Could Pan-Immune-Inflammation Value be a Marker for the Diagnosis of Coronary Slow Flow Phenomenon?

Inflammation plays a key role in the pathogenesis of the coronary slow flow phenomenon (CSFP). The newly developed inflammatory marker, pan-immune-inflammation value (PIV), is associated with adverse cardiovascular events. This study investigated the predictive value of PIV for diagnosing CSFP in comparison to other inflammation-based markers. A total of 214 patients, 109 in the CSFP group and 105 in the normal coronary flow (NCF) group, were retrospectively included in the study. Coronary flow was calculated using the Thrombolysis in Myocardial Infarction frame count method. In addition to PIV, other inflammatory markers such as neutrophil-lymphocyte ratio, platelet-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) were calculated for the patients. The average age of patients was 50.3 ± 8.4, with a male ratio of 55.1%. Compared to the NCF group, patients in the CSFP group had higher levels of hyperlipidemia, glucose, triglyceride, NLR, PLR, SII, and PIV, while their high-density lipoprotein cholesterol (HDL-C), was lower (p < 0.05). Logistic regression analysis demonstrated that HDL-C, glucose, triglyceride, and PIV were independent predictor factors for CSFP (p < 0.05). PIV is a strong and independent predictor factor for CSFP and superior in predicting CSFP compared to other inflammatory markers.

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

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.

Asymmetric Dimethylarginine Is Associated with the Phenomenon of Coronary Slow Flow in Patients with Nonvalvular Atrial Fibrillation.

INTRODUCTION: Coronary slow flow phenomena (CSFP) are associated with endothelial and blood component abnormalities in coronary arteries. Asymmetric dimethylarginine (ADMA) can damage the endothelium of the heart or blood vessels in patients with non-valvular atrial fibrillation (NVAF), causing changes in levels of biological indicators. Our aim was to analyze the relationship between ADMA and CSFP in NVAF patients. METHODS: We consecutively enrolled 134 patients diagnosed with NVAF and underwent coronary angiography, 50 control patients without a history of atrial fibrillation and with normal coronary angiographic flow were included at the same time. Based on the corrected TIMI frame count (CTFC), the NVAF patients were categorized into two groups, CTFC ≤27 frames and CTFC >27 frames. Plasma ADMA, P-selectin (p-sel), von Willebrand factor (vWF), D-dimer (D-Di), plasminogen activator inhibitor 1 (PAI-1), and nitric oxide (NO) were detected by ELISA in the different groups. RESULTS: We found that plasma ADMA levels were significantly higher among NVAF patients in the CTFC >27 grade group compared with the control or CTFC ≤27 group. In addition, the levels of blood cells and endothelium-related biomarkers (NO, P-selectin, vWF, D-Di, and PAI-1) were significantly altered and correlated with ADMA levels. Multifactorial analysis showed that plasma ADMA (odd ratio [OR; 95% CI]: 1.65 [1.21-2.43], p < 0.001) and left atrial internal diameter (OR [95% CI]: 1.04 [1.02, 1.1], p < 0.001) could be used as independent risk factors for the development of CSFP in patients with NVAF. The ROC curves of ADMA can predict the development of CSFP in NVAF patients. The minimum diagnostic concentration for the development of CSFP in patients was 2.31 µmol/L. CONCLUSION: Our study demonstrated that CSFP in NVAF patients was associated with high levels of ADMA and left atrial internal diameter. Therefore, aggressive preoperative detection and evaluation of ADMA and left atrial internal diameter can help deal with the intraoperative presence of CSFP.

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.

Post-occlusive reactive hyperemia and skeletal muscle capillary hemodynamics.

