ECMO versus IABP for STEMI Patients Complicated by Cardiogenic Shock undergoing Primary PCI: A Chinese National Study and Propensity-matched Analysis.

OBJECTIVES: This study investigated the association between the utilization of extracorporeal membrane oxygenation (ECMO) or intra-aortic balloon pump (IABP) and in-hospital mortality among patients with ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock undergoing primary percutaneous coronary intervention (PCI). METHODS: Data encompassing 9635 cases of STEMI complicated by cardiogenic shock and treated with primary PCI using ECMO/IABP support were retrieved from the Chinese Cardiovascular Association database (2019-2021). We conducted an analysis to assess in-hospital survival disparities among percutaneous mechanical circulatory device recipients and explore the potential advantages of ECMO through multivariable logistic regression analysis within a propensity score-matched (1:2) cohort population. RESULTS: ECMO was administered to 2028 patients, while IABP was utilized in 7607 patients. Patients supported by ECMO showed a lower in-hospital mortality compared with those supported by IABP (7.2% vs. 15.1%, p<0.001). Within the propensity-matched (case : control=1:2) cohort, we noted a 34% reduced risk of in-hospital mortality among patients supported by ECMO compared to those supported by IABP (7.7% vs. 11.7%; odds ratio = 0.66; 95% CI, 0.53-0.80; p< 0.001) independent of age, sex, systolic blood pressure, obesity, smoke, hypertension, diabetes, dyslipidaemia, family history of coronary artery disease, coronary artery disease, stroke, atrial filiation, peripheral artery disease, chronic kidney disease, vascular lesion sites, 3A-grade hospital, and regional distributions in China. CONCLUSIONS: Among patients undergoing primary PCI for STEMI complicated by cardiogenic shock, ECMO was associated with better in-hospital survival than IABP.

Knocking out USP7 attenuates cardiac fibrosis and endothelial-to-mesenchymal transition by destabilizing SMAD3 in mice with heart failure with preserved ejection fraction.

Background: Heart failure with preserved ejection fraction (HFpEF) is a predominant type of heart failure. Exploring new pathogenesis and identifying potential novel therapeutic targets for HFpEF is of paramount importance. Methods: HFpEF mouse model was established by the "Multiple-hit" strategy, in that 18- to 22-month-old female C57B6/J mice fed with a high-fat diet were further challenged with chronic infusion of Angiotensin II. RNA sequencing analysis showed that USP7 was significantly increased in the heart of HFpEF mice. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis, in conjunction with co-immunoprecipitation (Co-IP) techniques, identified expression of SMAD3, the key molecule of endothelial-to-mesenchymal transition (EndMT), was also significantly elevated. USP7 endothelium-specific knockout mice was generated to investigate the involvement of USP7 in HFpEF. The biological significance of the interaction between USP7 and SMAD3 was further explored. Results: USP7 promotes EndMT and cardiac fibrosis by binding to SMAD3 directly via its UBL (Ubiquitin-like) domain and cysteine at position 223 of USP7, leading SMAD3 deubiquitination to maintain the stability of SMAD3 by removing the K63 ubiquitin chain and preventing the degradation of SMAD3 by proteasomal process. USP7 also promotes SMAD3 phosphorylation and nuclear translocation, thereby aggravating EndMT and cardiac fibrosis. Endothelium-specific USP7 knockout led to improvement of HFpEF phenotypes and reduction of cardiac fibrosis. Overexpression of SMAD3 in endothelium-specific knockout HFpEF mice reversed the protective effects of USP7 knockout in this HFpEF mouse model. Conclusion: Our results indicated that USP7 is one of the key pathogenic molecules of HFpEF, and knocking out USP7 could attenuate HFpEF injury by promoting the degradation of SMAD3. USP7 and SMAD3 inhibition might be potential therapeutic options for HFpEF.

Association Between Patient and System Delays and In-Hospital Mortality in Primary PCI for STEMI: Findings from a Large, Nationwide Inpatients Sample.

