Relationship between blood viscosity and no-reflow phenomenon in ST-segment elevation myocardial infarction performed in primary percutaneous coronary interventions.

Background: This study aimed to analyze the associations between no-reflow (NR) phenomenon development and whole-blood viscosity in patients with ST-elevated myocardial infarction. Methods: A total of 217 patients with ST-elevated myocardial infarction were included. whole-blood viscosity values were assessed using hematocrit and total protein values, and low shear rate (LSR) and high shear rate (HSR) were calculated. Results: The average LSR and HSR values of the study group were significantly higher than the control group (p < 0.001). Multivariate logistic regression analysis showed that both HSR (odds ratio: 4.957; p < 0.001) and LSR (odds ratio: 1.114; p < 0.001) were independent predictors for NR development. Conclusion: This study found that increased blood viscosity was an independent predictor for NR development.

Lay abstract Following a heart attack, surgeons can attempt to repair the damage using a procedure called a percutaneous coronary intervention. In some cases, blood flow does not return to the heart tissue as expected ('failure of reperfusion') after this procedure, which is known as the no-reflow (NR) phenomenon. In this study, the researchers investigated whether there was a link between patients who had experienced a type of heart attack called an ST-elevated myocardial infarction (STEMI) and developed NR, and the viscosity (thickness) of their blood. The researchers looked at the viscosity of whole-blood samples from 98 STEMI patients with NR and 119 control individuals matched for age and gender. They found that whole-blood samples could be used to predict the likelihood of a STEMI patient experiencing NR.

Coronary Endothelium No-Reflow Injury Is Associated with ROS-Modified Mitochondrial Fission through the JNK-Drp1 Signaling Pathway.

Coronary artery no-reflow is a complex problem in the area of reperfusion therapy, and the molecular mechanisms underlying coronary artery no-reflow injury have not been fully elucidated. In the present study, we explored whether oxidative stress caused damage to coronary endothelial cells by inducing mitochondrial fission and activating the JNK pathway. The hypoxia/reoxygenation (H/R) model was induced in vitro to mimic coronary endothelial no-reflow injury, and mitochondrial fission, mitochondrial function, and endothelial cell viability were analyzed using western blotting, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence. Our data indicated that reactive oxygen species (ROS) were significantly induced upon H/R injury, and this was followed by decreased endothelial cell viability. Mitochondrial fission was induced and mitochondrial bioenergetics were impaired in cardiac endothelial cells after H/R injury. Neutralization of ROS reduced mitochondrial fission and protected mitochondrial function against H/R injury. Our results also demonstrated that ROS stimulated mitochondrial fission via JNK-mediated Drp1 phosphorylation. These findings indicate that the ROS-JNK-Drp1 signaling pathway may be one of the molecular mechanisms underlying endothelial cell damage during H/R injury. Novel treatments for coronary no-reflow injury may involve targeting mitochondrial fission and the JNK-Drp1 signaling pathway.

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.

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.

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.

Mitochondrial quality control in cardiac microvascular ischemia-reperfusion injury: New insights into the mechanisms and therapeutic potentials.

Thrombolytic therapy and revascularization strategies create a complete recanalization of the occluded epicardial coronary artery in patients with myocardial infarction (MI). However, about 35 % of patients still experience an impaired myocardial reperfusion, which is termed a no-reflow phenomenon mainly caused by cardiac microvascular ischemia-reperfusion (I/R) injury. Mitochondria are essential for microvascular endothelial cells' survival, both because of their roles as metabolic energy producers and as regulators of programmed cell death. Mitochondrial structure and function are regulated by a mitochondrial quality control (MQC) system, a series of processes including mitochondrial biogenesis, mitochondrial dynamics/mitophagy, mitochondrial proteostasis, and mitochondria-mediated cell death. Our review discusses the MQC mechanisms and how they are linked to cardiac microvascular I/R injury. Additionally, we will summarize the molecular basis that results in defective MQC mechanisms and present potential therapeutic interventions for improving MQC in cardiac microvascular I/R injury.

Coronary microvascular dysfunction.

