Role of endothelin in microvascular dysfunction following percutaneous coronary intervention for non-ST elevation acute coronary syndromes: a single-centre randomised controlled trial

Objectives Percutaneous coronary intervention (PCI) for acute coronary syndromes frequently fails to restore myocardial perfusion despite establishing epicardial vessel patency. Endothelin-1 (ET-1) is a potent vasoconstrictor, and its expression is increased in atherosclerosis and after PCI. In this study, we aim to define the role of endothelin in regulating coronary microvascular blood flow and myocardial perfusion following PCI in patients with non-ST elevation acute coronary syndromes (NSTACS), by assessing whether adjunctive therapy with a selective endothelin A (ETA) receptor antagonist acutely improves postprocedural coronary microvascular blood flow. Methods In a randomised, double-blinded, placebo-controlled trial, 23 NSTACS patients were enrolled to receive an intracoronary infusion of placebo (n=11) or BQ-123 (n=12) immediately before PCI. Post-PCI coronary microvascular blood flow and myocardial perfusion were assessed by measuring Doppler-derived average peak velocity (APV), and cardiac biomarker levels were quantified. Results Compared with the placebo group, APV was significantly higher in the drug group immediately after PCI (30 (20, 37) vs 19 (9, 26) cm/s; p=0.03). Hyperaemic APV, measured post-adenosine administration, was higher in the BQ-123 group, but the difference did not achieve statistical significance (56 (48, 72) vs 46 (34, 64) cm/s; p=0.090). Maximum coronary flow reserve postprocedure was not different between the two groups (2.1 (1.6, 2.3) vs 2.5 (1.8, 3.0)). Per cent change in creatine kinase isoenzyme MB from the time of PCI to 8 and 16 hours post-PCI was significantly lower in the drug group compared with the placebo group (−17 (−26, −10) vs 26 (−15, 134); p=0.02 and −17 (−38, 14) vs 107 (2, 446); p=0.007, respectively). Conclusions Endothelin is a mediator of microvascular dysfunction during PCI in NSTACS, and adjunctive selective ETA antagonist may augment myocardial perfusion during PCI. Trial registration number NCT00586820; Results.

[1]  A. Kaider,et al.  Systemic endothelin receptor blockade in ST-segment elevation acute coronary syndrome protects the microvasculature: a randomised pilot study. , 2012, EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology.

[2]  S. Neubauer,et al.  Systemic levels of endothelin correlate with systemic inflammation and not with myocardial injury or left ventricular ejection fraction in patients undergoing percutaneous coronary intervention and on-pump coronary artery bypass grafting. , 2011, Interactive cardiovascular and thoracic surgery.

[3]  B. Gersh,et al.  Reperfusion Injury, Microvascular Dysfunction, and Cardioprotection: The “Dark Side” of Reperfusion , 2009, Circulation.

[4]  B. Gersh,et al.  Mortality differences between men and women after percutaneous coronary interventions. A 25-year, single-center experience. , 2008, Journal of the American College of Cardiology.

[5]  A. Furber,et al.  Coronary Blood Flow Assessment After Successful Angioplasty for Acute Myocardial Infarction Predicts the Risk of Long-Term Cardiac Events , 2004, Circulation.

[6]  S. Baldassarre,et al.  Elevations in Troponin I After Percutaneous Coronary Interventions Are Associated With Abnormal Tissue-Level Perfusion in High-Risk Patients With Non–ST-Segment–Elevation Acute Coronary Syndromes , 2004, Circulation.

[7]  M. Mora.  Open Heart , 2003, Annals of Internal Medicine.

[8]  T. Akasaka,et al.  Coronary Flow Velocity Pattern Immediately After Percutaneous Coronary Intervention as a Predictor of Complications and In-Hospital Survival After Acute Myocardial Infarction , 2002, Circulation.

[9]  C. Di Mario,et al.  Effects of selective alpha1- and alpha2-adrenergic blockade on coronary flow reserve after coronary stenting. , 2002, Circulation.

[10]  C. Cannon,et al.  Elevations in Troponin T and I Are Associated With Abnormal Tissue Level Perfusion: A TACTICS-TIMI 18 Substudy , 2002, Circulation.