PURPOSE: System delay is associated with mortality in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). However, the influence of patient delay has been relatively overlooked. We aimed to evaluate the influence of patient and system delays on STEMI patients undergoing primary PCI in China. METHODS: STEMI patients registered at the Nationwide Chinese Cardiovascular Association Database-Chest Pain Center from January 2017 to September 2021 were screened. The exposures were total ischemic time (TIT), system delay and patient delay. The primary outcome was in-hospital mortality. RESULTS: Among 458,260 patients from 2529 centers, median TIT, system delay and patient delay were 4.1, 1.5 and 2.1 hours, respectively. The adjusted odds ratio of in-hospital mortality increased by 2.2% (odds ratio [OR], 1.022, 95% confidence interval [CI], 1.017-1.027), 2.3% (1.023, 1.006-1.040) and 2.2% (1.022, 1.017-1.027) for every one-hour increase in TIT, system delay and patient delay, respectively. CONCLUSIONS: Patient delay demonstrated a comparable impact to system delay on in-hospital mortality among STEMI patients undergoing primary PCI. Widespread primary PCI-capable center, improved awareness about myocardial infarction and regional transfer system are essential to shorten patient delay.

Outcome of Transcatheter Aortic Valve Replacement for Pure Native Aortic Regurgitation in Patients with Pulmonary Hypertension.

Background: In recent years, transcatheter aortic valve replacement (TAVR) has emerged as a pivotal treatment for pure native aortic regurgitation (PNAR). Given patients with severe aortic regurgitation (AR) are prone to suffer from pulmonary hypertension (PH), understanding TAVR's efficacy in this context is crucial. This study aims to explore the short-term prognosis of TAVR in PNAR patients with concurrent PH. Methods: Patients with PNAR undergoing TAVR at Zhongshan Hospital, Affiliated with Fudan University, were enrolled between June 2018 to June 2023. They were categorized based on pulmonary artery systolic pressure (PASP) into groups with or without PH. The baseline characteristics, imaging records, and follow-up data were collected. Results: Among the 103 patients recruited, 48 were afflicted with PH. In comparison to PNAR patients without PH, the PH group exhibited higher rates of renal dysfunction (10.4% vs. 0.0%, p = 0.014), increased Society of Thoracic Surgeons scores (6.4 ± 1.9 vs. 4.7 ± 1.6, p < 0.001), and elevated Nterminal fragment of pro-brain natriuretic peptide (NT-proBNP). Transthoracic ultrasound examination revealed that patients with PH displayed lower left ventricular ejection fraction, larger left ventricle dimension, and more frequent moderate to severe tcuspid regurgitation (TR). Following TAVR, both groups experienced significant reductions in PASP, mitral regurgitation (MR) and TR. There were no significant differences in the incidence of postoperative adverse events in patients with or without PH. Conclusions: We found TAVR to be a safe and effective treatment for patients with PNAR and PH, reducing the degree of aortic regurgitation and PH without increasing the risk of postoperative adverse events.

Variation in Secondary Prevention of Coronary Heart Disease: The INTERASPIRE Study.

BACKGROUND AND AIMS: INTERASPIRE is an international study of coronary heart disease (CHD) patients, designed to measure if guideline standards for secondary prevention and cardiac rehabilitation are being achieved in a timely manner. METHODS: Between 2020-2023, adults hospitalized in the preceding 6-24 months with incident or recurrent CHD were sampled in 14 countries from all 6 World Health Organization regions and invited for a standardized interview and examination. Direct age and sex standardization was used for country-level prevalence estimation. RESULTS: Overall, 4548 (21.1% female) CHD patients were interviewed a median of 1.05 (interquartile range 0.76-1.45) years after index hospitalization. Among all participants, 24% were obese (40% centrally). Only 38.5% achieved a blood pressure (BP) <130/80 mmHg and 19.2% a low-density lipoprotein cholesterol (LDL-C) of <1.4 mmol/l. Of those smoking at hospitalization, 48% persisted at interview. Of those with known diabetes, 56% achieved glycated hemoglobin (HbA1c) of <7.0%. A further 9.8% had undetected diabetes and 26.9% impaired glucose tolerance. Females were less likely to achieve targets: BP (females 37.4% males 38.6%), LDL-C (females 13.7% males 18.6%) and HbA1c in diabetes (females 47.7% males 57.5%). Overall, just 9.0% (inter-country range 3.8%-20.0%) reported attending cardiac rehabilitation and 1.0% (inter-country range 0.0%-2.4%) achieved the study definition of optimal guideline adherence. CONCLUSIONS: INTERASPIRE demonstrates inadequate and heterogeneous international implementation of guideline standards for secondary prevention in the first year after CHD hospitalization, with geographic and sex disparity. Investment aimed at reducing between-country and between-individual variability in secondary prevention will promote equity in global efforts to reduce the burden of CHD.

