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Thromb Haemost 2014; 112(01): 176-182
DOI: 10.1160/TH13-10-0832
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Peri-interventional endothelin-A receptor blockade improves long-term outcome in patients with ST-elevation acute myocardial infarction

Christopher Adlbrecht   *
1   Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
,
Raphael Wurm   *
1   Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
,
Michael Humenberger
2   Department of Trauma Surgery, Medical University of Vienna, Vienna, Austria
,
Martin Andreas
3   Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
,
Bassam Redwan
1   Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
,
Klaus Distelmaier
1   Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
,
Günter Klappacher
1   Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
,
Irene M. Lang
1   Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
› Author Affiliations Financial support: The study was supported by funds of the Oesterreichische Nationalbank (Anniversary Fund, project number: #12758) to CA, the Austrian Society of Cardiology to CA (2005, 2009 and 2014) and the Hans und Blanca Moser Stiftung to BR (2007). There are no conflicts of interest.
Further Information

Publication History

Received: 09 October 2013

Accepted after major revision: 08 February 2014

Publication Date:
01 December 2017 (online)

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Summary

Endothelin (ET)-1 is a pro-fibrotic vasoconstrictive peptide causing microvascular dysfunction and cardiac remodelling after acute ST-elevation myocardial infarction (STEMI). It acts via two distinct receptors, ET-A and ET-B, and is involved in inflammation and atherogenesis. Patients with posterior-wall STEMI were randomly assigned to intravenous BQ-123 at 400 nmol/minute (min) or placebo over 60 min, starting immediately prior to primary percutaneous coronary intervention (n=54). Peripheral blood samples were drawn at baseline as well as after 24 hours and 30 days. Myeloperoxidase (MPO), as a marker of neutrophil activation and matrix metalloproteinase 9 (MMP-9), a marker of extracellular matrix degradation were measured in plasma. Clinical follow-up was conducted by an investigator blinded to treatment allocation over three years. During the median follow-up period of 3.6 years (interquartile range [IQR] 3.3–4.1) we observed a longer event-free survival in patients randomised to receive BQ-123 compared with patients randomised to placebo (mean 4.5 years (95% confidence interval: 3.9–5) versus mean 3 years (2.2–3.7), p=0.031). Patients randomised to ET-A receptor blockade demonstrated a greater reduction of MPO levels from baseline to 24 hours compared to placebo-treated patients (-177 ng/ml (IQR 103–274) vs –108 ng/ml (74–147), p=0.006). In addition, a pronounced drop in MMP-9 levels (-568 ng/ml (44–1157) vs –117 ng/ml (57–561), p=0.018) was observed. There was no significant difference in amino-terminal propetide of pro-collagen type III levels. In conclusion, short-term administration of BQ-123 leads to a reduction in MPO, as well as MMP-9 plasma levels and to a longer event-free survival in patients with STEMI.

ClinicalTrials.gov Identifier: NCT00502528

Keywords

Acute myocardial infarction - endothelin - BQ-123 - percutaneous coronary intervention - remodelling - clinical outcome

* CA and RW contributed equally to this work.


 

