No-reflow in acute ischemic stroke: mechanisms, measurements, and molecular markers.

BACKGROUND: No-reflow is a critical microvascular phenomenon in acute ischemic stroke in which patients fail to achieve adequate tissue reperfusion despite successful recanalization of a large vessel occlusion. It affects at least 25% of patients after reperfusion and results from persistent microvascular dysfunction that prevents restoration of normal blood flow to ischemic tissue, leading to ongoing injury. OBJECTIVE: This paper synthesizes historical, mechanistic, diagnostic, and therapeutic perspectives on the no-reflow phenomenon to clarify its pathophysiology and highlight gaps limiting clinical translation. METHODS: A narrative review was conducted using foundational experimental studies and contemporary clinical literature. Evidence was organized into mechanistic domains, measurement modalities, and therapeutic strategies, integrating molecular, imaging, and neurointerventional findings. RESULTS: No-reflow arises from interacting mechanisms, including microvascular occlusions from embolic fragments, platelet aggregation, erythrocyte/fibrin deposition, and leukocyte plugging, where neutrophils can lodge within capillaries and impede flow. Vascular remodeling driven by endothelial dysfunction, oxidative stress, necroptosis, microglial activation, and pericyte constriction further compromises perfusion, while cytotoxic edema produces microvessel compression. Measurement remains inconsistent due to the absence of standardized diagnostic criteria, with current tools ranging from TICI-based angiographic assessments to perfusion imaging and molecular biomarkers. Emerging therapies target distal embolization, microvascular thrombosis, vasoconstriction, inflammation, and ischemic conditioning, while selective hypothermia shows promise in experimental models. CONCLUSION: No-reflow phenomenon is a multifactorial barrier to functional recovery after stroke, and its clinical impact is amplified by diagnostic ambiguity. Advancing real-time measurement tools and mechanism-based therapies is essential to improving outcomes after recanalization.