Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success.

Selma E. Kaffka genaamd Dengler,Niels P. van der Kaaij,Mudit Mishra,Gerardus P. J. van Hout,Max J. M. Silvis,Joost P. G. Sluijter,Dominique P. V. de Kleijn,Clémence A. Odille,Saskia C. A. de Jager,Pieter A. Doevendans,Lena Bosch

doi:10.3389/fimmu.2020.599511

Abstract

In the setting of myocardial infarction (MI), ischemia reperfusion injury (IRI) occurs due to occlusion (ischemia) and subsequent re-establishment of blood flow (reperfusion) of a coronary artery. A similar phenomenon is observed in heart transplantation (HTx) when, after cold storage, the donor heart is connected to the recipient’s circulation. Although reperfusion is essential for the survival of cardiomyocytes, it paradoxically leads to additional myocardial damage in experimental MI and HTx models. Damage (or danger)-associated molecular patterns (DAMPs) are endogenous molecules released after cellular damage or stress such as myocardial IRI. DAMPs activate pattern recognition receptors (PRRs), and set in motion a complex signaling cascade resulting in the release of cytokines and a profound inflammatory reaction. This inflammatory response is thought to function as a double-edged sword. Although it enables removal of cell debris and promotes wound healing, DAMP mediated signalling can also exacerbate the inflammatory state in a disproportional matter, thereby leading to additional tissue damage. Upon MI, this leads to expansion of the infarcted area and deterioration of cardiac function in preclinical models. Eventually this culminates in adverse myocardial remodeling; a process that leads to increased myocardial fibrosis, gradual further loss of cardiomyocytes, left ventricular dilation and heart failure. Upon HTx, DAMPs aggravate ischemic damage, which results in more pronounced reperfusion injury that impacts cardiac function and increases the occurrence of primary graft dysfunction and graft rejection via cytokine release, cardiac edema, enhanced myocardial/endothelial damage and allograft fibrosis. Therapies targeting DAMPs or PRRs have predominantly been investigated in experimental models and are potentially cardioprotective. To date, however, none of these interventions have reached the clinical arena. In this review we summarize the current evidence of involvement of DAMPs and PRRs in the inflammatory response after MI and HTx. Furthermore, we will discuss various current therapeutic approaches targeting this complex interplay and provide possible reasons why clinical translation still fails.

Highlights

Acute myocardial infarction (MI) is typically the result of hampered blood flow to the myocardium due to atherosclerotic plaque rupture or erosion [1]
This study indicates that HSP70 can serve as a biomarker of clinical outcome, albeit it does not prove a causal role of HSP70 as a key player of the post-MI inflammatory response [30]
Experimental evidence suggests that divergent effects and potential translation failure could be the case for the NLRP3 inflammasome inhibitors, since negative results have been published [163]

Summary

Introduction

Acute myocardial infarction (MI) is typically the result of hampered blood flow to the myocardium due to atherosclerotic plaque rupture or erosion [1]. Consequential to hampered blood flow, the myocardium becomes ischemic with subsequent loss of viable cardiac muscle. And adequate reperfusion leads to limitation of the infarct size (IS), partial preservation of cardiac function and subsequent reduction of morbidity and mortality [1]. Hypothermia reduces the metabolic demands and thereby protects the tissue from acute deprivation of nutrients. This protective effect is limited by time. Restoration of blood flow is essential for preservation of cardiac function and thereby outcome of HTx [2,3,4]

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Conclusion