Continued dysfunction of capillary pericytes promotes no-reflow after experimental stroke in vivo.

Incomplete reperfusion of the microvasculature ('no-reflow') after ischaemic stroke damages salvageable brain tissue. Previous ex vivo studies suggest pericytes are vulnerable to ischaemia and may exacerbate no-reflow, but the viability of pericytes and their association with no-reflow remains under-explored in vivo. Using longitudinal in vivo two-photon single-cell imaging over 7 days, we showed that 87% of pericytes constrict during cerebral ischaemia and remain constricted post reperfusion, and 50% of the pericyte population are acutely damaged. Moreover, we revealed ischaemic pericytes to be fundamentally implicated in capillary no-reflow by limiting and arresting blood flow within the first 24 h post stroke. Despite sustaining acute membrane damage, we observed that over half of all cortical pericytes survived ischaemia and responded to vasoactive stimuli, upregulated unique transcriptomic profiles and replicated. Finally, we demonstrated the delayed recovery of capillary diameter by ischaemic pericytes after reperfusion predicted vessel reconstriction in the subacute phase of stroke. Cumulatively, these findings demonstrate that surviving cortical pericytes remain both viable and promising therapeutic targets to counteract no-reflow after ischaemic stroke.

Glycoprotein IIb/IIIa Inhibitors in Acute Myocardial Infarction and Angiographic Microvascular Obstruction: The REVERSE-FLOW Trial.

BACKGROUND AND AIMS: Glycoprotein (GP) IIb/IIIa inhibitors are recommended in acute myocardial infarction (AMI) for bailout treatment in case of angiographic microvascular obstruction (MVO), also termed no-reflow phenomenon, after percutaneous coronary intervention (PCI) with, however, lacking evidence (class IIa, level C). METHODS: The investigator-initiated, international, multicenter REVERSE-FLOW trial randomized 120 patients with AMI and Thrombolysis In Myocardial Infarction flow grade ≤2 after primary PCI to optimal medical therapy with or without GP IIb/IIIa inhibitor. The primary endpoint was infarct size (%LV) assessed by cardiac magnetic resonance (CMR). Secondary endpoints included CMR-derived MVO and 30-day adverse clinical events. The trial is registered with ClinicalTrials.gov: NCT02739711. RESULTS: The population was predominantly male (76.7%) with a median age of 66 years and ST-elevation myocardial infarction in 73.3% of patients. Clinical and angiographic characteristics were well balanced between the cohorts. Patients in the treatment group (n=62) received eptifibatide (n=41) or tirofiban (n=21). Infarct size assessed by CMR imaging was similar in both study groups (25.4% of left ventricular mass [LV] vs. 25.2%LV; p=0.386). However, the number of patients with evidence of CMR-derived MVO (74.5% vs. 92.2%; p=0.017) and the extent of MVO (2.1%LV vs. 3.4%LV; p=0.025) were significantly reduced in the GP IIb/IIIa inhibitor group compared to controls. Thirty-day outcome showed an increased bleeding risk after GP IIb/IIIa inhibitor administration restricted to non-life-threatening bleedings (22.6% vs. 6.9%; p=0.016) without differences in all-cause mortality (4.8% vs. 3.4%; p=0.703). CONCLUSIONS: Bailout GP IIb/IIIa inhibition in AMI patients with angiographic MVO failed to reduce the primary endpoint infarct size but decreased CMR-derived MVO and led to an increase in non-fatal bleeding events.

Systemic biomarker associated with poor outcome after futile reperfusion.