Effectiveness of chest pain center accreditation on the hospital outcome of acute aortic dissection: a nationwide study in China.

BACKGROUND: The National Chest Pain Center Program (NCPCP) is a nationwide, quality enhancement program aimed at raising the standard of care for patients experiencing acute chest pain in China. The benefits of chest pain center (CPC) accreditation on acute coronary syndrome have been demonstrated. However, there is no evidence to indicate whether CPC accreditation improves outcomes for patients with acute aortic dissection (AAD). METHODS: We conducted a retrospective observational study of patients with AAD from 1671 hospitals in China, using data from the NCPCP spanning the period from January 1, 2016 to December 31, 2022. The patients were divided into 2 groups: pre-accreditation and post-accreditation admissions. The outcomes examined included in-hospital mortality, misdiagnosis, and Stanford type A AAD surgery. Multivariate logistic regression was employed to explore the relationship between CPC accreditation and in-hospital outcomes. Furthermore, we stratified the hospitals based on their geographical location (Eastern/Central/Western regions) or administrative status (provincial/non-provincial capital areas) to assess the impact of CPC accreditation on AAD patients across various regions. RESULTS: The analysis encompassed a total of 40,848 patients diagnosed with AAD. The post-accreditation group exhibited significantly lower rates of in-hospital mortality and misdiagnosis (12.1% vs. 16.3%, P < 0.001 and 2.9% vs. 5.4%, P < 0.001, respectively) as well as a notably higher rate of Stanford type A AAD surgery (61.1% vs. 42.1%, P < 0.001) compared with the pre-accreditation group. After adjusting for potential covariates, CPC accreditation was associated with substantially reduced risks of in-hospital mortality (adjusted OR 0.644, 95% CI 0.599-0.693) and misdiagnosis (adjusted OR 0.554, 95% CI 0.493-0.624), along with an increase in the proportion of patients undergoing Stanford type A AAD surgery (adjusted OR 1.973, 95% CI 1.797-2.165). Following CPC accreditation, there were significant reductions in in-hospital mortality across various regions, particularly in Western regions (from 21.5 to 14.1%). Moreover, CPC accreditation demonstrated a more pronounced impact on in-hospital mortality in non-provincial cities compared to provincial cities (adjusted OR 0.607 vs. 0.713). CONCLUSION: CPC accreditation is correlated with improved management and in-hospital outcomes for patients with AAD.

Mendelian randomization study on causal association of TEF and circadian rhythm with pulmonary arterial hypertension.

BACKGROUND: Previous research has revealed the potential impact of circadian rhythms on pulmonary diseases; however, the connection between circadian rhythm-associated Thyrotroph Embryonic Factor (TEF) and Pulmonary Arterial Hypertension (PAH) remains unclear. We aim to assess the genetic causal relationship between TEF and PAH by utilizing two sets of genetic instrumental variables (IV) and publicly available Pulmonary Arterial Hypertension Genome-Wide Association Studies (GWAS). METHODS: Total of 23 independent TEF genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study. Gain- and loss-of-function experiments were used to demonstrate the role of TEF in PAH. RESULTS: Our analysis revealed that as TEF levels increased genetically, there was a corresponding increase in the risk of PAH, as evidenced by IVW (OR = 1.233, 95% CI: 1.054-1.441; P = 0.00871) and weighted median (OR = 1.292, 95% CI for OR: 1.064-1.568; P = 0.00964) methods. Additionally, the up-regulation of TEF expression was associated with a significantly higher likelihood of abnormal circadian rhythm (IVW: P = 0.0024733, ß = 0.05239). However, we did not observe a significant positive correlation between circadian rhythm and PAH (IVW: P = 0.3454942, ß = 1.4980398). In addition, our in vitro experiments demonstrated that TEF is significantly overexpressed in pulmonary artery smooth muscle cells (PASMCs). And overexpression of TEF promotes PASMC viability and migratory capacity, as well as upregulates the levels of inflammatory cytokines. CONCLUSION: Our analysis suggests a causal relationship between genetically increased TEF levels and an elevated risk of both PAH and abnormal circadian rhythm. Consequently, higher TEF levels may represent a risk factor for individuals with PAH.

Force Analysis Using Self-Expandable Valve Fluoroscopic Imaging: a way Through Artificial Intelligence.

