REVIEW ARTICLE

The immunopathology of coronary microembolization and the underlying inflammopathophysiological mechanisms

Li Ma^a ^†, Liping Cai^b ^†, Jiayue Pan^c ^†, Zimin Cheng^a, Yuanyuan Lv^a, Jie Zheng^a, Peicheng Xu^a, Hong Zhang^a, Xinyu Chen^a, Yimeng Huang^a, Xiaolei Luo^a, Jinhe Zhao^a^*, Liang Xu^d^*

^aDepartment of Cardiovascular Medicine, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China

^bHealth Management Center, Wuhan Third Hospital, Wuhan, China

^cXiangtao College of Medicine, Xiangtao College Affiliated to Wuhan University of Science and Technology, Wuhan, China

^dDepartment of ICU, Wuhan Wuchang Hospital, Wuhan, China

^†Li Ma, Liping Cai, and Jiayue Pan are the first authors

Abstract

In coronary microembolization, inflammatory cell infiltration, patchy necrosis, and extensive intra-myocardial hemorrhage are dominant, which induce myocardial dysfunction with clinical symptoms of chronic ischemic cardiomyopathy. Microembolization can lead to obstruction of the coronary microvessels and result in the micro-infarction of the heart. The inflammation and elevated expression of the tumor necrosis factor in cardiomyocytes and the activation of extracellular ERK are involved in initiating the inflammatory response mechanism. The PI3K/Akt signaling pathway is the enriched pathway, and for controlling, inhibition of PI3K/Akt is necessary. Furthermore, the release of cytokines and the activation of inflammasomes contribute to the enhancement of vascular permeability, which results in edema within the myocardium. The immune response and inflammation represent the primary triggers in this process. The ability to control immune response and inflammation reactions may lead to the development of new therapies for microembolization.

Key words: coronary, emboli, heart, immunopathology, signaling

^*Corresponding author: Jinhe Zhao, Department of Cardiovascular Medicine, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China. Email address: [email protected]; Liang Xu, Department of ICU, Wuhan Wuchang Hospital, Wuhan, China. Email address: [email protected]; [email protected]

Received 9 June 2024; Accepted 22 August 2024; Available online 1 November 2024

DOI: 10.15586/aei.v52i6.1170

Copyright: Ma L, et al.
License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/

Introduction

Autopsy studies in the 1980s, on sudden deaths due to coronary artery disease, presented fissure or rupture of epicardial coronary atherosclerotic plaques and coronary microcirculatory obstruction. The endothelial dysfunction is triggered by mediators such as thromboxane A2, thrombin, and serotonin, and causes cyclic flow variations due to the embolization of platelet aggregates into the microcirculation.^1–4

The application of protection devices in percutaneous coronary intervention (PCI) enabled the retrieval of plaque debris, thrombotic material, and factors that are soluble and unable to be retrieved from graft coronary vessels. The increase in plaque erosion incidence was related to a quantitative shift from ST-segment elevation MI (STEMI) to non-STEMI (NSTEMI) over the past 25 years.^5–9

Coronary microembolization (CME) is produced during ulceration and spontaneous plaque rupture, as well as coronary intervention. In CME, microscopic examination revealed inflammatory cell infiltration and patchy necrosis, but there was no transmural damage and intra-myocardial or extensive intra-myocardial hemorrhages. Effectively, CME can decrease coronary reserve and induce dysfunction of myocardia with clinical symptoms of chronic ischemic cardiomyopathy.^10–13 Therefore, the early detection of CME-induced ischemic lesions plays a major role in the prognosis and prediction of ischemic heart disease and micro-infarct of cardiac injury in suspected patients.^14–16

CME causes left ventricular systolic dysfunction that is usually local and subtle, and it also induces microcirculatory impairment, which can cause patchy micro-infarction.^10,17–20 The occurrence of CME is a spontaneous phenomenon in the context of acute coronary syndromes (ACS), and it is also a potential consequence of percutaneous coronary interventions. The typical CME consequences include micro-infarcts’ formation, inflammatory responses, contractile dysfunction, and reduction in coronary reserve. Mechanical stress, from interventional manipulation of epicardial coronary atherosclerotic plaques or hemodynamic perturbations with inflammatory destabilization, releases thrombotic material, particulate debris, and other substances that are soluble in the coronary circulation.^21–28

The physical substance impedes the coronary microcirculation, while the soluble substance induces endothelium dysfunction and facilitates vasoconstriction. Blocking and dysfunction of the coronary microvascular result in patchy micro-infarcts accompanied by an immunoinflammatory reaction, both contributing to progressive dysfunction of the myocardial contractile. Distal protection devices have the potential to retrieve atherothrombotic debris and also, prevent embolization into the microcirculation. Nevertheless, their impact on clinical outcomes has been underwhelming, except for saphenous vein bypass grafts. The use of devices for the aspiration of thrombus-derived vasoconstrictors and thrombi, and immune-thrombogenic and inflammatory substances has been demonstrated to decrease the thrombus burden, provide protection, and improve perfusion in patients with acute MI.^29–34 In this review, we focus on the features and mechanisms of CME and discuss immunopathology and related mechanisms of coronary microembolization.

