Muscone inhibits the progression of atherosclerotic plaques in mice aorta by inhibiting the NF-κB/p65 pathway.

Atherosclerosis (AS) is considered to be one of the main pathogenic factors of coronary heart disease, cerebral infarction and peripheral vascular disease. Oxidative stress and inflammation run through the occurrence and development of atherosclerosis and related cardiovascular events. Muscone is a natural extract of deer musk and also the main physiological active substance of musk. This study investigated the impact of muscone on atherosclerosis. ApoE-/- mice were used to establised AS model and injected with low-dose (4 mg/kg/day) or high-dose (8 mg/kg/day) of muscone intraperitoneally for 4 weeks. Then aortic tissues were collected, and pathological sections of the aorta were prepared for oil red staining, HE and masson staining. The changes of MDA, SOD, VCAM-1, NF-κB, and TNF-α were observed by Western blotting or immunofluorescence staining. The results showed that high-dose muscone could effectively reduce the plaque area/aortic root area and relative atherosclerotic area, reduce the collagen composition in plaque tissue. In addition, we also found that high-dose muscone can effectively increase MDA level, reduce the level of SOD, and inhibit the expression of VCAM-1, NF-κB/p65, TNF-α in arterial plaques. Our results indicate that the administration of muscone has the benefit of inhibiting atherosclerosis. The potential mechanisms may be associated with antioxidant effect and inhibition of inflammatory reaction in arterial plaques. With the increasing understanding of the relationship between muscone and atherosclerosis, muscone has high potential value as a new drug to treat atherosclerosis.

METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis.

Doxorubicin (DOX) has toxic effects on the heart, causing cardiomyopathy and heart injury, but the underlying mechanisms of these effects require further investigation. This study investigated the role of DOX in promoting ferroptosis to induce myocardial injury. AC16 cardiomyocyte and neonatal rat ventricle cardiomyocytes were used as an in vitro model to study the molecules involved in myocardial injury using gene silencing, ectopic expression, and RNA immunoprecipitation. Messenger RNA and protein level analyses showed that DOX treatment resulted in the upregulation of methyltransferase-like 14 (METTL14), which catalyzes the m6A modification of the long non-coding RNA KCNQ1OT1, a miR-7-5p sponge. The RNA-binding protein IGF2BP1 is associated with KCNQ1OT1 to increase its stability and robustly inhibit miR-7-5p activity. Furthermore, a lack of miR-7-5p expression led to increased levels of transferrin receptor, promoting the uptake of iron and production of lipid reactive oxygen species and demonstrating that DOX-induced ferroptosis occurs in AC16 cells. Additionally, we found that miR-7-5p targets METTL14 in AC16 cells. Meanwhile, the role of METTL14/KCNQ1OT1/miR-7-5p axis in regulating ferroptosis in neonatal rat ventricle cardiomyocytes was also confirmed. Our results indicate that selectively inhibiting ferroptosis mediated by a METTL14/KCNQ1OT1/miR-7-5p positive feedback loop in cardiomyocytes could provide a new therapeutic approach to control DOX-induced cardiac injury.

LXRß is involved in the control of platelet production from megakaryocytes.

Liver X receptor ß (LXRß), a nuclear receptor involved in important cellular processes such as cholesterol, glucose and fatty acid metabolism, was suggested to be involved in platelet aggregation but its detailed roles are not clear. In the present study, we evaluated the contribution of LXRß to platelet functions and production. In the systemic collagen-epinephrine thrombosis mouse model, LXRß-deficient mice showed increased area of blood clots compared with control wide-type littermates. The aggregation of LXRß-deficient platelets in response to ADP was stronger than that of control mice platelets. More importantly, the number of platelets in blood of LXRß-deficient mice was significantly higher than that of wild-type mice, especially for female mice. Knockdown of LXRß expression in human megakaryoblastic Dami cells also enhanced cell polyploidization, formation of proplatelets and production of platelet-like particles. Increase in expression levels of proteins related to oxidative phosphorylation such as NADH:ubiquinone oxidoreductase core subunit V1 (Ndufv1) was observed in LXRß-knockdown Dami cells. The levels of Ndufv1 in LXRß-deficient mice platelets were also higher than that of wild-type mice. Taken together, our findings suggested LXRß might participate in control of platelet production from megakaryocytes by regulating mitochondrial metabolism.

