IntroductionPathological cardiac hypertrophy is a pivotal pathological process underlying various cardiac diseases, including heart failure (HF). Protosappanin A (PTA), a major biphenyl compound isolated from Caesalpinia sappan, has been shown to confer significant protective effects against multiple cardiovascular insults. However, its precise role in pressure overload-induced pathological cardiac hypertrophy remains elusive.MethodsIn the present study, a mouse model was established through transverse aortic constriction (TAC) surgery and then intragastrically administered with PTA for 4 weeks.ResultsOur results indicate that PTA treatment led to an improvement in cardiac contractile function, a reduction in cardiomyocyte hypertrophy, and an attenuation of myocardial fibrosis in TAC-operated mice. Notably, PTA exerted its anti-hypertrophic actions by mitigating myocardial oxidative stress injury and inhibiting cardiomyocyte pyroptosis. Nevertheless, the above cardioprotective effects of PTA were largely abrogated by the use of the nuclear factor erythroid 2-related factor 2 (Nrf2) specific inhibitor ML385 in TAC-treated mice or Nrf2 siRNA in angiotensin II (Ang II)-treated neonatal mouse cardiomyocytes (NMCMs).DiscussionOur study demonstrates for the first time that PTA ameliorates cardiac remodeling and dysfunction in mice with pathological cardiac hypertrophy by suppressing oxidative stress and cardiomyocyte pyroptosis through activating of the Nrf2 signaling pathway, highlighting additional therapeutic option for clinical prevention and treatment of HF patients.

This study aimed to evaluate the association between LAA metabolic parameters—particularly lactic acid, glucose, and calcium—and spontaneous echo contrast, and to develop and externally validate a multivariable prediction model incorporating these indicators. Consecutive patients with AF undergoing radiofrequency catheter ablation and/or left atrial appendage occlusion were retrospectively enrolled. All patients underwent preprocedural transesophageal echocardiography with direct LAA blood sampling for metabolic analysis. An internal cohort was used for feature selection by LASSO regression and multivariable logistic regression. Model performance was assessed using ROC analysis, calibration, and decision curve analysis, with external validation in an independent cohort. A total of 272 patients were included in the internal cohort, among whom 96 (35.3

Ferroptosis significantly contributes to myocardial injury in Type 2 Diabetes Mellitus (T2DM). Liver X Receptor (LXR) and Retinoid X Receptor (RXR) play crucial roles in lipid metabolism and inflammation, but their involvement in regulating ferroptosis in diabetic cardiomyocytes is not fully understood. High-fat diet/streptozotocin-induced T2DM mouse models and high glucose and high fat (HG)-exposed cardiomyocytes were used to assess the impact of LXR activation on myocardial injury and ferroptosis. The study also examined the role of the ROS/AMPK/Nrf2 pathway and the effect of LXR/RXR activation on Calpain1 and Calpastatin expression. Activation of LXR was shown to reduce myocardial injury susceptibility by protecting cardiomyocytes from ferroptosis. This protection occurs via relieving HG-induced ROS-mediated suppression of the AMPK/Nrf2 axis, preventing ferroptosis under hyperglycemic conditions. Moreover, pharmacological activation of LXR/RXR heterodimers was found to alleviate cardiomyocyte injury by downregulating Calpain1, a protein that induces ferroptosis through mitochondrial pathways. Mechanistically, LXR/RXR resulted in the transcriptional activation of Calpastatin, which in turn inhibited Calpain1 expression. This inhibition of Calpain1 led to reduction of mitochondrial ROS overproduction, thereby disinhibiting the AMPK/Nrf2 pathway, significantly reducing ferroptosis and myocardial injury. LXR activation protects against T2DM-induced myocardial injury by inhibiting ferroptosis, particularly through the LXR/RXR-Calpastatin-Calpain1 axis, offering a potential therapeutic strategy for T2DM-related heart damage.

