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.
OBJECTIVE
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.
Fragasso
Gabriele
G
Dipartimento di Cardiologia e Scienze Cardiovascolari-Unita' di Cardiologia Clinica, Universita' degli Studi di Milano, Istituto Scientifico/Universita' San Raffaele, Milan, Italy. gabriele.fragasso@hsr.it
Piatti
Pier Marco
PM
Monti
Lucilla
L
Palloshi
Altin
A
Lu
Chunzeng
C
Valsecchi
Gianpietro
G
Setola
Emanuela
E
Calori
Giliola
G
Pozza
Guido
G
Margonato
Alberto
A
Chierchia
Sergio
S
D000368:Aged; D000704:Analysis of Variance; D000925:Anticoagulants / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D004562:Electrocardiography; D019332:Endothelin-1 / Q000097:blood / Q000187:drug effects; D005080:Exercise Test; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006339:Heart Rate / Q000187:drug effects; D006493:Heparin / Q000008:administration & dosage*; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood; D012684:Sensory Thresholds / Q000187:drug effects*; D016896:Treatment Outcome; D014292:Trimetazidine / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000627:therapeutic use
D000925:Anticoagulants; D015415:Biomarkers; D019332:Endothelin-1; D005230:Fatty Acids, Nonesterified; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019344:Lactic Acid; D006493:Heparin; D014292:Trimetazidine