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Abstract Background Hypercholesterolemia has been identified as an independent predictor of cardiovascular disease (CVD). Inclisiran, an innovative small interfering RNA agent, is anticipated to result in a notable reduction of approximately 50% in low-density lipoprotein cholesterol (LDL-C) levels. Given its transformative impact, this study scrutinized the eligibility of the US population for inclisiran treatment and evaluated its potential effects on hypercholesterolemia and the primary prevention of CVD. Methods This study applied the eligibility criteria from the ORION 10 and 11 trials to the 1999–2018 National Health and Nutrition Examination Survey (NHANES) dataset to estimate the size of the eligible population for atherosclerotic cardiovascular disease (ASCVD) and ASCVD-risk equivalents. Utilizing the reduction in LDL-C levels from ORION 10, this study predicted the impact of inclisiran on LDL-C levels among ASCVD patients. Similarly, leveraging the changes in lipid levels from ORION 11, this study predicted inclisiran’s effect on the 10-year change in CVD risk and preventable CVD events in the ASCVD-risk equivalents population, employing the Framingham CVD Risk Score. Results The study identified 579 ASCVD patients (5 million) and 382 ASCVD-risk equivalents (2.66 million) who met the eligibility criteria from ORION 10 and 11. Among the ASCVD population, 3.5 million (70.2%) would achieve a ≥ 50% reduction in LDL-C levels after treatment. Furthermore, 4.6 million (91.3%) would achieve LDL-C levels

Abstract Background and Aim Remnant cholesterol (RC) is substantially related to negative outcomes in cardiac patients. Patients with coexisting hypertension and heart failure (HF) often develop left ventricular hypertrophy (LVH) and have poor prognoses. This study investigated baseline RC levels and LV remodelling and patients’ prognoses. Methods and results Six hundred thirty consecutive individuals with hypertension and HF participated in this prospective trial from October 2018 to August 2020. Based on left ventricular mass index (LVMI), 560 those eligible were separated into LVH and non-LVH groups. Multiple linear regression and receiver operating characteristic (ROC) curves examined the RC and LV relationship. A Cox regression analysis was conducted to examine the predictive value of RC for clinical outcomes. The LVH group presented significantly elevated values of RC, triglyceride, and cholesterol and decreased high-density lipoprotein cholesterol (HDLC). The optimal cutoff value for RC to predict LV remodelling was 0.49. The subjects were observed for a median of 58 months, and 104 participants met the primary endpoint. The risk models involving the two Cox models were adjusted to incorporate confounding factors, which revealed that those with elevated baseline levels of RC were more susceptible to cardiovascular mortality, as shown by an increased hazard ratio. (HR: 1.91, 95% CI: 1.62–2.26 vs. HR: 1.75, 95% CI: 1.43–2.16, P

