No-reflow after stroke reperfusion therapy: An emerging phenomenon to be explored.

In the field of stroke thrombectomy, ineffective clinical and angiographic reperfusion after successful recanalization has drawn attention. Partial or complete microcirculatory reperfusion failure after the achievement of full patency of a former obstructed large vessel, known as the "no-reflow phenomenon" or "microvascular obstruction," was first reported in the 1960s and was later detected in both experimental models and patients with stroke. The no-reflow phenomenon (NRP) was reported to result from intraluminal occlusions formed by blood components and extraluminal constriction exerted by the surrounding structures of the vessel wall. More recently, an emerging number of clinical studies have estimated the prevalence of the NRP in stroke patients following reperfusion therapy, ranging from 3.3% to 63% depending on its evaluation methods or study population. Studies also demonstrated its detrimental effects on infarction progress and neurological outcomes. In this review, we discuss the research advances, underlying pathogenesis, diagnostic techniques, and management approaches concerning the no-reflow phenomenon in the stroke population to provide a comprehensive understanding of this phenomenon and offer references for future investigations.

"No-reflow" phenomenon in acute ischemic stroke.

Acute ischemic stroke (AIS) afflicts millions of individuals worldwide. Despite the advancements in thrombolysis and thrombectomy facilitating proximal large artery recanalization, the resultant distal hypoperfusion, referred to "no-reflow" phenomenon, often impedes the neurological function restoration in patients. Over half a century of scientific inquiry has validated the existence of cerebral "no-reflow" in both animal models and human subjects. Furthermore, the correlation between "no-reflow" and adverse clinical outcomes underscores the necessity to address this phenomenon as a pivotal strategy for enhancing AIS prognoses. The underlying mechanisms of "no-reflow" are multifaceted, encompassing the formation of microemboli, microvascular compression and contraction. Moreover, a myriad of complex mechanisms warrant further investigation. Insights gleaned from mechanistic exploration have prompted advancements in "no-reflow" treatment, including microthrombosis therapy, which has demonstrated clinical efficacy in improving patient prognoses. The stagnation in current "no-reflow" diagnostic methods imposes limitations on the timely application of combined therapy on "no-reflow" post-recanalization. This narrative review will traverse the historical journey of the "no-reflow" phenomenon, delve into its underpinnings in AIS, and elucidate potential therapeutic and diagnostic strategies. Our aim is to equip readers with a swift comprehension of the "no-reflow" phenomenon and highlight critical points for future research endeavors.

Microcirculation No-Reflow Phenomenon after Acute Ischemic Stroke.

BACKGROUND: The no-reflow phenomenon refers to a failure to restore normal cerebral microcirculation despite brain large artery recanalization after acute ischemic stroke, which was observed over 50 years ago. SUMMARY: Different mechanisms contributing to no-reflow extend across the endovascular, vascular wall, and extravascular factors. There are some clinical tools to evaluate cerebral microvascular hemodynamics and represent biomarkers of the no-reflow phenomenon. As substantial experimental and clinical data showed that clinical outcome was better correlated with reperfusion status rather than recanalization in patients with ischemic stroke, how to address the no-reflow phenomenon is critical. But effective treatments for restoring cerebral microcirculation have not been well established until now, so there is an urgent need for novel therapeutic perspectives to improve outcomes after recanalization therapies. CONCLUSION: Here, we review the occurrence of the no-reflow phenomenon after ischemic stroke and discuss its impact, detection method, and therapeutic strategies on the course of ischemic stroke, from basic science to clinical findings.

State of the Art: No-Reflow Phenomenon.

Primary percutaneous coronary intervention is the preferred reperfusion strategy for the management of acute ST-segment elevation myocardial infarction. No reflow is characterized by the inadequate myocardial perfusion of a given segment without angiographic evidence of persistent mechanical obstruction of epicardial vessels. Both pharmacologic and device-based strategies have been tested to resolve coronary no reflow. This article provides an updated overview of the no-reflow phenomenon, discussing clinical evidence and ongoing investigations of existing and novel therapeutic strategies to counteract it.