Patients with coronary microvascular dysfunction (CMVD) represent a widespread population and despite the good prognosis, many of them have a poor quality of life with strong limitations in their daily activities because of the angina symptoms. This article summarizes the most frequent clinical presentation pictures like stable and unstable microvascular angina. Main risk factors are discussed, followed by the latest updates on the subject about different pathogenic hypotheses, diagnosis and treatment. Not very well understood microvascular alterations, like slow flow phenomenon and no reflow are discussed and both prognosis and the impact of the disease in the quality of life are analyzed.

Generation of an induced pluripotent stem cell line (SYSUi002-A) from a patient with coronary slow flow phenomenon.

The coronary slow flow phenomenon (CSFP) is characterized by delayed progression of the injected contrast medium through the coronary tree during coronary angiography due to unknown mechanisms. Here, a human induced pluripotent stem cell (iPSC) line (SYSUi002-A) was established using the Sendai-virus delivery system from dermal fibroblasts of a CSFP patient. This cell line may represent a valuable tool for investigating the pathogenesis and therapeutic strategies of CSFP.

The coronary circulation in acute myocardial ischaemia/reperfusion injury: a target for cardioprotection.

The coronary circulation is both culprit and victim of acute myocardial infarction. The rupture of an epicardial atherosclerotic plaque with superimposed thrombosis causes coronary occlusion, and this occlusion must be removed to induce reperfusion. However, ischaemia and reperfusion cause damage not only in cardiomyocytes but also in the coronary circulation, including microembolization of debris and release of soluble factors from the culprit lesion, impairment of endothelial integrity with subsequently increased permeability and oedema formation, platelet activation and leucocyte adherence, erythrocyte stasis, a shift from vasodilation to vasoconstriction, and ultimately structural damage to the capillaries with eventual no-reflow, microvascular obstruction (MVO), and intramyocardial haemorrhage (IMH). Therefore, the coronary circulation is a valid target for cardioprotection, beyond protection of the cardiomyocyte. Virtually all of the above deleterious endpoints have been demonstrated to be favourably influenced by one or the other mechanical or pharmacological cardioprotective intervention. However, no-reflow is still a serious complication of reperfused myocardial infarction and carries, independently from infarct size, an unfavourable prognosis. MVO and IMH can be diagnosed by modern imaging technologies, but still await an effective therapy. The current review provides an overview of strategies to protect the coronary circulation from acute myocardial ischaemia/reperfusion injury. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

Delayed therapeutic hypothermia protects against the myocardial no-reflow phenomenon independently of myocardial infarct size in a rat ischemia/reperfusion model.

BACKGROUND: Adjunctive therapies, given in addition to reperfusion to reduce myocardial infarct size, have been disappointing based on clinical trials. New therapeutic targets independent of infarct size modification are needed. The no-reflow phenomenon occurs commonly after the infarct-related coronary artery is opened and predicts poor clinical outcome. We investigated the effects of a single application of delayed (post-reperfusion) therapeutic hypothermia (TH) in a rat model of coronary artery occlusion/reperfusion. METHODS: Rats were subjected to 60min of coronary artery occlusion followed by 3h of reperfusion. Rats were divided into normothermic (n=5) and TH (n=5) groups. In the TH, hypothermia was initiated at 1min after coronary artery reperfusion by pumping room-temperature (22°C) saline into and out of the thoracic cavity for 1h. This decreased intrathoracic temperature to around 26°C within 12min. At 3h after reperfusion, hearts were excised for infarct size and no-reflow zone measurement. RESULTS: Ischemic risk area and infarct size were similar between the 2 groups. No-reflow area (expressed as % of risk area) was significantly reduced in TH group (18.0±4.4%) compared with normothermic group (39.5±2.9%,P=0.005). When expressed as % of necrotic area, no-reflow area was reduced by more than half in TH group (25.5±6.4%) versus innormothermic group (54.4±5.3%,P=0.01). CONCLUSIONS: In this preliminary study, hypothermia initiated after reperfusion following 60min of coronary artery occlusion had no effect on infarct size yet substantially reduced the extent of no-reflow.