BACKGROUND: Successful recanalization does not lead to complete tissue reperfusion in a considerable percentage of ischemic stroke patients. This study aimed to identify biomarkers associated with futile recanalization. Leukoaraiosis predicts poor outcomes of this phenomenon. Soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK), which is associated with leukoaraiosis degrees, could be a potential biomarker. METHODS: This study includes two cohorts of ischemic stroke patients in a multicentre retrospective observational study. Effective reperfusion, defined as a reduction of ≥8 points in the National Institutes of Health Stroke Scale (NIHSS) within the first 24 h, was used as a clinical marker of effective reperfusion. RESULTS: In the first cohort study, female sex, age, and high NIHSS at admission (44.7% vs. 81.1%, 71.3 ± 13.7 vs. 81.1 ± 6.7; 16 [13, 21] vs. 23 [17, 28] respectively; p < .0001) were confirmed as predictors of futile recanalization. ROC curve analysis showed that leukocyte levels (sensitivity of 99%, specificity of 55%) and sTWEAK level (sensitivity of 92%, specificity of 88%) can discriminate between poor and good outcomes. Both biomarkers simultaneously are higher associated with outcome after effective reperfusion (OR: 2.17; CI 95% 1.63-4.19; p < .0001) than individually (leukocytes OR: 1.38; CI 95% 1.00-1.64, p = .042; sTWEAK OR: 1.00; C I95% 1.00-1.01, p = .019). These results were validated using a second cohort, where leukocytes and sTWEAK showed a sensitivity of 100% and specificity of 66.7% and 75% respectively. CONCLUSIONS: Leukocyte and sTWEAK could be biomarkers of reperfusion failure and subsequent poor outcomes. Further studies will be necessary to explore its role in reperfusion processes.

Aspirin loading and coronary no-reflow after percutaneous coronary intervention in patients with acute myocardial infarction.

BACKGROUND: The association of aspirin loading with the risk of coronary no-reflow (CNR) after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) has not been investigated. We assessed the association of aspirin loading before PCI with CNR in patients with AMI. MATERIALS AND METHODS: This study included 3100 patients with AMI undergoing PCI. Of them, 2812 patients received aspirin loading (a single oral [or chewed] or intravenous dose of 150-300 mg) and 288 patients did not receive aspirin loading before PCI. The primary endpoint was CNR, defined as Thrombolysis in Myocardial Infarction blood flow grade of <3 after the PCI. RESULTS: CNR occurred in 130 patients: 127 patients in the group with aspirin loading and 3 patients in the group without aspirin loading before PCI (4.5% vs. 1.0%; odds ratio [OR] = 4.50, 95% confidence interval, [1.42-14.21], p = 0.005). After adjustment, the association between aspirin loading and CNR was significant (adjusted OR = 4.49 [1.56-12.92]; p < 0.001). There was no aspirin loading-by-P2Y12 inhibitor (ticagrelor or prasugrel) interaction (pint = 0.465) or aspirin loading-by-chronic aspirin therapy on admission (pint = 0.977) interaction with respect to the occurrence of CNR after PCI. Chronic low-dose aspirin therapy on admission was not independently associated with higher risk of CNR after PCI (adjusted OR = 1.06 [0.65-1.72]; p = 0.824). CONCLUSION: In patients with AMI undergoing PCI, aspirin loading before the PCI procedure at the guideline-recommended doses was associated with higher odds of developing CNR. However, due to the limited number of events, the findings should be considered as hypothesis generating.

The Role of Microvascular Obstruction and Intra-Myocardial Hemorrhage in Reperfusion Cardiac Injury. Analysis of Clinical Data.

Microvascular obstruction (MVO) of coronary arteries promotes an increase in mortality and major adverse cardiac events in patients with acute myocardial infarction (AMI) and percutaneous coronary intervention (PCI). Intramyocardial hemorrhage (IMH) is observed in 41-50% of patients with ST-segment elevation myocardial infarction and PCI. The occurrence of IMH is accompanied by inflammation. There is evidence that microthrombi are not involved in the development of MVO. The appearance of MVO is associated with infarct size, the duration of ischemia of the heart, and myocardial edema. However, there is no conclusive evidence that myocardial edema plays an important role in the development of MVO. There is evidence that platelets, inflammation, Ca 2 + overload, neuropeptide Y, and endothelin-1 could be involved in the pathogenesis of MVO. The role of endothelial cell damage in MVO formation remains unclear in patients with AMI and PCI. It is unclear whether nitric oxide production is reduced in patients with MVO. Only indirect evidence on the involvement of inflammation in the development of MVO has been obtained. The role of reactive oxygen species (ROS) in the pathogenesis of MVO is not studied. The role of necroptosis and pyroptosis in the pathogenesis of MVO in patients with AMI and PCI is also not studied. The significance of the balance of thromboxane A2, vasopressin, angiotensin II, and prostacyclin in the formation of MVO is currently unknown. Conclusive evidence regarding the role of coronary artery spasm in the development of MVhasn't been established. Correlation analysis of the neuropeptide Y, endothelin-1 levels and the MVO size in patients with AMI and PCI has not previously been performed. It is unclear whether epinephrine aggravates reperfusion necrosis of cardiomyocytes. Dual antiplatelet therapy improves the efficacy of PCI in prevention of MVO. It is unknown whether epinephrine or L-type Ca 2 + channel blockers result in the long-term improvement of coronary blood flow in patients with MVO.

