Acute myocardial infarction is associated with endothelial glycocalyx and cell damage and a parallel increase in circulating catecholamines

Excessive sympathoadrenal activation is a hallmark of acute critical illness and the accompanying increase in circulating catecholamines induces widespread dose-dependent effects on metabolism and the vascular system [1‐3]. This 'fight-or-flight' response may, however, become maladaptive and contribute to organ damage [2‐4], and in high concentrations, catecholamines directly damage the vascular endothelium resulting in local edema, endothelial cell swelling, necrosis and progressive de-endothelialization [5, 6]. In two independent cohorts of trauma patients, we recently reported that plasma adrenaline correlated strongly with circulating biomarkers of endothelial activation and damage [7, 8] and that the plasma adrenaline level was independently associated with circulating syndecan-1 [9], a recognized biomarker of endothelial glycocalyx degradation [10]. Furthermore, non-surviving trauma patients had increased levels of adrenaline and syndecan-1 and both predicted 30-day mortality [7, 9].

Acute myocardial ischemia and infarction (MI) immediately activates the sympathoadrenal system resulting in excessive increases in circulating levels of adrenaline and noradrenaline [11, 12], the latter through direct release from the infarcted myocardium [12]. Apparently, catecholamines induce opposite directed effects on the endothelium (progressive activation and damage) [4‐6] and circulating blood (initial hypercoagulability followed by progressive hypocoagulability and hyperfibrinolysis) [4, 13‐18], and we infer that this reflects an evolutionary adapted response aimed at maintaining blood flow through a damaged and procoagulant microvasculature in the (shocked) critically ill patient [4]. In accordance with this notion, patients with cardiac arrest present with hyperfibrinolysis on-scene (extreme hypocoagulability as a result of excessive endothelial release of pro-fibrinolytic factors) [19] and increased circulating levels of endothelial derived biomarkers (syndecan-1, thrombomodulin, sICAM-1, sVCAM-1, sE-selectin) in the hours after cardiopulmonary resuscitation [20, 21]. Although acute critical illness, with shock/hypotension, ischemia and reperfusion, massive tissue injury and systemic infection/inflammation, activates and potentially damages the endothelium [8, 9, 20‐27], the relative contribution of the concurrent neurohumoral, including sympathoadrenal, activation to the endothelial injury and ensuing (multiple) organ failure [2‐4] is not known.

MI patients have varying degrees of hypotension/shock and increases in circulating catecholamines, in the absence of massive tissue injury. Given this, the aim of the present study was to investigate associations I) between potential drivers of sympathoadrenal activation and/or endothelial damage and II) between circulating levels of catecholamines and biomarkers of endothelial glycocalyx (syndecan-1 [10]) and cell (soluble thrombomodulin, sTM [28‐30]) damage and organ failure/outcome, in patients with ST elevation MI (STEMI). We hypothesized that shock and high catecholamine levels would be associated with evidence of enhanced damage to the glycocalyx and endothelium and that high levels of both catecholamines and endothelial derived biomarkers would be associated with a poor outcome.

Here, we report that circulating adrenaline and noradrenaline levels in STEMI patients treated with percutaneous primary coronary intervention (pPCI) correlated weakly with syndecan-1 and sTM, biomarkers of glycocalyx and endothelial cell damage, respectively, with the strongest correlations and highest levels of adrenaline and syndecan-1 in patients with shock prior to pPCI. Furthermore, adrenaline was independently associated with short-and long-term mortality and heart failure (HF), and syndecan-1 was independently associated with long-term mortality. These findings indicate that acute MI causes significant endothelial glycocalyx and cell injury and a parallel increase in circulating catecholamines and they support the notion that a dose-dependent association exists between disease severity, sympathoadrenal activation and endothelial damage.

Here, we report that circulating adrenaline and noradrenaline levels in STEMI-patients treated with pPCI correlated with syndecan-1 and sTM, biomarkers of glycocalyx and endothelial cell damage, respectively, with the strongest correlations, and highest adrenaline and syndecan-1 levels, in patients with shock. Furthermore, circulating levels of adrenaline and syndecan-1 were associated independently with short-and long-term mortality and HF and with long-term mortality, respectively. These findings demonstrate that acute MI appears to cause significant endothelial cell and glycocalyx injury and a parallel increase in circulating catecholamines. They also support the notion that a dose-dependent association between disease severity, sympathoadrenal activation and endothelial damage exists in critically ill non-trauma patients in accordance with that previously observed in trauma patients [7, 9].

The vascular endothelium comprises a single layer of cells that lines every blood vessel in the body, covers a total surface area of 4 to 7,000 m², totaling a weight of 1 kilogram [32]. On top of the endothelium lies the glycocalyx, an approximately 1 μm thick carbohydrate-rich structure with antiadhesive and anticoagulant properties that protects the endothelium and maintains vascular barrier function [22, 23]. The endothelium is critically involved in the pathology of multiple diseases, in which there exist a well established association between endothelial dysfunction and/or damage and poor outcome [8, 9, 20‐24]. In the present study, we investigated associations between potential drivers of sympathoadrenal activation, endothelial damage and outcome in patients with increased sympathoadrenal activation in the absence of massive tissue injury. Our findings confirmed, in a different cohort of patients, the previous finding in trauma patients of associations between shock, catecholamines, biomarkers of glycocalyx and endothelial cell damage and outcome [7‐9]. Although the median circulating levels of adrenaline and noradrenaline in trauma patients (290 pg/ml (IQR 190 to 720) and 750 pg/ml (IQR 450 to 1,380), respectively) [7, 9] are four-to five-fold higher than the median levels observed in STEMI-patients in this study (Table 1), STEMI-patients in the highest adrenaline quartile, representing the most critically ill and shocked patients, had catecholamine levels comparable to those observed in trauma patients [7, 9]. Although we found correlations between catecholamines and biomarkers of endothelial damage in the whole patient cohort, these were weak and strongest in patients with shock, in accordance with the notion that a dose-response relationship may exist between catecholamine levels and infliction of endothelial injury [4‐6].

