Enhanced platelet/endothelial activation in depressed patients with acute coronary syndromes: evidence from recent clinical trials Victor L. Serebruany a , Alexander H. Glassman b , Alex I. Malinin a , David C. Sane c , Mitchell S. Finkel d , Ranga R. Krishnan e , Dan Atar f , Vladimir Lekht a and Christopher M. O’Connor e Platelets play a key role in the progression of acute coronary syndromes (ACS). Clinical depression alone is also associated with enhanced platelet activation. The purpose of this study was to compare concentrations of established biomarkers of enhanced platelet/endothelial activation in clinically depressed versus non-depressed patients enrolled in recent clinical trials for ACS. Two hundred and eighty-one baseline plasma samples from patients with acute myocardial infarction (ASSENT-2; n 41), with ACS (PRONTO; n 126) and with clinical depression plus previous acute coronary syndrome within 6 months (SADHART; n 64), and from normal healthy controls (n 50) were analyzed. Blood was drawn before applying any therapeutic strategies including interventions, thrombolytics, infusions, and selective serotonin re-uptake inhibitors. Platelet factor 4, â-thromboglobulin, platelet/ endothelial cell adhesion molecule-1, P-selectin, thromboxane, prostacyclin, vascular cell adhesion molecule-1, and E-selectin were measured by enzyme- linked immunosorbent assay by a single core laboratory. Patients with ACS exhibited a higher degree of platelet activation than controls independently of the presence of depression. Plasma levels of P-selectin, thromboxane, prostacyclin, and vascular cell adhesion molecule-1 were the highest in the acute myocardial infarction group when compared with ACS despite the presence or absence of clinical depression. Surprisingly, patients with ACS and depression exhibited the highest levels of platelet factor 4, â-thromboglobulin, and platelet/endothelial cell adhesion molecule-1 when compared with myocardial infarction or angina patients without clinical depression. E-selectin plasma level was constantly elevated compared with controls but did not differ among the groups dependent on the incidence of depression. The depressed plus ACS group had higher plasma levels of all biomarkers compared with the non-depressed patients. Retrospective analysis of the data from several clinical trials reveals that clinical depression is associated with enhanced activation of platelet/endothelial biomarkers even above the level expected in ACS. These findings may contribute to the unfavorable outcome associated with clinical depression in patients with ACS. Blood Coagul Fibrinolysis 14:563–567 & 2003 Lippincott Williams & Wilkins. Blood Coagulation and Fibrinolysis 2003, 14:563–567 Keywords: platelets, endothelium, biomarkers, depression, acute coronary syndromes, human a Sinai Center for Thrombosis Research, Johns Hopkins University, Baltimore, Maryland, b Columbia University, New York, New York, c Wake Forest University, Winston-Salem, North Carolina, d West Virginia University, Morgantown, West Virginia, e Duke University Medical Center, Durham, North Carolina, USA and f Aker University, Oslo, Norway. Correspondence and requests for reprints to Dr Victor L. Serebruany, Center for Thrombosis Research, Sinai Hospital of Baltimore, 2401 West Belvedere Avenue, Schapiro Research Building — R 202, Baltimore, MD 21215, USA. Tel: +1 410 601 5266; fax: +1 410 601 9061; e-mail: Heartdrug@aol.com Received 27 November 2002 Revised 7 March 2003 Accepted 18 March 2003 Introduction Platelet–endothelial activation plays a key role in the progression of acute coronary syndromes (ACS) includ- ing acute myocardial infarction (AMI), and unstable angina [1]. Acquired platelet dysfunction following coronary clot formation probably affects both short-term and long-term outcome in patients with ACS [2,3]. Clinical depression has recently been identified as an independent risk factor for increased mortality in patients following AMI [4,5]. Enhanced platelet– endothelial interactions has been suggested as a me- chanism that may contribute to this adverse association [6]. We sought to retrospectively compare concentra- tions of established biomarkers of platelet/endothelial activation in clinically depressed versus non-depressed patients enrolled in clinical trials for ACS. Methods Patients All studies were approved by the Investigational Re- view Board of Sinai Hospital. Results from the Assess- ment of the Safety and Efficacy of a New Thrombolytic Agent (ASSENT-2) study [7], the Plavix Reduction of New Thrombus Occurrence (PRONTO) study [8] and the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) [9] were in- Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Original article 563 0957–5235 & 2003 Lippincott Williams & Wilkins DOI: 10.1097/01.mbc.0000061336.06975.52