A Prediction Nomogram for No-Reflow in Acute Myocardial Infarction Patients after Primary Percutaneous Coronary Intervention.

Background: The coronary no-reflow (NR) phenomenon is an independent predictor of major adverse cardiac events (MACEs). This study aimed to establish a clinical and comprehensive nomogram for predicting NR in acute myocardial infarction (AMI) patients after primary percutaneous coronary intervention (pPCI). Methods: The multivariable logistic regression analysis was performed to determine the NR-related factors. A nomogram was established via several clinical and biochemical factors, and the performance was evaluated via discrimination, calibration, and clinical factors. Results: The study consisted of 3041 AMI patients after pPCI, including 2129 patients in the training set (70%) and 912 patients in the validation set (30%). The NR event was 238 in the training set and 87 in the validation set. The level of N-terminal prohormone B-type natriuretic peptide (NT-proBNP), basophil count (BASO), neutrophil count (NEUBC), D-dimer, hemoglobin (Hb), and red blood cell distribution width (RDW.CV) in NR patients showed statistically significant differences. In the training set, the C-index was 0.712, 95% CI 0.677 to 0.748. In the validation set, the C-index was 0.663, 95% CI 0.604 to 0.722. Conclusions: A nomogram that may predict NR in AMI patients undergoing pPCI was established and validated. We hope this nomogram can be used for NR risk assessment and clinical decision-making and significantly prevent potentially impaired reperfusion associated with NR.

Adenosine in Interventional Cardiology: Physiopathologic and Pharmacologic Effects in Coronary Artery Disease.

This review article focuses on the role of adenosine in coronary artery disease (CAD) diagnosis and treatment. Adenosine, an endogenous purine nucleoside, plays crucial roles in cardiovascular physiology and pathology. Its release and effects, mediated by specific receptors, influence vasomotor function, blood pressure regulation, heart rate, and platelet activity. Adenosine therapeutic effects include treatment of the no-reflow phenomenon and paroxysmal supraventricular tachycardia. The production of adenosine involves complex cellular pathways, with extracellular and intracellular synthesis mechanisms. Adenosine's rapid metabolism underscores its short half-life and physiological turnover. Furthermore, adenosine's involvement in side effects of antiplatelet therapy, particularly ticagrelor and cangrelor, highlights its clinical significance. Moreover, adenosine serves as a valuable tool in CAD diagnosis, aiding stress testing modalities and guiding intracoronary physiological assessments. Its use in assessing epicardial stenosis and microvascular dysfunction is pivotal for treatment decisions. Overall, understanding adenosine's mechanisms and clinical implications is essential for optimizing CAD management strategies, encompassing both therapeutic interventions and diagnostic approaches.

Cardio- and Vasoprotective Effects of Quinacrine in an In Vivo Rat Model of Myocardial Ischemia/Reperfusion Injury.