Effect of Elevated Reperfusion Pressure on "No Reflow" Area and Infarct Size in a Porcine Model of Ischemia-Reperfusion.

BACKGROUND: The "no reflow" phenomenon (microvascular obstruction despite restoration of epicardial blood flow) develops postreperfusion in acute myocardial infarction and is associated with poor prognosis. We hypothesized that increased reperfusion pressure may attenuate the no reflow phenomenon, as it could provide adequate flow to overcome the high resistance of the microvasculature within the no reflow zone. Thus, we investigated the effect of modestly elevated blood pressure during reperfusion on the extent of no reflow area and infarct size in a porcine model of ischemia-reperfusion. METHODS: Eighteen farm pigs underwent acute myocardial infarction by occlusion of the anterior descending coronary artery for 1 hour, followed by 2 hours of reperfusion. Just prior to reperfusion, animals were randomized into 2 groups: in group 1 (control group, n = 9), no intervention was performed. In group 2 (n = 9), aortic pressure was increased by ∼20% (compared to ischemia) by partial clamping of the ascending aorta during reperfusion. Following 2 hours of reperfusion, animals were euthanized to measure area at risk, infarct size, and area of no reflow. RESULTS: Partial clamping of the ascending aorta resulted in modest elevation of blood pressure during reperfusion. The area at risk did not differ between the 2 groups. The no reflow area was significantly increased in group 2 compared to control animals (50% ± 13% vs 37% ± 9% of the area at risk; P = .04). The infarcted area was significantly increased in group 2 compared to control animals (75% ± 17% vs 52% ± 23% of the area at risk; P = .03). Significant positive correlations were observed between systolic aortic pressure and no reflow area, between systolic aortic pressure and infarcted area and between infarcted area and no reflow area during reperfusion. CONCLUSIONS: Modestly elevated blood pressure during reperfusion is associated with an increase in no reflow area and in infarct size in a clinically relevant porcine model of ischemia-reperfusion.

Growth differentiation factor 15 may protect the myocardium from no­reflow by inhibiting the inflammatory­like response that predominantly involves neutrophil infiltration.

The aim of the current study was to investigate the time course of the expression of growth differentiation factor­15 (GDF­15) in rat ischemic myocardium with increasing durations of reperfusion, and to elucidate its physiopathological role in the no­reflow phenomenon. Wistar rats were randomly divided into ischemia reperfusion (I/R) and sham groups, and myocardial I/R was established by ligation of the left anterior descending coronary artery for 1 h followed by reperfusion for 2, 4, 6, 12, 24 h and 7 days whilst rats in the sham group were subjected to a sham operation. The expression levels of GDF­15 and ICAM­1 were measured, in addition to myeloperoxidase (MPO) activity. The myocardial anatomical no­reflow and infarction areas were assessed. The area at risk was not significantly different following various periods of reperfusion, while the infarct area and no­reflow area were significantly greater following 6 h of reperfusion (P<0.05). The mRNA and protein expression levels of GDF­15 were increased during the onset and development of no­reflow, and peaked following 24 h of reperfusion. MPO activity was reduced with increasing reperfusion duration, while ICAM­1 levels were increased. Hematoxylin and eosin staining demonstrated that myocardial neutrophil infiltration was significantly increased by I/R injury, in particular following 2, 4 and 6 h of reperfusion. GDF­15 expression levels were negatively correlated with MPO activity (r=­0.55, P<0.001), and the MPO activity was negatively correlated with the area of no­reflow (r=­0.46, P<0.01). By contrast, GDF­15 was significantly positively correlated with ICAM­1 levels (r=0.52, P<0.01), which additionally were demonstrated to be significantly positively associated with the size of the no­reflow area (r=0.39, P<0.05). The current study demonstrated the time course effect of reperfusion on the expression of GDF­15 in the myocardial I/R rat model, with the shorter reperfusion times (6 h) resulting in significant no­reflow in ischemic myocardium. GDF­15 may protect the I/R myocardium from no­reflow by inhibiting the inflammatory­like response, which involves neutrophil infiltration and transendothelial migration.