  • References

  • 1 Yanagisawa M, Kurihara H, Kimura S. et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411-415.
    CrossrefPubMedSearch in Google Scholar
  • 2 Russell FD, Davenport AP. Secretory pathways in endothelin synthesis. Br J Pharmacol 1999; 126: 391-398.
    CrossrefPubMedSearch in Google Scholar
  • 3 Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol 2001; 41: 851-876.
    CrossrefPubMedSearch in Google Scholar
  • 4 Adlbrecht C, Bonderman D, Plass C. et al. Active endothelin is an important vasoconstrictor in acute coronary thrombi. Thromb Haemost 2007; 97: 642-649.
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Lerman A, Edwards BS, Hallett JW. et al. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 1991; 325: 997-1001.
    CrossrefPubMedSearch in Google Scholar
  • 6 Niccoli G, Lanza GA, Shaw S. et al. Endothelin-1 and acute myocardial infarction: a no-reflow mediator after successful percutaneous myocardial revascularization. Eur Heart J 2006; 27: 1793-1798.
    CrossrefPubMedSearch in Google Scholar
  • 7 Bogoyevitch MA, Glennon PE, Andersson MB. et al. Endothelin-1 and fibrob-last growth factors stimulate the mitogen-activated protein kinase signaling cascade in cardiac myocytes.The potential role of the cascade in the integration of two signaling pathways leading to myocyte hypertrophy. J Biol Chem 1994; 269: 1110-1119.
    PubMedSearch in Google Scholar
  • 8 Eitel I, Nowak M, Stehl C. et al. Endothelin-1 release in acute myocardial infarction as a predictor of long-term prognosis and no-reflow assessed by contrast-enhanced magnetic resonance imaging. Am Heart J 2010; 159: 882-890.
    CrossrefPubMedSearch in Google Scholar
  • 9 Omland T, Lie RT, Aakvaag A. et al. Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation 1994; 89: 1573-1579.
    CrossrefPubMedSearch in Google Scholar
  • 10 Yip HK, Wu CJ, Chang HW. et al. Prognostic value of circulating levels of endothelin-1 in patients after acute myocardial infarction undergoing primary coronary angioplasty. Chest 2005; 127: 1491-1497.
    CrossrefPubMedSearch in Google Scholar
  • 11 Arai H, Hori S, Aramori I. et al. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990; 348: 730-732.
    CrossrefPubMedSearch in Google Scholar
  • 12 Sakurai T, Yanagisawa M, Takuwa Y. et al. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 1990; 348: 732-735.
    CrossrefPubMedSearch in Google Scholar
  • 13 Barton M, Haudenschild CC, d’Uscio LV. et al. Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice. Proc Natl Acad Sci USA 1998; 95: 14367-14372.
    CrossrefPubMedSearch in Google Scholar
  • 14 Iwasa S, Fan J, Miyauchi T. et al. Blockade of endothelin receptors reduces dietinduced hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice. Pathobiology 2001; 69: 1-10.
    CrossrefPubMedSearch in Google Scholar
  • 15 Carbone F, Nencioni A, Mach F. et al. Pathophysiological role of neutrophils in acute myocardial infarction. Thromb Haemost 2013; 110: 501-514.
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Distelmaier K, Adlbrecht C, Jakowitsch J. et al. Local complement activation triggers neutrophil recruitment to the site of thrombus formation in acute myocardial infarction. Thromb Haemost 2009; 102: 564-572.
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Toffoli MC, Gabra BH, Teixeira CF. et al. Endothelins mediate neutrophil activation, ProMMP-9 release and endothelial cell detachment. Inflammation 2007; 30: 28-37.
    CrossrefPubMedSearch in Google Scholar
  • 18 Webb CS, Bonnema DD, Ahmed SH. et al. Specific temporal profile of matrix metalloproteinase release occurs in patients after myocardial infarction: relation to left ventricular remodeling. Circulation 2006; 114: 1020-1027.
    CrossrefPubMedSearch in Google Scholar
  • 19 Kelly D, Cockerill G, Ng LL. et al. Plasma matrix metalloproteinase-9 and left ventricular remodelling after acute myocardial infarction in man: a prospective cohort study. Eur Heart J 2007; 28: 711-718.