This study aimed to investigate the cardioprotective effect of quinacrine in an in vivo model of myocardial ischemia/reperfusion injury. A 30-min regional myocardial ischemia followed by a 2-h reperfusion was modeled in anesthetized Wistar rats. Starting at the last minute of ischemia and during the first 9 min of reperfusion the rats in the control (n=8) and experimental (n=9) groups were injected with 0.9% NaCl and quinacrine solution (5 mg/kg), respectively. The area at risk and infarct size were evaluated by "double staining" with Evans blue and triphenyltetrazolium chloride. To assess vascular permeability in the area at risk zone, indocyanine green (ICG) and thioflavin S (ThS) were injected intravenously at the 90th and 120th minutes of reperfusion, respectively, to assess the no-reflow zone. The images of ICG and ThS fluorescence in transverse sections of rat hearts were obtained using a FLUM multispectral fluorescence organoscope. HR tended to decrease by 13% after intravenous administration of quinacrine and then recovered within 50 min. Quinacrine reduced the size of the necrotic zone (p=0.01), vascular permeability in the necrosis region, and the no-reflow area (p=0.027); at the same time, the area at risk did not significantly differ between the groups. Intravenous administration of quinacrine at the beginning of reperfusion of the rat myocardium reduces no-reflow phenomenon and infarct size.

[Influence of chronic obstructive pulmonary disease on hospital outcomes of percutaneous coronary interventions in patients with acute coronary syndrome].

AIM: To evaluate the impact of chronic obstructive pulmonary disease (COPD) on hospital outcomes of percutaneous coronary interventions (PCI) in patients with acute coronary syndrome (ACS). MATERIALS AND METHODS: A cohort prospective study of the COPD effect on mortality and coronary microvascular obstruction (CMVO, no-reflow) development after PCI in ACS was carried out. 626 patients admitted in 2019-2020 were included, 418 (67%) - men, 208 (33%) - women. Median age - 63 [56; 70] years. Myocardial infarction with ST elevation identified in 308 patients (49%), CMVO - in 59 (9%) patients (criteria: blood flow <3 grade according to TIMI flow grade; perfusion <2 points according to Myocardial blush grade; ST segment resolution <70%). 13 (2.1%) patients died. Based on the questionnaire "Chronic Airways Diseases, A Guide for Primary Care Physicians, 2005", 2 groups of patients were identified: 197 (31%) with COPD (≥17 points) and 429 (69%) without COPD (<17 points). Groups were compared on unbalanced data (÷2 Pearson, Fisher exact test). The propensity score was calculated, and a two-way logistic regression analysis was performed. The data were balanced by the Kernel "weighting" method, logistic regression analysis was carried out using "weighting" coefficients. Results as odds ratio (OR) and 95% confidence interval. RESULTS: The conducted research allowed us to obtain the following results, depending on the type of analysis: 1) analysis of unbalanced data in patients with COPD: OR death 3.60 (1.16-11.12); p=0.03; OR CMVO 0.65 (0.35-1.22); p=0,18; 2) two-way analysis with propensity score: OR death 3.86 (1.09-13.74); p=0.04; OR CMVO 0.61 (0.31-1.19); p=0.15; 3) regression analysis with "weight" coefficients: OR death 12.49 (2.27-68.84); p=0.004; OR CMVO 0.63 (0.30-1.33); p=0.22. CONCLUSION: The presence of COPD in patients with ACS undergoing PCI increases mortality and does not affect the incidence of CMVO.

Pathophysiology and Treatment of the No-Reflow Phenomenon in ST-Segment Elevation Myocardial Infarction: Focus on Low-Dose Fibrinolysis during Primary Percutaneous Intervention.

Primary percutaneous coronary intervention (PCI) is the current class I therapeutic approach to treat acute ST-elevation myocardial infarction (STEMI). While primary PCI can restore adequate flow in the infarcted artery in the majority of cases, some patients experience the 'no-reflow' phenomenon, i.e., an abnormal myocardial reperfusion occurring even after the occluded coronary artery has been opened. No-reflow occurs when microvascular obstruction arises from embolization of thrombus or components of the atheromatous plaques. These embolic materials travel downstream within the infarct-related artery at time of primary PCI, leading to compromised blood flow. Currently, no expert consensus documents exist to outline an optimal strategy to prevent or treat no-reflow. Interventional cardiologists frequently employ intracoronary adenosine, calcium channel blockers, nicorandil, nitroprusside or glycoprotein IIb/IIIa inhibitors. However, evidence suggests that these interventions consistently enhance myocardial blood flow in only a specific subset of patients experiencing no-reflow. A recent and innovative therapeutic approach gaining attention is low-dose fibrinolysis during primary PCI, which offers the potential to augment coronary flow post-myocardial revascularization.