This study aimed to develop a force analysis model correlating fluoroscopic images of self-expandable valves with stress distribution. For this purpose, a nonmetallic measuring device designed to apply diverse forces at specific positions on a valve stent while simultaneously measuring force magnitude was manufactured, obtaining 465 sets of fluorescent films under different force conditions, resulting in 5580 images and their corresponding force tables. Using the XrayGLM, a mechanical analysis model based on valve fluorescence images was trained. The accuracy of the image force analysis using this model was approximately 70% (50-88.3%), with a relative accuracy of 93.3% (75-100%). This confirms that fluoroscopic images of transcatheter aortic valve replacement (TAVR) valve stents contain a wealth of mechanical information, and machine learning can be used to train models to recognize the relationship between stent images and force distribution, enhancing the understanding of TAVR complications.

Identification of endothelial protein C receptor as a novel druggable agonistic target for reendothelialization promotion and thrombosis prevention of eluting stent.

The commercially available drug-eluting stent with limus (rapamycin, everolimus, etc.) or paclitaxel inhibits smooth muscle cell (SMC), reducing the in-stent restenosis, whereas damages endothelial cell (EC) and delays stent reendothelialization, increasing the risk of stent thrombosis (ST) and sudden cardiac death. Here we present a new strategy for promoting stent reendothelialization and preventing ST by exploring the application of precise molecular targets with EC specificity. Proteomics was used to investigate the molecular mechanism of EC injury caused by rapamycin. Endothelial protein C receptor (EPCR) was screened out as a crucial EC-specific effector. Limus and paclitaxel repressed the EPCR expression, while overexpression of EPCR protected EC from coating (eluting) drug-induced injury. Furthermore, the ligand activated protein C (APC), polypeptide TR47, and compound parmodulin 2, which activated the target EPCR, promoted EC functions and inhibited platelet or neutrophil adhesion, and enhanced rapamycin stent reendothelialization in the simulated stent environment and in vitro. In vivo, the APC/rapamycin-coating promoted reendothelialization rapidly and prevented ST more effectively than rapamycin-coating alone, in both traditional metal stents and biodegradable stents. Additionally, overexpression or activation of the target EPCR did not affect the cellular behavior of SMC or the inhibitory effect of rapamycin on SMC. In conclusion, EPCR is a promising therapeutical agonistic target for pro-reendothelialization and anti-thrombosis of eluting stent. Activation of EPCR protects against coating drugs-induced EC injury, inflammatory cell, or platelet adhesion onto the stent. The novel application formula for APC/rapamycin-combined eluting promotes stent reendothelialization and prevents ST.

RBM15 Protects From Myocardial Infarction by Stabilizing NAE1.

RNA-binding proteins play multiple roles in several biological processes. However, the roles of RBM15-an important RNA-binding protein and a significant regulator of RNA methylation-in cardiovascular diseases remain elusive. This study aimed to investigate the biological function of RBM15 and its fundamental mechanisms in myocardial infarction (MI). Methylated RNA immunoprecipitation sequencing was used to explore the N6-methyladenosine (m6A) difference between MI and normal tissues. Our findings showed the elevated level of m6A in MI, and its transcription profile in both MI and normal tissues. RBM15 was the main regulator and its overexpression attenuated apoptosis in cardiomyocytes and improved cardiac function in mice after MI. Then, we used one target NEDD8 activating enzyme E1 subunit and its inhibitor (MLN4924) to investigate the impact of RBM15 targets on cardiomyocytes. Finally, the enhanced m6A methylation in the presence of RBM15 overexpression led to the increased expression and stability of NEDD8 activating enzyme E1 subunit. Our findings suggest that the enhanced m6A level is a protective mechanism in MI, and RBM15 is significantly upregulated in MI and promotes cardiac function. This study showed that RBM15 affected MI by stabilizing its target on the cell apoptosis function, which might provide a new insight into MI therapy.

Long-term follow-up in outpatients with mildly elevated pulmonary artery systolic pressure on echocardiography: a single-centre retrospective cohort study in Shanghai, China.