Microembolization and Cardiac Function

The function of the global left ventricle (LV) is contingent upon the size and number of embolizing particles, as well as the size of the affected coronary perfusion territory. The response may range from transient and subtle LV dysfunction to severe cardiogenic shock.^35,36 In CME animal models, CT and MRI demonstrated not only a reduction in global and regional contractile function but also defects of patchy perfusion, edema, and micro-infarcts.^37,38–41 The clinical shape of coronary microembolization is unspecific. The elevation of biomarkers, such as troponin (a notable phenomenon, particularly when employing high-sensitivity assays) or creatine kinase, indicates myocardial injury but lacks specificity.^42,43

Transient elevations in serum levels of CK, its isoenzyme CK-MB, and troponin I or T following PCI are indicative of periprocedural myocardial injury.^44,45 The biomarker release magnitude depends on the clinical conditions of the patient (patients with chronic kidney disease or diabetes mellitus), the content of the vessel undergoing PCI (SVGs or native coronary arteries), and the type of procedure (the rot-ablation or simple stenting). The difference between primary and elective PCI in terms of resultant CME is simply the spontaneous versus iatrogenic nature of its origin in the culprit lesion.^46–54 Future investigations and therapies should prioritize elucidating the interaction between inflammatory reactions and platelet aggregation at the epicardial culprit lesion and in the CME. Further analyses of coronary aspirate or trans-coronary gradients from ACS patients could provide additional insights into the pathophysiological mechanisms of CME and facilitate the development of targeted therapies.

Microembolization and Inflammation Signals

Microembolization can lead to the obstruction of coronary vessels and results in micro-infarction of the heart. Nevertheless, the apoptosis contribution to cell death from micro-infarction is relatively minor in comparison to that from necrosis. The obstruction resulting in micro-infarct is characterized by a profound inflammatory reaction, which leads to pyroptotic cell death.^55,56 The presence of edema, macrophage, and neutrophil infiltration is observed in the vicinity of the micro-infarct site. The inflammatory reaction is continued by enhanced expression of TNF in cardiomyocytes and macrophages, as well as iNOS.^57–65

The activation of extracellular ERK1 and ERK2 plays a pivotal role in initiating the inflammatory response. The presence of inflammation around micro-infarcts is associated with an increase in IGF1 mRNA expression in infiltrating monocytes. This increase represents a potential start signal for the promotion of collateral growth and the angiogenic response, as observed in a long-term model of CME.^66,67

Among the inflammatory mediators, TNF exerts a particularly detrimental effect on the microembolized myocardium, exerting negative inotropic effects.^61,62,65 In anesthetized animals, NO is formed with increased TNF upstream, while sphingosine is synthesized with increased TNF downstream. The ultimate effect of inflammatory signal transduction appears to be the enhanced formation of ROS, oxidative modification of contractile myofibrils, and a reduction in Ca₂⁺ responsiveness of the contractile machinery.^68–70 In coronary microembolization, these pathways can lead to apoptosis via activation of caspase 3 and 9 in myocardium.⁷¹

The CANTOS trial presented the IL-1β pathogenetic role in previous MI patients and increased plasma concentrations of the CRP.⁷² The antagonism (in long-term) of IL-6 and IL-1β can stabilize epicardial atherosclerotic plaques and also inhibit their eventual erosion and/or rupture. In the context of an interventional procedure for a stable or acute coronary syndrome, in which CME can occur and an anti-inflammatory reaction in the CME may be important, the benefit of IL-receptor antagonists and other anti-inflammatory agents is less clear.^73,74 IL-6 inhibition not only stabilizes atherosclerotic plaques but also attenuates the downstream effects of inflammation and platelet aggregation.⁷⁵

Immunopathogenesis of Coronary Microembolization

The pathogenic mechanisms and immunopathology of coronary disease are complex. The PI3K/Akt signaling pathway and platelet activation are the enriched pathways, and pathways such as PI3K/Akt are necessary for the control and inhibition of inflammatory reactions and apoptosis in the cardiovascular direction. The inflammatory mediators, activated platelets, and exposed damaged endothelium interact with one another, resulting in impaired local microcirculation within the coronary artery. This, in turn, leads to the formation of thrombi. A high level of IL-6 is detectable in intracoronary aspirated platelet-leukocyte mixtures obtained from patients with PCI which signals an inflammatory storm as a result of the intervening operation.^76–78

