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.

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.

Tongmai Yangxin pill reduces myocardial no-reflow by regulating apoptosis and activating PI3K/Akt/eNOS pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongmai Yangxin pill (TMYX) is derived from the Zhigancao decoction recorded in Shang han lun by Zhang Zhongjing during the Han dynasty and was further improved by Professor Ruan Shiyi, a cardiovascular expert at Tianjin University of Traditional Chinese Medicine. TMYX is used for the clinical treatment of chest pain, heartache, and qi-yin-deficiency coronary heart disease and can improve vascular endothelial function in patients with angina pectoris or coronary heart disease by up-regulating nitric oxide activity and then regulating vascular tension. Whether TMYX can further improve myocardial no-reflow by up-regulating 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 up-regulating NO activity and then dilating blood vessels. The mechanism underlying PI3K/Akt/eNOS pathway activation and apoptosis regulation is also explored. MATERIALS AND METHODS: The left anterior descending coronary arteries of healthy adult male SD rats were ligated to establish a NR model. The rats were assigned to 14 groups: control, sham, NR, TMYX (4.0 g/kg), sodium nitroprusside (SNP), Tongxinluo capsule (TXL), PI3K blocker (LY), TMYX + LY, SNP + LY, TXL + LY, eNOS blocker (L-NAME), TMYX + L-NAME, SNP + L-NAME, and TXL + L-NAME groups. Cardiac function was measured through echocardiography. Thioflavin S, Evans Blue, and TTC staining were adopted to evaluate NR and ischemic areas. Cell inflammation degree and edema were assessed by hematoxylin-eosin staining. Automated biochemical analyzer and kit were used to detect the activities of myocardial oxidants, including reactive oxygen species, super oxide dismutase, malonaldehyde, and NO. The expression levels of genes and proteins in the PI3K/Akt/eNOS signaling pathway and apoptosis were detected via real-time fluorescence quantitative PCR and Western blot analysis, respectively. A microvascular tension sensor was adopted to detect coronary artery diastolic function in vitro. RESULTS: TMYX reduced NR and ischemic areas; suppressed LV-mass; enhanced EF, FS, LVOT peak, and LVSV; and improved cardiac structure and function. Moreover, it decreased creatine kinase (CK), CK-MB, and lactic dehydrogenase activities. TMYX increased NO and super oxide dismutase activities; inhibited malonaldehyde activity; reduced muscle fiber swelling and inflammatory cell infiltration; and improved vasodilation in vitro. In the NR myocardium, TMYX stimulated myocardial PI3K activities and PI3K (Tyr458) phosphorylation and enhanced Akt activities and Akt phosphorylation at Tyr315. TMYX increased the activities of eNOS and the phosphorylation of eNOS at Ser1177 in the NR myocardium and attenuated cardiomyocyte apoptosis by increasing the expression of Bcl-2 and decreasing that of caspase-3 and Bax. All these effects of TMYX were abolished by the specific inhibitors of PI3K (LY) and eNOS (L-NAME). CONCLUSIONS: TMYX attenuates myocardial NR after ischemia and reperfusion by activating the PI3K/Akt/eNOS pathway and regulating apoptosis, further up-regulating NO activity and relaxing coronary microvessels.

Long-term compound danshen dripping pills therapy reduces the no-reflow phenomenon in nondiabetes mellitus patients after primary percutaneous coronary intervention for acute myocardial infarction.