Distal coronary embolization following acute myocardial infarction increases early infarct size and late left ventricular wall thinning in a porcine model.

BACKGROUND: Distal coronary embolization (DCE) of thrombotic material occurs frequently during percutaneous interventions for acute myocardial infarction and can alter coronary flow grades. The significance of DCE on infarct size and myocardial function remains unsettled. The aims of this study were to evaluate the effects of DCE sufficient to cause no-reflow on infarct size, cardiac function and ventricular remodeling in a porcine acute myocardial infarction model. METHODS AND RESULTS: Female Yorkshire pigs underwent 60 min balloon occlusion of the left anterior descending coronary artery followed by reperfusion and injection of either microthrombi (prepared from autologous porcine blood) sufficient to cause no-reflow (DCE), or saline (control). Animals were sacrificed at 3 h (n = 5), 3 days (n = 20) or 6 weeks (n = 20) post-AMI. Cardiovascular magnetic resonance (CMR), serum troponin-I, and cardiac gelatinase (MMP) and survival kinase (Akt) activities were assessed. At 3d, DCE increased infarct size (CMR: 18.8% vs. 14.5%, p = 0.04; serum troponin-I: 13.3 vs. 6.9 ng/uL, p < 0.05) and MMP-2 activity levels (0.81 vs. 0.49, p = 0.002), with reduced activation of Akt (0.06 versus 0.26, p = 0.02). At 6 weeks, there were no differences in infarct size, ventricular volume or ejection fraction between the two groups, although infarct transmurality (70% vs. 57%, p< 0.04) and ventricular thinning (percent change in mid anteroseptal wall thickness:-25.6% vs. 0.7%, p = 0.03) were significantly increased in the DCE group. CONCLUSIONS: DCE increased early infarct size, but without affecting later infarct size, cardiac function or ventricular volumes. The significance of the later remodelling changes (ventricular thinning and transmurality) following DCE, possibly due to changes in MMP-2 activity and Akt activation, merits further study.

Sodium tanshinone IIA sulfonate ameliorates experimental coronary no-reflow phenomenon through down-regulation of FGL2.

AIMS: The effects of sodium tanshinone IIA sulfonate (STS) on coronary no-reflow (CNR) relevant to microvascular obstruction (MVO) remain unknown. Studies had shown that fibrinogen-like protein 2 (FGL2) expressed in microvascular endothelial cells (MECs) is a key mediator in MVO. Thus, we aimed to elucidate the roles of STS in CNR and relations between STS and FGL2. MAIN METHODS: Myocardial ischemia/reperfusion was selected to represent CNR model. The no-reflow zone and infarct area were assessed using Thioflavin S and TTC staining, and cardiac functional parameters were detected using echocardiography. Western blot was used to detected FGL2 level, fibrin level, protease-activated receptor-1 (PAR-1) activation and inflammation cells infiltration. FGL2 and inflammation cells were also identified by IHC. Microthrombus was detected by Carstairs' and MSB staining. We also detected the roles of STS on FGL2 expression, thrombin generation, phospho-Akt and NF-κB levels in MECs. KEY FINDINGS: Upon treatment with STS in CNR model, the no-reflow and infarct areas decreased significantly and cardiac function improved. The FGL2 expression was inhibited by STS in vivo as well as in vitro with thrombin generation inhibition. In addition, STS up-regulates Akt phosphorylation and suppressed NF-κB expression in activated MECs. Furthermore, fibrin deposition, PAR-1 activation and inflammatory response were inhibited with STS administration in CNR model. SIGNIFICANCE: Our results displayed a novel pharmacological action of STS on CNR. STS is able to ameliorate CNR through inhibition of FGL2 expression mediated by Akt and NF-κB pathways as well as prevention of MVO by suppressing fibrin deposition and inflammation.

Predictive Value of the No-Reflow Phenomenon and Epicardial Adipose Tissue for Clinical Outcomes After Primary Percutaneous Coronary Intervention.