Post-occlusive reactive hyperemia (PORH) is an accepted diagnostic tool for assessing peripheral macrovascular function. While conduit artery hemodynamics have been well defined, the impact of PORH on capillary hemodynamics remains unknown, despite the microvasculature being the dominant site of vascular control. Therefore, the purpose of this investigation was to determine the effects of 5 min of feed artery occlusion on capillary hemodynamics in skeletal muscle. We tested the hypothesis that, upon release of arterial occlusion, there would be: 1) an increased red blood cell flux (fRBC) and red blood cell velocity (VRBC), and 2) a decreased proportion of capillaries supporting RBC flow compared to the pre-occlusion condition. METHODS: In female Sprague-Dawley rats (n = 6), the spinotrapezius muscle was exteriorized for evaluation of capillary hemodynamics pre-occlusion, 5 min of feed artery occlusion (Occ), and 5 min of reperfusion (Post-Occ). RESULTS: There were no differences in mean arterial pressure (MAP) or capillary diameter (Dc) between pre-occlusion and post-occlusion (P > 0.05). During 30 s of PORH, capillary fRBC was increased (pre: 59 ± 4 vs. 30 s-post: 77 ± 2 cells/s; P < 0.05) and VRBC was not changed (pre: 300 ± 24 vs. 30 s post: 322 ± 25 µm/s; P > 0.05). Capillary hematocrit (Hctcap) was unchanged across the pre- to post-occlusion conditions (P > 0.05). Following occlusion, there was a 20-30% decrease in the number of capillaries supporting RBC flow at 30 s and 300 s-post occlusion (pre: 92 ± 2%; 30 s-post: 66 ± 3%; 300 s-post: 72 ± 6%; both P < 0.05). CONCLUSION: Short-term feed artery occlusion (i.e. 5 min) resulted in a more heterogeneous capillary flow profile with the presence of capillary no-reflow, decreasing the percentage of capillaries supporting RBC flow. A complex interaction between myogenic and metabolic mechanisms at the arteriolar level may play a role in the capillary no-reflow with PORH. Measurements at the level of the conduit artery mask significant alterations in blood flow distribution in the microcirculation.

Plasma atherogenic indices are independent predictors of slow coronary flow.

BACKGROUND: Although the pathophysiology of coronary slow flow (CSF) has not been fully elucidated, emerging data increasingly support potential role for subclinical diffuse atherosclerosis in the etiology of CSF. We aimed to investigate relationship between atherogenic indices and CSF. METHODS: 130 patients with CSF diagnosed according to Thrombolysis in Myocardial Infarction (TIMI)-frame count (TFC) method and 130 controls who had normal coronary flow (NCF) were included in this retrospective study. Atherogenic indices (atherogenic index of plasma [AIP], Castelli risk indices I and II [CRI-I and II]) were calculated using conventional lipid parameters. RESULTS: The logistic regression analyses demonstrated that AIP (OR, 5.463; 95% confidence interval [CI], 1.357-21.991; p = 0.017) and CRI-II (OR, 1.624; 95% CI, 1.138-2.319; p = 0.008) were independent predictors of CSF. Receiver operating characteristic analysis showed that the optimal cutoff value to predict the occurrence of CSF was 0.66 for AIP (sensitivity, 59%; specificity, 73%; area under curve [AUC], 0.695; p < 0.001) and 3.27 for CRI-II (sensitivity, 60%; specificity, 79%; AUC, 0.726; p < 0.001). CONCLUSIONS: AIP and CRI-II levels were independent predictors of CSF. Prospective studies in larger cohorts of patients may elucidate the role of atherogenic dyslipidemia in the pathophysiology of CSF.

Mechanism and potential treatment of the "no reflow" phenomenon after acute myocardial infarction: role of pericytes and GPR39.

