No-reflow in clinical settings

Even though recent advancements in endovascular therapy for acute ischemic stroke patients have led to an increased reperfusion rate, more than half of treated patients still experience a poor outcome. There is a growing body of evidence that the reason for poor outcome, despite successful reperfusion, could potentially be in the microvasculature.[1-4] This discrepancy between successful macrovascular reperfusion (i.e. successful treatment of the occluded blood vessel) and absence of reperfusion on the microvascular level has been named the “no-reflow” phenomenon.[4]

Presently, there are several controversies surrounding the no-reflow phenomenon, one of which is its pathophysiology. Proposals have been put that underlying mechanism behind no-reflow is related to intravascular clogging and aggregation of cellular elements. Others advocate that no-reflow is a result of an endothelial inflammatory response or a pericapillary pericyte constriction.[1,2,5] These different hypotheses on the cause of no-reflow have made it challenging to identify molecules and biomarkers that may be targeted for prognostic or therapeutic purposes.

Another debate for discussion is how to measure microvascular response after successful macrovascular reperfusion. A suggestion has been made for digital subtraction angiography imaging, as it allows detection of early or late appearance of arterial, capillary, and venous phases.[2] However, others have argued that CT- and MRI-based perfusion imaging might be more sensitive to provide additional information on tissue-level changes after the intervention. But even when using perfusion imaging, reported prevalence of no-reflow can range from <5% to >25% of all treated stroke patients.[4] These disparities seem to be due to use of different perfusion maps (Tmax, TTP, CBV, CBF, MTT) as well as the differences in their thresholds.  A suggested alternative to imaging has been put for the use of molecular markers, such as neutrophil count, neutrophil-to-lymphocyte ratio or interleukins.[5] Animal studies have shown promising results in the use of molecular markers and it has been proposed that these markers could also have potential value in a clinical settings.[2,5]

Lastly, in what subgroups of stroke patients can no-reflow be most accurately assessed? Most clinical studies on no-reflow include patients with successful macrovascular reperfusion i.e. patients who have Thrombolysis in Cerebral Infarction (TICI) ≥2b. However, if a patient has achieved 50% reperfusion of the initial target, there is still a substantial macrovascular perfusion deficit which may hinder the evaluation of microvascular reperfusion, irrespective of the imaging or biomarker modality used for its evaluation. A hypoperfusion on both macro- and microvascular level does not constitute a qualifying criterion for no-reflow. Therefore, a potentially better way to estimate no-reflow would be in patients with complete macrovascular reperfusion (TICI 3) as any findings of post-interventional hypoperfusion in these patients could not be explained by any macrovascular processes.

Despite these different methods and definitions, one thing upon which the majority agrees is that no-reflow has an impact on patient outcome: presence of no-reflow has been associated with lower rates of functional independence at 3 months (OR 0.2, 95% 0.1 – 0.3).[4] As microvascular status continues to receive more attention from the stroke community, a clearly defined question on no-reflow is urgently required. A concise definition which delineates not only what constitutes no-reflow, but also how to measure it and where to measure it, would undoubtedly help improve further scientific efforts in tackling this new frontier of stroke treatment.

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References:

1. Schiphorst AT, Turc G, Hassen WB, Oppenheim C, Baron JC. Incidence, severity and impact on functional outcome of persistent hypoperfusion despite large-vessel recanalization, a potential marker of impaired microvascular reperfusion: Systematic review of the clinical literature. J Cereb Blood Flow Metab. 2024 Jan;44(1):38-49. doi: 10.1177/0271678X231209069.
2. Sperring CP, Savage WM, Argenziano MG, Leifer VP, Alexander J, Echlov N, Spinazzi EF, Connolly ES Jr. No-Reflow Post-Recanalization in Acute Ischemic Stroke: Mechanisms, Measurements, and Molecular Markers. Stroke. 2023 Sep;54(9):2472-2480. doi: 10.1161/STROKEAHA.123.044240.
3. Zhang Y, Jiang M, Gao Y, Zhao W, Wu C, Li C, Li M, Wu D, Wang W, Ji X. “No-reflow” phenomenon in acute ischemic stroke. J Cereb Blood Flow Metab. 2024 Jan;44(1):19-37. doi: 10.1177/0271678X231208476.
4. Mujanovic A, Ng F, Meinel TR, Dobrocky T, Piechowiak EI, Kurmann CC, Seiffge DJ, Wegener S, Wiest R, Meyer L, Fiehler J, Olivot JM, Ribo M, Nguyen TN, Gralla J, Campbell BC, Fischer U, Kaesmacher J. No-reflow phenomenon in stroke patients: A systematic literature review and meta-analysis of clinical data. Int J Stroke. 2024 Jan;19(1):58-67. doi: 10.1177/17474930231180434.
5. El Amki M, Glück C, Binder N, Middleham W, Wyss MT, Weiss T, Meister H, Luft A, Weller M, Weber B, Wegener S. Neutrophils Obstructing Brain Capillaries Are a Major Cause of No-Reflow in Ischemic Stroke. Cell Rep. 2020 Oct 13;33(2):108260. doi: 10.1016/j.celrep.2020.108260.