Management of Percutaneous Coronary Intervention Complications: Algorithms From the 2018 and 2019 Seattle Percutaneous Coronary Intervention Complications Conference.

Complications of percutaneous coronary intervention (PCI) may have significant impact on patient survival and healthcare costs. PCI procedural complexity and patient risk are increasing, and operators must be prepared to recognize and treat complications, such as perforations, dissections, hemodynamic collapse, no-reflow, and entrapped equipment. Unfortunately, few resources exist to train operators in PCI complication management. Uncertainty regarding complication management could contribute to the undertreatment of patients with high-complexity coronary disease. We, therefore, coordinated the Learning From Complications: How to Be a Better Interventionalist courses to disseminate the collective experience of high-volume PCI operators with extensive experience in chronic total occlusion and high-risk PCI. From these conferences in 2018 and 2019, we developed algorithms that emphasize early recognition, effective treatment, and team-based care of PCI complications. We think that an algorithmic approach will result in a logical and systematic response to life-threatening complications. This construct may be useful for operators who plan to perform complex PCI procedures.

[No-reflow: update on diagnosis, pathophysiology and therapeutic strategies]. / "No-reflow": update su diagnosi, fisiopatologia e strategie terapeutiche.

Primary percutaneous coronary intervention (PCI) represents the reperfusion strategy of choice for patients presenting with ST-segment elevation myocardial infarction. However, despite the restoration of epicardial flow, primary PCI may not determine an effective reperfusion of myocardial tissue due to the occurrence of microvascular obstruction. This phenomenon also known as "no-reflow" may occur in 30-60% of patients treated with primary PCI. Of importance, no-reflow attenuates the benefit of reperfusion therapy and is associated with a poor clinical outcome in terms of adverse ventricular remodeling, heart failure and mortality. The pathophysiology of no-reflow is complex and multiple players may be involved. Indeed, distal embolization, ischemia-reperfusion injury and an individual predisposition to microvascular dysfunction synergically interact to determine the occurrence of no-reflow. In this review, we will analyze the pathophysiological mechanisms, the diagnostic tools and the main therapeutic targets of no-reflow, with particular attention to the most recent acquisitions in this field.

No-Reflow Complicating Chronic Total Occlusion Coronary Revascularization.

OBJECTIVES: To assess the incidence of no-reflow in patients undergoing chronic total occlusion (CTO) percutaneous coronary intervention (PCI), analyze possible causes and differential diagnoses, and identify useful management approaches. METHODS: In this multicenter observational study, all CTO-PCIs performed between January 2018 and April 2019 were reviewed to collect no-reflow complications, defined as Thrombolysis in Myocardial Infarction (TIMI) flow ≤1 in a patent epicardial artery. Patient clinical, anatomical, and procedural characteristics were analyzed. RESULTS: Out of 461 PCIs, two (0.43%) were complicated by no-reflow. In 1 case, PCI was performed on a long segment of the right coronary artery, after use of a dissection-re-entry technique by knuckle wiring. In the second patient, no-reflow developed after proximal left anterior descending coronary artery stenting, with a short subintimal tracking. Intravascular ultrasound was used to exclude complications in the epicardial vessel in both cases. Distal embolization seems the most plausible cause, and intracoronary adenosine effectively improved flow. Both patients had a type 4a myocardial infarction, asymptomatic in the first case, and associated with chest pain, electrocardiographic changes, and new regional wall-motion abnormality at echocardiography in the second case. CONCLUSIONS: No-reflow in CTO recanalization is rare, but associated with a high risk of periprocedural myocardial infarction, with incomplete protection from ischemia offered by the pre-existing collateral network.

Pathophysiology and diagnosis of coronary microvascular dysfunction in ST-elevation myocardial infarction.