BackgroundChronic intermittent hypobaric hypoxia (CIHH) can effectively alleviate type 2 diabetes mellitus (T2DM). In this process, the underlying mechanism in its association with the epigenetic regulation of DNA methylation in the promoter regions of glucose metabolism key enzyme genes remains unclear yet.ObjectiveTo investigate the effects of CIHH on expression and promoter region methylation of key enzyme genes related to glucose metabolism in diabetes mice, and to explore the underlying mechanism by which CIHH regulates glucose metabolism.MethodsForty C57BL/6J male mice were divided randomly into a normobaric normoxic control (NN/CON) group, a chronic intermittent hypobaric hypoxia intervention control (CIHH/CON) group, a normobaric normoxic diabetic model (NN/DM) group, and a chronic intermittent hypobaric hypoxia intervention diabetic model (CIHH/DM) group. The mice in the NN/DM and the CIHH/DM groups were fed for 7 weeks with high-fat and high-sugar diet. Subsequently, these mice were intraperitoneally injected consecutively with 50 mmol·L−1 streptozotocin (STZ) for 5 d at a dose of 40 mg·kg−1 (body weight) per day to create T2DM model mice. The mice in the CIHH/DM and the CIHH/CON groups were intervened by simulating hypobaric hypoxia at 5000 m altitude for 6 h per day, while the mice in the NN/DM and the NN/CON groups were always placed in a normobaric normoxic environment. All mice were continuously treated for 4 weeks, and blood glucose were monitored during this period. After the CIHH intervention experiment, the glucose tolerance and insulin sensitivity of mice were evaluated. A set of indicators involved in key glycolytic enzymes glucokinase (GK) and pyruvate kinase (PK), as well as key gluconeogenic enzymes phosphoenolpyruvate carboxyl kinase (PEPCK) and glucose-6-phosphatase (G6P) were measured in the liver of mice, including enzyme activity, relative mRNA expression level, and DNA methylation level in the gene promoter regions.ResultsCompared with the mice in the NN/DM group, the blood glucose levels of the mice in the CIHH/DM group decreased after the 25th day of the CIHH intervention (P0.05), and their correlations with mRNA expression levels were also not statistically significant (P>0.05).ConclusionCIHH intervention may reduce blood glucose level, improve glucose tolerance, alleviate insulin resistance, and regulate the key enzyme activities of glucose metabolism and the relative mRNA expression of their corresponding genes in T2DM mice, but the above phenomena are not related to the DNA methylation levels in the promoter regions of these key enzymes.

Background: There is no consensus on optimal time points or systolic blood pressure (SBP) ranges for calculating SBP time in target range (TTR). Objectives: The purpose of this study was to examine the association between various SBP TTR metrics and long-term major adverse cardiovascular events (MACEs). Methods: This post hoc analysis of SPRINT (Systolic Blood Pressure Intervention Trial) included participants with complete SBP records and excluded those with events in the initial 2 years. SBP TTR indices were calculated using 3 distinct time points and 3 SBP ranges. The SBP TTR index was the percentage of BP segments within the target SBP ranges. MACE, a composite of heart attack, stroke, heart failure, and cardiovascular death, was the primary outcome. Results: The study included 7,134 participants, of which 280 had a MACE. The median follow-up was 3.91 years. The SBP TTR 110-140 mm Hg in the initial 3 months (3-month TTR 110-140) had the optimal association with incident MACEs (HR per SD increase: 0.898 [95% CI: 0.788-1.022], relative informativeness = 24,398%). Furthermore, a cutoff value of 0.65 for 3-month TTR 110 to 140 index was identified by threshold saturation analysis and used to evaluate early SBP control. No difference in MACE was seen between different mean SBP subgroups in those with good early control (3-month TTR >0.65) (P = 0.88), but in those with poor early control (3-month TTR ≤0.65), a higher mean SBP of 130 to 140 mm Hg was related to increased MACEs risk (P = 0.019). Conclusions: In nondiabetic hypertensive patients, the 3-month TTR 110 to 140 mm Hg index was independently associated with 2-year MACEs. A cutoff of TTR index as 0.65 indicated that the patient was within BP target range 65% of the time, combined with mean SBP, could potentially be used as a metric for early control stability and late cardiovascular risks. (Systolic Blood Pressure Intervention Trial [SPRINT]; NCT01206062)