Incomplete endothelialization (IDE) of left atrial appendage closure (LAAC) devices increases the risk of device-related thrombosis (DRT) and stroke. Insulin resistance (IR) may contribute to IDE by impairing endothelial function, but its role remains unclear. This study aimed to investigate the association between IR markers and IDE and develop a predictive model for identifying high-risk patients. This retrospective observational study included 168 patients with nonvalvular atrial fibrillation (AF) who underwent successful LAAC at Shanghai Ninth People’s Hospital between January 2022 and December 2023. IDE was assessed using transesophageal echocardiography (TEE) and cardiac computed tomography angiography (CCTA) at 6 months post-procedure. IR was evaluated using the triglyceride-glucose (TyG) index, triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-c) ratio, and metabolic score for insulin resistance (METs-IR). Logistic regression analysis was performed to identify independent predictors of IDE, and a predictive model was constructed. Among the 168 patients included in the analysis, 43 (25.5

tRNA-derived small RNAs (tsRNAs) are a newly recognized class of non-coding RNAs involved in regulating RNA processing and translational control. Pathological cardiac hypertrophy, characterized by left ventricular remodeling under chronic stress, serves as a critical precursor to severe cardiovascular pathologies including myocardial ischemia, infarction, and heart failure. Utilizing an angiotensin II (Ang II)-induced mouse cardiac hypertrophy model combined with tsRNA transcriptome profiling, we identified differentially expressed tsRNAs and investigated their functional relevance. Validation in neonatal mouse ventricular myocytes (NMVMs) revealed five upregulated tsRNAs associated with hypertrophic progression. Functional characterization showed that overexpressing tRF-Glu-CTC-013 significantly reduced cardiomyocyte hypertrophy and inhibited inflammation and fibrosis. Further luciferase reporter assays revealed that tRF-Glu-CTC-013 could bind to the 3' UTR of TAS1R3, thereby inhibiting its expression and enhancing the level of autophagy in NMVMs. Taken together, these findings suggest that tsRNAs may act as novel regulators of cardiac remodeling, with tRF-Glu-CTC-013 emerging as a promising therapeutic candidate for cardioprotection via anti-hypertrophic, anti-inflammatory, and anti-fibrotic mechanisms.

Background:Coronary artery disease (CAD) is a leading cause of global mortality, primarily due to the accumulation of atheromatous plaques in coronary arteries. The current diagnostic standards include X-ray coronary angiography, which evaluates morphological features of the coronary arteries. The primary goal of this modality is to quantify stenosis severity, but variability and complexities in the resultant images make consistent interpretation challenging. This study developed a deep learning-based approach for segmenting and grading vessel stenosis via X-ray coronary angiography. Methods:Based on 383 angiographic images from 168 patients, we developed a dual-output deep convolutional neural network (CNN) to automatically diagnose stenosis. For clinical relevance, we manually annotated stenosis severity into five distinct levels: nonobstructive lesion (1-49%), intermediate lesion (50-70%), severe lesion (71-95%), sub-total occlusion (96-99%), and total occlusion (100%). Results:We built a coronary stenosis segmentation and grading method based on X-ray coronary angiography. The model achieved an average intersection over union (IoU) of 0.92, a Dice score of 0.95, a precision of 0.93, and a sensitivity of 0.96. Conclusions:We introduce an image-based vascular analysis method that localizes and grades stenosis in X-ray coronary angiography. This method can automatically identify clinically critical grades, especially within the 71-100% range. Deep learning methods can potentially facilitate the diagnosis of CAD and patient-centric treatment planning.

BackgroundAcute coronary syndrome (ACS) is a leading cause of morbidity and mortality worldwide. In recent years, ACS has been reported to be associated with age, and the incidence has become more common in younger patients. Previous studies have identified various risk factors that contribute to the stratification of ACS patients. However, it remains unclear whether these risk factors, along with proteomic and clinical characteristics, are applicable to young ACS patients, as they are for middle-aged and elderly patients. This study aimed to investigate the proteomics, risk factors, and clinical characteristics of young ACS patients, as well as the differences between them and middle-aged and elderly ACS patients. By comparing these findings with those of middle-aged and elderly patients, we aimed to identify any discrepancies and these findings possibly may have implications for future management strategies of this specific population.MethodsThis observational study included a total of 187 participants diagnosed with ACS and 17 young healthy individuals as the control group. ACS patients were divided into three age groups: <45 years old, 45–60 years old, and 61–75 years old. The control group consisted of healthy individuals under the age of 45 who underwent coronary angiography and were excluded from CAD. We collected clinical characteristics, laboratory data, and echocardiographic results from each participant. Additionally, blood samples were collected for further analysis of relevant proteomic and arteriosclerosis marker data using proteomics analysis.ResultsOur findings revealed that the presence of certain key factors was associated with a significantly difference in patients with ACS aged younger than 45 years, and this association differed from that of traditional cardiovascular risk factors in patients older than 45 years. Specifically, a higher body mass index and hyperlipidemia were found to be associated with an increased risk of ACS morbidity in young adults (<45 years old) compared to middle-aged and elderly individuals. Furthermore, our findings indicated that the expression levels of growth differentiation factor 15, osteopontin, and NT-proBNP were significantly different among the groups.ConclusionIn summary, our study revealed that the main pathogenic factors of ACS patients under 45 years of age differed from those of middle-aged and elderly patients. These findings may contribute to the prevention and treatment strategies for young patients with ACS.