BACKGROUND: Cases with no-reflow increased significantly and accounted for about 5-50% of cases in primary percutaneous coronary intervention (PPCI) patients in recent years. It is important to identify patients at high risk of no-reflow. Ingredients of compound danshen dripping pills (CDDP), a popular Chinese traditional medicine, can alleviate myocardial ischemia, inhibit inflammation and angiotensin convert enzyme, and reduce cell apoptosis, among other effects. In this study, we aimed to assess whether long-term treatment with CDDP (>1 year, could reduce the no-reflow phenomenon in non-diabetes mellitus (DM) patients after PPCI for acute myocardial infarction (AMI). METHODS: We enrolled patients according to inclusion and exclusion criteria. Clinical and PPCI data were collected. Patients were divided into 2 groups according to history of CDDP therapy. Data of the CDDP group and non-CDDP group were compared. Single and multivariate analysis was used to find factors associated with no-reflow. RESULTS: Among these 399 patients, the no-reflow phenomenon occurred in 96 patients (24.1%). The results showed that patients with long-term CDDP treatment had lower incidence of no-reflow than those without CDDP treatment within 1 year (9/68 vs. 87/331, 13.2% vs. 26.3%, P=0.0219). Univariate and multivariate stepwise logistic regression analysis identified a few admission parameters associated with the no-reflow phenomenon: prior myocardial infarction (MI) [odds ratio (OR) 3.13, 95% CI: 1.42-4.89], systolic blood pressure (SBP) <100 mmHg (OR 1.78, 95% CI: 1.28-4.06), cardiac troponin T (cTnT) (OR 1.78, 95% CI: 1.28-4.06), high-sensitivity C-reactive protein (hs-CRP) (OR 1.08, 95% CI: 1.01-1.15), brain natriuretic peptide (BNP) (OR 3.76, 95% CI: 1.31-9.75), interleukin-6 (IL-6) (OR 1.42, 95% CI: 1.17-3.29), ejection fraction (EF) (OR 1.39, 95% CI: 1.09-3.28), left ventricular end-diastolic diameter (LVEDD) (OR 1.28, 95% CI: 1.05-4.23), anterior wall infarction (OR 2.83, 95% CI: 1.69-5.76), and long-term CDDP treatment (OR 0.44, 95% CI: 0.89-0.21). CONCLUSIONS: Prior MI, SBP, cTnT, hs-CRP, BNP, and IL-6 on admission, along with EF, LVEDD, and anterior wall infarction are all predictors for no-reflow phenomenon. Long-term treatment with CDDP can reduce no-reflow phenomenon.

Effect of Chinese Medicine on No or Slow Reflow after Percutaneous Coronary Intervention in Myocardial Infarction Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematic review the effect of Chinese medicine (CM) on no or slow reflow after percutaneous coronary intervention (PCI) in myocardial infarction (MI) patients. METHODS: The PubMed, EMBASE databases, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database (CBM), Wanfang Knowledge Service Platform (Wanfang Database) and Chinese Scientific Journal Database (VIP) were searched up to December 2017. Randomized controlled trials (RCTs) which evaluated the effect of CM therapies on no or slow reflow after PCI in MI patients were included. The primary outcome was the effect of reperfusion. Secondary outcomes were left ventricular ejection fraction, incidence of major adverse cardiovascular events and adverse effect. RESULTS: Ten RCTs covering 814 patients were included. Two studies revealed that the incidence of no or slow reflow was less in Shenmai Injection () group than in the control group measured by thrombolysis in myocardial infarction (TIMI) ⩽ 2 (risk ratio=0.55, 95% confidence interval 0.38 to 0.81, P=0.003, I2=37%). Two studies indicated that Salvianolate Injection showed no additional benefit on no or slow reflow measured by corrected TIMI frame count compared with the conventional treatment (mean difference -4.24, 95% confidence interval -13.03 to 4.54, P=0.34, I2=86%). In addition, Tongxinluo Capsules (), Danhong Injection () and Xuesaitong Injection () may have the potential to reduce no or slow reflow measured during or after PCI in individual studies. CONCLUSIONS: Current evidence from RCTs are not sufficient to evaluate the effect of CM adjuvant therapies on no or slow reflow after PCI for MI patients. The included studies are limited by small sample size and unclear baseline conditions. Further rigorously designed researches and verification studies with sufficient number of patients are warranted.

Effect of Vitamin D and parathyroid hormone levels on the coronary slow-flow phenomenon.