Early mechanical reperfusion of the epicardial coronary artery by primary percutaneous coronary intervention (PCI) is the guideline-recommended treatment for ST-elevation myocardial infarction (STEMI). Successful restoration of epicardial coronary blood flow can be achieved in over 95% of PCI procedures. However, despite angiographically complete epicardial coronary artery patency, in about half of the patients perfusion to the distal coronary microvasculature is not fully restored, which is associated with increased morbidity and mortality. The exact pathophysiological mechanism of post-ischaemic coronary microvascular dysfunction (CMD) is still debated. Therefore, the current review discusses invasive and non-invasive techniques for the diagnosis and quantification of CMD in STEMI in the clinical setting as well as results from experimental in vitro and in vivo models focusing on ischaemic-, reperfusion-, and inflammatory damage to the coronary microvascular endothelial cells. Finally, we discuss future opportunities to prevent or treat CMD in STEMI patients.

Impella CP and Veno-Arterial Extracorporeal Membrane Oxygenator as a sequential add-on combination circulatory support in ST-segment elevation myocardial infarction complicated by cardiogenic shock.

A 48-year-old male was admitted to our institution with an anteroseptal ST-elevation myocardial infarction and angiographic evidence of a thrombotic occlusion in the ostial segment of the left anterior descending coronary artery. The percutaneous coronary intervention resulted in "no-reflow" and cardiogenic shock. We describe our successful management strategy with sequentially combined implantation of Impella CP and Extracorporeal Membrane Oxygenator.

Advances in Coronary No-Reflow Phenomenon-a Contemporary Review.

PURPOSE OF REVIEW: Coronary artery no-reflow phenomenon is an incidental outcome of percutaneous coronary intervention in patients presenting with acute myocardial infarction. Despite advances in pharmacologic and non-pharmacologic therapies, coronary no-reflow phenomenon occurs more commonly than desired. It often results in poor clinical outcomes and remains as a relevant consideration in the cardiac catheterization laboratory. In this systematic review, we have sought to discuss the topic in detail, and to relay the most recent discoveries and data on management of this condition. RECENT FINDINGS: We discuss several pharmacologic and non-pharmacologic treatments used in the prevention and management of coronary no-reflow and microvascular obstruction. Covered topics include the understanding of pharmacologic mechanisms of current and future agents, and recent discoveries that may result in the development of future treatment options. We conclude that the pathophysiology of coronary no-reflow phenomenon and microvascular obstruction still remains incompletely understood, although several plausible theories have led to the current standard of care for its management. We also conclude that coronary no-reflow phenomenon and microvascular obstruction must be recognized as a multifactorial condition that has certain predispositions and characteristics, therefore its prevention and treatment must begin pre-procedurally and be multi-faceted including certain medications and operator techniques in the cardiac catheterization laboratory.

No-reflow phenomenon in the heart and brain.

The no-reflow phenomenon refers to the observation that when an organ is made ischemic by occlusion of a large artery supplying it, restoration of patency in that artery does not restore perfusion to the microvasculature supplying the parenchyma of that organ. This has been observed after prolonged arterial occlusions in the heart (30-90 min), brain, skin, and kidney. In experimental models, zones of no reflow in the heart are characterized by ultrastructural microvascular damage, including focal endothelial swelling obstructing the lumen of small vessels. Blood elements such as neutrophil plugs, platelets, and stacking of erythrocytes have also been implicated. No reflow is associated with poor healing of the myocardial infarction. In patients, no reflow is associated with a poor clinical outcome independent of infarct size, suggesting that therapy for no reflow may be an important approach to improving outcome for ST elevation myocardial infarction. No reflow occurs after reperfusion of experimental cerebral ischemia and may be observed after only 5-min episodes of ischemia. Aggregation of blood elements may play a greater role than in cardiac no reflow. No reflow in the brain may involve cortical spreading depression with disturbed local vascular control and high, vasculotonic levels of extracellular K+ concentration, postischemic swelling in endothelial cells and abutting end feet of pericytes, pericyte contraction and death, interstitial edema with collapse of cerebral capillaries, and inflammatory reaction. New guidelines suggesting that reperfusion for stroke may be considered as late as 24 h after the onset of symptoms suggest that clinicians may be seeing more no reflow in the future.

