze Cardiovascolari, Istituto Scientifico/Università San Raffaele, Via Olgettina 60, 20132 Milan, Italy.
gabriele.fragasso{at}hsr.it

OBJECTIVES: We sought to assess the effects of heparin and the potential protective effects of trimetazidine (TMZ) on exercise performance, plasma nitric oxide (NO), endothelin-1 (ET-1) and free fatty acid (FFA) release in patients with stable coronary artery disease (CAD).

BACKGROUND: Heparin has been shown to reduce the ischemic threshold in patients with CAD. Trimetazidine may affect myocardial substrate utilization by shifting energy production from FFA to glucose oxidation.

METHODS: In four consecutive days, nine patients with CAD each received one of the following four regimens: 1) one tablet of placebo the evening before and at 8 AM and 4 PM on the day of the study, 10 ml of saline in a bolus 10 min before exercise, followed by an infusion of the same preparation; 2) placebo at the same times as in the first regimen, 5,000 IU of heparin 10 min before exercise, followed by 1,000 IU/h; 3) 20 mg TMZ at the same times as in the first regimen, 5,000 IU of heparin 10 min before exercise, followed by 1,000 IU/h; or 4) TMZ at the same times as in the first regimen, 10 ml of saline 10 min before exercise, followed by an infusion of the same preparation.

RESULTS: During placebo (test 2), heparin reduced the time to 1-mm ST-segment depression and prolonged the recovery time, as compared with the results of test 1. When heparin was administered after TMZ (test 3), the time to 1-mm ST-segment depression and the recovery time were similar to those recorded during saline (test 1). Finally, compared with all study phases, TMZ during saline (test 4) prolonged the time to 1 mm. No changes in NO release were found, whereas ET-1 was decreased at peak exercise and during recovery, when the patients were receiving TMZ (tests 3 and 4). Free fatty acids increased after heparin, both with placebo and TMZ.

CONCLUSIONS: In patients with CAD, heparin reduces the ischemic threshold. Trimetazidine reduces the effects of heparin, probably by inhibiting FFA oxidation and enhancing glucose metabolism. The concomitant novel observation of reduced ET-1 release is likely to be also dependent on TMZ-induced improvement of endothelial metabolism or reduction of myocardial ischemia.

Abbreviations and Acronyms   ANOVA   analysis of variance   ATP   adenosine triphosphate   CAD   coronary artery disease   ECG   electrocardiogram or electrocardiographic   ET-1   endothelin-1   FFA   free fatty acid   NO   nitric oxide   RIA   radioimmunoassay   RPP   rate–pressure product   TMZ   trimetazidine

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