Background: For patients with nonvalvular atrial fibrillation (NVAF), left atrial appendage closure (LAAC) is an alternative to oral anticoagulants (OACs). However, incomplete device endothelialization (IDE) after LAAC has been linked to device-related thrombus (DRT) and subsequent thromboembolic events. Here, the differences in device endothelialization between the Watchman plug device and the LACBES pacifier occluder after implantation were investigated. Methods: Of 201 consecutive patients with indications for LAAC, 101 received a Watchman 2.5 device, and 100 received a LACBES occluder. IDE was defined as a residual flow of contrast agent inside the left atrial appendage (LAA) on cardiac computed tomography angiography (CCTA) without peri-device leak (PDL) at the 3-month and 6-month follow-ups. Results: There were no significant differences in DRT or PDL incidence between the two groups. However, the IDE rate in the absence of PDL was higher in the LACBES group than in the Watchman group at 3 months (42.4% versus 25.8%; p = 0.025) and at the 6-month follow-up (24.7% versus 11.2%; p = 0.028) as determined by CCTA. Conclusions: Our findings indicated that the LACBES occluder took longer to complete endothelialization than the Watchman device after successful LAAC therapy. CCTA is a reliable imaging method for assessing the sealing of LAAC devices and confirming complete device endothelialization.

Shock wave therapy (SWT) is a new alternative therapy for patients with severe coronary artery disease that improves myocardial ischemic symptoms by delivering low-energy shock wave stimulation to ischaemic myocardium with low-energy pulsed waves. However, the specific mechanism of its protective effect is not fully understood, especially for the protective mechanism in cardiomyocytes after hypoxia/reoxygenation (H/R). We selected a rat H9c2 cardiomyocyte cell line to establish a stable H/R cardiomyocyte injury model by hypoxia/reoxygenation, and then used SWT for therapeutic intervention to explore its cardiomyocyte protective mechanisms. The results showed that SWT significantly increased cell viability and GSH levels while decreasing LDH levels, ROS levels, and MDA levels. SWT also improved mitochondrial morphology and function of cells after H/R. Meanwhile, we found that SWT could increase the expression of GPX4, xCT, and Bcl-2, while decreasing the expression of Bax and cleaved caspase-3, and inhibiting cardiomyocyte apoptosis and ferroptosis. Moreover, this protective effect of SWT on cardiomyocytes could be significantly reversed by knockdown of xCT, a key regulator protein of ferroptosis. In conclusion, our study shows that SWT can attenuate hypoxia-reoxygenation-induced myocardial injury and protect cardiomyocyte function by inhibiting H/R-induced apoptosis and ferroptosis, and this therapy may have important applications in the treatment of clinical myocardial ischemic diseases.