Effect of 1,5-anhydroglucitol levels on culprit plaque rupture in diabetic patients with acute coronary syndrome.

BACKGROUND: Postprandial hyperglycemia was reported to play a key role in established risk factors of coronary artery diseases (CAD) and cardiovascular events. Serum 1,5-anhydroglucitol (1,5-AG) levels are known to be a clinical marker of short-term postprandial glucose (PPG) excursions. Low serum 1,5-AG levels have been associated with occurrence of CAD. However, the relationship between 1,5-AG levels and coronary plaque rupture has not been fully elucidated. The aim of this study was to evaluate 1,5-AG as a predictor of coronary plaque rupture in diabetic patients with acute coronary syndrome (ACS). METHODS: A total of 144 diabetic patients with ACS were included in this study. All patients underwent intravascular ultrasound examination, which revealed 49 patients with plaque rupture and 95 patients without plaque rupture in the culprit lesion. Fasting blood glucose (FBG), hemoglobin A1c (HbA1c) and 1,5-AG levels were measured before coronary angiography. Fasting urinary 8-iso-prostaglandin F2α (8-iso-PGF2α) level was measured and corrected by creatinine clearance. RESULTS: Patients with ruptured plaque had significantly lower serum 1,5-AG levels, longer duration of diabetes, higher HbA1c and FBG levels than patients without ruptured plaque in our study population. In multivariate analysis, low 1,5-AG levels were an independent predictor of plaque rupture (odds ratio 3.421; P = 0.005) in diabetic patients with ACS. The area under the receiver-operating characteristic curve for 1,5-AG (0.658, P = 0.002) to predict plaque rupture was superior to that for HbA1c (0.587, P = 0.087). Levels of 1,5-AG were significantly correlated with urinary 8-iso-prostaglandin F2α levels (r = - 0.234, P = 0.005). CONCLUSIONS: Serum 1,5-AG may identify high risk for coronary plaque rupture in diabetic patients with ACS, which suggests PPG excursions are related to the pathogenesis of plaque rupture in diabetes.

Requirement for integrin-linked kinase in neural crest migration and differentiation and outflow tract morphogenesis.

BACKGROUND: Neural crest defects lead to congenital heart disease involving outflow tract malformation. Integrin-linked-kinase (ILK) plays important roles in multiple cellular processes and embryogenesis. ILK is expressed in the neural crest, but its role in neural crest and outflow tract morphogenesis remains unknown. RESULTS: We ablated ILK specifically in the neural crest using the Wnt1-Cre transgene. ILK ablation resulted in abnormal migration and overpopulation of neural crest cells in the pharyngeal arches and outflow tract and a significant reduction in the expression of neural cell adhesion molecule (NCAM) and extracellular matrix components. ILK mutant embryos exhibited an enlarged common arterial trunk and ventricular septal defect. Reduced smooth muscle differentiation, but increased ossification and neurogenesis/innervation were observed in ILK mutant outflow tract that may partly be due to reduced transforming growth factor ß2 (TGFß2) but increased bone morphogenetic protein (BMP) signaling. Consistent with these observations, microarray analysis of fluorescence-activated cell sorting (FACS)-sorted neural crest cells revealed reduced expression of genes associated with muscle differentiation, but increased expression of genes of neurogenesis and osteogenesis. CONCLUSIONS: Our results demonstrate that ILK plays essential roles in neural crest and outflow tract development by mediating complex crosstalk between cell matrix and multiple signaling pathways. Changes in these pathways may collectively result in the unique neural crest and outflow tract phenotypes observed in ILK mutants.

Evidence-based interventions to improve sleep quality after thoracic surgery:A retrospective analysis of clinical studies.

