No-reflow after recanalization in ischemic stroke: From pathomechanisms to therapeutic strategies

Abstract

Endovascular reperfusion therapy is the primary strategy for acute ischemic stroke. No-reflow is a common phenomenon, which is defined as the failure of microcirculatory reperfusion despite clot removal by thrombolysis or mechanical embolization. It has been reported that up to 25% of ischemic strokes suffer from no-reflow, which strongly contributes to an increased risk of poor clinical outcomes. No-reflow is associated with functional and structural alterations of cerebrovascular microcirculation, and the injury to the microcirculation seriously hinders the neural functional recovery following macrovascular reperfusion. Accumulated evidence indicates that pathology of no-reflow is linked to adhesion, aggregation, and rolling of blood components along the endothelium, capillary stagnation with neutrophils, astrocytes end-feet, and endothelial cell edema, pericyte contraction, and vasoconstriction. Prevention or treatment strategies aim to alleviate or reverse these pathological changes, including targeted therapies such as cilostazol, adhesion molecule blocking antibodies, peroxisome proliferator-activated receptors (PPARs) activator, adenosine, pericyte regulators, as well as adjunctive therapies, such as extracorporeal counterpulsation, ischemic preconditioning, and alternative or complementary therapies. Herein, we provide an overview of pathomechanisms, predictive factors, diagnosis, and intervention strategies for no-reflow, and attempt to convey a new perspective on the clinical management of no-reflow post-ischemic stroke.

Keywords: No-reflow; ischemic stroke; pathogenesis; recanalization; therapy.

Figure 1.

No-reflow phenomenon after recanalization in ischemic stroke. Several pathomechanisms have been postulated. Due to calcium overload and stimulation by oxygen and nitrogen radicals during ischemia and reperfusion, constriction of the pericytes leads to a smaller lumen and low/no reflow. Adhesion and aggregation of blood components (erythrocytes, leukocytes, fibrin, platelets, etc.) and rolling along the endothelium, which may form microthrombi to block the microcirculation. Neutrophils stay in the capillaries and prevent recanalization. Energy deficiency, inflammatory response and oxidative stress induce cytotoxic edema and vasogenic edema after BBB destruction, causing astrocyte end-foot, endothelial cell edema, and brain tissue swelling, which causes mechanical compression of microvasculature. Embolic pieces from the dissolution of the primary thrombus may also block small vessels causing no-reflow.

Figure 2.

Capillaries remain stalled after recanalization of the MCA. (a, b, c) In ischemic stroke, thrombolysis did not result in successful reperfusion of the distal microvascular network. After thrombolysis, microvascular dysfunction may be caused by neutrophil stagnation in the capillaries. The use of neutrophil-depleting antibodies may restore capillary flow and improve prognosis. (d) After recanalization, representative images of a stall caused by neutrophils, RBCs, or platelets distinguished by fluorescence labels and morphology and (e) Percentages of capillaries stalled specifically with neutrophils, RBCs, or platelets in the core and penumbra ROI for control and t-PA-treated mice. Obviously, it is clear from the figure that neutrophils are always predominant in capillary arrest in the ischemic core and semidark areas after thrombolysis. Copyright 2020, Cell Press.

Figure 3.

Ischemia induces persistent pericyte constriction that does not restore even after complete recanalization of the occluded artery. (a) Node-like discontinuities were noted along the course of microvessels in the ischemic hemisphere. (b) The DIC images illustrate frequent interruptions in the erythrocyte column in an ischemic capillary contrary to a continuous row of erythrocytes flowing through an intact capillary. (Green, c) Nodal constrictions on the ischemic capillaries colocalized with α-SMA-positive pericytes. These nodal constrictions might be brought on by pericytes. Indeed, when labeled pericytes with an antibody against α-smooth muscle actin (SMA), it suggested that the constricted microvessels segments colocalized with pericytes. Copyright 2009, Springer Nature.

Figure 4.

No-reflow on CT perfusion. No-reflow identified on CT perfusion (a–d) and a patient with right frontal infarct and normal follow-up perfusion imaging for comparison. (c). Quantitative analysis in the patient showed 29% rCBF reduction. Mean transit time (MTT) showed foci of very high values within the infarct on CT perfusion cases of no-reflow (a, b, and d). The corresponding Tmax lesions of these foci differed from that usually seen in arterial occlusions and exhibited a heterogeneous patchy pattern (a), was not present (b), or coincided with areas of contrast leakage (d). Copyright 2022, American Academy of Neurology.

Figure 5.

No-reflow on MR perfusion. No-reflow is manifested by reduction of rCBV or rCBF with darker blue on perfusion maps. Reocclusion was excluded on magnetic resonance (MR) angiography at the time of perfusion imaging. A corresponding well-demarcated area of reduced mean transit time (MTT) was frequently seen in no-reflow cases identified by MR perfusion imaging (a–d). Copyright 2022, American Academy of Neurology.

Figure 6.

Cilostazol suppressed no-reflow phenomenon. (a) Representative images of CBF at the indicated time points pre- and post-MCAO/R in vehicle- and cilostazol-treated mice. Arrows indicate suppression of no-reflow phenomenon with cilostazol. (b) Temporal profile of CBF of vehicle- and cilostazol-treated mice after 45-minute MCAO/R. CBF was expressed as a ratio to the baseline level and (c) Cilostazol preserved microvascular blood flow in ischemic areas by suppressing platelet aggregation and leukocyte plugging in microvessels. Copyright 2012, Elsevier.