The "no reflow" phenomenon, where the coronary artery is patent after treatment of acute myocardial infarction (AMI) but tissue perfusion is not restored, is associated with worse outcome. The mechanism of no reflow is unknown. We hypothesized that pericytes contraction, in an attempt to maintain a constant capillary hydrostatic pressure during reduced coronary perfusion pressure, causes capillary constriction leading to no reflow and that this effect is mediated through the orphan receptor, GPR39, present in pericytes. We created AMI (coronary occlusion followed by reperfusion) in GPR39 knock out mice and littermate controls. In a separate set of experiments, we treated wild-type mice undergoing coronary occlusion with vehicle or VC43, a specific inhibitor of GPR39, before reperfusion. We found that no reflow zones were significantly smaller in the GPR39 knockouts compared with controls. Both no reflow and infarct size were also markedly smaller in animals treated with VC43 compared with vehicle. Immunohistochemistry revealed greater capillary density and larger capillary diameter at pericyte locations in the GPR39-knockout and VC43-treated mice compared with controls. We conclude that GPR39-mediated pericyte contraction during reduced coronary perfusion pressure causes capillary constriction resulting in no reflow during AMI and that smaller no reflow zones in GPR39-knockout and VC43-treated animals are associated with smaller infarct sizes. These results elucidate the mechanism of no reflow in AMI, as well as providing a therapeutic pathway for the condition.NEW & NOTEWORTHY The mechanism of "no reflow" phenomenon, where the coronary artery is patent after treatment of acute myocardial infarction but tissue perfusion is not restored, is unknown. This condition is associated with worse outcome. Here, we show that GPR39-mediated pericyte contraction during reduced coronary perfusion pressure causes capillary constriction resulting in no reflow. Smaller no-reflow zones in GPR39-knockout animals and those treated with a GPR39 inhibitor are associated with smaller infarct size. These results could have important therapeutic implications.

Effect of GP IIb/IIIa inhibitor duration on the clinical prognosis of primary percutaneous coronary intervention in ST-segment elevation myocardial infarction with no-/slow-reflow phenomenon.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) accompanied by the no-/slow-reflow phenomenon, the maintenance duration of GP IIb/IIIa inhibitor (GPI) is controversial. We compare the efficacy and safety of short- and long-term GPI infusion in STEMI patients with the no-/slow-reflow phenomenon. METHODS: From June 2016 to December 2019, we continuously included patients with on-set STEMI who underwent pPCI, accompanied by the no-/slow-reflow, during interventional procedures at Guangdong Provincial People's Hospital and Zhuhai Golden Bay Hospital. The hemorrhage events, heart function, and major adverse cardiovascular events (MACE) were compared between < 24 h and ≥ 24 h GPI duration groups. The Kaplan-Meier curve was used to estimate the 1-year MACE-free survival at different GPI utility times. RESULTS: In total, 127 patients were divided into two groups based on the duration of tirofiban use (less and more than 24 h). There was no significant difference between two groups in terms of baseline characteristics, plaque condition, and coronary physiological function. The two groups showed similar in-hospital MACE (1 [1.85%] vs. 4 [5.48%], p = 0.394) and 1-year MACE-free survival (log-rank test p = 0.9085). The 1-year MACE remained consistent between the two groups in all subgroups of different risk factors of no-/slow-reflow. There was no significant difference in heart function and in-hospital hemorrhage events (3.7% vs. 1.37%, p = 0.179). CONCLUSION: In the real world, prolonging the duration of GPI may not significantly improve the clinical outcome in patients with STEMI with no-/slow-reflow.

CHA2DS2-VASc score predicts the slow flow/no-reflow phenomenon in ST-segment elevation myocardial infarction patients with multivessel disease undergoing primary percutaneous coronary intervention.

ABSTRACT: ST-segment elevation myocardial infarction (STEMI) patients with multivessel disease (MVD) have a higher incidence of slow-flow/no-reflow (SF-NR) phenomenon during primary percutaneous coronary intervention (PPCI) than those with single vessel disease. Currently, no effective tools exist to predict the risk of SF-NR in this population. The present study aimed to evaluate whether CHA2DS2-VASc score can be used as a simple tool to predict this risk.This study consecutively included STEMI patients hospitalized in Beijing Anzhen Hospital from January 2005 to January 2015. Among these patients, 1032 patients with MVD were finally enrolled. Patients were divided into SF-NR (+) group and SF-NR (-) group according to whether SF-NR occurred during PPCI. SF-NR was defined as the thrombolysis in myocardial infarction (TIMI) grade ≤2.There were 134 patients (13%) in the SF-NR (+) group. Compared with the SF-NR (-) group, patients in the SF-NR (+) group are elder, with lower left ventricular ejection fraction and higher CHA2DS2-VASc score. Multiple logistic regression analysis indicated that CHA2DS2-VASc score ≥3 (odds ratio [OR], 2.148; 95% confidence interval [CI], 1.389-3.320; P = .001), current smoking (OR, 1.814; 95% CI, 1.19-2.764; P = .006), atrial fibrillation (OR, 2.892; 95% CI, 1.138-7.350; P = .03), complete revascularization (OR, 2.307; 95% CI, 1.202-4.429; P = .01), and total length of stents ≥40 mm (OR, 1.482; 95% CI, 1.011-2.172; P = .04) were independent risk factors of SF-NR. The incidence of SF-NR in patients with CHA2DS2-VASc score ≥3 was 1.7 times higher than that in patients with CHA2DS2-VASc score <3. Additionally, patients with CHA2DS2-VASc score ≥3 plus ≥2 risk factors have 3 times higher incidence of SF-NR than those with CHA2DS2-VASc score ≥3 plus 0 to 1 risk factor.CHA2DS2-VASc score ≥3 can be used as a simple and sensitive indicator to predict SF-NR phenomenon and guide the PPCI strategy in STEMI patients with MVD.

