Background
No-reflow can occur in all percutaneous coronary interventions (PCIs), especially in emergency PCIs, and has a strong negative impact on clinical outcomes of acute coronary syndrome (ACS). Indeed, patients with no-reflow exhibit a higher prevalence of mortality, heart failure, and early postinfarction complications [
1‐
3]. Consequently, early detection and appropriate prevention strategies of no-reflow have an important impact on the outcome of ACS.
Calprotectin, a heterotetramer of proteins S100A8 and S100A9, is identified to be a novel diagnostic and prognostic biomarker of cardiovascular diseases [
4]. Calprotectin increases in the high-risk unstable or vulnerable atherosclerotic plaques in coronary arteries [
5]. Increasing plasma calprotectin was associated with a higher risk of a recurrent cardiovascular event and significantly increased risk of cardiovascular death or myocardial infarction in ACS patients [
6,
7]. Besides, circulating calprotectin is associated with thromboxane-dependent platelet activation in ACS [
8]. Higher platelet reactivity and activation were found to be associated with an elevated prevalence of no-reflow after PCI in ACS patients [
9].
Despite these studies, the association of plasma calprotectin with platelet activation and no-reflow phenomenon in ACS is not clear. The objective of this study was to investigate the relationship between calprotectin and platelet activation and evaluate the value of plasma calprotectin in predicting the development of a no-reflow phenomenon in ACS patients.
Discussion
In this study, we have demonstrated that ACS patients with higher plasma calprotectin had an elevated level of platelet activation and a higher incidence of no-reflow. The plasma calprotectin level was independently associated with platelet activation and no-reflow in patients with ACS. Despite that platelet activation biomarker PMA was associated with no-flow, only plasma calprotectin and serum LDL-c acted as independent predictors of no-reflow in patients with ACS as shown in the present study.
In humans, no-reflow may occur in emergency PCI or elective PCI for ACS. The occurrence of no-reflow after PCI decreased the efficacy of reperfusion therapy and is associated with worse clinical outcomes [
15]. Following primary PCI for acute myocardial infarction (AMI), no-reflow measured by angiography remarkably increases the short-term mortality risk at 30 days [
2] and long-term mortality risk at 1 year [
16,
17] and 5 years respectively [
18]. Therefore, the discovery of a biomarker that can early predict the occurrence of no-reflow has great clinical significance.
Calprotectin is an inflammation-associated peptide with proinflammatory properties, mainly secreted from activated neutrophils and monocytes under various conditions [
4]. Calprotectin is traditionally thought to be involved in the pathophysiology of various inflammatory conditions such as rheumatoid arthritis [
19]. However, some recent studies implied that calprotectin may be implicated in the pathogenesis of cardiovascular and cardiometabolic diseases based on low-grade chronic inflammation [
6,
20].
High levels of calprotectin were found in human atherosclerotic plaques and it is correlated with the characteristics of rupture-prone lesions [
5]. As a result, calprotectin is supposed to be a biomarker of plaque instability [
21]. Calprotectin is also found to be specifically expressed in neutrophils and macrophages in infarcted myocardium [
22]. Blood calprotectin levels are markedly higher in ACS patients than in stable CAD or healthy subjects [
20,
23] and plasma levels of calprotectin were significantly elevated in patients with AMI than in patients with unstable angina pectoris [
22]. Moreover, levels of calprotectin were also found to be higher in STEMI patients who died after a median 12 months follow-up compared to the STEMI patients who survived [
7]. Calprotectin has been associated with an increased risk of cardiovascular death or myocardial infarction after ACS [
6]. What’s more, calprotectin is found to be correlated with first and recurrent cardiovascular events in middle-aged healthy individuals [
24]. Similarly, our study revealed that calprotectin was positively correlated with admission cTnI, BNP, and GRACE score. A negative association between calprotectin and LVEF was also present in our study.
Despite the important roles of calprotectin in ACS, the role of calprotectin in the no-reflow phenomenon of ACS patients has not been clarified. The pathophysiology of post-PCI no-reflow is complex and it involves inflammation, vasoconstriction, higher platelet reactivity, and microcirculation embolization [
25]. Micro-embolization in distal coronary circulation may occur after plaque rupture or erosion and subsequent thrombosis. Thrombotic material from the originally occurred thrombus may move distally and embolize smaller arteries, thus causing no-reflow. Increased calprotectin concentration was found in aspirated coronary artery blood distal to the culprit ACS lesion associated with thrombosis and is related to local leukocyte activation. Thus, calprotectin is supposed to be a biomarker of inflammation and thrombosis in ACS [
26]. In the current study, we firstly demonstrated that calprotectin was an independent predictor of no-reflow in ACS patients.