    CrossrefPubMedSearch in Google Scholar
  • 20 Ozdemir R, Parlakpinar H, Polat A. et al. Selective endothelin a (ETA) receptor antagonist (BQ-123) reduces both myocardial infarct size and oxidant injury. Toxicology 2006; 219: 142-149.
    CrossrefPubMedSearch in Google Scholar
  • 21 Nguyen QT, Cernacek P, Calderoni A. et al. Endothelin A receptor blockade causes adverse left ventricular remodeling but improves pulmonary artery pressure after infarction in the rat. Circulation 1998; 98: 2323-2330.
    CrossrefPubMedSearch in Google Scholar
  • 22 Alberola Aguilar AM, Revert F, Moya A. et al. Intravenous BQ-123 and phosphoramidon reduce ventricular ectopic beats and myocardial infarct size in dogs submitted to coronary occlusion and reperfusion. Gen Pharmacol 2000; 35: 143-147.
    CrossrefPubMedSearch in Google Scholar
  • 23 Maxwell L, Harrison WR, Gavin JB. Endothelin antagonists diminish postischemic microvascular incompetence and necrosis in the heart. Microvasc Res 2000; 59: 204-212.
    CrossrefPubMedSearch in Google Scholar
  • 24 Adlbrecht C, Andreas M, Redwan B. et al. Systemic endothelin receptor blockade in ST-segment elevation acute coronary syndrome protects the microvasculature: a randomised pilot study. EuroIntervention 2012; 07: 1386-1395.
    CrossrefPubMedSearch in Google Scholar
  • 25 Reriani M, Raichlin E, Prasad A. et al. Long-term administration of endothelin receptor antagonist improves coronary endothelial function in patients with early atherosclerosis. Circulation 2010; 122: 958-966.
    CrossrefPubMedSearch in Google Scholar
  • 26 Raichlin E, Prasad A, Mathew V. et al. Efficacy and safety of atrasentan in patients with cardiovascular risk and early atherosclerosis. Hypertension 2008; 52: 522-528.
    CrossrefPubMedSearch in Google Scholar
  • 27 Jaovisidha P, Peeples ME, Brees AA, Carpenter LR, Moy JN. Respiratory syncytial virus stimulates neutrophil degranulation and chemokine release. J Immunol 1999; 163: 2816-2820.
    PubMedSearch in Google Scholar
  • 28 Peake J, Wilson G, Hordern M. et al. Changes in neutrophil surface receptor expression, degranulation, and respiratory burst activity after moderate- and high-intensity exercise. Journal of applied physiology 2004; 97: 612-8.
    CrossrefPubMedSearch in Google Scholar
  • 29 Poulsen SH, Host NB, Jensen SE. et al. Relationship between serum amino-terminal propeptide of type III procollagen and changes of left ventricular function after acute myocardial infarction. Circulation 2000; 101: 1527-1532.
    CrossrefPubMedSearch in Google Scholar
  • 30 Spratt JC, Goddard J, Patel N. et al. Systemic ETA receptor antagonism with BQ-123 blocks ET-1 induced forearm vasoconstriction and decreases peripheral vascular resistance in healthy men. Br J Pharmacol 2001; 134: 648-654.
    CrossrefPubMedSearch in Google Scholar
  • 31 Kalla K, Christ G, Karnik R. et al. Implementation of guidelines improves the standard of care: the Viennese registry on reperfusion strategies in ST-elevation myocardial infarction (Vienna STEMI registry). Circulation 2006; 113: 2398-2405.
    CrossrefPubMedSearch in Google Scholar
  • 32 Verma A, Meris A, Skali H. et al. Prognostic implications of left ventricular mass and geometry following myocardial infarction: the VALIANT (VALsartan In Acute myocardial iNfarcTion) Echocardiographic Study. JACC Cardiovasc Imag 2008; 01: 582-591.
    CrossrefPubMedSearch in Google Scholar
  • 33 Pitt B, Latini R, Maggioni AP. et al. Neurohumoral effects of aliskiren in patients with symptomatic heart failure receiving a mineralocorticoid receptor antagonist: the Aliskiren Observation of Heart Failure Treatment study. Eur J Heart Fail 2011; 13: 755-764.
    CrossrefPubMedSearch in Google Scholar
  • 34 Lau D, Mollnau H, Eiserich JP. et al. Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins. Proc Natl Acad Sci USA 2005; 102: 431-436.
