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

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

Ischemia preconditioning alleviates ischemia/reperfusion injury-induced coronary no-reflow and contraction of microvascular pericytes in rats.

BACKGROUND: Ischemia preconditioning (IPC) ameliorates coronary no-reflow induced by ischemia/reperfusion (I/R) injury, and pericytes play an important role in microvascular function. However, it is unclear whether IPC exerts a protective effect on coronary microcirculation and regulates the pericytes. OBJECTIVE: The purpose of this study was to assess whether IPC improves coronary microvascular perfusion and reduces pericyte constriction after myocardial I/R injury. METHODS: Rats were randomly divided into three groups: the sham group, the I/R group, and the IPC + I/R group. The left anterior descending artery (LAD) of rats in the I/R group were ligated for 45 min, and the rats in the IPC + I/R group received 4 episodes of 6min occlusion followed by 6min reperfusion before the LAD was ligated. After 24 h of reperfusion, the area of no-reflow, and area at risk were evaluated with thioflavin-S and Evens blue staining, and infarct size with triphenyl tetrazolium chloride staining, respectively. Besides, fluorescent microspheres were perfused to enable visualization of the non-obstructed coronary vessels. Cardiac pericytes and microvascular were observed by immunofluorescence, and the diameter of microvascular at the site of the pericyte somata was analyzed. RESULTS: The infarct size, and area of no-reflow in the IPC + I/R group were significantly reduced compared with the I/R group (infarct size, 33.5% ± 11.9% vs. 49.2% ± 9.4%, p = 0.021；no-reflow, 12.7% ± 5.2% vs. 26.6% ± 5.0%, p < 0.001). IPC improved microvascular perfusion and reduced the percentage of the blocked coronary capillary. Moreover, we found that cardiac pericytes were widely distributed around the microvascular in various regions of the heart, and expressed the contractile protein α-smooth muscle actin. The microvascular lumen diameter at pericyte somata was reduced after I/R (4.3 ± 1.0 µm vs. 6.5 ± 1.2 µm, p < 0.001), which was relieved in IPC + I/R group compared with the I/R group (5.2 ± 1.0 µm vs. 4.3 ± 1.0 µm, p < 0.001). Besides, IPC could reduce the proportion of apoptotic pericytes compared to the I/R group (22.1% ± 8.4% vs. 38.5% ± 7.5%, p < 0.001). CONCLUSION: IPC reduced no-reflow and inhibited the contraction of microvascular pericytes induced by cardiac I/R injury, suggesting that IPC might play a protective role by regulating the pericyte function.

Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy.

Emerging evidence suggests a potential role of neutrophil extracellular traps (NETs) in linking sterile inflammation and thrombosis. We hypothesized that NETs would be induced during myocardial ischemia-reperfusion (I/R), and NET-mediated microthrombosis may contribute to myocardial "no-reflow". Male Wistar rats were randomly divided into I/R control, DNase (DNase I, 20 µg/rat), recombinant tissue-type plasminogen activator (rt-PA, 420 µg/rat), DNase + rt-PA, and sham control groups after 45-min myocardial ischemia. In situ NET formation, the anatomic "no re-flow" area, and infarct size were evaluated immediately after 3 h of reperfusion. Long-term left ventricular (LV) functional and histological analyses were performed 45 days after operation. Compared with the I/R controls, the DNase + rt-PA group exhibited reduced NET density [8.38 ± 1.98 vs. 26.86 ± 3.07 (per 200 × field), P < 0.001] and "no-flow" area (15.22 ± 0.06 vs. 34.6 ± 0.05%, P < 0.05) in the ischemic region, as well as reduced infarct size (38.39 ± 0.05 vs. 71.00 ± 0.03%, P < 0.001). Additionally, compared with the I/R controls, DNase + rt-PA treatment significantly ameliorated I/R injury-induced LV remodeling (LV ejection fraction: 64.22 ± 3.37 vs. 33.81 ± 2.98%, P < 0.05; LV maximal slope of the LV systolic pressure increment: 3,785 ± 216 vs. 2,596 ± 299 mmHg/s, P < 0.05). The beneficial effect was not observed in rats treated with DNase I or rt-PA alone. Our study provides evidence for the existence of NETs in I/R-challenged myocardium and confirms the long-term benefit of a novel DNase-based reperfusion strategy (DNase I + rt-PA), which might be a promising option for the treatment of myocardial I/R injury and coronary no-reflow.

Treatment and Care of Patients with ST-Segment Elevation Myocardial Infarction-What Challenges Remain after Three Decades of Primary Percutaneous Coronary Intervention?

Primary percutaneous coronary intervention (pPCI) has revolutionized the prognosis of ST-segment elevation myocardial infarction (STEMI) and is the gold standard treatment. As a result of its success, the number of pPCI centres has expanded worldwide. Despite decades of advancements, clinical outcomes in STEMI patients have plateaued. Out-of-hospital cardiac arrest and cardiogenic shock remain a major cause of high in-hospital mortality, whilst the growing burden of heart failure in long-term STEMI survivors presents a growing problem. Many elements aiming to optimize STEMI treatment are still subject to debate or lack sufficient evidence. This review provides an overview of the most contentious current issues in pPCI in STEMI patients, with an emphasis on unresolved questions and persistent challenges.

Coronary No-Reflow after Primary Percutaneous Coronary Intervention-Current Knowledge on Pathophysiology, Diagnosis, Clinical Impact and Therapy.