An unusual no-reflow phenomenon due to neointimal tissue embolization during drug eluting balloon intervention in stent restenosis: A case report.

Acute coronary syndrome is one of the leading causes of death worldwide. Percutaneous coronary intervention (PCI), along with various devices, have been technically developed to dramatically improve mortality risk in patients with acute myocardial infarction. However, no-reflow phenomenon still remains a problematic complication during a PCI, even in the era of drug eluting stents. There are various hypotheses and mechanisms for no-reflow phenomenon, but none have been confirmed. Treatment for no-reflow phenomenon also depends on various underlying conditions, but have not yet shown effective improvement. We presented a case of no-reflow phenomenon caused by an unusual cause.

Mitigating the risk of flow deterioration by deferring stent optimization in STEMI patients with large thrombus burden: Insights from a prospective cohort study.

OBJECTIVES: It is uncertain, if omitting post-dilatation and stent oversizing (stent optimization) is safe and may decrease the risk for distal thrombus embolization (DTE) in STEMI patients with large thrombus burden (LTB). BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) with stenting, (DTE) and flow deterioration are common and increase infarct size leading to worse outcomes. METHODS: From a prospective registry, 74 consecutive STEMI patients with LTB undergoing pPCI with stenting and intentionally deferred stent optimization were analyzed. Imaging data and outcomes up to 2 years follow-up were analyzed. RESULTS: Overall, 74 patients (18% females) underwent deferred stent optimization. Direct stenting was performed in 13 (18%) patients. No major complications occurred during pPCI. Staged stent optimization was performed after a median of 4 (interquartile range (IQR) 3; 7) days. On optical coherence tomography, under-expansion and residual thrombus were present in 59 (80%) and 27 (36%) cases, respectively. During deferred stent optimization, we encountered no case of flow deterioration (slow or no-reflow) or side branch occlusion. Minimal lumen area (mm2) and stent expansion (%) were corrected from 4.87±1.86mm to 6.82±2.36mm (p<0.05) and from 69±18% to 91±12% (p<0.001), respectively. During follow-up, 1 patient (1.4%) required target lesion revascularization and 1 (1.4%) patient succumbed from cardiovascular death. CONCLUSIONS: Among STEMI patients with LTB, deferring stent optimization in the setting of pPCI appears safe and potentially mitigates the risk of DTE. The impact of this approach on infarct size and clinical outcomes warrants further investigation in a dedicated trial.

No-reflow phenomenon in acute ischemic stroke: an angiographic evaluation.

BACKGROUND: Futile recanalization (FR) is de fined as a poor 90-day outcome or lack of neurological improvement at 24 h despite successful recanalization in acute ischemic stroke (AIS) with large vessel occlusion (LVO) treated by mechanical throbectomy (MT). The No-reflow phenomenon (NRP) could be a possible cause of FR, but its evidence in AIS patients is scarce. METHODS: We retrospectively analyzed 185 digital subtraction angiographies (DSA) of AIS patients with anterior circulation LVO after endovascular treatment. To better define NRP, we designed a score called the modified capillary index score (mCIS). The score is obtained by dividing the middle cerebral artery territory in three segments. For each segment, we gave 2 points if the capillary blush was present without any delay, 1 if delayed, and 0 if absent. The primary endpoint was to use mCIS to identify NRP on post-interventional DSA and to test whether this marker may predict FR and failure of early neurological improvement (fENI). The secondary endpoint was to search for a correlation between NRP, lesion volume, and hemorrhagic transformation. We used the ROC curve to define mCIS ≤ 3 as the cut-off and marker of NRP. RESULTS: NRP was present in 35.1% of patients. NRP predicted fENI at 24 h (aOR 2.825, 95% CI 1.265-6.308, P = 0.011) and at 7 days (aOR 2.191, 95% CI 1.008-4.762, P = 0.048), but not 90-day FR. Moreover, NRP predicted hemorrhagic transformation (aOR 2.444, 95% CI 1.266-4.717, P = 0.008). CONCLUSIONS: The modified capillary index score (mCIS) seems useful in identifying NRP in AIS. In addition, mCIS was able to predict NRP that correlated with early clinical outcome and hemorrhagic transformation of the ischemic lesion. An external validation of the score is warranted.