In “platelet-inflammation-microthrombosis,” inhibition of platelet adhesion and the inflammatory state can improve cardiac function. Leukocytes and platelets aggregate to form a bridge between leukocytes and endothelial cells, mediated by P-selectin activation. This process, also known as “immunothrombosis,” exacerbates local embolism in the coronary artery. Furthermore, the regulation of integrin conformation via the PI3K/Akt pathway has been demonstrated to attenuate sodium laurate–induced coronary thrombosis. Cardiac dysfunction, as evidenced by the sodium laurate–induced coronary microthrombosis, is cumulative, manifesting as subtle alterations of the left ventricular function and severe cardiogenic shock.^79–83

CD62p is a marker of thrombus formation and platelet activation, and Ca₂⁺ serves as the crucial second messenger in cellular processes. The αIIbβ3 is an important membrane protein present on the platelets, which binds to RGD-containing ligands such as fibrin, von Willebrand factor (vWF), and fibrinogen, ultimately cross-linking the platelets to form tight fibrin–platelet thrombi. The αIIbβ3 activation spreads into a high-affinity conformation from the extracellular structural domain that is referred to as an “inside-out” signal. Subsequently, the sites of αIIbβ3-exposed receptor initiate an “outside-in” positive feedback pathway, which causes irreversible clot stabilization and retraction. This process is influenced by the PI3K/AKT pathway. Moreover, the vWF acts as an adhesion molecule that enhances the binding of αIIbβ3 to fibrinogen and promotes the formation of more stable platelet aggregates.^84–89

The morphology of platelet cytoskeleton is a significant indicator of their activation status. The platelet cytoskeleton is composed of two actin filament-based components: (a) the cytoplasmic actin filaments, responsible for mediating contractile events and filling the cytoplasm; (b) the membrane skeleton, which coats the plasma membrane and helps regulate its properties including its contours and stability. Upon activation, platelets undergo a rapid increase in actin polymerization, with new filaments rapidly filling extended filamentous pseudopods and forming a network at the periphery of the platelets. The PI3K/Akt pathway is the most important one for αIIbβ3 (ITGB3/ITGA2B) and platelet activation. Upon stimulation of the vWF receptor GPIb-IX-V, the PI3Kβ stimulates Akt phosphorylation. The simulation of G protein-coupled receptors activates ITGB3/ITGA2B, which in turn triggers phospholipase and calcium and release regulatory pathways. In the context of the PI3K/Akt pathway-mediated activation of thrombocytes, the PI3K family of enzymes phosphorylate phospholipase enzymes at the 3′ position of the inositol ring, specifically generating 1,4,5-trisphosphatidylinositol phospholipids (PIP3). The Akt family of protein kinases plays a pivotal role in the PIP3–PI3K signaling cascade, functioning as a major binding protein. PIP3^3–5 recruits the pH domain-containing kinases PDK1 and Akt to the membrane where PDK1 phosphorylates Akt on Thr308 in the T-loop. On the other hand, Akt is phosphorylated by mTORC2 on Ser473, which results in maximal Akt activity. The three isoforms of Akt (1–3) play an important role in platelet aggregation and thrombus stabilization.^90–97

Myocardial Infarction and Coronary Adhesion Molecules

Coronary endothelial cells exhibit relative resistance to ischemia and are capable of surviving hypoxia in vitro for extended periods. However, in vivo, the interruption of antegrade pulsatile flow and shear stress leads to the induction of endothelial cell swelling and blebbing.^98–100 The reperfused endothelium exhibits altered calcium homeostasis, which increases cytosolic calcium. This, in turn, activates the endothelial contractile elements, thereby promoting the formation of intercellular gaps and increasing permeability to large molecules. The expression of adhesion molecules by activated platelets and endothelial cells results in the adhesion of platelets and platelet–leukocyte aggregates to the coronary microvasculature.^101,102

Moreover, the release of cytokines impairs the stability of cell junctions and enhances vascular permeability. This occurs via the activation of Src and the dissociation of the VEGFR2/vascular endothelial (VE)–cadherin complex.^103,104 Activation of the NLRP3 inflammasome in endothelial cells can result in caspase 1-mediated cell death. Endothelium-initiated inflammation, in conjunction with debris from cardiomyocyte necrosis, exerts proinflammatory effects, which result in the recruitment of inflammatory cells and the release of proinflammatory factors, including VEGF, thrombin, matrix metalloproteases, PAF, and myeloperoxidase.^105–109 These factors increase vascular permeability, which results in edema of the myocardium via various mechanisms, including the activation of endothelial NO synthase (eNOS) in caveolae by VEGF.^110,111

In cardiomyocytes, the reversal of intracellular edema is facilitated by the restoration of ion pump activation, particularly that of the sarcolemmal Na+/K+-ATPase. During ischemia, the accumulation of metabolites elevates interstitial osmolality. Exposure to normal osmotic blood at reperfusion induces immediate interstitial edema.^112,113

