Background: The no-reflow (NR) phenomenon exists despite percutaneous coronary intervention (PCI), and is especially prevalent in diabetics. The causes(s) of NR are not fully elucidated, but may be associated with impaired residual platelet and inflammatory reactivity during dual-antiplatelet therapy. Objective: To assess the relationship between dual-antiplatelet therapy, NR and conventional biomarkers suggestive of platelet and inflammatory response in diabetics following ST-segment elevation myocardial infarction (STEMI) treated with PCI. Methods: Sixty diabetics with (n = 27) and without NR (n = 33) were prospectively enrolled. All patients were treated with clopidogrel and aspirin. Platelet and inflammatory biomarkers were assessed serially in the peripheral blood and right atrium before and after PCI and then at 24 h, 7 days and 30 days. Results: Arachidonic acid (AA)-induced platelet aggregation and the serum thromboxane B2 level before and after PCI (in the peripheral and right atrium blood) were significantly higher in the NR patients than in those with no NR. AA-induced aggregation >100 (AUC*min) before PCI predicted NR in diabetic patients with 96.2% sensitivity and 38.5% specificity (AUC 0.66; 95% CI 0.52-0.71; p = 0.029). There were no other correlations between NR and platelet reactivity (collagen, adenosine diphosphate, thrombin receptor agonist peptide-induced aggregation, vasodilator-stimulated phosphoprotein platelet reactivity index, soluble P-selectin, soluble CD40 ligand, platelet-derived growth factor AB and the level of platelet-monocyte aggregates) or between NR and inflammatory indices (i.e. high-sensitivity C-reactive protein, interleukin 6 and interleukin 10). Conclusion: An inadequate response to aspirin, but not to clopidogrel, may be associated with the occurrence of the NR phenomenon in diabetics with STEMI who have been treated with primary PCI.

Jaffe R, Dick A, Strauss BH: Prevention and treatment of microvascular obstruction-related myocardial injury and coronary no-reflow following percutaneous coronary intervention: a systematic approach. JACC Cardiovasc Interv 2010;3:695-704.
Niccoli G, Burzotta F, Galiuto L, Crea F: Myocardial no-reflow in humans. J Am Coll Cardiol 2009;54:281-292.
Iwakura K, Ito H, Kawano S, Okamura A, Kurotobi T, Date M, et al: Chronic pretreatment of statins is associated with the reduction of the no-reflow phenomenon in the patients with reperfused acute myocardial infarction. Eur Heart J 2006;27:534-539.
Henriques JP, Zijlstra F, van ‘t Hof AW, de Boer MJ, Dambrink JH, Gosselink M, et al: Angiographic assessment of reperfusion in acute myocardial infarction by myocardial blush grade. Circulation 2003;107:2115-2119.
Ndrepepa G, Tiroch K, Fusaro M, Keta D, Seyfarth M, Byrne RA, et al: 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction. J Am Coll Cardiol 2010;55:2383-2389.
Niccoli G, Giubilato S, Russo E, Spaziani C, Leo A, Porto I, et al: Plasma levels of thromboxane A2 on admission are associated with no-reflow after primary percutaneous coronary intervention. Eur Heart J 2008;29:1843-1850.
Campo G, Valgimigli M, Gemmati D, Percoco G, Tognazzo S, Cicchitelli G, et al: Value of platelet reactivity in predicting response to treatment and clinical outcome in patients undergoing primary coronary intervention: insights into the STRATEGY study. J Am Coll Cardiol 2006;48:2178-2185.
Oduncu V, Tanalp AC, Erkol A, Sirma D, Dundar C, Akgun T, et al: Impact of chronic pre-treatment of statins on the level of systemic inflammation and myocardial perfusion in patients undergoing primary angioplasty. Am J Cardiol 2011;107:179-185.
Niccoli G, Lanza GA, Shaw S, Romagnoli E, Gioia D, Burzotta F, et al: Endothelin-1 and acute myocardial infarction: a no-reflow mediator after successful percutaneous myocardial revascularization. Eur Heart J 2006;27:1793-1798.
Takahashi T, Hiasa Y, Ohara Y, Miyazaki S, Ogura R, Miyajima H, et al: Relation between neutrophil counts on admission, microvascular injury, and left ventricular functional recovery in patients with an anterior wall first acute myocardial infarction treated with primary coronary angioplasty. Am J Cardiol 2007;100:35-40.
Yip HK, Chen MC, Chang HW, Hang CL, Hsieh YK, Fang CY, et al: Angiographic morphologic features of infarct-related arteries and timely reperfusion in acute myocardial infarction: predictors of slow-flow and no-reflow phenomenon. Chest 2002;122:1322-1332.
McLaughlin MG, Stone GW, Aymong E, Gardner G, Mehran R, Lansky AJ, et al: Prognostic utility of comparative methods for assessment of ST-segment resolution after primary angioplasty for acute myocardial infarction: the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. J Am Coll Cardiol 2004;44:1215-1223.