IntroductionEven under the standard medical care, patients with left ventricular (LV) failure or heart failure (HF) often progress to pulmonary hypertension and right ventricular (RV) hypertrophy. We previously showed that inflammation and regulatory T cells (Tregs) modulate HF progression in mice with preexisting LV failure. The main objective of this study is to determine the role of CD8+ T cells in modulating LV failure and the consequent pulmonary inflammation and RV hypertrophy in mice with preexisting LV failure.MethodsMice with LV failure produced by transverse aortic constriction (TAC) were randomized to depletion of cytotoxic CD8+ T cells, Tregs, or both using specific blocking antibodies. Cardiac function, lung inflammation, fibrosis, vascular remodeling, and right ventricular remodeling were determined.ResultsLV failure caused pulmonary inflammation, fibrosis, vascular remodeling, and RV hypertrophy. Depletion of CD8+ T cells significantly attenuated above changes in mice with preexisting LV failure. LV failure was associated with increased CD4+ and CD8+ T cell activation, and increased ratios of activated T cells to Tregs. Treg depletion exacerbated lung inflammation and HF progression, as well as lung CD4+ and CD8+ T cell infiltration and activation in HF mice. However, CD8+ T cells depletion rescue these mice from exacerbated lung inflammation and RV hypertrophy after Treg depletion.DiscussionOur findings demonstrate an important role of CD8+ T cells in promoting pulmonary inflammation and RV hypertrophy in mice with preexisting LV failure. Depletion of CD8+ T cells also rescued HF mice from the exacerbated HF progression by Treg depletion.

Background: Left atrial appendage closure (LAAC) was effective in preventing thromboembolic events and stroke in patients with atrial fibrillation (AF). However, whether left atrial spontaneous echo contrast (LA-SEC) poses a higher risk for thromboembolism is contradictory. We aimed to investigate whether LA-SEC is a risk factor for thromboembolic events in patients who underwent LAAC. Methods: 258 consecutive patients who underwent successful LAAC were enrolled and divided according to the presence or absence of LA-SEC detected by transesophageal echocardiography (TEE). Propensity score matching (PSM) was used to eliminate covariate imbalances. Baseline characteristics, periprocedural details, and clinical outcomes were compared between LA-SEC and non-LA-SEC groups and PSM-matched groups. Results: Of the 258 patients enrolled, mean age was 71.8 ± 8.3 years and 59.3 % were male. LA-SEC group had a higher percentage of persistent AF and worse cardiac function. No significant difference in peri-procedure parameters was found. Through follow-up of 38.1 ± 10.7 months, the total incidence of thromboembolic events and stroke was 7.8 % and 6.6 %, respectively. Though the event-free survival rate of thromboembolic events (Log-Rank P = 0.042) and stroke (Log-Rank P = 0.010) was significantly lower in the LA-SEC group, multivariable COX regression analysis showed LA-SEC was not an independent predictor of thromboembolic events (Hazard ratio 2.073, 95 % Confidence interval 0.845–5.082, P = 0.111). Further survival analysis between PSM-matched groups with comparable baseline characteristics presented no significant difference in survival free from thromboembolic events (Log-Rank P = 0.616) and stroke (Log-Rank P = 0.312). Conclusion: Patients with LA-SEC had worse condition, while LA-SEC per se did not increase the incidence of thromboembolic events and stroke for patients who underwent LAAC.

Summary: Von Hippel-Lindau (VHL) syndrome is a rare autosomal dominant disorder, where renal cell carcinoma (RCC) serves as a significant cause of mortality. We collected peripheral blood from 61 VHL-RCC patients and 31 healthy individuals, along with 19 paired RCC tumor and adjacent non-malignant samples. Using liquid chromatography-mass spectrometry, we identified 238 plasma and 241 tissue differentially abundant metabolites (DAMs), highlighting key pathways such as arginine and proline metabolism. The top 10 of the 23 DAMs, common to both plasma and tissue, were instrumental in constructing a high-performance diagnostic model. These DAMs demonstrated significant correlations with VHL gene mutation types. Cox regression analysis revealed that plasma levels of N2,N2-dimethylguanosine were associated with the timing of RCC onset in VHL patients, acting as an independent predictive factor. This study enhances diagnostic accuracy for this rare condition and opens new avenues for exploring metabolic mechanisms of the disease and potential therapeutic directions.