Echocardiographic and laboratory findings in coronary slow flow phenomenon: cross-sectional study and review.

BACKGROUND: Coronary sow-flow phenomenon (CSFP) is defined as slow passage of the contrast injected into the coronary arteries without distal obstruction of the vessel. METHODS: The present study was a cross-sectional, descriptive-analytical study performed at the Seyed-al-Shohada Heart Center during 2018-2019. The eligible patients based on the inclusion and exclusion criteria were divided into the study group showing the CSFP and the control group with normal epicardial coronary arteries. RESULTS: The study included 124 patients. 67.9% of the study group and 39.4% of the control group were male patients (p-value = 0.001), and the mean patient age was 52.18 ± 12.55 and 51.77 ± 10.36 years in the study and control groups, respectively (p-value = 0.18). The study group had a significantly higher BMI than the control group (p < 0.05) and also a higher prevalence of smoking and hypertension. The variables of ALC, Hct, Plt, MPV, RDW, Cr, triglyceride, TC, and LDL, were higher in the study group. Given the echocardiographic findings, the mean E wave was significantly lower in the study group, while the control group had a significantly higher GLS (p-value = 0.01). Also, left anterior descending artery was the most common artery involved with CSFP. CONCLUSION: The CSFP was significantly more common in men, smokers, hypertensive patients, and patients with high BMI. Moreover, these patients had significantly higher platelet count, MPV, LDL, and FBS. Some other laboratory variables were also higher in these patients. Given the echocardiographic findings, mild diastolic dysfunction and low GLS were also observed in the study group.

The effect of coronary slow flow on left atrial structure and function.

The coronary slow flow phenomenon (CSFP) is common in coronary angiography, however its impact on left atrial (LA) function is still controversial. This study aims to evaluate the LA structure and function of patients with CSFP using two-dimensional speckle tracking echocardiography (2D-STE). Consecutive patients scheduled for coronary angiography from January 2016 to September 2017 were enrolled in this study. Patients' demographic data, clinical histories, laboratory and angiographic findings were collected and recorded. Diagnostic criteria for CSFP is based on Beltrame et al. proposed in 2012. Meanwhile 139 patients who have no significant stenosis (≤ 40%) and normal blood flow were selected as control. All patients received an echocardiographic examination 24 h before coronary angiography. LA structure and function were measured with echocardiography and 2D-STE. Our results showed that among the 1,954 patients who had received coronary angiography, 512 patients were included in the analysis after the exclusion criteria was implemented. Of those, 101 patients met the CSFP criteria (5.5%). CSFP is mainly seen in LAD (~ 70%). There was no statistical difference in baseline characteristics between the CSFP group and control group, except for a higher proportion of smokers in the CSFP group (P = 0.001). The percentage of monocytes is an independent risk factor for the occurrence of CSFP (P = 0.036) after binary logistic regression analysis. The LA global longitudinal strain (LA-GLS, represents reservoir functions) decreased and LA strain rate at late diastole (LA-SRa, represents booster function) increased in patients with CSFP compared to the control group (P < 0.05). Correlation test of continuous variables by Pearson test suggested that LA-GLS was negatively correlated with TIMI frame count (TFC). We concluded that the percentage of monocytes is an independent risk factor for the CSFP; the LA reservoir and booster functions were impaired in patients with CSFP; LA-GLS is negatively correlated with TFC.