    CrossrefPubMedSearch in Google Scholar
  • 35 Baldus S, Heeschen C, Meinertz T. et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation 2003; 108: 1440-1445.
    CrossrefPubMedSearch in Google Scholar
  • 36 Brennan ML, Penn MS, Van Lente F. et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003; 349: 1595-1604.
    CrossrefPubMedSearch in Google Scholar
  • 37 MacCarthy PA, Pegge NC, Prendergast BD, Shah AM, Groves PH. The physiological role of endogenous endothelin in the regulation of human coronary vasomotor tone. J Am Coll Cardiol 2001; 37: 137-143.
    CrossrefPubMedSearch in Google Scholar
  • 38 Halcox JP, Nour KR, Zalos G, Quyyumi AA. Coronary vasodilation and improvement in endothelial dysfunction with endothelin ET(A) receptor blockade. Circulation Res 2001; 89: 969-976.
    CrossrefPubMedSearch in Google Scholar
  • 39 Yoon MH, Reriani M, Mario G. et al. Long-term endothelin receptor antagonism attenuates coronary plaque progression in patients with early atherosclerosis. Int J Cardiol 2013; 168: 1316-1321.
    CrossrefPubMedSearch in Google Scholar
  • 40 Browatzki M, Pfeiffer CA, Schmidt J. et al. Endothelin-1 induces CD40 but not IL-6 in human monocytes via the proinflammatory transcription factor NFkappaB. Eur J Med Res 2005; 10: 197-201.
    PubMedSearch in Google Scholar
  • 41 Babaei S, Picard P, Ravandi A. et al. Blockade of endothelin receptors markedly reduces atherosclerosis in LDL receptor deficient mice: role of endothelin in macrophage foam cell formation. Cardiovasc Res 2000; 48: 158-167.
    CrossrefPubMedSearch in Google Scholar
  • 42 Morand-Contant M, Anand-Srivastava MB, Couture R. Kinin B1 receptor upregulation by angiotensin II and endothelin-1 in rat vascular smooth muscle cells: receptors and mechanisms. Am J Physiol Heart Circul Physiol 2010; 299: H1625-1232.
    CrossrefPubMedSearch in Google Scholar
  • 43 Fraccarollo D, Hu K, Galuppo P. et al. Chronic endothelin receptor blockade attenuates progressive ventricular dilation and improves cardiac function in rats with myocardial infarction: possible involvement of myocardial endothelin system in ventricular remodeling. Circulation 1997; 96: 3963-3973.
    CrossrefPubMedSearch in Google Scholar
  • 44 Clozel M, Qiu C, Qiu CS. et al. Short-term endothelin receptor blockade with te-zosentan has both immediate and long-term beneficial effects in rats with myocardial infarction. J Am Coll Cardiol 2002; 39: 142-147.
    PubMedSearch in Google Scholar
  • 45 Rodriguez-Vita J, Ruiz-Ortega M, Ruperez M. et al. Endothelin-1, via ETA receptor and independently of transforming growth factor-beta, increases the connective tissue growth factor in vascular smooth muscle cells. Circulation Res 2005; 97: 125-134.
    CrossrefPubMedSearch in Google Scholar
  • 46 Katwa LC, Guarda E, Weber KT. Endothelin receptors in cultured adult rat cardiac fibroblasts. Cardiovasc Res 1993; 27: 2125-2129.
    CrossrefPubMedSearch in Google Scholar
  • 47 Nguyen QT, Cernacek P, Sirois MG. et al. Long-term effects of nonselective endothelin A and B receptor antagonism in postinfarction rat: importance of timing. Circulation 2001; 104: 2075-2081.
    CrossrefPubMedSearch in Google Scholar
  • 48 Fraccarollo D, Galuppo P, Bauersachs J, Ertl G. Collagen accumulation after myocardial infarction: effects of ETA receptor blockade and implications for early remodeling. Cardiovasc Res 2002; 54: 559-567.
    CrossrefPubMedSearch in Google Scholar
  • 49 Manhenke C, Orn S, von Haehling S. et al. Clustering of 37 circulating biomarkers by exploratory factor analysis in patients following complicated acute myocardial infarction. Int J Cardiol 2013; 166: 729-735.
    CrossrefPubMedSearch in Google Scholar
  • 50 Adlbrecht C, Wurm R, Pezawas T. et al. Effects of endothelin A receptor blockade in patients with ST-elevation acute coronary syndrome - A rhythmologic substudy. Life Sci. 2014 Epub ahead of print.
    PubMedSearch in Google Scholar