[11]  A. Quyyumi,et al.  Coronary Vasodilation and Improvement in Endothelial Dysfunction With Endothelin ETA Receptor Blockade , 2001, Circulation research.

[12]  D. Webb,et al.  Systemic ETA receptor antagonism with BQ‐123 blocks ET‐1 induced forearm vasoconstriction and decreases peripheral vascular resistance in healthy men , 2001, British journal of pharmacology.

[13]  P. Ganz,et al.  Role of Endothelin-1 in the Active Constriction of Human Atherosclerotic Coronary Arteries , 2001, Circulation.

[14]  B. Prendergast,et al.  The physiological role of endogenous endothelin in the regulation of human coronary vasomotor tone. , 2001, Journal of the American College of Cardiology.

[15]  A. DeMaria,et al.  Ischemia-Reperfusion Injury at the Microvascular Level: Treatment by Endothelin A–Selective Antagonist and Evaluation by Myocardial Contrast Echocardiography , 2000, Circulation.

[16]  D. Webb,et al.  Endogenous endothelin maintains coronary artery tone by endothelin type A receptor stimulation in patients undergoing coronary arteriography , 2000, Heart.

[17]  T Akasaka,et al.  Relation of phasic coronary flow velocity characteristics with TIMI perfusion grade and myocardial recovery after primary percutaneous transluminal coronary angioplasty and rescue stenting. , 2000, Circulation.

[18]  R. de Caterina,et al.  Endothelin-1 release from atherosclerotic plaque after percutaneous transluminal coronary angioplasty in stable angina pectoris and single-vessel coronary artery disease. , 1999, The American journal of cardiology.

[19]  C. Heeschen,et al.  Angiographic findings in patients with refractory unstable angina according to troponin T status. , 1999, Circulation.

[20]  T. Kawamoto,et al.  Can Coronary Blood Flow Velocity Pattern After Primary Percutaneous Transluminal Coronary Angiography Predict Recovery of Regional Left Ventricular Function in Patients With Acute Myocardial Infarction , 1999 .

[21]  A. Jaffe,et al.  2001--a biomarker odyssey. , 1999, Clinica chimica acta; international journal of clinical chemistry.

[22]  T. Kawamoto,et al.  Can coronary blood flow velocity pattern after primary percutaneous transluminal coronary angioplasty [correction of angiography] predict recovery of regional left ventricular function in patients with acute myocardial infarction? , 1999, Circulation.

[23]  R. Califf,et al.  Myonecrosis after revascularization procedures. , 1998, Journal of the American College of Cardiology.

[24]  Y Nishikawa,et al.  Contribution of nitric oxide to metabolic coronary vasodilation in the human heart. , 1997, Circulation.

[25]  W. Edwards,et al.  Mechanical pressure and stretch release endothelin-1 from human atherosclerotic coronary arteries in vivo. , 1997, Circulation.

[26]  A. Lerman,et al.  The role of endothelin in coronary atherosclerosis. , 1996, Mayo Clinic proceedings.

[27]  M. Bell,et al.  Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans. , 1995, Circulation.

[28]  D. Baim,et al.  Incidence and treatment of 'no-reflow' after percutaneous coronary intervention. , 1994, Circulation.

[29]  R. T. Lie,et al.  Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. , 1994, Circulation.

[30]  S. Kaul,et al.  Effect of percutaneous transluminal coronary angioplasty on circulating endothelin levels. , 1993, The American journal of cardiology.

[31]  L. Malatino,et al.  Release of immunoreactive endothelin from the heart during percutaneous transluminal coronary angioplasty. , 1993, American heart journal.

[32]  D. Webb,et al.  The endothelin family of peptides: local hormones with diverse roles in health and disease? , 1993, Clinical science.

[33]  H. M. Payne,et al.  Validation of A Doppler Guide Wire for Intravascular Measurement of Coronary Artery Flow Velocity , 1992, Circulation.

[34]  J. Mair,et al.  Early detection of acute myocardial infarction by measurement of mass concentration of creatine kinase-MB. , 1991, The American journal of cardiology.

[35]  A. Lerman,et al.  Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. , 1991, The New England journal of medicine.

[36]  F. Klocke,et al.  Measurements of coronary flow reserve: defining pathophysiology versus making decisions about patient care. , 1987, Circulation.