OBJECTIVE: To investigate and rank the evidence for the efficacy of interventions in improving sleep quality after cardiac surgery using comprehensive comparisons. BACKGROUND: Clinical evidence suggests that over 80 % of adult cardiac surgery patients experience sleep disturbances during the first week postoperatively. While certain interventions have been shown to improve post-thoracic surgery sleep quality, a systematic description of the effects of these varied interventions is lacking. METHODS: This systematic search was conducted across PubMed, Web of Science, Cochrane, Embase, and CINAHL databases to collate all published randomized clinical trials as evidence. Two researchers independently extracted pertinent information from eligible trials and assessed the quality of included studies. Based on statistical heterogeneity, traditional meta-analysis using fixed or random-effects models was employed to assess the efficacy of interventions, and a Frequentist network meta-analysis using a consistency model was conducted to rank the effectiveness of intervention protocols. RESULTS: Our review incorporated 37 articles (n = 3569), encompassing 46 interventions, including 9 reports on pharmacological interventions (24.3 %), 28 on non-pharmacological interventions (75.7 %), and 5 on anesthetic management interventions (13.5 %). The analysis indicated the efficacy of Benson's relaxation technique, Progressive muscle relaxation, Education, Aromatherapy, Acupressure, Massage, and Eye masks in enhancing postoperative sleep quality. Specifically, Benson's relaxation technique (cumulative ranking curve area: 0.80; probability: 98.3 %) and Acupressure (cumulative ranking curve area: 0.96; probability: 58.3 %) were associated with the highest probability of successfully improving postoperative sleep quality, while Progressive muscle relaxation (cumulative ranking curve area: 0.70; probability: 35.2 %) and Eye masks (cumulative ranking curve area: 0.81; probability: 78.8 %) were considered secondary options. Eye masks and Massage significantly reduced postoperative sleep latency, with Eye masks (cumulative ranking curve area: 0.82; probability: 51.0 %) being most likely to enhance sleep quality postoperatively, followed by Massage (cumulative ranking curve area: 0.60; probability: 27.2 %). Education, Music, Massage, Eye masks, and Handholding were effective in alleviating pain intensity, with Education being most likely to successfully reduce postoperative pain (cumulative ranking curve area: 0.92; probability: 54.3 %), followed by Music (cumulative ranking curve area: 0.91; probability: 54 %). CONCLUSIONS: Our findings can be utilized to optimize strategies for managing post-thoracic surgery sleep disturbances and to develop evidence-based approaches for this purpose. Benson's relaxation technique, Progressive muscle relaxation, Education, Aromatherapy, Acupressure, Massage, and Eye masks significantly improve sleep quality in postoperative patients. KEY: disorders of initiating and maintaining sleep, sleep wake disorders, thoracic surgical procedures, cardiac surgical procedures, sleep quality, pain, network meta-analysis.

Echinacoside ameliorates doxorubicin­induced cardiac injury by regulating GPX4 inhibition­induced ferroptosis.

Echinacoside (ECH) is a compound derived from the natural herbs Cistanche and Echinacea, which has considerable protective effects on heart failure (HF). HF is characterized by myocardial damage and abnormal ferroptosis. Glutathione peroxidase 4 (GPX4) is an important regulator of ferroptosis, which plays a role in ferroptosis-related diseases. Despite this, the therapeutic mechanisms of ECH against HF remain unknown. Therefore, the aim of the present study was to investigate the cardioprotective effect and underlying mechanisms of ECH in the treatment of doxorubicin (DOX)-induced chronic HF (CHF). Cell proliferation was assessed using a CCK-8 assay. Furthermore, cardiac cell injury and oxidative stress were determined by measuring the lactate dehydrogenase (LDH), malondialdehyde (MDA), and glutathione (GSH) levels. The levels of Fe2+ and lipid reactive oxygen species (ROS), and expression of the biomarkers of ferroptosis, including GPX4 and prostaglandin-endoperoxide synthase 2 (PTGS2), were measured to examine cardiomyocyte ferroptosis. Additionally, RNA interference was used to silence Gpx4. In vitro and in vivo, ECH considerably reduced the MDA and LDH levels and increased the GSH level, thereby attenuating DOX-induced cardiac injury and oxidative stress. Meanwhile, ECH treatment decreased the lipid ROS levels and PTGS2 expression while increasing GPX4 expression, thereby alleviating DOX-induced cardiomyocyte ferroptosis. Moreover, knockdown of Gpx4 inhibited the protective effects of ECH on DOX-induced accumulation of lipid ROS in cardiomyocytes. These findings indicate that ECH can reduce DOX-induced cardiac injury by inhibiting ferroptosis via GPX4, highlighting its value as a potentially valuable therapeutic target in the management of CHF.

Factors contributing to exercise tolerance in patients with coronary artery disease undergoing percutaneous coronary intervention.