BACKGROUND: The presence of vitamin D, and parathyroid hormone receptors has been demonstrated in the vascular endothelium. Variations in vitamin D, and parathyroid hormone levels may affect coronary flow and cause the coronary slow-flow phenomenon (CSF). METHODS: We enrolled 93 patients who had undergone coronary angiography and had near-normal coronary arteries. Blood samples were taken to determine the calcium, phosphorus, 25-hydroxy vitamin D, and parathyroid hormone levels. Vitamin D deficiency was defined as a serum 25-hydroxy vitamin D level of less than 20 ng/mL. We divided the study population into two groups according to thrombolysis in myocardial infarction frame count (TFC) levels. RESULTS: Patients with TFC ≤27 were in the control group (n = 39), and those with TFC >27 were in the CSF group (n = 54). 25-Hydroxy vitamin D levels were similar in both groups: 17.5 [3.3-36.1] ng/ml in the CSF group and 15.2 [5.3-34] ng/ml in the control group (P = 0.129). When we analyzed TFC for each of the coronary arteries, we found a weak negative correlation between vitamin D level and TFC of the right coronary artery in the CSF group (r = -0.314, P = 0.021). Parathyroid hormone levels were similar in both groups: 48 [16-140] pg/ml in the CSF group and 52 [25-125] pg/ml in the control group (P = 0.297). CONCLUSION: The study failed to demonstrate a relationship between serum parathyroid hormone level and CSF. However, a weak negative correlation was found between vitamin D level and TFC of the right coronary artery.

Effect of Shexiang Tongxin Dropping Pills () on the Immediate Blood Flow of Patients with Coronary Slow Flow.

OBJECTIVE: To observe the immediate effect and safety of Shexiang Tongxin dropping pills (, STDP) on patients with coronary slow flow (CSF), and furthermore, to explore new evidence for the use of Chinese medicine in treating ischemic chest pain. METHODS: Coronary angiography (CAG) with corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) was applied (collected at 30 frames/s). The treatment group included 22 CSF patients, while the control group included 22 individuals with normal coronary flow. CSF patients were given 4 STDP through sublingual administration, and CAG was performed 5 min after the medication. The immediate blood flow frame count, blood pressure, and heart rate of patients before and after the use of STDP were compared. The liver and kidney functions of patients were examined before and after treatments. RESULTS: There was a significant difference in CTFC between groups (P<0.05). The average CTFC values of the vessels with slow blood flow in CSF patients were, respectively, 49.98 ± 10.01 and 40.42 ± 11.33 before and after the treatment with STDP, a 19.13% improvement. The CTFC values (frame/s) measured before and after treatment at the left anterior descending coronary artery, left circumflex artery, and right coronary artery were, respectively, 48.00 ± 13.32 and 41.80 ± 15.38, 59.00 ± 4.69 and 50.00 ± 9.04, and 51.90 ± 8.40 and 40.09 ± 10.46, giving 12.92%, 15.25%, and 22.76% improvements, respectively. The CTFC values of vessels with slow flow before treatment were significantly decreased after treatment (P<0.05). There were no apparent changes in the heart rate, blood pressure, or liver or kidney function of CSF patients after treatment with STDP (all P>0.05). CONCLUSIONS: The immediate effect of STDP in treating CSF patients was apparent. This medication could significantly improve coronary flow without affecting blood pressure or heart rate. Our findings support the potential of Chinese medicine to treat ischemic chest pain.

Effect of Shexiang Tongxin Dropping Pills () on the Immediate Blood Flow of Patients with Coronary Slow Flow / 中国结合医学杂志

OBJECTIVE@#To observe the immediate effect and safety of Shexiang Tongxin dropping pills (, STDP) on patients with coronary slow flow (CSF), and furthermore, to explore new evidence for the use of Chinese medicine in treating ischemic chest pain.@*METHODS@#Coronary angiography (CAG) with corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) was applied (collected at 30 frames/s). The treatment group included 22 CSF patients, while the control group included 22 individuals with normal coronary flow. CSF patients were given 4 STDP through sublingual administration, and CAG was performed 5 min after the medication. The immediate blood flow frame count, blood pressure, and heart rate of patients before and after the use of STDP were compared. The liver and kidney functions of patients were examined before and after treatments.@*RESULTS@#There was a significant difference in CTFC between groups (P0.05).@*CONCLUSIONS@#The immediate effect of STDP in treating CSF patients was apparent. This medication could significantly improve coronary flow without affecting blood pressure or heart rate. Our findings support the potential of Chinese medicine to treat ischemic chest pain.

Effect of intracoronary agents on the no-reflow phenomenon during primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction: a network meta-analysis.