Slow Coronary Flow: Pathophysiology, Clinical Implications, and Therapeutic Management.

Coronary slow flow (CSF) is an angiographic phenomenon with specific epidemiologic characteristics, associated clinical presentation, and prognosis. Although patients with CSF are diagnosed as having "normal coronary arteries," it seems appropriate to consider CSF as a distinct disease entity requiring specific treatment. The patient with CSF is usually male, smoker, obese, with a constellation of risk factors suggestive of metabolic syndrome. Unstable angina is the most common clinical presentation, with recurrent episodes of chest pain at rest associated with electrocardiographic changes often requiring readmission and reevaluation. Regarding definition and diagnosis, interventionists should first exclude possible "secondary" causes of CSF, use objective means for definition and then differentiate from other similar conditions such as microvascular angina. Although the phenomenon is generally benign, patients with CSF are severely symptomatic with recurrent episodes of chest pain and poor quality of life. Furthermore, acute presentation of the phenomenon is commonly life-threatening with ventricular tachyarrhythmias, conduction abnormalities, or cardiogenic shock. Acute treatment of CSF includes, but is not restricted to, intracoronary infusion of dipyridamole, adenosine, or atropine. Chronic management of patients with CSF encompasses dipyridamole, diltiazem, nebivolol, telmisartan, and/or atorvastatin associated with amelioration of angina symptoms, improved quality of life, and good prognosis.

Clinical characteristics in patients with coronary slow flow phenomenon: A retrospective study.

ABSTRACT: Coronary slow flow phenomenon (CSFP) is a coronary artery disease in which coronary angiography shows no obvious stenosis, but there is a delay in blood flow perfusion. The etiopathogenic mechanisms of CSFP are still unclear. The aim of the present study was to investigate the role of clinical characteristics in patients with CSFP, and to provide a reference for exploring the potential mechanisms of CSFP. Patients with angiographically normal epicardial arteries were enrolled (145 patients with CSFP and 145 normal controls). Collected clinical information and laboratory indexes, which measured by peripheral venous blood samples before coronary angiography. Logistic regression analysis was performed for statistical analysis. The present study found 19 clinical and laboratory indexes with statistical differences between the two groups in univariate analysis. Multivariate analysis showed that monocyte count, haemoglobin, serum creatinine and globulin were independent predictors of CSFP. Moreover, the monocyte count, haemoglobin, creatinine and globulin levels were significantly higher in the CSFP patients than the controls, with positive associations between these parameters and the extent of CSFP. In addition, ROC analysis showed the diagnostic value of the above indexes for CSFP.

In-Hospital Peak Glycemia in Predicting No-Reflow Phenomenon in Diabetic Patients with STEMI Treated with Primary Percutaneous Coronary Intervention.

Although percutaneous coronary intervention (PCI) significantly improves the prognosis for myocardial infarction, the no-reflow phenomenon is still the major adverse complication of PCI leading to increased mortality, especially for the patients with ST-segment elevation myocardial infarction (STEMI) combined with diabetes. To reduce the occurrence of no-reflow, prognostic factors must be identified for no-reflow phenomenon before PCI. A total of 262 participants with acute STEMI and diabetes were recruited into our cardiovascular center and underwent primary PCI for the analyses of prognostic factors of no-reflow. The patients were divided into two groups according to thrombolysis in myocardial infarction (TIMI): the normal flow and no-reflow groups, and related factors were analyzed with different statistical methods. In the present investigation, the in-hospital peak glycemia was significantly higher in the no-reflow group than the normal flow group, while more narrowed vessels, higher level of initial TIMI flow, were observed in the patients of the no-reflow group. A multivariate logistic regression analysis further demonstrated that peak glycemia was an independent predictor for no-reflow in the diabetic patients with STEMI. Our data indicated the importance of the proper control of glucose before PCI for the diabetic patients with STEMI before PCI to reduce the occurrence of the no-reflow after operation.

Cardiac pericytes function as key vasoactive cells to regulate homeostasis and disease.