BACKGROUND: Exercise tolerance plays a vital role in the process of cardiac rehabilitation in patients undergoing percutaneous coronary intervention (PCI). The study sought to determine the characteristics, risks and correlates of post-PCI exercise tolerance in patients with coronary artery disease (CAD). METHODS: We analyzed clinical data of 299 CAD patients undergoing elective PCI and completing cardiopulmonary exercise testing (CPET). According to the Weber classification, post-PCI exercise tolerance was evaluated by peak oxygen uptake (VO2 peak). We assessed the impact of 34 predefined clinical features, cardiac functional parameters, and blood biochemistry data on exercise tolerance by univariate analysis and logistics regression analysis. RESULTS: Of 299 patients, 74.92% were men and average age was 60.90 ± 10.68 years. VO2 peak in the entire population was 17.54 ± 3.38 ml/kg/min, and 24.41% (n = 73) were less than 16 ml/kg/min, who were considered to have exercise intolerance. Multivariate logistics regression results showed that sex, diabetes mellitus, number of stents, left atrial diameter (LAD), end-diastolic volume (EDV), and hemoglobin influenced the peak oxygen uptake of CAD patients undergoing elective PCI. (All p < 0.05). CONCLUSIONS: Nearly one quarter of CAD patients have exercise intolerance in the early post-PCI period. Female, diabetes mellitus, number of stents, LAD, EDV might negatively impacted post-PCI exercise tolerance, which need further warrant by large scale cohort study.

Baicalin inhibited both the Furin/TGFß1/Smad3/TSP-1 pathway in endothelial cells and the AKT/Ca2+/ROS pathway in platelets to ameliorate inflammatory coagulopathy.

Inflammatory coagulopathy is resulted from endothelial dysfunction and platelet hyperactivation in inflammatory diseases. In this study, the effects of baicalin, an active component of the traditional Chinese medicine Huangqin, on inflammatory coagulopathy were observed both in vivo and in vitro. In LPS-induced rats, baicalin ameliorated coagulation indexes, inhibited platelet hyperactivation and decreased the expression of thrombospondin-1 (TSP-1) in vessels. In cultured endothelial cells, baicalin decreased the expression of TSP-1 and collagen as well as the TNF-α-induced increase in the levels of TSP-1 and ICAM-1. Baicalin could significantly decrease the platelet adhesion on endothelial cells treated with TNF-α. Baicalin also could inhibit the increase of ROS level and the activation of the NLRP3/Caspase-1/GSDMD pathway in TNF-α-induced endothelial cells. Furin was found to be the direct target of baicalin in HUVECs. Knockdown of Furin using siRNA could ameliorate the effects of baicalin on the activation of TGFß1/Smad3 pathway, TSP-1 expression and the adhesion of platelets on TNF-α-treated endothelial cells. At the same time, baicalin inhibited platelet aggregation induced by collagen or combination of collagen and TSP-1 peptide. Collagen-induced Ca2+ mobilization, ROS level increase, AKT1 phosphorylation, platelet degranulation and TSP-1 release could be all inhibited by baicalin. In all, baicalin ameliorated endothelial dysfunction by inhibiting Furin/TGFß1/Smad3/TSP-1 pathway and also ameliorated platelet activation by inhibiting AKT-related pathway. Both the inhibiting effects of baicalin on endothelial dysfunction and platelet activation might contribute to its ameliorating effects on inflammatory coagulopathy.

Exosomal MiR-29a in Cardiomyocytes Induced by Angiotensin II Regulates Cardiac Microvascular Endothelial Cell Proliferation, Migration and Angiogenesis by Targeting VEGFA.