Sorajja P, Gersh BJ, Costantini C, McLaughlin MG, Zimetbaum P, Cox DA, et al: Combined prognostic utility of ST-segment recovery and myocardial blush after primary percutaneous coronary intervention in acute myocardial infarction. Eur Heart J 2005;26:667-674.
Van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist C, Crea F, Falk V, et al: Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008;29:2909-2945.
Gibson CM, Cannon CP, Murphy SA, Ryan KA, Mesley R, Marble SJ, et al: Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation 2000;101:125-130.
Aleil B, Meyer N, Cazenave JP, Mossard JM, Gachet C: High stability of blood samples for flow cytometric analysis of VASP phosphorylation to measure the clopidogrel responsiveness in patients with coronary artery disease. Thromb Haemost 2005;94:886-887.
Schwarz UR, Geiger J, Walter U, Eigenthaler M: Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets - definition and detection of ticlopidine/clopidogrel effects. Thromb Haemost 1999;82:1145-1152.
Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R, et al: Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010;56:919-933.
Angiolillo DJ: Antiplatelet therapy in diabetes: efficacy and limitations of current treatment strategies and future directions. Diabetes Care 2009;32:531-540.
Zmudka K, Zalewski J, Przewlocki T, Zajdel W, Czunko P, Durak M, et al: The degree of restored myocardial perfusion in acute myocardial infarction influences immediate and long-term results of primary coronary angioplasty. Kardiol Pol 2004;61:316-327.
Martinez-Rios MA, Rosas M, Gonzalez H, Pena-Duque MA, Martinez-Sanchez C, Gaspar J, et al: Comparison of reperfusion regimens with or without tirofiban in ST-elevation acute myocardial infarction. Am J Cardiol 2004;93:280-287.
Zhang Q, Shen J, Zhang RY, Qiu JP, Lu JD, Zhang Y, et al: Outcomes after primary coronary intervention with drug-eluting stent implantation in diabetic patients with acute ST elevation myocardial infarction. Chin Med J (Engl ) 2007;120:1862-1867.
Hovens MM, Snoep JD, Eikenboom JC, van der Bom JG, Mertens BJ, Huisman MV: Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review. Am Heart J 2007;153:175-181.
Kuliczkowski W, Witkowski A, Polonski L, Watala C, Filipiak K, Budaj A, et al: Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J 2009;30:426-435.
Breet NJ, Van Werkum JW, Bouman HJ, Kelder JC, Ruven HJ, Bal ET, et al: Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 2010;303:754-762.
Santilli F, Rocca B, De CR, Lattanzio S, Pietrangelo L, Habib A, et al: Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin ‘resistance'. J Am Coll Cardiol 2009;53:667-677.
TRACER Executive and Steering Committees: The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial: study design and rationale. Am Heart J 2009;158:327-334.
Vanhoorelbeke K, Ulrichts H, Schoolmeester A, Deckmyn H: Inhibition of platelet adhesion to collagen as a new target for antithrombotic drugs. Curr Drug Targets Cardiovasc Haematol Disord 2003;3:125-140.
Niccoli G, Lanza GA, Spaziani C, Altamura L, Romagnoli E, Leone AM, et al: Baseline systemic inflammatory status and no-reflow phenomenon after percutaneous coronary angioplasty for acute myocardial infarction. Int J Cardiol 2007;117:306-311.
Ndrepepa G, Tiroch K, Keta D, Fusaro M, Seyfarth M, Pache J, et al: Predictive factors and impact of no reflow after primary percutaneous coronary intervention in patients with acute myocardial infarction. Circ Cardiovasc Interv 2010;3:27-33.
Wang J, Zhang S, Jin Y, Qin G, Yu L, Zhang J: Elevated levels of platelet-monocyte aggregates and related circulating biomarkers in patients with acute coronary syndrome. Int J Cardiol 2007;115:361-365.
Zhang SZ, Jin YP, Qin GM, Wang JH: Association of platelet-monocyte aggregates with platelet activation, systemic inflammation, and myocardial injury in patients with non-ST elevation acute coronary syndromes. Clin Cardiol 2007;30:26-31.
Pulcinelli FM, Riondino S, Celestini A, Pignatelli P, Trifirò E, Di Renzo L, Violi F: Persistent production of platelet thromboxane A2 in patients chronically treated with aspirin. J Thromb Haemost 2005;3:2784-2789.
Pignatelli P, Di Santo S, Barillà F, Gaudio C, Violi F: Multiple anti-atherosclerotic treatments impair aspirin compliance: effects on aspirin resistance. J Thromb Haemost 2008;6:1832-1834.
Niccoli G, Spaziani C, Marino M, Pontecorvo ML, Cosentino N, Bacà M, Porto I, Leone AM, Crea F: Effect of chronic aspirin therapy on angiographic thrombotic burden in patients admitted for a first ST-elevation myocardial infarction. Am J Cardiol 2010;105:587-591.
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