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

Abstract

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.

Role of the endothelin system in sexual dimorphism in cardiovascular and renal diseases

“…ET-1 induces proinflammatory mechanisms, superoxide anion production, cytokine secretion [29, 30], endoplasmic reticulum stress [31], and synthesis of cell adhesion molecules, such as soluble ICAM-1 [28]. Several studies have suggested a potential interaction between the ET and the immune systems in the pathogenesis of pulmonary hypertension [29], portal hypertension [32, 33], preeclampsia (elevated blood pressure in pregnancy) [34, 35], and myocardial infarction [36]. For example, TNF-α is an important stimulus for ET-1 in response to placental ischemia during preeclampsia [34].…”

“…In addition, chronic exposure to activated CD4(+) T cells in response to placental ischemia results in ET-1 activation as a mechanism to increase blood pressure during pregnancy [35]. In myocardial infarction patients, BQ-123 leads to reduction in plasma myeloperoxidase (MPO), a marker of neutrophil activation [36]. …”