BACKGROUND: Despite the restoration of epicardial flow after primary percutaneous coronary intervention (PPCI), myocardial reperfusion remains impaired in a significant proportion of patients. We performed a network meta-analysis to assess the effect of 7 intracoronary agents (adenosine, anisodamine, diltiazem, nicorandil, nitroprusside, urapidil, and verapamil) on the no-reflow phenomenon in patients with ST-elevation myocardial infarction (STEMI) undergoing PPCI. METHODS: Database searches were conducted to identify randomized controlled trials (RCTs) comparing the 7 agents with each other or with standard PPCI. Outcome measures included thrombolysis in myocardial infarction flow grade (TFG), ST-segment resolution (STR), left ventricular ejection fraction (LVEF), major adverse cardiovascular events (MACEs), and adverse events. RESULTS: Forty-one RCTs involving 4069 patients were analyzed. The addition of anisodamine to standard PPCI for STEMI was associated with improved post-procedural TFG, more occurrences of STR, and improvement of LVEF. The cardioprotective effect of anisodamine conferred a MACE-free survival benefit. Additionally, nitroprusside was regarded as efficient in improving coronary flow and clinical outcomes. Compared with standard care, adenosine, nicorandil, and verapamil improved coronary flow but had no corresponding benefits regarding cardiac function and clinical outcomes. The ranking probability for the 7 treatment drugs showed that anisodamine consistently ranked the highest in efficacy outcomes (TFG < 3, STR, LVEF, and MACEs). No severe adverse events, such as hypotension and malignant arrhythmia, were observed in patients treated with anisodamine. Network meta-regression analysis showed that age, the time to reperfusion, and study follow-up did not affect the treatment effects. CONCLUSIONS: The intracoronary administration of anisodamine appears to improve myocardial reperfusion, cardiac function, and clinical outcomes in patients with STEMI undergoing PPCI. Given the limited quality and quantity of the included studies, more rigorous RCTs are needed to verify the role of this inexpensive and well-tolerated regimen.

Effects of First High-Dose Atorvastatin Loading in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

To determine the effects of 80-mg atorvastatin administration for the first time in patients with acute ST segment elevation myocardial infarction (STEMI) before emergency percutaneous coronary intervention (PCI). A total of 118 patients with STEMI who underwent emergency PCI were enrolled in this study. The patients were divided into 80-mg group (n = 59) and 40-mg group (n = 59), according to the loading dose of atorvastatin firstly before operation. The occurrence of no-reflows and changes of HbA1c were observed preoperatively and postoperatively on second and fifth days. All patients were followed up for 1 year with major adverse cardiac events (MACE) recorded. The incidence of no-reflow in 80-mg group was obviously lower than in 40-mg group (13.56% vs. 25.42%) (χ = 4.374, P = 4.374). The preoperative HbA1c levels exhibited no significant difference between 80-mg group and 40-mg group (P > 0.05). The postoperative HbA1c levels in 2 groups showed a trend of gradual decline, which were lower in 80-mg group than in 40-mg group for second day, fifth day, first month, sixth month, and 12th month (all P < 0.05). The postoperative incidence of MACE in 80-mg group was significantly lower than in 40-mg group for sixth and 12th months (both P < 0.05). The incidence of MACE in patients with reflow in 80-mg and 40-mg groups was significantly higher than in patients with no-reflow who were in 80-mg and 40-mg groups for postoperative 12th month (both P < 0.05). The first loading high dose of atorvastatin can significantly prevent occurrence of postoperative no-reflow in patients with STEMI after PCI, reduce HbA1c levels and the incidence of MACE. Clinical randomized controlled trial with larger sample size is required to confirm this finding.

Pretreatment with and ongoing use of omega-3 fatty acid ethyl esters reduce the slow-flow phenomenon and prevent in-stent restenosis in patients undergoing carotid artery stenting.