BACKGROUND:Myocardial ischemia-reperfusion injury (MIRI) poses a prevalent challenge in current reperfusion therapies, with an absence of efficacious interventions to address the underlying causes. AIM:To investigate whether the extracellular vesicles (EVs) secreted by adipose mesenchymal stem cells (ADSCs) derived from subcutaneous inguinal adipose tissue (IAT) under γ-aminobutyric acid (GABA) induction (GABA-EVsIAT) demonstrate a more pronounced inhibitory effect on mitochondrial oxidative stress and elucidate the underlying mechanisms. METHODS:We investigated the potential protective effects of EVs derived from mouse ADSCs pretreated with GABA. We assessed cardiomyocyte injury using terminal deoxynucleotidyl transferase dUTP nick end-labeling and Annexin V/propidium iodide assays. The integrity of cardiomyocyte mitochondria morphology was assessed using electron microscopy across various intervention backgrounds. To explore the functional RNA diversity between EVsIAT and GABA-EVsIAT, we employed microRNA (miR) sequencing. Through a dual-luciferase reporter assay, we confirmed the molecular mechanism by which EVs mediate thioredoxin-interacting protein (TXNIP). Western blotting and immunofluorescence were conducted to determine how TXNIP is involved in mediation of oxidative stress and mitochondrial dysfunction. RESULTS:Our study demonstrates that, under the influence of GABA, ADSCs exhibit an increased capacity to encapsulate a higher abundance of miR-21-5p within EVs. Consequently, this leads to a more pronounced inhibitory effect on mitochondrial oxidative stress compared to EVs from ADSCs without GABA intervention, ultimately resulting in myocardial protection. On a molecular mechanism level, EVs regulate the expression of TXNIP and mitigating excessive oxidative stress in mitochondria during MIRI process to rescue cardiomyocytes. CONCLUSION:Administration of GABA leads to the specific loading of miR-21-5p into EVs by ADSCs, thereby regulating the expression of TXNIP. The EVs derived from ADSCs treated with GABA effectively ameliorates mitochondrial oxidative stress and mitigates cardiomyocytes damage in the pathological process of MIRI.

DEAD-box helicase 17 (DDX17) is a typical member of the DEAD-box family with transcriptional cofactor activity. Although DDX17 is abundantly expressed in the myocardium, its role in heart is not fully understood. We generated cardiomyocyte-specific Ddx17-knockout mice (Ddx17-cKO), cardiomyocyte-specific Ddx17 transgenic mice (Ddx17-Tg), and various models of cardiomyocyte injury and heart failure (HF). DDX17 is downregulated in the myocardium of mouse models of heart failure and cardiomyocyte injury. Cardiomyocyte-specific knockout of Ddx17 promotes autophagic flux blockage and cardiomyocyte apoptosis, leading to progressive cardiac dysfunction, maladaptive remodeling and progression to heart failure. Restoration of DDX17 expression in cardiomyocytes protects cardiac function under pathological conditions. Further studies showed that DDX17 can bind to the transcriptional repressor B-cell lymphoma 6 (BCL6) and inhibit the expression of dynamin-related protein 1 (DRP1). When DDX17 expression is reduced, transcriptional repression of BCL6 is attenuated, leading to increased DRP1 expression and mitochondrial fission, which in turn leads to impaired mitochondrial homeostasis and heart failure. We also investigated the correlation of DDX17 expression with cardiac function and DRP1 expression in myocardial biopsy samples from patients with heart failure. These findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway in heart failure.

Background The diameter of the ostial and proximal left main coronary artery can be greater than 5.0 mm. However, the diameters of the mostly available coronary drug-eluting stents (DESs) are ≤ 4.0 mm. Whether high-pressure dilatation can increase the diameter of stents from 4.0 to 5.0 mm and whether post-dilatation leads to longitudinal stent deformation (LSD) of 4.0-mm-diameter stents have rarely been studied. Therefore, this study aims to evaluate LSD and stent malapposition of six types of commercially available 4.0-mm-diameter stents in China in a 5.0-mm-diameter artificial blood vessel model by optical coherence tomography (OCT) in vitro. Methods The left main coronary artery was simulated by a truncated cone-shaped silicone tube. The internal diameters were 4.0 mm at one end of the silicone tube and 5.0 mm at the other end. Six different types of coronary stents widely used in China were selected for this study. Each stent was respectively implanted into the simulated blood vessel and dilated to a diameter of 4.2 mm according to the stent-balloon pressure compliance table. The stents were subjected to post-dilatation with a 5.0 × 15-mm noncompliant balloon. The LSD ratio of the longitudinal axis of each stent and stent malapposition were measured through OCT, and any fractures of the stents were determined. Results None of the six types of stents fractured following post-dilatation. The longitudinal axes of the BuMA and Excrossal stents were slightly shortened, while the other stents were elongated after high-pressure post-dilatation. All stents expanded to a diameter of 5.0 mm without incomplete stent apposition, except for the Nano Plus stent, which remained malapposed after high-pressure post-dilatation. Conclusion All 4.0-mm-diameter stents can be expanded to a diameter of 5.0 mm by noncompliant balloon post-dilatation without stent strut fracture. Most stents were found to be well apposed after high-pressure post-dilatation. However, LSD was observed after post-balloon dilatation. Stent malapposition might be positively correlated with the percentage change in stent length.