Coronary no-reflow (CNR) is a frequent phenomenon that develops in patients with ST-segment elevation myocardial infarction (STEMI) following reperfusion therapy. CNR is highly dynamic, develops gradually (over hours) and persists for days to weeks after reperfusion. Microvascular obstruction (MVO) developing as a consequence of myocardial ischemia, distal embolization and reperfusion-related injury is the main pathophysiological mechanism of CNR. The frequency of CNR or MVO after primary PCI differs widely depending on the sensitivity of the tools used for diagnosis and timing of examination. Coronary angiography is readily available and most convenient to diagnose CNR but it is highly conservative and underestimates the true frequency of CNR. Cardiac magnetic resonance (CMR) imaging is the most sensitive method to diagnose MVO and CNR that provides information on the presence, localization and extent of MVO. CMR imaging detects intramyocardial hemorrhage and accurately estimates the infarct size. MVO and CNR markedly negate the benefits of reperfusion therapy and contribute to poor clinical outcomes including adverse remodeling of left ventricle, worsening or new congestive heart failure and reduced survival. Despite extensive research and the use of therapies that target almost all known pathophysiological mechanisms of CNR, no therapy has been found that prevents or reverses CNR and provides consistent clinical benefit in patients with STEMI undergoing reperfusion. Currently, the prevention or alleviation of MVO and CNR remain unmet goals in the therapy of STEMI that continue to be under intense research.

Coronary no-reflow and adverse events in patients with acute myocardial infarction after percutaneous coronary intervention with current drug-eluting stents and third-generation P2Y12 inhibitors.

BACKGROUND: The frequency and prognostic value of coronary no-reflow (CNR) was investigated in studies that have used an outdated reperfusion therapy in terms of stent technology and antithrombotic drugs. We assessed the association of CNR with adverse outcomes in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES) and newer antithrombotic drugs, ticagrelor or prasugrel. METHODS: This study included 3100 patients with AMI who underwent PCI with current DES and third-generation P2Y12 inhibitors. CNR was defined as Thrombolysis in Myocardial Infarction (TIMI) blood flow grade ≤ 2 at the end of PCI. The primary end point was 1-year incidence of net adverse clinical and cerebral events-a composite end point of death of any cause, myocardial infarction, stroke or major bleeding. RESULTS: CNR was diagnosed in 130 patients (4.2%). The primary end point occurred in 28 patients in the CNR group and 354 patients in the reflow group (cumulative incidence 23.2% and 12.8%; adjusted hazard ratio = 1.53, 95% confidence interval 1.01-2.33; P = 0.049). The 1-year incidences of death or myocardial infarction (14.6% vs. 7.6%; P = 0.003), myocardial infarction (8.8% vs. 3.9%; P = 0.007) and major bleeding (10.9% vs. 5.6%; P = 0.008) were significantly higher in patients with CNR than patients with reflow. The risk of adverse events in patients with CNR was highest within the first 30 days after PCI. CONCLUSION: In patients with AMI undergoing PCI with current DES and third generation P2Y12 receptor inhibitors, CNR was associated with a higher risk of adverse outcomes at 1 year.

Utility of electrocardiogram to predict the occurrence of the no-reflow phenomenon in patients undergoing primary percutaneous coronary intervention (PPCI): a systematic review and meta-analysis.

Background: The no-reflow phenomenon affects about one out of five patients undergoing Primary Percutaneous Coronary Intervention (PPCI). As the prolonged no-reflow phenomenon is linked with unfavorable outcomes, making early recognition is crucial for effective management and improved clinical outcomes in these patients. Our review study aimed to determine whether electrocardiogram (ECG) findings before PCI could serve as predictors for the occurrence of the no-reflow phenomenon. Methods and materials: We systematically searched MEDLINE, Scopus, and Embase to identify relevant studies. The random-effect model using inverse variance and Mantel-Haenszel methods were used to pool the standardized mean differences (SMD) and odds ratios (OR), respectively. Result: Sixteen eligible articles (1,473 cases and 4,264 controls) were included in this study. Based on our meta-analysis of baseline ECG findings, the no-reflow group compared to the control group significantly had a higher frequency of fragmented QRS complexes (fQRS) (OR (95% CI): 1.35 (0.32-2.38), P-value = 0.01), and Q-waves (OR (95% CI): 1.97 (1.01-2.94), P-value <0.001). Also, a longer QRS duration (QRSD) (SMD (95% CI): 0.72 (0.21, 1.23), p-value <0.001) and R wave peak time (RWPT) (SMD (95% CI): 1.36 (0.8, 1.93), P < 0.001) were seen in the no-reflow group. The two groups had no significant difference regarding P wave peak time (PWPT), and P wave maximum duration (Pmax) on baseline ECG. Conclusion: Our findings suggest that prolonged QRSD, delayed RWPT, higher fQRS prevalence, and the presence of a Q wave on baseline ECG may predict the occurrence of the no-reflow phenomenon in patients undergoing PPCI.

Adiponectin improves coronary no-reflow injury by protecting the endothelium in rats with type 2 diabetes mellitus.

To determine the effect of adiponectin (APN) on the coronary no-reflow (NR) injury in rats with Type 2 diabetes mellitus (T2DM), 80 male Sprague-Dawley rats were fed with a high-sugar-high-fat diet to build a T2DM model. Rats received vehicle or APN in the last week and then were subjected to myocardial ischemia reperfusion (MI/R) injury. Endothelium-dependent vasorelaxation of the thoracic aorta was significantly decreased and serum levels of endothelin-1 (ET-1), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were noticably increased in T2DM rats compared with rats without T2DM. Serum APN was positively correlated with the endothelium-dependent vasorelaxation, but negatively correlated with the serum level of ET-1. Treatment with APN improved T2DM-induced endothelium-dependent vasorelaxation, recovered cardiac function, and decreased both NR size and the levels of ET-1, ICAM-1 and VCAM-1. Hypoadiponectinemia was associated with the aggravation of coronary NR in T2DM rats. APN could alleviate coronary NR injury in T2DM rats by protecting the endothelium and improving microcirculation.

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.