OBJECTIVE: To investigate the correlation between mildly elevated pulmonary artery systolic pressure (PASP) on echocardiography and mortality, as well as long-term changes in PASP. DESIGN: Retrospective cohort study. SETTING: Shanghai, China, a single centre. PARTICIPANTS: A total of 910 patients were enrolled in this study. From January to June 2016, 1869 patients underwent echocardiography at the Zhongshan Hospital affiliated with Fudan University. Patients with malignant tumours, previous heart or other solid organ transplantation, previous or scheduled ventricular assist device implantation, severe kidney dysfunction (uraemia and patients on dialysis) and a life expectancy of less than 1 year for any medical condition were excluded. INTERVENTIONS: No interventions were done. PRIMARY AND SECONDARY OUTCOME MEASURES: The predictors of death in patients with mild echocardiographic pulmonary hypertension were analysed using univariate and multivariate Cox regression analyses. Paired t-tests were used to calculate changes in the PASP values at baseline and follow-up for different patient groups. RESULTS: The 5-year survival of patients was 93.2%. Patients were grouped according to whether they had combined organic heart disease (OHD). The PASP value was an independent predictor of all-cause mortality in patients with OHD, with each 1 mm Hg increase associated with an HR of 1.02 (95% CI: 1.01-1.03, p=0.038) but not in patients without OHD. Of the total, 46% (419/910) of the patients with 5-6 years of echocardiography were investigated for changes in the PASP value. We found significant PASP reduction in patients without OHD (42.8±2.4 mm Hg vs 39.3±8.2 mm Hg, p<0.001), but no significant change was observed for patients with OHD (42.8±2.5 mm Hg vs 42.4±8.8 mm Hg, p=0.339). CONCLUSIONS: The PASP was associated with all-cause mortality in patients with OHD and mildly elevated PASP compared with patients without OHD. After 5-6 years of follow-up, the PASP on echocardiography was not further elevated in patients without OHD.

Prognostic value of first 24-hour urine output in patients with acute myocardial infarction in intensive care units: a retrospective study based on the MIMIC-IV database.

PURPOSE: To investigate the effect of first 24-hour (24-h) urine output (UO) on in-hospital and 1-year mortality in patients admitted to intensive care units due to acute myocardial infarction. METHODS: This was a retrospective cohort study based on the medical information mart for intensive care IV database involving patients admitted to intensive care units due to acute myocardial infarction. Patients were classified as low UO (LUO), high UO (HUO), and middle UO with a first 24-h UO below 800 ml, over 2500 ml, or in between, respectively. The primary outcome was in-hospital mortality and the secondary outcome was 1-year mortality. RESULTS: A total of 4337 patients were involved. Taking middle UO group as reference, after adjusting for confounders including age, gender, height, weight, comorbidity, occurrence of cardiogenic shock, revascularization, blood pressure, creatinine, N-terminal pro-brain natriuretic peptide, and use of loop diuretics, LUO was independently associated with higher in-hospital mortality [odds ratio 4.05, 95% confidence interval (CI): 3.12-5.26], while HUO was an independent protective factor (odds ratio 0.52, 95% CI: 0.35-0.77). In the multivariant Cox regression model, LUO was an independent risk factor for 1-year mortality (hazard ratio 2.65, 95% CI: 2.16-3.26), while HUO did not show significant association. CONCLUSION: In patients admitted to intensive care units due to acute myocardial infarction, first 24-h UO <800 ml was a strong predictor for higher in-hospital and 1-year mortality, while first 24-h UO over 2500 ml was associated with lower in-hospital mortality but not long-term mortality.

Acute hepatotoxicity of intravenous amiodarone in a Becker muscular dystrophy patient with decompensated heart failing and ABCB4 gene mutation: as assessed for causality using the updated RUCAM.

BACKGROUND: Cardiac dysfunction, including arrhythmias, may be one of the main clinical manifestations of Becker muscular dystrophy (BMD). Amiodarone is widely used to treat arrhythmia. However, multi-systemic toxicity caused by amiodarone, especially hepatotoxicity, should not be neglected. Here, we introduce a novel case of multi-systemic amiodarone toxicity involving the liver, renal and coagulation in BDM patient with ABCB4 gene mutation. CASE PRESENTATION: We present a case of a 16-year-old boy admitted with heart failure and atrial fibrillation (AF). He was diagnosed with Becker muscular dystrophy (BMD) and gene testing showed comorbid mutations in gene DMD, ABCB4 and DSC2. Amiodarone was prescribed to control the paroxysmal atrial fibrillation intravenously. However, his liver enzyme levels were sharply elevated, along with cardiac shock, renal failure and coagulation disorders. After bedside continuous renal replacement therapy, the patient's liver function and clinical status rehabilitated. CONCLUSIONS: ABCB4 gene mutation might be involved in amiodarone-induced hepatotoxicity. Studies in a cohort might help to prove this hypothesis in the future.

