REVIEW published: 28 April 2021 doi: 10.3389/fcvm.2021.647785 Post-ischemic Myocardial Inflammatory Response: A Complex and Dynamic Process Susceptible to Immunomodulatory Therapies Niek J. Pluijmert 1, Douwe E. Atsma 1 and Paul H. A. Quax 2,3* 1 Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands, 2 Department of Surgery, Leiden University Medical Center, Leiden, Netherlands, 3 Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands Following acute occlusion of a coronary artery causing myocardial ischemia and implementing first-line treatment involving rapid reperfusion, a dynamic and balanced inflammatory response is initiated to repair and remove damaged cells. Paradoxically, Edited by: restoration of myocardial blood flow exacerbates cell damage as a result of myocardial JeanSébastien Silvestre, ischemia–reperfusion (MI-R) injury, which eventually provokes accelerated apoptosis. In Institut National de la Santé et de la Recherche Médicale the end, the infarct size still corresponds to the subsequent risk of developing heart (INSERM), France failure. Therefore, true understanding of the mechanisms regarding MI-R injury, and Reviewed by: its contribution to cell damage and cell death, are of the utmost importance in the Clement Cochain, search for successful therapeutic interventions to finally prevent the onset of heart University Hospital Würzburg, Germany failure. This review focuses on the role of innate immunity, chemokines, cytokines, and Nikolaos G. Frangogiannis, inflammatory cells in all three overlapping phases following experimental, mainly murine, Albert Einstein College of Medicine, United States MI-R injury known as the inflammatory, reparative, and maturation phase. It provides a *Correspondence: complete state-of-the-art overview including most current research of all post-ischemic Paul H. A. Quax processes and phases and additionally summarizes the use of immunomodulatory [email protected] therapies translated into clinical practice. Specialty section: Keywords: myocardial infarction, myocardial ischemia-reperfusion injury, inflammatory phase, reparative phase, This article was submitted to innate immunity, chemokines, cytokines, inflammatory cells Cardiovascular Biologics and Regenerative Medicine, a section of the journal INTRODUCTION Frontiers in Cardiovascular Medicine Received: 30 December 2020 Ischemic myocardial injury causes decreased oxygen tension within the cell, subsequent Accepted: 02 March 2021 degradation and loss of oxidative phosphorylation, and decreased generation of high-energy Published: 28 April 2021 phosphates resulting in loss of membrane integrity (1). Irreversible cardiomyocyte injury, Citation: demonstrated by sarcolemmal disruption and presence of small amorphous densities in the Pluijmert NJ, Atsma DE and mitochondria develops after 20–40 min of sustained severe ischemia (2). Cardiomyocyte cell death Quax PHA (2021) Post-ischemic causes release of cardiomyocyte-specific proteins, such as myoglobin, cardiac troponin (cTn) T Myocardial Inflammatory Response: A and I, creatine kinase MB (CK-MB), and creatine phosphokinase (CPK), which are used clinically Complex and Dynamic Process Susceptible to Immunomodulatory as markers for early detection (3), especially by the use of high-sensitivity cTn assays nowadays Therapies. (4). The dominant mechanism of cardiomyocyte death is coagulation necrosis, peaking after Front. Cardiovasc. Med. 8:647785. 12 h up to 4 days, with cell swelling and rupture of cell membranes resulting in extrusion of doi: 10.3389/fcvm.2021.647785 intracellular contents after passing the point of no return even though reperfusion is applied at Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 April 2021 | Volume 8 | Article 647785 Pluijmert et al. Post-ischemic Myocardial Inflammatory Response a certain moment. This triggers an extensive inflammatory zone despite patency of the infarcted-related artery (14, 15), and reaction activating reparative pathways ultimately contributing lethal reperfusion injury, which may account for up to 50% of the to mature scar formation (5). The other mechanism is apoptosis, final infarct size (11). peaking after 6–8 h, concerning programmed cell death, in The innate immune system is triggered following tissue particular, induced by reperfusion and also affecting non- injury resulting in the release of soluble inflammatory mediators infarcted areas of the LV wall and interventricular septum (6). soon after reperfusion, inducing an extensive inflammatory Myocardial infarct repair comprises three overlapping response as described above. Recruitment of inflammatory cells, phases: the inflammatory, reparative, and maturation phase. oxidative stress, and endothelial barrier dysfunction