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.

R wave peak time and no reflow following primary percutaneous coronary intervention: Immediate and short-term outcomes.

BACKGROUND: No reflow (NR) remains an important constraint in management of ST elevation myocardial Infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). Most ECG parameters validated till date including ST resolution are postprocedural. R wave peak time (RWPT) is a dynamic parameter and reflects conduction delay in ischaemic myocardium in selected leads supplied by infarct related artery (IRA). The present study was undertaken to see whether preprocedural RWPT per se or RWPT following primary PCI can predict persistence of NR along with immediate and short-term clinical outcome. METHODS: 200 patients were enrolled after exclusion. Clinical, Biochemical, ECG parameters including RPWT and angiographic parameters (pre- and post-procedure) were recorded. ECG papers was analysed using digital image processing software (http://imagej.nih.gov/ij/). All patients were followed up for 6 months. RESULTS: NR was observed in 35% of the patients. Age, Diabetes, symptom to balloon time, higher thrombus burden, peak CPK-MB level (pre and post procedure) were significantly higher in NR group. On ECG analysis, baseline RWPT, QRS duration and pathological Q wave were significantly higher in NR group. On multivariate analysis, age (OR 1.10 CI 1.00-1.21 P = 0.04), thrombus grade ≥ 3 in IRA (OR 12.38 CI 2.08-73.58 P = 0.006), symptom to balloon time (OR 2.18 CI 1.6-3.0 P < 0.001) and baseline RWPT on ECG [OR 1.86 CI 1.24-2.78, P = 0.003] were found to be independent predictors of NR. Increase in RWPT following primary PCI was found to both highly sensitive and specific for diagnosing persistence of NR after primary PCI. Follow up at the end of 6 months has shown that patients with increased RWPT following primary PCI had worse short-term cardiovascular outcomes compared to those with decreased RWPT following primary PCI. CONCLUSION: Baseline RWPT is a significant predictor of NR in patients of STEMI undergoing primary PCI. A persistently increased RWPT following primary PCI is also a highly sensitive and specific ECG marker of persistence of NR which is associated with adverse short-term clinical outcome.

Shenlian extract decreases mitochondrial autophagy to regulate mitochondrial function in microvascular to alleviate coronary artery no-reflow.