Wearable device-measured moderate to vigorous physical activity and risk of degenerative aortic valve stenosis.

BACKGROUND AND AIMS: Physical activity has proven effective in preventing atherosclerotic cardiovascular disease, but its role in preventing degenerative valvular heart disease (VHD) remains uncertain. This study aimed to explore the dose-response association between moderate to vigorous physical activity (MVPA) volume and the risk of degenerative VHD among middle-aged adults. METHODS: A full week of accelerometer-derived MVPA data from 87 248 UK Biobank participants (median age 63.3, female: 56.9%) between 2013 and 2015 were used for primary analysis. Questionnaire-derived MVPA data from 361 681 UK Biobank participants (median age 57.7, female: 52.7%) between 2006 and 2010 were used for secondary analysis. The primary outcome was the diagnosis of incident degenerative VHD, including aortic valve stenosis (AS), aortic valve regurgitation (AR), and mitral valve regurgitation (MR). The secondary outcome was VHD-related intervention or mortality. RESULTS: In the accelerometer-derived MVPA cohort, 555 incident AS, 201 incident AR, and 655 incident MR occurred during a median follow-up of 8.11 years. Increased MVPA volume showed a steady decline in AS risk and subsequent AS-related intervention or mortality risk, levelling off beyond approximately 300 min/week. In contrast, its association with AR or MR incidence was less apparent. The adjusted rates of AS incidence (95% confidence interval) across MVPA quartiles (Q1-Q4) were 11.60 (10.20, 13.20), 7.82 (6.63, 9.23), 5.74 (4.67, 7.08), and 5.91 (4.73, 7.39) per 10 000 person-years. The corresponding adjusted rates of AS-related intervention or mortality were 4.37 (3.52, 5.43), 2.81 (2.13, 3.71), 1.93 (1.36, 2.75), and 2.14 (1.50, 3.06) per 10 000 person-years, respectively. Aortic valve stenosis risk reduction was also observed with questionnaire-based MVPA data [adjusted absolute difference Q4 vs. Q1: AS incidence, -1.41 (-.67, -2.14) per 10 000 person-years; AS-related intervention or mortality, -.38 (-.04, -.88) per 10 000 person-years]. The beneficial association remained consistent in high-risk populations for AS, including patients with hypertension, obesity, dyslipidaemia, and chronic kidney disease. CONCLUSIONS: Higher MVPA volume was associated with a lower risk of developing AS and subsequent AS-related intervention or mortality. Future research needs to validate these findings in diverse populations with longer durations and repeated periods of activity monitoring.

Impact of the gut microbiome on atherosclerosis.

Atherosclerosis is a chronic inflammatory metabolic disease with a complex pathogenesis. However, the exact details of its pathogenesis are still unclear, which limits effective clinical treatment of atherosclerosis. Recently, multiple studies have demonstrated that the gut microbiota plays a pivotal role in the onset and progression of atherosclerosis. This review discusses possible treatments for atherosclerosis using the gut microbiome as an intervention target and summarizes the role of the gut microbiome and its metabolites in the development of atherosclerosis. New strategies for the treatment of atherosclerosis are needed. This review provides clues for further research on the mechanisms of the relationship between the gut microbiota and atherosclerosis.

Inflammatory Reprogramming Mediates Changes in Three-Dimensional Strain Capacity and Cardiac Function in Beagle Dogs with Doxorubicin-Related Cardiomyopathy.