Abstract Soil moisture (SM) plays an important role in regulating regional weather and climate. However, the simulations of SM in current land surface models (LSMs) contain large biases and model spreads. One primary reason contributing to such model biases could be the misrepresentation of soil texture in LSMs, since current available large‐scale soil texture data are often generated from extrapolation algorithm based on a scarce number of in‐situ geological measurements. Fortunately, recent advancements in satellite technology provide a unique opportunity to constrain the soil texture data sets by introducing observed information at large spatial scales. Here, two major soil texture baseline data sets (Global Soil Data sets for Earth system science, GSDE and Harmonized World Soil Data from Food and Agriculture Organization, HWSD) are optimized with satellite‐estimated soil hydraulic parameters. The optimized soil maps show increased (decreased) sand (clay) content over arid regions. The soil organic carbon (SOC) content increases globally especially over regions with dense vegetation cover. The optimized soil texture data sets are then used to run simulations in one example LSM, that is, Noah LSM with Multiple Parameters. Results show that the simulated SM with satellite‐optimized soil texture maps is improved at both grid and in‐situ scales. Intercase comparison analyses show the SM improvement differs between simulations using different soil maps and soil hydraulic schemes. Our results highlight the importance of incorporating observation‐oriented calibration on soil texture in current LSMs. This study also joins the call for a better soil profile representation in the next generation of Earth System Models (ESMs).

Abstract Background Recent studies highlighted that stress hyperglycemia ratio (SHR) is a potential predictor for future risk in heart failure (HF) patients. However, its implications specifically in HF with preserved ejection fraction (HFpEF) are not yet fully elucidated. We aimed to investigate the association between SHR and long-term clinical outcomes in HFpEF patients. Methods HFpEF patients enrolled between 2015 and 2023, were followed (mean 41 months) for a composite outcome of all-cause, cardiovascular mortality, and HF rehospitalization. SHR was established as the ratio of acute-chronic glycemia from admission blood glucose and glycated hemoglobin. The optimal cut-off for SHR to predict outcomes based on event prediction was determined through ROC analysis, and the cutoff was identified at 0.99. The effect of SHR on adverse risk was examined through the Cox hazards and Kaplan-Meier survival methods. A Pearson correlation analysis was conducted to assess the relationship between SHR and the severity of HF, as indicated by N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Furthermore, the incremental prognostic value of SHR was further assessed by the integrated discrimination improvement (IDI) and the net reclassification improvement (NRI). Results Among the 400 enrolled patients, 190 individuals (47.5%) encountered composite events over the 41-month follow-up period. SHR was significantly elevated in patients with events compared with those without (p 0.99) in comparison to the other groups (log-rank p

Abstract Background The combined procedure of left atrial appendage closure (LAAC) with concomitant pulmonary vein isolation (PVI) has demonstrated its efficacy and safety. However, there is still a lack of comparative investigations regarding the long-term benefits of the combined procedure when compared to LAAC alone. Our study aims to assess the long-term outcomes of combined procedure of LAAC with concomitant PVI in comparison with a propensity matched LAAC alone group. Methods Propensity score matching (PSM) was employed to rectify covariate imbalances, resulting in the inclusion of 153 comparable patients from the initial cohort of 333 non-valvular atrial fibrillation (AF) patients. Clinical outcomes, encompassing thrombotic events, major cardiocerebrovascular adverse events (MACCE), re-hospitalization due to cardiovascular disease (CVD), and atrial tachycardia (AT), were juxtaposed between the two groups. Bleeding events and peri-device complications, such as residual flow, device-related thrombus, and device replacement, were also compared. Additionally, a patients group underwent PVI alone was included for comparing AF recurrence rates between the PVI alone group and the combined group. Results Following PSM, 153 patients (mean age 70.3 ± 8.9, 62.7% men) were included, with 102 undergoing the combined procedure and 51 undergoing LAAC alone. No significant differences were found in baseline characteristics between the two groups. The mean follow-up time was 37.6 ± 7.9 months, and two patients were lost to follow-up in the combined procedure group. Thrombotic events were observed in 4 (7.8%) patients in the LAAC alone group and 4 (4.0%) in the combined group (Log-rank p = 0.301). The proportion of patients experiencing MACCE, re-hospitalization due to CVD, and AT between the two groups was comparable, as were bleeding events and peri-device complications. Among patients from the combined procedure group without AF recurrence, a significant difference was noted in prior-procedure left ventricular ejection fraction (LVEF) and LVEF at the 12th month after the procedure (57.2% ± 7.1% vs. 60.5% ± 6.5%, p = 0.002). Conclusion The concomitant PVI and LAAC procedure did not increase procedure-related complications, nor did it confer significant benefits in preventing thrombotic events or reducing other cardiovascular events. However, the combined procedure improved heart function, suggesting potential long-term benefits.