Cardiac shockwave therapy (CSWT) is a noninvasive treatment for patients with refractory angina or myo-cardial ischemia. This study aims to evaluate the potential beneficial effect and safety of CSWT in patients with severe coronary artery disease (CAD) who have undergone coronary artery bypass grafting (CABG). This was a single-arm prospective cohort study. A total of 30 patients with severe CAD who were not suit-able for coronary revascularization and who had undergone CABG were enrolled. All patients received CSWT for nine sessions. Evaluation was performed before and after CSWT, including the Canadian Cardiovascular So-ciety (CCS) classification, New York Heart Association (NYHA) classification, 6-minute walk test (6MWT), Se-attle Angina Questionnaire (SAQ) score, nitroglycerin dosage, echocardiography, myocardial perfusion imaging (MPI), and safety parameters. All patients were followed up at both 1 month and 9 months after CSWT. After treatment, CSWT significantly improved CCS classification (P < 0.05), NYHA classification (P < 0.05), nitroglycerin dosage (P < 0.001), and 6MWT (P < 0.05) at 1 month and 9 months after CSWT. SAQ score (P < 0.05) and left ventricular ejection fraction (LVEF; P = 0.037) by echocardiography significantly im-proved at 1 month after CSWT. Significant decreases in summed stress score (SSS), summed difference score (SDS), ischemic area stress, and ischemic area difference by MPI were observed at 1 month and 9 months after CSWT (P < 0.01). There were no changes in safety parameters before and after CSWT. CSWT may have a beneficial effect on improving myocardial perfusion, clinical symptoms, exertional ca-pacity, and quality of life and is a safe alternative treatment for patients with severe CAD who have undergone CABG.

Abstract Background: Previous studies reached inconsistent conclusions about the relationship between alcohol or cigarette consumption and coronary artery calcification (CAC). We aim to explore the association between drinking and smoking with CAC in men. Methods: Male patients who underwent coronary angiography (CAG) and intravascular ultrasound (IVUS) and diagnosed with coronary heart disease (CHD) were retrospectively included. Maximum angle of calcified plaque (Arc) and calcium length were measured by IVUS to evaluate CAC severity. Drinking and smoking details were collected. Drinking and smoking were stratified to 4 layers according to weekly alcohol intake(g) and total smoking(package*years), respectively. Uni- and multivariable analysis were performed to explore the association between drinking and smoking with severe coronary artery calcification (SCAC). Results: Totally, 359 men with CHD were included, of whom 151 were regular drinkers and 275 were smokers. Compared with non-drinkers, calcium length in light drinkers decreased (P<0.05), both Arc and calcium length in moderate and heavy drinkers increased (all P<0.05). Weekly alcohol intake was positively correlated with Arc and calcium length (r=0.490, P<0.001; r=0.381, P<0.001). A negative association was found between light drinking and SCAC (OR: 0.492, 95%CI: 0.177-1.372, P=0.175), while moderate (OR: 5.244, 95%CI: 2.245-12.252, P＜0.001) and heavy drinking (OR: 15.238, 95%CI: 5.695-40.767, P＜0.001) were positively associated with SCAC. No associations were found between smoking and SCAC (P>0.05). Conclusions: Light drinking showed a slight negative association with SCAC, whereas moderate and heavy drinking were positively associated with SCAC in Chinese men. No associations were found between smoking and SCAC.