Management of No-Reflow Phenomenon in the Catheterization Laboratory.

At the conclusion of a primary percutaneous coronary intervention for ST-segment elevation myocardial infarction, and after the cardiologist makes certain that there is no residual stenosis following stenting, assessment of coronary flow becomes the top priority. The presence of no-reflow is a serious prognostic sign. No-reflow can result in poor healing of the infarct and adverse left ventricular remodeling, increasing the risk for major adverse cardiac events, including congestive heart failure and death. To achieve normal flow, features associated with a high incidence of no-reflow must be anticipated, and measures must be undertaken to prevent its occurrence. In this review, the authors discuss various preventive strategies for no-reflow as well as pharmacological and nonpharmacological interventions that improve coronary blood flow, such as intracoronary adenosine and nitroprusside. Nonpharmacological therapies, such as induced hypothermia, were successful in animal studies, but their effectiveness in reducing no-reflow in humans remains to be determined.

Efficacy and Safety of Local Intracoronary Drug Delivery in Treatment of No-Reflow Phenomenon: A Pilot Study.

BACKGROUND: Successful reopening of epicardial coronary artery does not always mean optimal myocardial reperfusion in a sizable portion of patients, mostly because of no-reflow phenomenon. OBJECTIVES: We investigated whether local injection of adrenaline ± verapamil in the distal coronary bed is more effective than their intracoronary (IC) injection through the guiding catheter in the treatment of no-reflow phenomenon following percutaneous coronary intervention (PCI). METHODS: A total of 40 patients with no-reflow following PCI were randomized into two groups. Group 1 received IC adrenaline ± verapamil through a well-cannulated guiding catheter while Group 2 received the above-mentioned drugs in the distal coronary bed through a perfusion balloon or selective microcatheter. The primary end points were the achievement of TIMI III flow with MBG II or III. Secondary end points were the occurrence of hypotension, arrhythmias, and major adverse cardiac events (MACEs) during hospital stay. RESULTS: After drug injection, the percentage of patients achieving Thrombolysis in Myocardial Infarction (TIMI) III flow in Group 1 was 40% versus 80% in Group 2, P = 0.032. MBG II and III was significantly lower in Group 1; 10% and 25% versus 15% and 65% in Group 2, respectively, P = 0.033. Primary end points were achieved in only 35% of patients in Group 1 and in 80% of patients in Group 2 (odds ratio, 7.43, 95% confidence interval 1.78-31.04, P < 0.01). Secondary end points were not different between both groups. CONCLUSION: Local intra-coronary delivery of adrenaline ± verapamil is a safe and effective method for the treatment of no-reflow phenomenon complicating PCI.

Effects of liraglutide on no-reflow in patients with acute ST-segment elevation myocardial infarction.

BACKGROUND: The 'no-reflow' phenomenon after a percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI) is a strong predictor of both short- and long-term mortality. Glucagon-like peptide-1 (GLP-1) exerts a cardioprotective effect during ischemia reperfusion injury. We planned to evaluate the effects of liraglutide on myocardial no-reflow after PCI for STEMI. METHODS: A total of 284 patients with STEMI undergoing PCI were enrolled in this study between September 2013 and March 2015. Of these, 210 patients were randomized 1:1 to receive either liraglutide or placebo 30 min before PCI (1.8 mg). RESULTS: The primary end point, the prevalence of no-reflow, was significantly lower in the liraglutide group than in the control group (5% vs. 15%, P=0.01). Administration of liraglutide was consistently identified as a significant determinant for no-reflow ratio. There was a significant decrease in serum high-sensitivity C-reactive protein levels at 6-hour reperfusion in the liraglutide group compared to the control group (0.87 ± 0.09 mg/dL vs. 0.96 ± 0.10mg/dL, P<0.001). During a 3-month follow-up period, no difference was observed in the incidence of major adverse cardiovascular event. CONCLUSIONS: Liraglutide may be associated with less no-reflow in STEMI, which should be confirmed by larger-scale trials.

The challenges and impact of microvascular injury in ST-elevation myocardial infarction.