OBJECTIVE: Carotid artery stenting (CAS) is a less invasive alternative to carotid endarterectomy, but it is essential to prevent thromboembolic complications during CAS and to suppress in-stent restenosis (ISR) after CAS because of the relatively high risk of periprocedural and follow-up stroke events. Clinical trials have demonstrated the strong relationship of carotid plaque vulnerability with the subsequent risk of ipsilateral ischemic stroke and thromboembolic complications during CAS. Recent studies demonstrated that both low eicosapentaenoic acid (EPA) and low docosahexaenoic acid (DHA) levels were significantly associated with lipid-rich coronary and carotid plaques, but little is known about the effect of administration of omega-3 fatty acids (O-3FAs) containing EPA and DHA before and after CAS for stabilizing carotid plaque, preventing thromboembolic complications, and suppressing ISR. In this study, the efficacy of pretreatment with and ongoing daily use of O-3FA in addition to statin treatment was evaluated in patients undergoing CAS. METHODS: This study was a nonrandomized prospective trial with retrospective analysis of historical control data. From 2012 to 2015, there were 100 consecutive patients with hyperlipidemia undergoing CAS for carotid artery stenosis who were divided into two groups. Between 2012 and 2013 (control period), 47 patients were treated with standard statin therapy. Between 2014 and 2015 (O-3FA period), patients were treated with statin therapy and add-on oral O-3FA ethyl esters containing 750 mg/d DHA and 1860 mg/d EPA from 4 weeks before CAS, followed by ongoing daily use for at least 12 months. In all patients, the plaque morphology by virtual histology intravascular ultrasound, the incidence of new ipsilateral ischemic lesions on the day after CAS, the slow-flow phenomenon during CAS, and ISR within 12 months after CAS were compared between the periods. RESULTS: The slow-flow phenomenon during CAS with filter-type embolic protection devices decreased in the O-3FA period (1 of 53 patients [2%]) compared with the control period (7 of 47 patients [15%]; P = .02). Furthermore, ISR for 12 months after CAS was significantly decreased in the O-3FA period (1 of 53 patients [2%]) compared with the control period (10 of 47 patients [21%]; P = .01). On virtual histology intravascular ultrasound analysis, the fibrofatty area was significantly smaller and the fibrous area was significantly greater in the O-3FA period. On multivariate logistic regression analysis, a low EPA/arachidonic acid ratio and a symptomatic lesion were the factors related to vulnerable plaque (P = .01 [odds ratio, 5.24; 95% confidence interval, 1.65-16.63] and P = .01 [odds ratio, 11.72; 95% confidence interval, 2.93-46.86], respectively). CONCLUSIONS: Pretreatment with O-3FA reduces the slow-flow phenomenon generated by plaque vulnerability during CAS, and on-going daily use of O-3FA suppresses ISR after CAS.

Opium addiction as an independent risk factor for coronary microvascular dysfunction: A case-control study of 250 consecutive patients with slow-flow angina.

BACKGROUND: Approximately 20% to 30% of patients who undergo coronary angiography for assessment of typical cardiac chest pain display microvascular coronary dysfunction (MCD). This study aimed to determine potential relationships between baseline clinical characteristics and likelihood of MCD diagnosis in a large group of patients with stable angina symptoms, positive exercise test and angiographic ally normal epicardial coronary arteries. MATERIAL AND METHODS: This cross-sectional study included 250 Iranian with documented evidence of cardiac ischemia on exercise testing, class I or II indication for coronary angiography, and either: (1) angiographically normal coronary arteries and diagnosis of MCD with slow-flow phenomenon, or (2) normal angiogram and no evidence of MCD. All patients completed a questionnaire designed to capture key data including clinical demographics, past medical history, and social factors. Data was evaluated using single and multivariable logistic regression models to identify potential individual patient factors that might help to predict a diagnosis of MCD. RESULTS: 125 (11.2% of total) patients were subsequently diagnosed with MCD. 125 consecutive control subjects were selected for comparison. The mean age was similar among the two groups (52.38 vs. 53.26%, p=ns), but there was a higher proportion of men in the study group compared to control (42.4 vs. 27.2%, p=0.012). No significant relationships were observed between traditional cardiovascular risk factors (diabetes, hypertension, and dyslipidemia) or body mass index (BMI), and likelihood of MCD diagnosis. However, opium addiction was found to be an independent predictor of MCD on single and multivariable logistic regression model (OR=3.575, 95%CI: 1.418-9.016; p=0.0069). CONCLUSIONS: We observed a significant relationship between opium addiction and microvascular angina. This novel finding provides a potential mechanistic insight into the pathogenesis of MCD with slow-flow phenomenon.

Effects of tripterygium glycosides on restenosis following endovascular treatment.