BACKGROUND: Exosomes released from cardiomyocytes (CMs) potentially play an important role in angiogenesis through microRNA (miR) delivery. Studies have reported an important role for miR-29a in regulating angiogenesis and pathological myocardial hypertrophy. However, whether CMderived exosomal miR-29a is involved in regulating cardiac microvascular endothelial cell (CMEC) homeostasis during myocardial hypertrophy has not been determined. METHODS: Angiotensin II (Ang II) was used to induce CM hypertrophy, and ultracentrifugation was then used to extract exosomes from a CM-conditioned medium. CMECs were cocultured with a conditioned medium in the presence or absence of exosomes derived from CMs (Nor-exos) or exosomes derived from angiotensin II-induced CMs (Ang II-exos). Moreover, a rescue experiment was performed using CMs or CMECs infected with miR-29a mimics or inhibitors. Tube formation assays, Transwell assays, and 5-ethynyl-20-deoxyuridine (EdU) assays were then performed to determine the changes in CMECs treated with exosomes. The miR-29a expression was measured by qRT-PCR, and Western blotting and flow cytometry assays were performed to evaluate the proliferation of CMECs. RESULTS: The results showed that Ang II-induced exosomal miR-29a inhibited the angiogenic ability, migratory function, and proliferation of CMECs. Subsequently, the downstream target gene of miR- 29a, namely, vascular endothelial growth factor (VEGFA), was detected by qRT-PCR and Western blotting, and the results verified that miR-29a targeted the inhibition of the VEGFA expression to subsequently inhibit the angiogenic ability of CMECs. CONCLUSION: Our results suggest that exosomes derived from Ang II-induced CMs are involved in regulating CMCE proliferation, migration, and angiogenesis by targeting VEGFA through the transfer of miR-29a to CMECs.

Preparation of Nanocomposite Peptide and Its Inhibitory Effect on Myocardial Injury in Type-II Diabetic Rats.

Complications of diabetes are the main cause of death and disability in diabetic patients. Cardiovascular diseases, especially diabetic cardiomyopathy, are one of the major complications and causes of death in type 2 diabetes. Peptide drugs have a better effect on improving cellular oxidative damage, reducing tissue inflammation and inhibiting intracellular calcium overload. The application of nanotechnology to the preparation of peptide drugs and myocardial injury can effectively improve myocardial stun, arrhythmia and myocardial systolic dysfunction in patients with type 2 diabetes. The use of nanotechnology to develop more stable Glucagon-like peptide 1 analogues or sustained-release preparations, improve patient compliance and improve the efficacy of diabetes, is of great significance for the prevention and treatment of diabetic cardiomyopathy. Therefore, this study used nanotechnology to prepare PLGA-GLP-1 nanoparticles using polyglycolic acid glycolic acid as a drug carrier, which achieved long-acting drug and its morphology by transmission electron microscopy. At the same time, this study explored the anti-cardiomyocyte injury and anti-myocardial damage of PLGA-GLP-1 nanocomposite peptide and its molecular mechanism by using animal models and cell models. Experimental studies have shown that PLGA-GLP-1 nanocomposite peptide has a protective effect on myocardial injury in diabetic rats. Its mechanism is related to the PLGA-GLP-1 nanocomposite peptide enhancing the body's antioxidant capacity, anti-cardiomyocyte apoptosis, and promoting mitochondrial DNA repair in cardiomyocytes.

SYVN1/GPX5 axis affects ischemia/reperfusion induced apoptosis of AC16 cells by regulating ROS generation.

Ischemia/reperfusion (I/R) induced injury is a major cause of coronary heart disease (CHD). Increased production of reactive oxygen species (ROS) can lead to an I/R injury in CHD, and the ROS level can be regulated by Glutathione peroxidase (GPX) enzyme family. In this study, we investigated the role and underlying molecular mechanism of GPX5 in I/R-induced AC16 cells. We found that the serum level of GPX5 was down-regulated in patients with CHD and I/R-induced AC16 cells. Overexpression of GPX5 inhibited I/R-induced apoptosis by suppressing the production of ROS. On the other hand, knock-down of GPX5 promoted apoptosis in AC16 cells by up-regulating the level of ROS. Furthermore, we found that GPX5 was regulated by synovial apoptosis inhibitor 1 (SYVN1)-mediated ubiquitination in AC16 cells. In I/R-induced AC16 cells, the expression of SYVN1 was up-regulated, and SYVN1 knock-down decreased the ROS levels and apoptotic rate but increased GPX5 levels. Moreover, GPX5 knockdown promoted ROS production and apoptosis, while its effects were attenuated by SYVN1 knockdown. Furthermore, SYVN1 was up-regulated while GPX5 was down-regulated in the myocardial tissue of I/R-injured rats. Taken together, our data demonstrate that GPX5 inhibits I/R-induced apoptosis of AC16 cells by down-regulating ROS level, and its stabilization is regulated by SYVN1-mediated ubiquitination.

