Peri-interventional endothelin--a receptor blockade improves long-term outcome in patients with ST-elevation acute myocardial infarction.
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.
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Adlbrecht
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Wurm
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Humenberger
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Andreas
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Redwan
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Distelmaier
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Klappacher
Irene M. Lang, MD, Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria, Tel.: +431 40 400 4614, Fax: +431 40 400 4216, E-mail: irene.lang@meduniwien.ac.at.
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D000368:Aged; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D005109:Extracellular Matrix / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000009:adverse effects; D062645:Percutaneous Coronary Intervention; D059035:Perioperative Period; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism*; D016019:Survival Analysis; D016896:Treatment Outcome
D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D009195:Peroxidase; D020780:Matrix Metalloproteinase 9; C072247:cyclo(Trp-Asp-Pro-Val-Leu)
Acute myocardial infarction; BQ-123; clinical outcome; endothelin; percutaneous coronary intervention; remodelling