INTRODUCTION: The determinants of clinical outcomes in patients with acute ST-elevation myocardial infarction (STEMI) are still being debated. The aim of this study was to investigate the prognostic value of the no-reflow phenomenon and epicardial adipose tissue (EAT) thickness for clinical outcomes in patients undergoing primary percutaneous coronary intervention (pPCI) for STEMI. METHODS: The present study prospectively included 114 consecutive patients (mean age 54 ± 10 years, 15 women) who underwent successful pPCI. Patients were divided into two groups according to the occurrence of the no-reflow phenomenon and further subdivided according to the tertile of EAT thickness (Group I <5.1 mm, Group II ≥5.1 mm). We assessed the composite and separate occurrence of major adverse cardiac events. RESULTS: Throughout the 3-year follow up, the number of admissions for heart failure was significantly higher in patients with no-reflow (n=5 [20%] vs. n=1 [1%], p=0.003) and in female patients (n=4 [26%] vs. n=2 [2%], p=0.004). In the subgroup analysis, group I patients with no-reflow showed a higher frequency of admission for heart failure (n=4 [44%] vs. n=1 [6%], p=0.04). However, multivariate logistic regression analysis demonstrated that only no-reflow and female sex independently predicted admission for heart failure (OR: 19.3, 95%CI: 1.4-269.7, p=0.03, and OR: 24.9, 95%CI: 2.2-288.8, p=0.01, respectively). CONCLUSION: No-reflow and female sex are independent predictors of admission for heart failure in the longterm follow up of patients with STEMI. However, EAT thickness is not associated with clinical outcomes after pPCI.

Intravascular ultrasound observation of the mechanism of no-reflow phenomenon in acute myocardial infarction.

OBJECTIVE: To study the mechanism of the no-reflow phenomenon using coronary angiography (CAG) and intravascular ultrasound (IVUS). METHODS: A total of 120 patients with acute myocardial infarction (AMI) who successfully underwent indwelling intracoronary stent placement by percutaneous coronary intervention (PCI). All patients underwent pre- and post-PCI CAG and pre-IVUS. No-reflow was defined as post-PCI thrombolysis in myocardial infarction (TIMI) grade 0, 1, or 2 flow in the absence of mechanical obstruction. Normal reflow was defined as TIMI grade 3 flow. The pre-operation reference vascular area, minimal luminal cross-sectional area, plaque cross-sectional area, lesion length, plaque volume and plaque traits were measured by IVUS. RESULTS: The no-reflow group was observed in 14 cases (11.6%) and normal blood-flow group in 106 cases (89.4%) based on CAG results. There was no statistically significant difference in the patients' medical history, reference vascular area (no-flow vs. normal-flow; 15.5 ± 3.2 vs. 16.2 ± 3.3, p > 0.05) and lesion length (21.9 ± 5.1 vs. 19.5 ± 4.8, p > 0.05) between the two groups. No-reflow patients had a longer symptom onset to reperfusion time compared to normal blood-flow group [(6.6 ± 3.1) h vs (4.3 ± 2.7) h; p < 0.05] and higher incidence of TIMI flow grade < 3 (71.4% vs 49.0%, p < 0.05). By IVUS examination, the no-reflow group had a significantly increased coronary plaque area and plaque volume compared to normal blood-flow group [(13.7 ± 3.0) mm2 vs (10.2 ± 2.9) mm2; (285.4 ± 99.8) mm3 vs (189.7 ± 86.4) mm3; p < 0.01]. The presence of IVUS-detected soft plaque (57.1% vs. 24.0%, p < 0.01), eccentric plaque (64.2% vs. 33.7%, p < 0.05), plaque rupture (50.0% vs. 21.2%, p < 0.01), and thrombosis (42.8% vs. 15.3%) were significantly more common in no-reflow group. CONCLUSION: There was no obvious relationship between the coronary risk factors and no-reflow phenomenon. The symptom onset to reperfusion time, TIMI flow grade before stent deployment, plaque area, soft plaques, eccentric plaques, plaque rupture and thrombosis may be risk factors for the no-reflow phenomenon after PCI.