Despite successful restoration of epicardial coronary blood flow, a significant proportion of patients with ST-elevation myocardial infarction suffer from an impairment of the microvascular perfusion - a phenomenon termed no-reflow or microvascular injury (MVI). The underlying pathophysiology is complex and likely multifactorial. It is well established that MVI is associated with worse clinical outcome. Although MVI can be detected during coronary intervention and the post-infarction period, its prevention and treatment strategies remain a major challenge since most results of clinical studies have been disappointing so far. This review provides an overview on the main pathophysiological mechanisms of MVI and its diagnostic approaches. Moreover, it will discuss its clinical consequences and current strategies of prevention and treatment.

No reflow leading to catastrophic hemodynamic collapse in a patient with severe aortic stenosis and its management.

We report a case of an 87-year-old female who underwent percutaneous coronary intervention (PCI) for non-ST elevation myocardial infarction while she was being worked up for transcatheter aortic valve procedure. Hemodynamic compromise occurred during the PCI, which could only be mitigated by doing a balloon aortic valvuloplasty and Impella™ insertion. This case report will help in preparedness for any untoward events in patients with aortic stenosis and undergoing percutaneous coronary intervention.

Randomized evaluation of intralesion versus intracoronary abciximab and aspiration thrombectomy in patients with ST-elevation myocardial infarction: The COCTAIL II trial.

BACKGROUND: Thrombus burden and distal embolization are predictive of no-reflow during primary percutaneous coronary intervention (PCI) in patients with acute ST-elevation myocardial infarction (STEMI). We sought to compare the efficacy of pharmacological and catheter-based strategies for thrombus in patients with STEMI and high atherothrombotic burden. METHODS: Between January 2012 and December 2013, 128 STEMI patients undergoing primary PCI at 5 centers were randomly assigned in a 2 × 2 factorial design to intracoronary (IC) abciximab bolus (via the guide catheter) versus intralesion (IL) abciximab bolus, each with versus without aspiration thrombectomy (AT). Study end points were residual intrastent atherothrombotic burden, defined as the number of cross-sections with residual tissue area >10% as assessed by optical coherence tomography, and indices of angiographic and myocardial reperfusion. RESULTS: Residual intrastent atherothrombotic burden did not significantly differ with IL versus IC abciximab (median [interquartile range] 6.0 [1-15] vs 6.0 [2-11], P = .806) and with AT versus no aspiration (6.0 [1-13] vs 6.0 [2-12], P = .775). Intralesion abciximab administration was associated with improved angiographic myocardial reperfusion in terms of thrombolysis in myocardial infarction (TIMI) flow (3 [3-3] vs 3 [2-3], P = .040), corrected TIMI frame count (12 ± 5 vs 17 ± 16, P = .021), and myocardial blush grade (3 [2-3] vs 3 [2-3], P = .035). In particular, IL abciximab was associated with higher occurrence of final TIMI 3 flow (90% vs 73.8%, P = .032) and myocardial blush grade 3 (71.6% vs 52.4%, P = .039). Conversely, AT had no significant effect on indices of angiographic or myocardial reperfusion. CONCLUSIONS: In patients with STEMI and high thrombotic burden, neither IL versus IC abciximab nor AT versus no aspiration reduced postprocedure intrastent atherothrombotic burden in patients with STEMI undergoing primary PCI. However, IL abciximab improved indices of angiographic and myocardial reperfusion compared to IC abciximab, benefits not apparent with AT.

Novel insights into an "old" phenomenon: the no reflow.

Coronary artery diseases and particularly acute myocardial infarction are the leading causes of mortality and morbidity in western countries. Despite the achievements of the last decades with the advent of double antiplatelet therapy, new antithrombotics and reperfusion strategies (either pharmacological or mechanical), many patients still have adverse cardiovascular events after ST-segment elevation acute myocardial infarction; at least some of these adverse events are related to the no reflow phenomenon that occurs after primary percutaneous coronary intervention. In our review we will discuss the various aspects of this phenomenon.