eComment: Endothelin-1 correlation with myocardial injury and no-reflow phenomenon

We read with great interest the study of Cuculi et al. [1]. Yet, in as many as 40% of patients, myocardial perfusion in the infarct-related artery territory is insufficient, thus negating the potential advantages of a successful restoration of epicardial coronary artery patency (2). This phenomenon, known as no-reflow, is associated with a high incidence of left ventricular (LV) failure and a poor prognosis. Several mechanisms responsible for no-reflow have been identified in experimental models, including extravascular compression, microvascular vasoconstriction, and platelet – leukocyte capillary plugging [2]. Reperfusion injury is a multifactorial process that focuses on coronary microcirculation [3]. Coronary endothelium is the most important regulator at this level. Endothelin-1 (ET-1) released by activated endothelial cells can favour no-reflow. The vasoconstrictor effects of ET-1 are mainly exerted on small-resistance coronary arteries; hence, enhanced release of ET-1 from ischaemia-reperfusion injured endothelium may result in intense and sustained microvascular constriction [2]. ET-1 levels increase 3–4 h after the onset of ST-elevation myocardial infarction (MI), peak within the first 24 h and remain elevated after 48 h. Notably, unstable plaques display a high content of ET-1 [3]. High ET-1 values after percutaneous interventions (PCI) have been linked to poor prognosis, including higher 30-day mortality [3]. Also, an up-regulation of ET-1 receptor has been demonstrated in the heart of MI patients and transcardiac extraction of ET-1 seems to play a significant role in modulating post-infarct LV remodelling [2]. Although clinical experience is still insufficient, animal models have associated endothelin receptor antagonists with significant reduction of ischemic reperfusion injury after AMI and improvement in myocardial protection after cardiac surgery [3]. Freixa et al. [3] demonstrated that higher ET-1 levels were significantly associated with microvascular obstruction (MO) and lower myocardial salvage index, but they did not find a significant association with infarct size, LVEF and BARI (bypass angioplasty revascularization investigation area) at risk. A possible explanation is that ET-1 levels were more likely to be associated with the reperfusion outcomes of a specific area at risk. Niccoli et al. [2] revealed that in patients admitted with ST-elevation MI, ET-1 plasma levels predict angiographic no-reflow after successful primary or rescue PCI. Thus, an anterior location of AMI was also an independent predictor of no-reflow. This might be due to a greater area at risk and in turn to more extensive microvascular damage. In line with this interpretation, peak CM-MB tended to be higher in these patients compared with those without no-reflow (although this difference did not achieve statistical significance). Similarly, Eitel et al. [4] reported that ET-1 levels on admission are associated with no-reflow assessed by angiographic, electrocardiographic, and MRI methods after primary PCI and, further, with increased long-term mortality in a high-risk ST-elevation MI population. Thus, patients with elevated ET-1 levels on admission also had a slight trend for larger infarcts. The important role of ET-1 for infarct size reduction has previously been shown in a rat model, after administration of a monoclonal ET-1 antibody [5].