Shenlian (SL) extract has been proven to be effective in the prevention and treatment of atherosclerosis and myocardial ischemia. However, the function and molecular mechanisms of SL on coronary artery no-reflow have not been fully elucidated. This study was designed to investigate the contribution of SL extract in repressing excessive mitochondrial autophagy to protect the mitochondrial function and prevent coronary artery no-reflow. The improvement of SL on coronary artery no-reflow was observed in vivo experiments and the molecular mechanisms were further explored through vitro experiments. First, a coronary artery no-reflow rat model was built by ligating the left anterior descending coronary artery for 2 hr of ischemia, followed by 24 hr of reperfusion. Thioflavin S (6%, 1 ml/kg) was injected into the inferior vena cava to mark the no-reflow area. Transmission electron microscopy was performed to observe the cellular structure, mitochondrial structure, and mitochondrial autophagy of the endothelial cells. Immunofluorescence was used to observe the microvascular barrier function and microvascular inflammation. Cardiac microvascular endothelial cells (CMECs) were isolated from rats. The CMECs were deprived of oxygen-glucose deprivation (OGD) for 2 hr and reoxygenated for 4 hr to mimic the Myocardial ischemia-reperfusion (MI/R) injury-induced coronary artery no-reflow in vitro. Mitochondrial membrane potential was assessed using JC-1 dye. Intracellular adenosine triphosphate (ATP) levels were determined using an ATP assay kit. The cell total reactive oxygen species (ROS) levels and cell apoptosis rate were analyzed by flow cytometry. Colocalization of mitochondria and lysosomes indirectly indicated mitophagy. The representative ultrastructural morphologies of the autophagosomes and autolysosomes were also observed under transmission electron microscopy. The mitochondrial autophagy-related proteins (LC3II/I, P62, PINK, and Parkin) were analyzed using Western blot analysis. In vivo, results showed that, compared with the model group, SL could reduce the no-reflow area from 37.04 ± 9.67% to 18.31 ± 4.01% (1.08 g·kg-1 SL), 13.79 ± 4.77% (2.16 g·kg-1 SL), and 12.67 ± 2.47% (4.32 g·kg-1 SL). The extract also significantly increased the left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS) (p < 0.05 or p < 0.01). The fluorescence intensities of VE-cadherin, which is a junctional protein that preserves the microvascular barrier function, decreased to ~74.05% of the baseline levels in the no-reflow rats and increased to 89.87%(1.08 g·kg-1 SL), 82.23% (2.16 g·kg-1 SL), and 89.69% (4.32 g·kg-1 SL) of the baseline levels by SL treatment. SL administration repressed the neutrophil migration into the myocardium. The oxygen-glucose deprivation/reoxygenation (OGD/R) model was induced in vitro to mimic microvascular ischemia-reperfusion injury. The impaired mitochondrial function after OGD/R injury led to decreased ATP production, calcium overload, the excessive opening of the Mitochondrial Permeability Transition Pore, decreased mitochondrial membrane potential, and reduced ROS scavenging ability (p < 0.05 or p < 0.01). The normal autophagosomes (double-membrane vacuoles with autophagic content) in the sham group were rarely found. The large morphology and autophagosomes were frequently observed in the model group. By contrast, SL inhibited the excessive activation of mitochondrial autophagy. The mitochondrial autophagy regulated by the PINK/Parkin pathway was excessively activated. However, administration of SL prevented the activation of the PINK/Parkin pathway and inhibited excessive mitochondrial autophagy to regulate mitochondrial dysfunction. Results also demonstrated that mitochondrial dysfunction stimulated endothelial cell barrier dysfunction, but Evans blue transmission was significantly decreased and transmembrane resistance was increased significantly by SL treatment (p < 0.05 or p < 0.01). Carbonylcyanide-3-chlorophenylhydrazone (CCCP) could activate the PINK/Parkin pathway. CCCP reversed the regulation of SL on mitochondrial autophagy and mitochondrial function. SL could alleviate coronary artery no-reflow by protecting the microvasculature by regulating mitochondrial function. The underlying mechanism was related to decreased mitochondrial autophagy by the PINK/Parkin pathway.

The Relationship Between TIMI Flow and MAPH Score in Patients Undergoing Primary Percutaneous Coronary Intervention for STEMI.

The MAPH (mean platelet volume, age, total protein and hematocrit) score is a newly developed simple scoring system for patients with STEMI that has been associated with satisfactory predictive values to determine thrombus burden in STEMI patients. Therefore, the aim of our study was to determine the relationship between the MAPH risk score and TIMI flow in patients with STEMI.The study included 260 patients who underwent primary percutaneous coronary intervention between December 2019 to July 2022, and had TIMI 0 flow in the responsible coronary artery due to STEMI. According to the TIMI flow score after stent implantation, the patients were classified into either the no-reflow group (n = 59) or the normal flow group (n = 201). In order to calculate the MAPH score, ROC analysis was performed to find the cutoff point for each component of the MAPH score. MAPH scores were calculated (MPV + Age + Protein + Hematocrit) for both groups. Our study was a retrospective, observational study.In the multivariable regression analysis, the MAPH score (OR: 0.567; 95%CI: 0.330-0.973, P = 0.04) and glycoprotein IIb/IIIa inhibitors (OR: 0.249; 95%CI: 0.129-0.483, P < 0.001) were parameters found to be independent predictors of TIMI flow. An MAPH score value > 2.5 predicted the presence of low TIMI coronary flow in patients with STEMI, with 78% specificity and 45% sensitivity (ROC area under curve: 0.691, 95% CI: 0.617-0.766, P < 0.001).The MAPH risk score is simple, inexpensive, and quick to calculate. A high MAPH score may be an indicator of coronary no-reflow in patients with STEMI.