Pericytes (PCs)-mural cells that envelop endothelial cells (ECs) of microvessels-regulate tissue-specific vasculature development as well as maturation and maintenance of endothelial barrier integrity. However, little is known about their tissue-specific function in the heart. Specifically, the mechanism by which cardiac PCs constrict coronary capillaries remains undetermined. To gain insights into the function of cardiac PCs at the cellular level, we isolated NG2+ PDGFRß+ CD146+ CD34- CD31- CD45- PCs for detailed characterization. Functionally, we provide evidence that these PCs increased transepithelial electrical resistance and decreased endothelial permeability. We show for the first time that this population of PCs express contractile proteins, are stimulated by adrenergic signaling, and demonstrate stereotypical contraction and relaxation. Furthermore, we also studied for the first time, the PCs in in vitro models of disease. PCs in hypoxia activated the hypoxia-inducible factor 1 alpha pathway, increased secretion of angiogenic factors, and caused cellular apoptosis. Supraphysiological levels of low-density lipoprotein decreased PC proliferation and induced lipid droplet accumulation. Elevated glucose levels triggered a proinflammatory response. Taken together, our study characterizes cardiac PCs under in vitro disease conditions and supports the hypothesis that cardiac PCs are key vasoactive cells that can regulate blood flow in the heart.

Tongmai Yangxin pill reduces myocardial No-reflow via endothelium-dependent NO-cGMP signaling by activation of the cAMP/PKA pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The Tongmai Yangxin pill (TMYX) is derived from the Zhigancao decoction recorded in Shang han lun by Zhang Zhongjing during the Han dynasty. TMYX is used for the clinical treatment of chest pain, heartache, and qi-yin-deficiency coronary heart disease. Previous studies have confirmed that TMYX can improve vascular endothelial function in patients with coronary heart disease by upregulating nitric oxide activity and then regulating vascular tension. Whether TMYX can further improve myocardial NR by upregulating NO activity and then dilating blood vessels remains unclear. AIM OF THE STUDY: This study aimed to reveal whether TMYX can further improve myocardial NR by upregulating NO activity and then dilating blood vessels. The underlying cAMP/PKA and NO-cGMP signaling pathway-dependent mechanism is also explored. MATERIALS AND METHODS: The left anterior descending coronary arteries of healthy adult male SD rats were ligated to establish the NR model. TMYX (4.0 g/kg) was orally administered throughout the experiment. Cardiac function was measured through echocardiography. Thioflavin S, Evans Blue, and TTC staining were used to evaluate the NR and ischemic areas. Pathological changes in the myocardium were assessed by hematoxylin-eosin staining. An automated biochemical analyzer and kit were used to detect the activities of myocardial enzymes and myocardial oxidants, including CK, CK-MB, LDH, reactive oxygen species, superoxide dismutase, malonaldehyde, and NO. The expression levels of genes and proteins related to the cAMP/PKA and NO/cGMP signaling pathways were detected via real-time fluorescence quantitative PCR and Western blot analysis, respectively. A microvascular tension sensor was used to detect coronary artery diastolic function in vitro. RESULTS: TMYX elevated the EF, FS, LVOT peak, LVPWd and LVPWs values, decreased the LVIDd, LVIDs, LV-mass, IVSd, and LV Vols values, demonstrating cardio-protective effects, and reduced the NR and ischemic areas. Pathological staining showed that TMYX could significantly reduce inflammatory cell number and interstitial edema. The activities of CK, LDH, and MDA were reduced, NO activity was increased, and oxidative stress was suppressed after treatment with TMYX. TMYX not only enhanced the expression of Gs-α, AC, PKA, and eNOS but also increased the expression of sGC and PKG. Furthermore, TMYX treatment significantly decreased ROCK expression. We further showed that TMYX (25-200 mg/mL) relaxed isolated coronary microvessels. CONCLUSIONS: TMYX attenuates myocardial NR after ischemia and reperfusion by activating the cAMP/PKA and NO/cGMP signaling pathways, further upregulating NO activity and relaxing coronary microvessels.

Serum Endocan Levels Predict Angiographic No-Reflow Phenomenon in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Coronary Intervention.