compose The inflammatory phase contains activation of chemokine and myocardial healing in the early phase. Cytokines activate and cytokine cascades resulting in recruitment of local infiltration recruit neutrophils to the injured infarct area, which cause direct of leukocytes into the infarct area. Dead cells and matrix injury to the endothelial cells via production of reactive oxygen debris are cleared by neutrophils and macrophages. During the species (ROS) (16), inflammatory cytokines, and adhesion reparative or proliferative phase, activated mononuclear cell molecules that facilitate binding of leucocytes and platelets. Other and macrophage subpopulations release cytokines and growth mediators of myocardial reperfusion injury are the opening of factors that recruit and activate predominantly myofibroblasts the mitochondrial permeability transition pore, cardiomyocyte and vascular cells, while pro-inflammatory mediators are calcium overload with hypercontracture, and intracellular pH suppressed. Activated myofibroblasts abundantly produce changes resulting in a wave front of reperfusion injury with extracellular matrix proteins, and an extensive microvascular a strict therapeutic window (17). Reperfusion also induces network is formed with preservation of the structural integrity. and aggravates apoptosis (6). Through binding and ingestion In the maturation phase, reparative fibroblasts and vascular of dying cells, myeloid cells can markedly influence immune cells become apoptotic, and a cross-linked collagen-based responses. MI-R-induced apoptosis results in changes in cellular scar is formed (7). This review addresses the post-ischemic structures including loss of the asymmetric distribution of plasma inflammatory response in its entirety focusing on the role of membrane phospholipids (18). innate immunity, chemokines, cytokines, and inflammatory cells in all three overlapping inflammatory, reparative, and Innate Immunity maturation phases following experimental myocardial ischemia– Cell death induced by necrosis causes a release of intracellular reperfusion (MI-R) injury. The complexity of this process makes contents and triggers an inflammatory response by activating it amenable to pharmacologic interventions of which some has the innate immune system (Figure 1). Expression of endogenous been successfully translated toward clinical practice as discussed ligands upon reperfusion are judged as “danger signals.” These in the final section. danger-associated molecular patterns (DAMPs) are recognized by both signaling and endocytic pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), expressed by cells of MYOCARDIAL ISCHEMIA–REPERFUSION the innate immune system. Activation of inflammatory pathways INJURY by activation of, e.g., TLR-mediated pathways, chemoattractants, the complement cascade, and ROS as a result of MI induces the As mentioned previously, early reperfusion by primary expression of a large panel of pro-inflammatory genes driven by percutaneous coronary intervention (pPCI) is the recommended the activation of mitogen-activated protein kinases (MAPKs) and therapy in acute myocardial infarction (MI) since reperfusion especially nuclear factor (NF)-κB(7). restores oxygen and nutrient supply accentuating the post- ischemic inflammatory response and accelerating wound Danger-Associated Molecular Patterns healing, making it a prerequisite for cardiomyocyte salvage (8). The innate immune system can be triggered by endogenous, Even late reperfusion showed to be beneficial in humans, where non-pathogenous signals, referred to as DAMPs (19). These it results in considerable myocardial salvage (9), as well as in endogenous ligands released in response to MI include high- animals, exhibiting permanent reduction of infarct expansion mobility group box-1 (HMGB1), heat shock proteins (HSPs) and ventricular remodeling (10). Paradoxically, restoration of and S100-proteins, nuclear and mitochondrial DNAs, RNAs, myocardial blood flow comes at a price, as it initiates myocardial adenosine triphosphate (ATP), low molecular weight hyaluronic reperfusion injury by a series of events, which eventually provoke acid, and fibronectin fragments (20). Oxidation-specific epitopes accelerated apoptosis (11). (OSEs) can act as endogenous DAMPs as well (21). There are four types of MI-R injury recognized. The first two HMGB1, the best characterized danger signal, is a key initiator are reversible and consist of reperfusion-induced arrhythmias, of inflammatory injury following myocardial ischemia controlled in particular, ventricular arrhythmias, which are usually self- by action mechanisms involving TLRs (22, 23) and RAGEs, terminating or effectively treated (12), and myocardial stunning, the