Saphenous Vein Graft Failure: From Pathophysiology to Prevention and Treatment Strategies.

Saphenous vein grafts (SVGs) remain the most frequently used conduits in coronary artery bypass graft surgery (CABG). Despite advances in surgical techniques and pharmacotherapy, SVG failure rates remain high, often leading to repeat coronary revascularization. The no-touch SVG harvesting technique (minimal graft manipulation with preservation of vasa vasorum and nerves) reduces the risk of SVG failure, whereas the effect of the off-pump technique on SVG patency remains unclear. Use of buffered storage solutions, intraoperative graft flow measurement, careful selection of the target vessels, and physiological assessment of the native coronary circulation before CABG may also reduce the incidence of SVG failure. Perioperative aspirin and high-intensity statin administration are the cornerstones of secondary prevention after CABG. Dual antiplatelet therapy is recommended for off-pump CABG and in patients with a recent acute coronary syndrome. Intermediate (30%-60%) SVG stenoses often progress rapidly. Stenting of intermediate SVG stenoses failed to improve outcomes; hence, treatment focuses on strict control of coronary artery disease risk factors. Redo CABG is associated with higher perioperative mortality compared with percutaneous coronary intervention (PCI); hence, the latter is preferred for most patients requiring repeat revascularization after CABG. SVG PCI is limited by high rates of no-reflow and a high incidence of restenosis during follow-up. Drug-eluting and bare metal stents provide similar long-term outcomes in SVG PCI. Embolic protection devices reduce no-reflow and should be used when feasible. PCI of the corresponding native coronary artery is associated with better short- and long-term outcomes and is preferred over SVG PCI, if technically feasible.

Inflammation and the Link to Vascular Brain Health: Timing Is Brain.

Inflammation and its myriad pathways are now recognized to play both causal and consequential roles in vascular brain health. From acting as a trigger for vascular brain injury, as evidenced by the COVID-19 pandemic, to steadily increasing the risk for chronic cerebrovascular disease, distinct inflammatory cascades play differential roles in varying states of cerebrovascular injury. New evidence is regularly emerging that characterizes the role of specific inflammatory pathways in these varying states including those at risk for stroke and chronic cerebrovascular injury as well as during the acute, subacute, and repair phases of stroke. Here, we aim to highlight recent basic science and clinical evidence for many distinct inflammatory cascades active in these varying states of cerebrovascular injury. The role of cerebrovascular infections, spotlighted by the severe acute respiratory syndrome coronavirus 2 pandemic, and its association with increased stroke risk is also reviewed. Rather than converging on a shared mechanism, these emerging studies implicate varied and distinct inflammatory processes in vascular brain injury and repair. Recognition of the phasic nature of inflammatory cascades on varying states of cerebrovascular disease is likely essential to the development and implementation of an anti-inflammatory strategy in the prevention, treatment, and repair of vascular brain injury. Although advances in revascularization have taught us that time is brain, targeting inflammation for the treatment of cerebrovascular disease will undoubtedly show us that timing is brain.

Luteolin alleviates ischemia/reperfusion injury-induced no-reflow by regulating Wnt/ß-catenin signaling in rats.

The no-reflow phenomenon induced by ischemia-reperfusion (I/R) injury seriously limits the therapeutic value of coronary recanalization and leads to a poor prognosis. Previous studies have shown that luteolin (LUT) is a vasoprotective factor. However, whether LUT can be used to prevent the no-reflow phenomenon remains unknown. Positron emission tomography perfusion imaging, performed to detect the effects of LUT on the no-reflow phenomenon in vivo, revealed that LUT treatment was able to reduce the no-reflow area in rat I/R models. In vitro, LUT was shown to reduce the hypoxia-reoxygenation injury-induced endothelial permeability and apoptosis. The levels of malondialdehyde, reactive oxygen species and NADPH were also measured and the results indicated that LUT could inhibit the oxidative stress. Western blot analysis revealed that LUT protected endothelial cells from I/R injury by regulating the Wnt/ß-catenin pathway. Overall, we concluded that the use of LUT to minimize I/R induced microvascular damage is a feasible strategy to prevent the no-reflow phenomenon.