No-reflow phenomenon (NRP) is an important problem in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). Endocan is synthesized and secreted by activated vascular endothelium, and it has been shown to be related to endothelial dysfunction and inflammation. We aimed to evaluate the relationship between endocan levels and NRP. Consecutive patients (n = 137) with STEMI who had undergone coronary angiography and pPCI were enrolled into the study. The clinical characteristics of the patients were obtained and endocan levels were measured. Endocan levels were significantly higher in the NRP (+) group compared with the NRP (-) group (P < .001). In multivariate analysis, endocan (P < .001, OR = 2.39, 95% CI = 1.37-4.15) was found to be an independent predictor of NRP. An endocan value of >2.7 ng/mL has 89.6% sensitivity and 74.2% specificity for the prediction of the NRP (area under the curve: 0.832, P < .001). The present study demonstrated that the endocan level is an independent predictor of the NRP in patients with STEMI who underwent pPCI. Endocan levels may be helpful in detecting patients with a higher risk of insufficient myocardial perfusion and worse clinical outcome.

Neutrophils Obstructing Brain Capillaries Are a Major Cause of No-Reflow in Ischemic Stroke.

Despite successful clot retrieval in large vessel occlusion stroke, ∼50% of patients have an unfavorable clinical outcome. The mechanisms underlying this functional reperfusion failure remain unknown, and therapeutic options are lacking. In the thrombin-model of middle cerebral artery (MCA) stroke in mice, we show that, despite successful thrombolytic recanalization of the proximal MCA, cortical blood flow does not fully recover. Using in vivo two-photon imaging, we demonstrate that this is due to microvascular obstruction of ∼20%-30% of capillaries in the infarct core and penumbra by neutrophils adhering to distal capillary segments. Depletion of circulating neutrophils using an anti-Ly6G antibody restores microvascular perfusion without increasing the rate of hemorrhagic complications. Strikingly, infarct size and functional deficits are smaller in mice treated with anti-Ly6G. Thus, we propose neutrophil stalling of brain capillaries to contribute to reperfusion failure, which offers promising therapeutic avenues for ischemic stroke.

Plasma calprotectin was associated with platelet activation and no-reflow phenomenon in acute coronary syndrome.

BACKGROUND: No-reflow occurs in 3-4% of all percutaneous coronary interventions (PCIs) and has a strong negative impact on clinical outcomes of acute coronary syndrome (ACS). Therefore, the discovery of a biomarker that can early predict the occurrence of no-reflow has great clinical significance. Multiple factors including platelet activation are relevant to no-reflow. Calprotectin is found to be a biomarker of plaque instability and is identified to be a novel diagnostic and prognostic biomarker of cardiovascular diseases. The association of plasma calprotectin with platelet activation and no-reflow phenomenon in ACS is not clear. METHODS: In this prospective study performed at Yantai Yuhuangding Hospital from 2017 to 2018, a total of 176 Chinese patients with ACS who had undergone PCIs were recruited consecutively, aged from 30 to 88 years. Angiographic no-reflow was defined as thrombolysis in myocardial infarction grade less than 3. Blood samples were collected immediately at admission for the detection of plasma calprotectin and platelet-monocyte aggregates formation. Statistical analysis was performed for the variable's comparisons between groups and the prediction value of plasma calprotectin for no-reflow. RESULTS: The mean age of the 176 included ACS patients were 64(±11) years and acute ST-segment elevation myocardial infarction (STEMI) was present in 41.5% of patients. Twenty-two patients had no-reflow during the PCI procedures and the prevalence was 12.5%. Patients with higher plasma calprotectin had a higher level of platelet-monocyte aggregates (PMA) and a higher prevalence of no-reflow (p < 0.001). The multivariate regression showed that plasma calprotectin and admission hs-cTnI were independently associated with PMA, while plasma calprotectin and serum LDL-c were independent predictors of no-reflow (p < 0.001 and p = 0.017). AUC of calprotectin for predicting no-reflow were 0.898. The cut-off value of plasma calprotectin for no-reflow was 4748.77 ng/mL with a sensitivity of 0.95 and a specificity of 0.77. CONCLUSION: Plasma calprotectin was associated with platelet activation and may act as an early predictive biomarker of no-reflow in patients with acute coronary syndrome.

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.