The mechanism and associated factors of restenosis following intravascular stent implantation remain to be elucidated. The present two­part experimental and clinical study aimed to investigate the effects of tripterygium glycosides on in­stent restenosis subsequent to intra­arterial therapy. Following endovascular stent implantation in rabbit iliac arteries, post­stent outcomes were evaluated in cyclosporine groups, low­dose and high­dose tripterygium glycosides groups and controls. Post­operative angiography indicated that vessel diameters were similar between groups; however, at 28 days after receiving the therapeutic agents, vessels of the cyclosporine and tripterygium glycosides groups were significantly larger than those of the controls. Furthermore, three groups of patients had comparable baseline levels of interleukin (IL)­10, IL­18 and C­reactive protein, and intima­media thickness. However, 1 month after stent implantation, levels of IL­10 and IL­18 were markedly reduced in the high­ and low­dose tripterygium glycosides groups compared with controls. At 6 months after surgery, the stent patency rate in patients with bare stents was significantly lower than in patients receiving tripterygium glycosides (P≤0.009). In addition, the ankle­brachial index was also higher than in those without tripterygium glycosides (P<0.001). Results of the experimental and clinical studies suggest that tripterygium glycosides may inhibit and possibly aid in the prevention of in­stent restenosis formation following endovascular treatment of lower­extremity artery disease.

Cardiac microvascular barrier function mediates the protection of Tongxinluo against myocardial ischemia/reperfusion injury.

OBJECTIVE: Tongxinluo (TXL) has been shown to decrease myocardial necrosis after ischemia/reperfusion (I/R) by simulating ischemia preconditioning (IPC). However, the core mechanism of TXL remains unclear. This study was designed to investigate the key targets of TXL against I/R injury (IRI) among the cardiac structure-function network. MATERIALS AND METHODS: To evaluate the severity of lethal IRI, a mathematical model was established according to the relationship between myocardial no-reflow size and necrosis size. A total of 168 mini-swine were employed in myocardial I/R experiment. IRI severity among different interventions was compared and IPC and CCB groups were identified as the mildest and severest groups, respectively. Principal component analysis was applied to further determine 9 key targets of IPC in cardioprotection. Then, the key targets of TXL in cardioprotection were confirmed. RESULTS: Necrosis size and no-reflow size fit well with the Sigmoid Emax model. Necrosis reduction space (NRS) positively correlates with I/R injury severity and necrosis size (R2=0.92, R2=0.57, P<0.01, respectively). Functional and structural indices correlate positively with NRS (R2=0.64, R2=0.62, P<0.01, respectively). TXL recovers SUR2, iNOS activity, eNOS activity, VE-cadherin, ß-catenin, γ-catenin and P-selectin with a trend toward the sham group. Moreover, TXL increases PKA activity and eNOS expression with a trend away from the sham group. Among the above nine indices, eNOS activity, eNOS, VE-cadherin, ß-catenin and γ-catenin expression were significantly up-regulated by TXL compared with IPC (P>0.05) or CCB (P<0.05) and these five microvascular barrier-related indices may be the key targets of TXL in minimizing IRI. CONCLUSIONS: Our study underlines the lethal IRI as one of the causes of myocardial necrosis. Pretreatment with TXL ameliorates myocardial IRI through promoting cardiac microvascular endothelial barrier function by simulating IPC.

The preventive effect of garlicin on a porcine model of myocardial infarction reperfusion no-reflow.

OBJECTIVE: To evaluate whether garlicin can prevent reperfusion no-reflow in a catheter-based porcine model of acute myocardial infarction (AMI). METHODS: Twenty-two male Chinese mini swines were randomized into 3 groups: sham-operation group (n=6), control group (n=8), and garlicin group (n=8). The distal part of left anterior descending coronary artery (LAD) in swines of the latter two groups was completely occluded by dilated balloon for 2 h and a successful AMI model was confirmed by coronary angiography (CAG) and electrocardiograph (ECG), which was then reperfused for 3 h. In the sham-operation group, balloon was placed in LAD without dilatation. Garlicin at a dosage of 1.88 mg/kg was injected 10 min before LAD occlusion until reperfusion for 1 h in the garlicin group. To assess serial cardiac function, hemodynamic data were examined by catheter method before AMI, 2 h after occlusion and 1, 2, and 3 h after reperfusion. Myocardial contrast echocardiography (MCE) and double staining with Evans blue and thioflavin-S were performed to evaluate myocardial no-reflow area (NRA) and risk area (RA). RESULTS: Left ventricular systolic pressure and left ventricular end-diastolic pressure significantly improved in the garlicin group after reperfusion compared with the control group P<0.05) and 2 h after AMI (P<0.05). MCE showed garlicin decreased reperfusion NRA after AMI compared with the control group (P <0.05). In double staining, NRA/RA in the garlicin group was 18.78%, significantly lower than that of the control group (49.84%, P<0.01). CONCLUSIONS: Garlicin has a preventive effect on the porcine model of myocardial infarction reperfusion no-reflow by improving hemodynamics and decreasing NRA.