Intramyocardial hemorrhage: an enigma for cardiac MRI?

Cardiovascular magnetic resonance (CMR) is a useful noninvasive technique for determining the presence of microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH), frequently occurring in patients after reperfused myocardial infarction (MI). MVO, or the so-called no-reflow phenomenon, is associated with adverse ventricular remodeling and a poor prognosis during follow-up. Similarly, IMH is considered a severe damage after revascularization by percutaneous primary coronary intervention (PPCI) or fibrinolysis, which represents a worse prognosis. However, the pathophysiology of IMH is not fully understood and imaging modalities might help to better understand that phenomenon. While, during the past decade, several studies examined the distribution patterns of late gadolinium enhancement with different CMR sequences, the standardized CMR protocol for assessment of IMH is not yet well established. The aim of this review is to evaluate the available literature on this issue, with particular regard to CMR sequences. New techniques, such as positron emission tomography/magnetic resonance imaging (PET/MRI), could be useful tools to explore molecular mechanisms of the myocardial infarction healing process.

Effect of inflammatory factor-induced cyclo-oxygenase expression on the development of reperfusion-related no-reflow phenomenon in acute myocardial infarction.

No reflow after reperfusion therapy for myocardial infarction is a strong predictor of clinical outcome. Increased levels of inflammatory factors, including C-reactive protein (CRP), in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) may affect myocardial perfusion. However, why the no-reflow phenomenon increases in inflammation stress after PCI is not clear. The aim of the present study was to determine the effects and molecular mechanisms underlying the effects of CRP on the expression of cyclo-oxygenase (COX) on the development of the no-reflow phenomenon. There was a significant increase in plasma levels of CRP and interleukin (IL)-6 in no-reflow patients, suggesting that inflammatory factors play an important role in the development of the no-reflow phenomenon. The mechanisms involved were further evaluated after reperfusion in a rat model mimicking the no-reflow phenomenon. Compared with normal reflow rats, there were significant increases in both COX-1 and COX-2 in cardiac tissue from no-reflow rats. The COX inhibitor indomethacin (5 mg/kg, i.p.) significantly reduced the no-reflow area. In another series of experiments, human coronary artery endothelial cells (HCAEC) were treated with CRP at clinically relevant concentrations (5-25 µg/mL). C-Reactive protein significantly increased COX-1 and COX-2 levels in a time- and concentration-dependent manner. In addition, extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) were activated in CRP (5, 10, 25 µg/mL)-treated HCAEC cultures. Furthermore, the ERK inhibitor pd98059 (30 µmol/L) and the JNK inhibitor sp600125 (10 µmol/L) blocked CRP-induced COX-1 and COX-2 expression for 12 h. Together, the findings of the present study suggest that CRP can promote the development of the no-reflow phenomenon by increasing COX-1 and COX-2 expression, which is regulated, in part, via ERK and JNK activity.

Plasma factor XI and XII activity in patients with slow coronary flow.

The exact pathophysiology of slow coronary flow (SCF) phenomenon, characterized by delayed opacification of coronary arteries during coronary angiography, is still unknown, although endothelial dysfunction, inflammation, vasomotor disorders and atherosclerosis are shown. The present study was conducted to investigate whether there is a coagulation pathway abnormality in patients with SCF measuring plasma factor XI and XII activity. The study included 55 patients with angiographically proven SCF (group I) and 40 individuals with normal coronary flow (NCF, group II). Baseline demographic properties were similar in both groups. Echocardiographic parameters were also similar in patients with SCF and NCF. Factor XI activity was significantly higher in group I when compared with group II. Factor XII activity was also significantly higher in group I when compared with group II (108.9 ±â€Š19 vs. 98.8 ±â€Š20, P = 0.018 and 131.2 ±â€Š17 vs. 119.1 ±â€Š16, P = 0.001, respectively). We conclude that SCF phenomenon appears to be associated with enhanced procoagulant state, which may support the role of inflammation and atherosclerosis in the pathogenesis of this phenomenon.