Review article
Role of inflammation in the regulation of coronary blood flow in ischemia and reperfusion: Mechanisms and therapeutic implications

https://doi.org/10.1016/j.yjmcc.2011.08.027Get rights and content

Abstract

A multitude of factors, including increased coronary vascular resistance and dysregulated coronary microcirculatory function, contribute to the impairment of coronary blood flow (CBF) regulation and the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. CBF is primarily determined by coronary vascular resistance, which is affected by the balance between various vasodilators and vasoconstrictors. Myocardial I/R causes reduced production of endogenous vasodilators, such as nitric oxide (NO), leaving unopposed vasoconstriction that is caused mainly by continued presence of endothelin-1 (ET-1) and serotonin (5-HT); this imbalance in turn enhances vascular tone, triggers inflammatory response, decreases CBF and exacerbates reperfusion injury. Various inflammatory cytokines participate in the regulation of coronary vasomotor function by affecting the balance between vasodilators and vasoconstrictors. In addition to the enhanced coronary vasoconstriction, coronary microembolization, inflammatory cell infiltration and post-ischemic hyperpermeability contribute to the impairment of coronary microcirculatory function and myocardial perfusion during I/R. Ongoing research examining the role of inflammation in the regulation of CBF and coronary microcirculatory function in myocardial I/R is expected to yield new insights that will lead to therapies for ameliorating the vascular inflammatory response in coronary artery diseases (CADs) in the clinical setting. This article is part of a Special Issue entitled “Coronary Blood Flow”.

Highlights

► Inflammatory cytokines participate in the regulation of coronary vasomotor function. ► Vascular inflammation is involved in microcirculatory obstruction and hyperpermeability. ► Reduced coronary blood flow and inadequate microcirculatory perfusion lead to I/R injury.

Introduction

Coronary blood flow (CBF) regulation in myocardial ischemia/reperfusion (I/R), particularly perfusion at the microcirculatory level, is critical to the outcome of ischemic heart disease. Coronary vascular tone is a crucial factor influencing CBF. The impaired vasodilatory response of coronary arteries during I/R injury was first documented by Ku et al. in 1982 [1]. To date, a variety of vasodilators and vasoconstrictors including endothelium-derived vasoactive factors, autacoids, metabolic messengers, and neurohormonal factors are found to be involved in the regulation of coronary vascular resistance and are emerging as therapeutic targets for the restoration of CBF following I/R injury. In addition to the enhanced vascular constriction, the dysregulation of coronary microcirculatory function during myocardial I/R, which is characterized by microembolization, inflammatory cell infiltration and hyperpermeability, lead to reduced CBF and inadequate myocardial reperfusion. A number of inflammatory cytokines and inflammatory cells are actively involved in the regulation of coronary vascular resistance and microcirculatory function. Elucidating the role of inflammation in CBF dysregulation in myocardial I/R would facilitate the development of novel therapeutics and improve clinical outcomes. Within this context, this review focuses on: (1) the role of inflammation in the regulation of coronary vascular resistance and CBF; (2) the role of inflammation in coronary microcirculatory dysfunction in myocardial I/R injury.

Section snippets

Inflammation and the regulation of coronary vascular resistance in I/R

Coronary vascular resistance serves as a primary determinant of CBF. Regulation of coronary vascular tone is the result of a balance between a myriad of vasodilator and vasoconstrictor signals, in which endothelium-derived vasoactive factors, metabolic messengers, neurohormones, and various autocoids are crucially involved.

Inflammation and coronary microvascular dysfunction in I/R

The aim of thrombolysis, angioplasty, and coronary artery bypass surgery is to restore CBF; however, successful restoration of epicardial coronary artery patency may not always lead to adequate reperfusion at the microvascular level [52], [53], primarily due to microvascular dysfunction caused by coronary microembolization, inflammatory cell infiltration, and impaired microvascular integrity following I/R injury.

Perspectives

Although great progress has been made in elucidating the mechanisms of CBF regulation in myocardial I/R injury, we are experiencing a failure in the translation of these exciting scientific results to patients. First, it remains unclear if myocardial I/R injury occurs to the same extent in man as it does in animal models; the experimental models of myocardial I/R are lacking certain aspects that are frequently present in the clinical environment [52]. Second, results from mice and rats may not

Sources of funding

This study was supported by grants from NIH grants (RO1-HL077566 and RO1-HL085119 to C.Z.) and American Heart Association Predoctoral Fellowship (10PRE4300043 to H.Z.).

Disclosures

None.

Acknowledgments

N/A

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