Disseminated Intravascular Coagulation and Immune Responses

Disseminated intravascular coagulation (DIC) is a common occurrence in critical diseases. It represents the activation of the tissue factor pathway, cascade, and deposition of platelet–fibrin thrombi in the microvasculature.^114,115 The hypercoagulability observed in DIC is further compounded by the presence of several other factors, including dehydration, hypoxia, and relative immobility, which are commonly observed in critical conditions. Several pathogenic mechanisms have been identified that may contribute to the development of DIC (Figure 1).^116,117

Figure 1 Proinflammatory cytokines, mediators, and cells, related to disseminated intravascular coagulation.

In infection-associated coagulopathy, the inflammatory response and innate immune activation are the primary drivers. It is presumed that coagulation and fibrin deposition are adaptive in the early phase of infection. However, continued inflammation results in a deleterious hyperinflammatory response mediated by a cytokine storm, and also macrophage activation syndrome. A cytokine storm is defined as an auto-amplifying proinflammatory cytokine release that significantly contributes to multiorgan dysfunction syndrome.^118–121 Macrophage activation syndrome is a related proinflammatory cascade that is associated with a high incidence of thrombosis and mortality (Figure 2).^122,123

Figure 2 Summarized pathway from inflammation to the ST-elevation in ECG.

Numerous proinflammatory cytokines are increased including TNF-α and IL-6, IL-2R, IL-10, and IL-8 (Figure 1).^124,125 There is an association between elevated levels of IL-6 and fibrinogen.¹²⁶ During infections, mononuclear cells express high levels of procoagulant genes including tissue factor, serpins, fibrinogen, and Factors II and X that are related to immune-mediated thrombosis and induce hypercoagulability.^127,128 These cells also express genes TLR-9 and thromboxane synthase that promote endothelial dysfunction, platelet activation and aggregation, and vasoconstriction.¹²⁹

The activation of complement cascade recruits and activates leukocytes, which leads to greatly amplified local secretion of the proinflammatory cytokines and subsequent microvascular damage. The complement system inhibition ameliorates coagulopathy and endothelial dysfunction in sepsis.^130,131

Conclusions and Remaining Questions

CME is a prevalent phenomenon in ischemic heart disease, occurring spontaneously in patients with typical consequences such as contractile dysfunction and malignant arrhythmias. Several studies have indicated that CME may be a potential cause of dysfunction of the regional myocardial contractile, which is related to immuno-inflammatory reactions, coagulation thrombi with embolization into the coronary microcirculation, and also, lethal arrhythmias.^132–135

The pathological observations found CME as the common cause of death from ischemic heart disease. The microemboli are associated with an inflammatory reaction and micro-infarcts. CME also can induce a marked inflammatory reaction, which is characterized by infiltration of eosinophils, and mulitifocal micro-infarcts.^136–138 CME is associated with the development of patchy micro-infarcts, which affect approximately 2% of the respective myocardium. Some of the cardiomyocytes may undergo apoptosis, which is associated with the micro-infarcts and characterized by leukocyte infiltration. Conversely, elevated myocardial TNF-α levels are linked to contractile impairment following CME and result in dysfunction when exogenous TNF-α is infused directly into the coronary artery, even in the absence of microembolization.^60,139 TNF-α is found in leukocytes that have infiltrated the area surrounding and within micro-infarcts. Additionally, it is present in cardiomyocytes in the viable border zone surrounding the micro-infarcts. The concentration of TNF-α and sphingosine in the myocardium is increased by microembolization. Pretreatment with NO-synthase inhibitor attenuates the progressive myocardial contractile dysfunction.^68,140,141 Here, a signal cascade of TNF-α, NO, and sphingosine is identified and associated with CME (Figure 1). Immune response and inflammation are the key triggers of CME, and CME in turn triggers immune response initiation and inflammation reactions.^142–144 Further experimental studies are also required to elucidate the specific immune response and therapeutic targets for the treatment of CME and its consequences.

Ethics Approval and Consent to Participate

The study was approved by the Medical Ethics Committee of Tianyou Hospital Affiliated with Wuhan University of Science and Technology.

Consent for Publication

Not Applicable.

Availability of Data and Materials

Not applicable.

Conflicts of Interests

There are no conflicts of interest.

Funding

Health Commission of Hubei Province Scientific Research Project: subsidy number: B2019013.

Hubei Provincial Health and Health Committee Joint Fund: WJ2019H230.

Authors’ Contributions

LM, LC, JP, ZC, YL, JZ, PX, HZ, XC, YH, XL, JZ, and LX participated in the planning, study, drafting, and writing of the manuscript.

Acknowledgments

Not applicable.

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