Advances in Pathophysiology and Novel Therapeutic Strategies for Coronary No-Reflow Phenomenon

Abstract

Coronary no-reflow (CNR) is the failure of blood to reperfuse ischemic myocardial tissue after restoration of the vasculature. CNR poses a significant clinical challenge in the treatment of patients with ST-segment elevation myocardial infarction (STEMI), as it increases mortality and the risk of major adverse cardiac events (MACEs). Myocardial ischemia with subsequent reperfusion results in severe damage to the cardiac microcirculation. The pathophysiological causes of CNR include cardiomyocyte vulnerability, capillary and endothelial damage, leukocyte activation, reactive oxygen species (ROS) production, and changes in microRNA profiles and related gene expression. The impact of percutaneous coronary intervention (PCI) on the occurrence of CNR cannot be overlooked, as it can provoke distal atherothrombotic embolization. Current standards of pharmacological therapy for CNR are confined to intracoronary vasodilators and antiplatelet agents. As our understanding of the pathogenesis of the CNR phenomenon improves, opportunities emerge for developing novel therapeutic strategies. The following literature review provides an overview of the pathophysiology of the no-reflow phenomenon (based on animal and preclinical studies), contemporary treatment trends, and current therapeutic approaches.

Keywords: animal models; coronary no-reflow; ischemia/reperfusion injury; microvascular obstruction; myocardial infarction; pathophysiology.

Figure 1

No-reflow phenomenon risk factors. TIMI—thrombolysis in myocardial infarction, CAD—coronary artery disease, CK—creatine kinase, LVEF—left ventricular ejection fraction. Created in BioRender. Borzuta, H. (2025) https://BioRender.com/q86cdtq, accessed on 9 July 2025.

Figure 2

Establishment of a CNR animal model and histopathological characterization of myocardial injury. Created in BioRender. Borzuta, H. (2025) https://BioRender.com/iowv8mx, accessed on 9 July 2025.

Figure 3

The summary of pathomechanisms underlying the development of CNR. LTs—leukotrienes, TXA—thromboxane A, ROS—reactive oxygen species, ATP—adenosine triphosphate, ET-1—endothelin-1, IL-1β—interleukin-1β, GPR39—G-protein coupled receptor 39. Created in BioRender. Borzuta, H. (2025) https://BioRender.com/zs3vs9e, accessed on 9 July 2025.

Figure 4

Role of miRNAs in the pathophysiology of CNR. (A) Several miRNAs have been found to regulate cardiomyocyte apoptosis and autophagy, facilitate clearance of necrotic cardiomyocytes and maintain endothelial integrity during I/R injury. (B) MiRNAs may serve as potential biomarkers in prediction of CNR, as some of them are upregulated or downregulated in serum or plasma in patients with CNR. Created in BioRender. Borzuta, H. (2025) https://BioRender.com/m1k77bh, accessed on 9 July 2025.