Clinical implication of quantitative flow ratio to predict clinical events after drug-coated balloon angioplasty in patients with in-stent restenosis.

BACKGROUND: The association between the quantitative flow ratio (QFR) and adverse events after drug-coated balloon (DCB) angioplasty for in-stent restenosis (ISR) lesions has not been investigated. HYPOTHESIS: Post-procedural QFR is related to adverse events in patients undergoing DCB angioplasty for ISR lesions. METHODS: This retrospective study included data from patients undergoing DCB angioplasty for drug-eluting stent (DES) ISR between January 2016 and February 2019. The QFR was measured at baseline and after DCB angioplasty. The endpoint was the vessel-oriented composite endpoint (VOCE), defined as a composite of cardiac death, vessel-related myocardial infarction, and ischemia-driven target vessel revascularization. RESULTS: Overall, 177 patients with 185 DES-ISR lesions were included. During 1-year follow-up, 27 VOCEs occurred in 26 patients. The area under curve (AUC) of the post-procedural QFR was statistically greater than that of the in-stent percent diameter stenosis (0.77, 95% confidence interval [CI] 0.67-0.87 vs. 0.64, 95% CI 0.53-0.75; p = .032). Final QFR cutoff of 0.94 has the best predictive accuracy for VOCE. A QFR > 0.94 was associated with a lower risk of VOCE compared to a QFR ≤ 0.94 (log-rank test, p < .0001). Survival analysis using the multivariable Cox model showed that a post-procedural QFR ≤ 0.94 was an independent predictor of 1-year VOCE (hazard ratio 6.53, 95% CI 2.70-15.8, p < .001). CONCLUSIONS: A lower QFR value was associated with worse clinical outcomes at 1 year after DCB angioplasty for DES-ISR.

WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m6A modification of ATF4 mRNA.

Myocardial infarction (MI) is one of the leading causes of death. Wilms' tumor 1-associating protein (WTAP), one of the components of the m6A methyltransferase complex, has been shown to affect gene expression via regulating mRNA modification. Although WTAP has been implicated in various diseases, its role in MI is unclear. In this study, we found that hypoxia/reoxygenation (H/R) time-dependently increased WTAP expression, which in turn promoted endoplasmic reticulum (ER) stress and apoptosis, in human cardiomyocytes (AC16). H/R effects on ER stress and apoptosis were all blocked by silencing of WTAP, promoted by WTAP overexpression, and ameliorated by administration of ER stress inhibitor, 4-PBA. We then investigated the underlying molecular mechanism and found that WTAP affected m6A methylation of ATF4 mRNA to regulate its expression, and that the inhibitory effects of WTAP on ER stress and apoptosis were ATF4 dependent. Finally, WTAP's effects on myocardial I/R injury were confirmed in vivo. WTAP promoted myocardial I/R injury through promoting ER stress and cell apoptosis by regulating m6A modification of ATF4 mRNA. These findings highlight the importance of WTAP in I/R injury and provide new insights into therapeutic strategies for MI.

Clinical implication of QFR in patients with ST-segment elevation myocardial infarction after drug-eluting stent implantation.

The feasibility and prognostic value of quantitative flow ratio (QFR) after percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) patients have not been assessed. The aim of this study was to investigate the prognostic utility of post-PCI QFR to predict outcomes in STEMI and determine the influence of functional results, in both culprit and nonculprit lesions, after PCI. Patients undergoing PCI of culprit lesions and receiving staged procedures of nonculprit lesions after 7 days were enrolled from 2 centers and underwent post-PCI QFR. The primary outcome was the vessel-oriented composite endpoints (VOCEs), defined as vessel-related cardiovascular death, vessel-related myocardial infarction, and target vessel revascularization. Four hundred fifteen vessels (186 culprit lesions and 219 nonculprit lesions) in 186 patients were analyzed. Measured at staged PCI, the post-PCI QFR of culprit lesions was significantly lower than that of nonculprit lesions (0.92 ± 0.10 versus 0.95 ± 0.08, p < 0.001). The multivariable model demonstrated that low post-PCI QFR was an independent predictor of 2-year VOCE (20.8% versus 5.7%; hazard ratio 2.718; 95% CI 1.347-5.486; p = 0.005). In STEMI patients with a low angiography-derived index of microcirculatory resistance (≤ 40U), a good correlation and agreement between post-PCI QFR value of culprit lesions at primary and staged procedures (r = 0.942; mean difference: - 0.0017 [- 0.074 to 0.070]) was identified. In conclusion, culprit lesions suffered from suboptimal functional results more frequently compared to nonculprit lesions after PCI in STEMI patients. Low post-PCI QFR was associated with subsequent adverse clinical outcomes. After stenting, culprit lesions may feasibly be assessed through QFR without significant microvascular dysfunction.