Cardiovascular risk factors, such as smoking, hypercholesterolemia, diabetes mellitus, and other inflammatory biomarkers are thought to be conventional risk predictors for no-reflow [
27,
28]. Diabetes mellitus and hypercholesterolemia are the main risk factor of ACS and is associated with coronary thrombosis, microvascular dysfunction and inflammation processes [
29]. In the present study, we demonstrated that plasma calprotectin was related to these risk factors such as admission glucose, LDL-c, WBC, and N/L ratio. Besides, diabetes mellitus, admission glucose, LDL-c, WBC, and N/L ratio were predictors of no-reflow consistent with previous studies [
25,
27,
28,
30]. These findings explain to some extent why plasma calprotectin can act as a predictor of no-reflow.
LDL-c was an independent predictor of no-reflow with lower sensitivity and specificity compared with calprotectin in ACS patients as shown in the current study. LDL-c plays a fundamental role in the pathophysiology of CAD. By now, it is well known that the property of atherosclerotic plaques may determine their thrombogenicity [
31]. Vulnerable plaques like lipid-rich plaques with thin caps are more likely to form thrombus than stable plaques with thick caps and poor lipid cores [
32]. Erosion or rupture of a vulnerable plaque directly activates platelets and causing thrombus formation by the exposure of thrombogenic materials including collagens and a lipid-rich atheromatous core comprising of oxidized LDL particles and cholesterol sulfate. It has been confirmed by intra-coronary imaging that the lipid-rich and necrotic core rich culprit plaques may act as an important predictor of distal embolization and no-reflow in ACS patients [
33]. Compared with normocholesterolemic rabbits, hypercholesterolemic rabbits demonstrated markedly increased no-reflow [
34]. Patients undergoing elective PCI with preprocedural statin therapy have a decreased incidence of periprocedural myocardial infarction compared with that in patients with no statin therapy [
35]. In patients with AMI, long-term use of statins improved coronary flow and reduced the incidence of no-reflow [
36]. White blood cell subtypes play crucial roles in modulating the inflammation in the atherosclerotic process and N/L ratio is thought to be an independent predictor of no-reflow after primary PCI [
30]. In the present study, we also found that WBC and N/L ratios were associated with no-reflow. Moreover, WBC and N/L ratios were positively correlated with calprotectin and PMA. Some studies have confirmed neutrophil activation and accumulation in the myocardial area affected by acute coronary occlusion [
37]. This accumulation is further increased after reperfusion and is another potential source of free radicals [
37]. Interaction between activated neutrophils and damaged endothelium may induce endothelial dysfunction and vasoconstriction [
38]. Inhibition of selectin adhesion molecules influencing the interaction between activated neutrophils and damaged endothelium has been shown to limit infarct size in animal models [
39].
The essential role of platelets for the pathogenic thrombosis development in ACS is highlighted by a large body of evidence. There are increased plasma concentrations of indicators of platelet activation in patients with ACS compared to those with stable CAD or normal populations [
40,
41]. Platelet magnifies chronic inflammation and interaction of platelet with leukocytes, endothelial cells and macrophages promote a proinflammatory and prothrombotic setting leading to plaque instability and subsequent intracoronary thrombosis [
42]. Platelets may induce inflammatory reactions directly and indirectly by promoting inflammation and recruitment of inflammatory cells. Platelets adhere to the endothelium of small coronary arteries get activated and release several leukocyte recruitment molecules and vasoactive molecules [
43]. For these reasons, platelets contribute to ACS not only by inducing the intraluminal thrombosis but also by micro-embolization in the distal coronary circulation, by local thrombosis and vasoconstriction in the microcirculation, and by platelet-mediated inflammatory reactions [
44]. Accordingly, higher platelet reactivity and activation were found to be associated with an elevated prevalence of no-reflow after PCI in ACS patients [
9]. Correlation between plasma calprotectin and thromboxane-dependent platelet activation has been demonstrated in ACS patients [
8]. In the current study, we also found that plasma calprotectin was positively correlated with platelet activation biomarker PMA in ACS patients and PMA was positively correlated with no-reflow in ACS patients.
In this study, we demonstrated that ACS patients with higher plasma calprotectin had a higher incidence of no-reflow and plasma calprotectin might act as an independent predictor of no-reflow in patients with ACS. The mechanism of no-reflow seems to imply many pathways and probably only a part has been clarified. Further basic researches are needed to better understand the specific mechanism of calprotectin in the development of no-reflow.
Our study has some limitations. It was a single-center, prospectively designed study with relatively small sample size. Bias may exist and the findings should be interpreted cautiously. We detected only an admission blood sample of plasma calprotectin with no information about the temporal trend of changes. Optimal predictive cut-off levels and the predictive performance of plasma calprotectin for no-reflow in ACS patients will require validation in a larger scale, prospective, multi-center studies.
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