Background: The cardiotoxicity of doxorubicin (DOX) limits its use in cancer treatment. To address this limitation, we developed a novel animal model that uses beagle dogs to investigate DOX-induced cardiac disorders. Unfortunately, the lack of effective cardioprotection strategies against DOX-induced cardiotoxicity poses a significant challenge. To establish a canine model for low-mortality DOX-induced cardiac dysfunction and explore the relationship between inflammatory reprogramming and DOX-related cardiotoxicity. Methods: Twenty male beagle dogs aged two years were randomly assigned into the DOX (N = 10) and control (CON) (N = 10) groups. DOX was infused (1.5 mg/kg) every two weeks until doses cumulatively reached 12 mg/kg. Serum biomarkers and myocardial pathology were evaluated, while real-time fluorescence-based quantitative polymerase chain reaction (RTFQ-PCR), two- and three-dimensional echocardiography (2DE and RT3DE), functional enrichment, and matrix correlation were also performed. Results: In the DOX group, high-sensitive cardiac troponin T (hs cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were significantly increased. Myocardial pathology indicated early to medium myocardial degeneration via a decreased cardiomyocyte cross-sectional area (CSA). Increased levels of inflammatory gene transcripts (interleukin 6 (IL6), tumor necrosis factor (TNF), transforming growth factor ß (TGF ß ), intercellular adhesion molecule 1 (ICAM1), interleukin 1 (IL1), interleukin 1 ß (IL1 ß ), and interleukin 8 (IL8)), of collagen metabolism and deposition regulatory genes (matrix metalloproteinase (MMP) family and tissue inhibitor of matrix metalloproteinase (TIMP) family), and the natriuretic peptide family (NPS) (natriuretic peptide A, B and C (NPPA, NPPB, and NPPC)) were observed. Strain abnormalities in the right ventricular longitudinal septal strain (RVLSS), right ventricular longitudinal free-wall strain (RVLFS), left ventricular global longitudinal strain (LVGLS), and left ventricular global circumferential strain (LVGCS) were detected at week 28 (vs. week 0 or CON group, p < 0.05, respectively). A significant decline in RVLSS and RVLFS occurred at week 16, which was earlier than in the corresponding left ventricular areas. A significant right ventricular ejection fraction (RVEF) decline was noted at week 16 (vs. week 0, 33.92 ± 3.59% vs. 38.58 ± 3.58%, p < 0.05), which was 12 weeks earlier than for the left ventricular ejection fraction (LVEF), which occurred at week 28 (vs. week 0, 49.02 ± 2.07% vs. 54.26 ± 4.38%, p < 0.01). The right ventricular strain and functional damages correlated stronger with inflammatory reprogramming (most R from 0.60 to 0.90) than the left ones (most R from 0.30 to 0.65), thereby indicating a more pronounced correlation. Conclusions: Inflammatory reprogramming mediated disorders of strain capacity and cardiac function predominantly in the right side of the heart in the newly established DOX-related cardiomyopathy beagle dog model.

Single-cell sequencing of immune cells from the coronary sinus reveals immune mechanisms of the progression of persistent atrial fibrillation.

Identifying the atlas of immune cells from coronary sinus circulation (CSC) of patients with persistent atrial fibrillation (PerAF) may provide new insights into the role of immune cells in the progression of AF. Single-cell sequencing revealed substantial alterations in immune cells from CSCs of patients with PerAF, especially a markedly elevated abundance of T cells, after which we identified a T cell subset: FGFBP2(+)TRDC(-)CD4(-) T cells (Ftc-T cells), which can promote the proliferation of cardiac fibroblasts (CFs),and the proportion of Ftc-T had a positive linear with AF recurrence post catheter ablation (CA). Moreover, IFI27 was found to be highly enriched in Ftc-T cells and promoted CFs proliferation and collagen expression. Altogether, our findings represent a unique resource providing in-depth insights into the heterogeneity of the immune cell from CSC of patients with PerAF and highlight the potential role of Ftc-T cells and IFI27 for AF progression.

Simultaneous ST-elevation in lead augmented vector right (aVR) and III in non-ST-elevation acute coronary syndromes.