Non-invasive assessment of left ventricular relaxation during atrial fibrillation using mitral flow propagation velocity.

AIMS: To elucidate the usefulness of the early diastolic mitral flow propagation velocity (V(p)) obtained from colour M-mode Doppler for non-invasively assessing left-ventricular (LV) relaxation during atrial fibrillation (AF). METHODS AND RESULTS: Ten healthy adult dogs were studied to correlate V(p) with the invasive minimum value of the first derivative of LV pressure decay (dP/dt(min)) and the time constant of isovolumic LV pressure decay (tau) at baseline, during rapid and slow AF, and during AF after inducing myocardial infarction. There were significant positive and negative curvilinear relationships between V(p) and dP/dt(min) and tau, respectively, during rapid AF. After slowing the ventricular rate, the average value of V(p) increased, while dP/dt(min) increased and tau decreased. After inducing myocardial infarction, the average value of V(p) decreased, while dP/dt(min) decreased and tau increased. CONCLUSION: The non-invasively obtained V(p) evaluates LV relaxation even during AF regardless of ventricular rhythm or the presence of pathological changes.

The Integrative Regulatory Network of circRNA, microRNA, and mRNA in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common irregular heart rhythm which influence approximately 1-2% of the general population. As a potential factor for ischemic stroke, AF could also cause heart failure. The mechanisms behind AF pathogenesis is complex and remains elusive. As a new category of non-coding RNAs (ncRNAs), circular RNAs (circRNAs) have been known as the key of developmental processes, regulation of cell function, pathogenesis of heart diseases and pathological responses which could provide novel sight into the pathogenesis of AF. circRNAs function as modulators of microRNAs in cardiac disease. To investigate the regulatory mechanism of circRNA in AF, especially the complex interactions among circRNA, microRNA and mRNA, we collected the heart tissues from three AF patients and three healthy controls and profiled their circRNA expressions with circRNA Microarray. The differentially expressed circRNAs were identified and the biological functions of their interaction microRNAs and mRNAs were analyzed. Our results provided novel insights of the circRNA roles in AF and proposed highly possible interaction mechanisms among circRNAs, microRNAs, and mRNAs.

Comparison of coronary plaque composition among patients with acute coronary syndrome and stable coronary artery disease.

BACKGROUND: The identification of vulnerable plaques before rupture is an important clinical goal. The purpose of the present study was to assess the difference in plaque composition among patients with acute coronary syndrome (ACS) and stable coronary artery disease (SCAD) by intravascular ultrasound virtual histologic analysis. METHODS: One hundred and thirty-nine patients were divided into ACS group and SCAD group according to clinical presentation. A total of 229 de novo lesions with >50% stenosis in native coronary arteries with diameters >2.5 mm were studied with intravascular ultrasonography. Geometric and compositional data were obtained using intravascular ultrasound virtual histology software. RESULTS: There were no significant differences in overall lesions for fibrous ((52.0+/-11.9)% vs (54.3+/-8.5)%, P>0.05), fibrolipidic ((12.3+/-10.1)% vs (13.8+/-9.5)%, P > 0.05), calcium ((14.0+/-9.1)% vs (19.3+/-13.1)%, P>0.05), or necrotic core ((22.0+/-11.1)% vs (19.7 +/- 5.4)%, P > 0.05) percentages in ACS and SCAD patients, respectively. There were also no significant differences in culprit lesions for fibrous ((46.4+/-12.0)% vs (53.6+/-8.8)%, P>0.05), fibrolipidic ((9.1+/-9.0)% vs (12.9+/-9.7)%, P>0.05), calcium ((16.6+/-9.7)% vs (21.8+/-26.3)%, P>0.05), or necrotic core ((28.0+/-12.6)% vs (20.6+/-5.2)%, P>0.05) percentages in ACS and SCAD patients, respectively. High density lipoprotein-cholesterol levels >1.04 mmol/L were associated with more fibrolipidic ((14.5+/-10.4)% vs (7.1+/-6.5)%, P<0.05) and less necrotic core ((20.6+/-9.7)% vs (27.9+/-12.6)%, P<0.05) percentages in the cohort with ACS. CONCLUSIONS: In this study, coronary plaque composition assessed by intravascular ultrasound virtual histologic analysis was not significantly different between ACS and SCAD patients. The anatomic relationship of the specific plaque components to the lumen of the vessel was more important than the quantitative information of plaque composition for plaque stability.