Apigenin is a natural flavonoid which is widely found in vegetables and fruits. However, the mechanism of apigenin in oxidative stress-induced myocardial injury has not been fully elucidated. We established an isoproterenol (Iso)-induced myocardial injury mouse model and a hypoxia/reoxygenation (H/R)-induced H9c2 cell injury model, followed by pretreatment with apigenin to explore its protective effects. Apigenin can significantly alleviate isoproterenol-induced oxidative stress, cell apoptosis and myocardial remodeling in vivo. Apigenin pretreatment can also significantly improve cardiomyocyte morphology, decrease H/R induced oxidative stress, and attenuate cell apoptosis and inflammation in vitro. Further mechanism study revealed that apigenin treatment reversed isoprenaline and H/R-induced decrease of Sirtuin1 (SIRT1). Molecular docking results proved that apigenin can form hydrogen bond with 230 Glu, a key site of SIRT1 activation, indicating that apigenin is an agonist of SIRT1. Moreover, SIRT1 knockdown by siRNA significantly reversed the protective effect of apigenin in H/R-induced myocardial injury. In conclusion, apigenin protects cardiomyocyte function from oxidative stress-induced myocardial injury by modulating SIRT1 signaling pathway, which provides a new potential therapeutic natural compound for the clinical treatment of cardiovascular diseases.

目的 探索冠心病患者心脏体外震波治疗(cardiac shock wave therapy,CSWT)护理流程及安全性.方法 选取2016年12月至2022年8月在北京医院就诊的冠心病并行CSWT的患者.收集临床基本资料,总结护理流程的关键点.收集加拿大心绞痛(Canadian Cardiology Society,CCS)分级、西雅图量表(Seattle Angina Questionnaire,SAQ)、6分钟步行试验(6-minute walk test,6MWT)、治疗中的心电图参数和血清心肌标志物的结果.比较治疗前后生命体征、心电图参数、血清心肌标志物、SAQ和6MWT距离的变化.结果 共有105例患者最终纳入了此研究,男性79例,女性26例,平均年龄为(69.39±9.35)岁.人文关怀贯穿于治疗前后和治疗中.CSWT前后,心率、收缩压、舒张压、血氧饱和度数值变化差异有统计学意义(P<0.001),但均在正常范围内波动.肌酸激酶同工酶(creatine kinase MB type,CK-MB)在治疗前后没有变化(P=0.840),血清心肌标志物包括肌钙蛋白(troponin T,TNT)(P=0.007)和脑钠肽(brain na-triuretic peptide,BNP)(P=0.033),变化差异具有统计学意义,但其中位数均在正常范围内.治疗前后的QRS间期(P=0.236)无明显改变,心率(P<0.001)、PR间期(P<0.001)和QT间期(P<0.001)均具有显著变化,但均在正常范围.CCS分级在治疗后明显改善(2.62级vs.1.92级,P<0.001)、SAQ的5个条目均在治疗后显著改善(P<0.001)、6MWT距离在治疗后明显提高(P<0.001).结论 CSWT的护理过程中需要人文关怀.冠心病患者接受CSWT安全,CSWT可以改善患者心绞痛症状、提高活动能力及改善生活质量.

PurposeSubtraction coronary CT angiography (CCTA) may reduce blooming and beam-hardening artifacts. This study aimed to assess its value in improving the diagnostic accuracy of readers with different experience levels.MethodWe prospectively enrolled patients with target segment who underwent CCTA and invasive coronary angiography (ICA). Target segment images were independently evaluated by three groups of radiologists with different experience levels with CCTA using ICA as the standard reference. Diagnostic accuracy was measured by the area under the curve (AUC), using ≥50% stenosis as the cut-off value.ResultsIn total, 134 target segments with severe calcification from 47 patients were analyzed. The mean specificity of conventional CCTA for each group ranged from 22.4 to 42.2%, which significantly improved with subtraction CCTA, ranging from 81.3 to 85.7% (all p < 0.001). The mean sensitivity of conventional CCTA for each group ranged from 83.3 to 88.0%. Following calcification subtraction, the mean sensitivity decreased for the novice (p < 0.001) and junior (p = 0.017) radiologists but was unchanged for the senior radiologists (p = 0.690). With subtraction CCTA, the mean AUCs of CCTA significantly increased: values ranged from 0.53, 0.54, and 0.61 to 0.70, 0.74, and 0.85 for the novice, junior, and senior groups (all p < 0.001).ConclusionSubtraction CCTA could improve the diagnostic accuracy of radiologists at all experience levels of CCTA interpretation.