Donor simvastatin treatment abolishes rat cardiac allograft ischemia/reperfusion injury and chronic rejection through microvascular protection.

BACKGROUND: Ischemia/reperfusion injury may have deleterious short- and long-term consequences for cardiac allografts. The underlying mechanisms involve microvascular dysfunction that may culminate in primary graft failure or untreatable chronic rejection. METHODS AND RESULTS: Here, we report that rat cardiac allograft ischemia/reperfusion injury resulted in profound microvascular dysfunction that was prevented by donor treatment with peroral single-dose simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase and Rho GTPase inhibitor, 2 hours before graft procurement. During allograft preservation, donor simvastatin treatment inhibited microvascular endothelial cell and pericyte RhoA/Rho-associated protein kinase activation and endothelial cell-endothelial cell gap formation; decreased intragraft mRNA levels of hypoxia-inducible factor-1α, inducible nitric oxide synthase, and endothelin-1; and increased heme oxygenase-1. Donor, but not recipient, simvastatin treatment prevented ischemia/reperfusion injury-induced vascular leakage, leukocyte infiltration, the no-reflow phenomenon, and myocardial injury. The beneficial effects of simvastatin on vascular stability and the no-reflow phenomenon were abolished by concomitant nitric oxide synthase inhibition with N-nitro-l-arginine methyl ester and RhoA activation by geranylgeranyl pyrophosphate supplementation, respectively. In the chronic rejection model, donor simvastatin treatment inhibited cardiac allograft inflammation, transforming growth factor-ß1 signaling, and myocardial fibrosis. In vitro, simvastatin inhibited transforming growth factor-ß1-induced microvascular endothelial-to-mesenchymal transition. CONCLUSIONS: Our results demonstrate that donor simvastatin treatment prevents microvascular endothelial cell and pericyte dysfunction, ischemia/reperfusion injury, and chronic rejection and suggest a novel, clinically feasible strategy to protect cardiac allografts.

Persistent coronary no flow after wire insertion is an early and readily available mortality risk factor despite successful mechanical intervention in acute myocardial infarction: a pooled analysis from the STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) trials.

OBJECTIVES: These studies sought to investigate the impact on mortality of coronary flow after passage of the wire through the culprit vessel in patients with ST-segment elevation myocardial infarction (STEMI) undergoing mechanical reperfusion. BACKGROUND: Reduced spontaneous coronary flow before percutaneous coronary intervention influences mortality in patients with STEMI. Response to vessel wiring in patients with an occluded coronary artery before intervention might further discriminate outcomes irrespective of pre- and post-intervention coronary flow. METHODS: Data from the STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) trials were pooled: of 919 index procedures, 902 films (98%) were technically adequate for core laboratory TIMI (Thrombolysis In Myocardial Infarction) flow determination. RESULTS: TIMI flow grade 0 was present before percutaneous coronary intervention in 59% of infarct vessels, TIMI flow grade 1 to 2 was found in 21%, whereas the remainder of infarct arteries presented with TIMI flow grade 3. In 49% of patients who showed persistent TIMI flow grade 0 after wire insertion (AWI), mortality was higher at 30 days (5.3%) and 1 year (9.4%) compared with patients in whom TIMI flow grade before percutaneous coronary intervention was either >0 (0.8%; p < 0.003 and 3.6%, p < 0.008) or improved from 0 AWI (1.5%, p < 0.04 and 3.6%, p < 0.02). After correcting for multiple imbalances, including baseline and final flow, persistent TIMI flow grade 0 AWI remained associated at 30 days to 2-fold (risk ratio [RR]: 2.1, 95% confidence interval [CI]: 1.08 to 5.00; p = 0.038) and at 1 year to almost 3-fold increases of mortality (RR: 2.7, 95% CI: 1.3 to 5.6; p = 0.008). CONCLUSIONS: STEMI patients displaying persistent no-flow AWI have a lower survival rate despite an apparently successful mechanical intervention. As an early marker for high residual mortality risk, persistent no-flow AWI may qualify STEMI patients for dedicated pharmacomechanical treatment strategies.