Glycocalyx damage is associated with pathophysiologic sequels, such as capillary leakage and edema formation, accelerated inflammation, platelet activation and hypercoagulability and loss of vascular responsiveness [22]. It is becoming increasingly evident that glycocalyx damage represents the earliest stage of endothelial perturbation [22, 23]. In STEMI-patients, several factors may contribute to glycocalyx damage, that is, ischemia-reperfusion injury, shock, inflammation (TNF-α), hyperglycemia, atrial natriuretic peptide and oxidized low density lipoprotein (LDL). Thus, in accordance with previous studies reporting that shock [21, 25‐27] and hyperglycemia/diabetes [7, 23, 33] are associated with glycocalyx damage, shock and diabetes were independently associated with circulating syndecan-1 in the present study (Table 2). With increasing syndecan-1 quartile, the neutrophil and platelet count and CRP increased whereas eGFR decreased. The finding that patients with shock displayed the strongest correlations between catecholamines and endothelial damage supports the notion that a threshold level exists above which catecholamines exert deleterious effects on the endothelial glycocalyx and cells.

We also found that syndecan-1 was associated independently with mortality and, to the best of our knowledge, this association has not been reported previously. Given the emerging evidence for devastating effects of glycocalyx damage in acute [9, 22, 27] and chronic [23] illness, including cardiovascular disease [21‐23], this finding is notable.

In accordance with previous studies, higher age [34], male gender [34, 35], non-smoking [34, 35], diabetes [34] and impaired kidney function [36] were associated with higher circulating sTM, in addition to higher adrenaline levels, lower BMI, myocardial cell damage (TnI) and multivessel disease. Circulating adrenaline, BMI, diabetes and eGFR were independently associated with sTM (Table 3), indicating that both life style factors and acute critical illness may contribute to endothelial damage.

In the present study, more patients in the highest adrenaline quartile died or developed HF. Adrenaline was independently associated with mortality and HF which is in accordance with previous findings reporting (varying degrees of) association between early increases in circulating adrenaline levels and mortality in MI-patients [11, 37, 38]. From a pathophysiologic point of view, MI-induced sympathoadrenal activation may later aggravate chronic atherosclerosis [39]. In some studies the early adrenaline surge in MI-patients has been correlated with the extent of myocardial damage/infarct size [11, 40] and left ventricular ejection fraction (LVFE) [38]. Although we could not replicate these associations, we found a borderline significant association between adrenaline levels and complex lesions (Table 1). It should be emphasized that the above findings do not prove any cause-effect relationship between early adrenaline levels, endothelial damage and poor outcome post-MI since it is expected that the most critically ill patients have the highest sympathoadrenal response and the poorest outcome. Also, it is possible that differences in the sympathoadrenal response attributed to gene polymorphisms in adrenergic receptors may in part explain our findings [41]. However, it is notable that the most critically ill and shocked MI patients presented with evidence of enhanced endothelial damage that correlated more strongly with catecholamines than in less sick patients. Whatever drivers among shock, ischemia-reperfusion injury, catecholamines, hyperglycemia, and so on that inflict the greatest endothelial damage, the magnitude of increase in endothelial derived biomarkers may be interpreted as a surrogate for concurrent organ damage and this may, in part, explain the negative predictive value associated with these biomarkers.

With regard to noradrenaline, this was a univariate predictor of long-term HF and CV mortality in this study. Although noradrenaline is a strong predictor of poor outcome in patients with asymptomatic left ventricular dysfunction [42] and chronic HF [3], the weak predictive value for outcome compared with adrenaline may both reflect that we investigated an early noradrenaline response, which may peak after PCI [43], and that noradrenaline release is much more heterogeneous compared to adrenaline release; for example, noradrenaline is released directly from the infarcted myocardium [12].

The results presented here are subject to the limitations inherent to observational studies and, therefore, do not allow independent evaluation of the cause and effect relationship between catecholamine levels, endothelial damage and outcome, so evidence of potential cause and effect relationships should come from adequately designed prospective trial(s). We found a relatively low prevalence of diabetes, previous MI and known HF prior to STEMI. Thus, care should be taken if the results are to be extrapolated to populations with very different distributions of potential risk factors and logistic facilities. Also, our geographical and organizational conditions may not necessarily apply to other countries and regions, and our findings should not be extrapolated to settings without high volume PCI centers. Finally, we did not have data on predictive ICU scores (Sequential Organ Failure Assessment, Acute Physiology and Chronic Health Evaluation, and so on) and we did not have data on previous β-adrenergic receptor blockers before admission.

The present study found an association between shock, circulating catecholamine levels, biomarkers indicative of endothelial damage, and outcome in STEMI-patients treated with pPCI, in accordance with previous findings in trauma patients. Patients in shock presented with the highest levels of adrenaline and syndecan-1, and the correlations between catecholamines and endothelial-derived biomarkers were particularly strong in patients in shock. These findings demonstrate that acute MI appears to cause significant endothelial cell and glycocalyx injury and a parallel increase in circulating catecholamines. The predictive value of the endothelial-derived biomarkers for outcome in STEMI patients may indicate that these, in part, reflect the extent of acute (ischemic/catecholamine induced) organ damage, thereby providing a prognostic value.