BACKGROUND Extracellular vesicles (EVs) derived from hypoxia-preconditioned (HP) mesenchymal stem cells (MSCs) have better cardioprotective effects against myocardial infarction (MI) in the early stage than EVs isolated from normoxic (NC)-MSCs. However, the cardioprotective mechanisms of HP-EVs are not fully understood. AIM To explore the cardioprotective mechanism of EVs derived from HP MSCs. METHODS We evaluated the cardioprotective effects of HP-EVs or NC-EVs from mouse adipose-derived MSCs (ADSCs) following hypoxia in vitro or MI in vivo, in order to improve the survival of cardiomyocytes (CMs) and restore cardiac function. The degree of CM apoptosis in each group was assessed by the terminal deoxynucleotidyl transferase dUTP nick end-labeling and Annexin V/PI assays. MicroRNA (miRNA) sequencing was used to investigate the functional RNA diversity between HP-EVs and NC-EVs from mouse ADSCs. The molecular mechanism of EVs in mediating thioredoxin-interacting protein (TXNIP) was verified by the dual-luciferase reporter assay. Co-immunoprecipitation, western blotting, and immunofluorescence were performed to determine if TXNIP is involved in hypoxia-inducible factor-1 alpha (HIF-1α) ubiquitination and degradation via the chromosomal region maintenance-1 (CRM-1)-dependent nuclear transport pathway. RESULTS HP-EVs derived from MSCs reduced both infarct size (necrosis area) and apoptotic degree to a greater extent than NC-EVs from CMs subjected to hypoxia in vitro and mice with MI in vivo. Sequencing of EV-associated miRNAs showed the upregulation of 10 miRNAs predicted to bind TXNIP, an oxidative stress-associated protein. We showed miRNA224-5p, the most upregulated miRNA in HP-EVs, directly combined the 3’ untranslated region of TXNIP and demonstrated its critical protective role against hypoxia-mediated CM injury. Our results demonstrated that MI triggered TXNIP-mediated HIF-1α ubiquitination and degradation in the CRM-1-mediated nuclear transport pathway in CMs, which led to aggravated injury and hypoxia tolerance in CMs in the early stage of MI. CONCLUSION The anti-apoptotic effects of HP-EVs in alleviating MI and the hypoxic conditions of CMs until reperfusion therapy may partly result from EV miR-224-5p targeting TXNIP.

Abstract Background Clopidogrel is a widely-used antiplatelet and acts as an adenosine diphosphate receptor inhibitor. Neutropenia is a rare but serious adverse effect of clopidogrel. It is unknown whether this adverse effect has any association with impaired kidney function. Case presentation An 80-year-old male with chronic kidney disease was diagnosed with non-ST elevation myocardial infarction and underwent percutaneous coronary intervention. During hospitalization, the patient was diagnosed with contrast-induced nephropathy, treated symptomatically, and discharged with a back-to-baseline creatinine level. Two weeks later, the patient presented to the emergency department with fever and chills. Complete blood count showed leukopenia (0.84 × 103/mm3) and severe neutropenia (0.13 × 103/mm3). Blood cultures were positive for Pseudomonas aeruginosa. Clopidogrel was stopped immediately and switched into ticagrelor. Imipenem and granulocyte colony-stimulating factor were administered to the patient. The patient’s white blood cell and absolute neutrophil count were within the normal range after four days of treatment. The patient was discharged after a 10-day hospitalization, and his complete blood counts were normal during further follow-ups. Conclusions Clopidogrel was the most likely primary cause of neutropenia in our case. The incidence of clopidogrel-induced neutropenia is low and the exact mechanism is not fully explained. We provide suggestions on the management of clopidogrel-associated neutropenia, and summarize all five cases of clopidogrel-induced neutropenia in patients with impaired kidney function.

Review question / Objective: We have previously demonstrated that cardiac shock wave therapy (CSWT) effectively improves myocardial perfusion in patients with coronary artery disease (CAD). In this study, we want to address whether CSWT could decrease the risk of adverse cardiovascular events in CAD patients unsuitable for revascularization. Eligibility criteria: Trials are considered eligible if they meet these criteria: (1) patients included are diagnosed as refractory angina or ischemic heart failure; (2) the study i a randomized controlled trial (RCT) or a prospective cohort study; (3) intervention consisted of CSWT; (4) patients in the control group are treated with optimal medical therapy, (5)the primary outcome of interest Is rate of MACE. Exclusion criteria were (1) patients with acute myocardial infarction, (2) repeated CSWT, (3) with coronary artery revascularization, (4) without primary outcome, (5) retrospective study, and (6)duplicated data.