Background: The value of ST-elevation in lead augmented vector right (aVR) remains controversial in clinical practice. This study aimed to investigate the association of simultaneous ST-elevation in lead aVR and III with angiographic findings and clinical outcomes in patients with non-ST-elevation acute coronary syndromes (NSTEACS). Methods: In this observational study, patients who had been diagnosed with NSTEACS and presented with ST-elevation in lead aVR and without ST-elevation in any other two contiguous leads were enrolled from January 2018 to June 2019. Demographic, baseline clinical, angiographic and interventional characteristics as well as clinical outcomes were collected and recorded on standardized case report forms. Results: A total of 157 patients meeting the criteria were finally enrolled in this study and classified into two groups according to the presence of ST-elevation in lead III. Patients in the two groups were similar in average age and previous history of hypertension, diabetes mellitus, hyperlipidemia, chronic kidney disease, stroke, and peripheral vascular diseases (all P>0.05). Patients with ST-elevation in lead III tended to present with myocardial hypertrophy in the echocardiography (P=0.02). The cases with ST-elevation in lead III showed higher high sensitivity troponin T (hs-TnT; P=0.08) and creatinine kinase MB isoenzyme (CK-MB; P<0.01) whereas those without ST-elevation in lead III showed higher N-terminal pro brain natriuretic peptide (NT-proBNP; P=0.02). Of note, patients with ST-elevation in lead III presented with more ST-depression in multiple leads [especially in lead I, augmented vector left (aVL), V3-V6] as well as higher degree of ST-depression (all P<0.05) and were more likely to develop multi-vessel and left main trunk (LM) lesions (P=0.04), with 20% of the cases having a LM lesion and 60% having triple vessel lesions. Patients with ST-elevation in lead III were at increased risk of 3-year major adverse cardiovascular events (MACEs), despite no significant statistical difference between the two groups (hazard ratio =1.29; P=0.26). Conclusions: The NSTEACS cases with simultaneous ST-elevation in lead III and aVR tended to present with more multiple leads with ST-depression, higher degree of ST-depression, and more LM or multi-vessel lesions, suggesting a broader range of severe myocardial ischemia. The concurrent presentation of ST-elevation in lead III and aVR may play a vital role in the diagnosis, risk-stratification, and prediction of poor prognosis during the management of NSTEACS patients.

TRIM25-mediated XRCC1 ubiquitination accelerates atherosclerosis by inducing macrophage M1 polarization and programmed death.

BACKGROUND: Macrophage-mediated cleaning up of dead cells is a crucial determinant in reducing coronary artery inflammation and maintaining vascular homeostasis. However, this process also leads to programmed death of macrophages. So far, the role of macrophage death in the progression of atherosclerosis remains controversial. Also, the underlying mechanism by which transcriptional regulation and reprogramming triggered by macrophage death pathways lead to changes in vascular inflammation and remodeling are still largely unknown. TRIM25-mediated RIG-I signaling plays a key role in regulation of macrophages fate, however the role of TRIM25 in macrophage death-mediated atherosclerotic progression remains unclear. This study aims to investigate the relationship between TRIM25 and macrophage death in atherosclerosis. METHODS: A total of 34 blood samples of patients with coronary stent implantation, including chronic total occlusion (CTO) leisions (n = 14) or with more than 50% stenosis of a coronary artery but without CTO leisions (n = 20), were collected, and the serum level of TRIM25 was detected by ELISA. Apoe-/- mice with or without TRIM25 gene deletion were fed with the high-fat diet (HFD) for 12 weeks and the plaque areas, necrotic core size, aortic fibrosis and inflammation were investigated. TRIM25 wild-type and deficient macrophages were isolated, cultured and stimulated with ox-LDL, RNA-seq, real-time PCR, western blot and FACS experiments were used to screen and validate signaling pathways caused by TRIM25 deletion. RESULTS: Downregulation of TRIM25 was observed in circulating blood of CTO patients and also in HFD-induced mouse aortas. After HFD for 12 weeks, TRIM25-/-ApoeE-/- mice developed smaller atherosclerotic plaques, less inflammation, lower collagen content and aortic fibrosis compared with TRIM25+/+ApoeE-/- mice. By RNA-seq and KEGG enrichment analysis, we revealed that deletion of TRIM25 mainly affected pyroptosis and necroptosis pathways in ox-LDL-induced macrophages, and the expressions of PARP1 and RIPK3, were significantly decreased in TRIM25 deficient macrophages. Overexpression of TRIM25 promoted M1 polarization and necroptosis of macrophages, while inhibition of PARP1 reversed this process. Further, we observed that XRCC1, a repairer of DNA damage, was significantly upregulated in TRIM25 deficient macrophages, inhibiting PARP1 activity and PARP1-mediated pro-inflammatory change, M1 polarization and necroptosis of macrophages. By contrast, TRIM25 overexpression mediated ubiquitination of XRCC1, and the inhibition of XRCC1 released PARP1, and activated macrophage M1 polarization and necroptosis, which accelerated aortic inflammation and atherosclerotic plaque progression. CONCLUSIONS: Our study has uncovered a crucial role of the TRIM25-XRCC1Ub-PARP1-RIPK3 axis in regulating macrophage death during atherosclerosis, and we highlight the potential therapeutic significance of macrophage reprogramming regulation in preventing the development of atherosclerosis.