Ramipril-like activity of Spondias mombin linn against no-flow ischemia and isoproterenol-induced cardiotoxicity in rat heart.

The cardioprotective property of Spondias mombin (SM) was investigated and compared with that of the ACE inhibitor, ramipril. Alterations to markers of myocardial injury and indices of antioxidant capacity by isoproterenol (ISP) intoxication were significantly corrected in groups treated with SM. The inflammatory index was increased by 24% in ISP-intoxicated group compared with control (P < 0.001) but reduced in the groups administered ISP and treated with 100 or 250 mg/kg SM by 17% (P < 0.001) and 11% (P < 0.05) respectively. Serum lactate dehydrogenase activity and cholesterol level which were significantly increased in ISP-intoxicated group compared with control were reduced in groups administered ISP and treated with SM. Serum phosphate levels in groups administered ISP and treated with SM were significantly lower than values obtained for the ISP-intoxicated group (P < 0.001). Tissue catalase and superoxide dismutase activities as well as glutathione level were significantly increased in groups administered ISP and treated with SM compared to ISP-intoxicated group while MDA and nitrite levels were decreased. Disruption in the structure of cardiac myofibrils by ISP intoxication was reduced by treatment with SM. Comparable results were obtained for ramipril. These results are indicative of the potent cardioprotective property of SM.

[Effect of intracoronary injection with xuesaitong in treating post-PCI slow-reflow phenomenon in patients with ST-segment elevation myocardial infarction].

OBJECTIVE: To evaluate the effect and safety of Xuesaitong (XST, a Panax Notoginseng extract preparation) via intracoronary injection for treating post-PCI slow-reflow phenomenon in patients with ST-segment elevation myocardial infarction (STEMI) and its impact on patients' prognosis. METHODS: Thirty-nine STEMI patients who suffered from post-PCI slow-reflow after received percutaneous transluminal coronary angioplasty or stenting were assigned to two groups, 20 patients in the treated group and 19 in the control group. Intracoronary administering of 10 mL (0.5 mg) tirofiban and 400 mg XST were given to the treated group through guiding catheter, and followed with 36 h continuous intravenous dripping of tirofiban 10 mL/h and 400 mg XST in 250 mL of saline for dripping, while to the control group, the same intracoronary administering and intravenous dripping of tirofiban but without XST was given. The treatment was implemented for two days. Patients' coronary flow was assessed by the TIMI frame count method (TFC) at 1 min, 5 min and 10 min after injection; and the changes of ST-segment in 2 h, and incidence of bleeding in 48 h after medication were recorded. All patients were followed-up for 6 months to observe the incidence of cardiovascular events. RESULTS: Before the medication, the TIMI flow grade and the TFC in the treated group and the control group showed insignificantly statistical difference between groups (P > 0.05). After medication, 11 patients (55%) in the treated group and 8 patients (42%) in the control group with their blood flow reaching TIMI grade 3; the TFC decreased at 1, 5 and 10 min to 57.6 +/- 12.6, 46.1 +/- 9.3, 49.8 +/- 10.9 in the treated group and to 69.3 +/- 16.1, 61.2 +/- 15.3, 63.7 +/- 18.3 in the control group; and the 2 h ST segment fallback in them was 1.85 +/- 0.31 mm and 1.40 +/- 0.21 mm respectively, showing that the coronary blood flow in both groups were improved significantly after medication but the improvement in the former was better than in the latter group (P < 0.05). No case of death occurred in the hospitalization period. Results of 6-month follow-up study showed that the incidence of major adverse cardiac events, including angina pectoris, myocardial infarction, heart failure and cardiac death, was 33% in treated group and 44% in the control group, showing insignificant difference between groups (P > 0.05). CONCLUSION: Concomitant coronary injection with tirofiban and XST is more effective than that with tirofiban alone in improving the coronary blood flow and shows no increasing on the incidence of hemorrhagic complication.