[Comparison of coronary plaque composition between patients with acute coronary syndrome and stable coronary artery disease].

OBJECTIVE: The purpose of the present study was to compare the plaque composition between patients with acute coronary syndrome (ACS) and stable coronary artery disease (SCAD) by intravascular ultrasound virtual histological analysis. METHODS: Two hundred and ten patients were divided into ACS group (n = 131, 188 diseased vessels) and SCAD group (n = 79, 158 diseased vessels). A total of 346 de novo lesions with > 50% stenosis in native coronary arteries with diameters > 2.5 mm were studied with intravascular ultrasonography. Geometric and compositional data were obtained using intravascular ultrasound virtual histology software. RESULTS: There were no significant differences in overall lesions for fibrous (51.2% +/- 12.5% vs. 52.6% +/- 9.6%), fibrolipidic (11.3% +/- 10.6% vs. 12.9% +/- 9.4%), calcium (15.1% +/- 8.9% vs. 20.5% +/- 12.5%) or necrotic core (23.1% +/- 9.8% vs. 20.4% +/- 6.8%, all P > 0.05) components between ACS and SCAD patients. Culprit lesions for fibrous (49.1% +/- 11.2% vs. 50.3% +/- 9.7%), fibrolipidic (10.2% +/- 9.5% vs. 12.7% +/- 9.5%), calcium (15.4% +/- 8.9% vs. 17.4% +/- 24.8%), or necrotic core (24.0% +/- 11.5% vs. 19.7% +/- 5.3%, all P > 0.05) components were also similar between ACS and SCAD patients. High density lipoprotein-cholesterol (HDL) levels > 1.04 mmol/L was associated with more fibrolipidic (15.6% +/- 9.6% vs. 7.4% +/- 5.9%) and less necrotic core (19.4% +/- 8.6% vs. 28.6% +/- 11.2%, all P < 0.05 vs. patients with HDL < or = 1.04 mmol/L) components in ACS patients. CONCLUSION: Coronary plaque composition was similar between ACS and SCAD patients.

Temporal requirements for ISL1 in sympathetic neuron proliferation, differentiation, and diversification.

Malformations of the sympathetic nervous system have been associated with cardiovascular instability, gastrointestinal dysfunction, and neuroblastoma. A better understanding of the factors regulating sympathetic nervous system development is critical to the development of potential therapies. Here, we have uncovered a temporal requirement for the LIM homeodomain transcription factor ISL1 during sympathetic nervous system development by the analysis of two mutant mouse lines: an Isl1 hypomorphic line and mice with Isl1 ablated in neural crest lineages. During early development, ISL1 is required for sympathetic neuronal fate determination, differentiation, and repression of glial differentiation, although it is dispensable for initial noradrenergic differentiation. ISL1 also plays an essential role in sympathetic neuron proliferation by controlling cell cycle gene expression. During later development, ISL1 is required for axon growth and sympathetic neuron diversification by maintaining noradrenergic differentiation, but repressing cholinergic differentiation. RNA-seq analyses of sympathetic ganglia from Isl1 mutant and control embryos, together with ISL1 ChIP-seq analysis on sympathetic ganglia, demonstrated that ISL1 regulates directly or indirectly several distinct signaling pathways that orchestrate sympathetic neurogenesis. A number of genes implicated in neuroblastoma pathogenesis are direct downstream targets of ISL1. Our study revealed a temporal requirement for ISL1 in multiple aspects of sympathetic neuron development, and suggested Isl1 as a candidate gene for neuroblastoma.