Abstract Cardiac aging, particularly cardiac cell senescence, is a natural process that occurs as we age. Heart function gradually declines in old age, leading to continuous heart failure, even in people without a prior history of heart disease. To address this issue and improve cardiac cell function, it is crucial to investigate the molecular mechanisms underlying cardiac senescence. This review summarizes the main mechanisms and key proteins involved in cardiac cell senescence. This review further discusses the molecular modulators of cellular senescence in aging hearts. Furthermore, the discussion will encompass comprehensive descriptions of the key drugs, modes of action and potential targets for intervention in cardiac senescence. By offering a fresh perspective and comprehensive insights into the molecular mechanisms of cardiac senescence, this review seeks to provide a fresh perspective and important theoretical foundations for the development of drugs targeting this condition.

Abstract There lacks real‐world study with a large sample size assessing olmesartan medoxomil‐amlodipine besylate (OM‐AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM‐AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM‐AML (20/5 mg) tablet were analyzed in the current prospective, single‐arm, multi‐center, real‐world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was ‐10.8 ± 0.4/‐6.6 ± 0.3 mmHg at W4 and ‐12.7 ± 0.5/‐7.6 ± 0.3 mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home‐measured SeSBP and SeDBP decreased from W1 to W8 (both p

Summary: Background: The public health burden of cardiomyopathies and competency in their management by health agencies in China are not well understood. Methods: This study adopted a multi-stage sampling method for hospital selection. In the first stage, nationwide tertiary hospital recruitment was performed. As a result, 88 hospitals with the consent of the director of cardiology and access to an established electronic medical records system, were recruited. In the second stage, we sampled 66 hospitals within each geographic-economic stratification through a random sampling process. Data on (1) the outpatient and inpatient visits for cardiomyopathies between 2017 and 2021 and (2) the competency in the management of patients with cardiomyopathies, were collected. The competency of a hospital to provide cardiomyopathy care was evaluated using a specifically devised scale. Findings: The outpatient and inpatient visits for cardiomyopathies increased between 2017 and 2021 by 38.6% and 33.0%, respectively. Most hospitals had basic facilities for cardiomyopathy assessment. However, access to more complex procedures was limited, and the integrated management pathway needs improvement. Only 4 (6.1%) of the 66 participating hospitals met the criteria for being designated as a comprehensive cardiomyopathy center, and only 29 (43.9%) could be classified as a primary cardiomyopathy center. There were significant variations in competency between hospitals with different administrative and economic levels. Interpretation: The health burden of cardiomyopathies has increased significantly between 2017 and 2021 in China. Although most tertiary hospitals in China can offer basic cardiomyopathy care, more advanced facilities are not yet universally available. Moreover, inconsistencies in the management of cardiomyopathies across hospitals due to differing administrative and economic levels warrants a review of the nation allocation of medical resources. Funding: This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2023-I2M-1-001) and the National High Level Hospital Clinical Research Funding (2022-GSP-GG-17).

Background: Contrast retention (CR) is an important predictor of left atrial appendage thrombus (LAAT) and stroke in patients with non-valvular atrial fibrillation (AF). We sought to explore the underlying mechanisms of CR using computational fluid dynamic (CFD) simulations. Methods: A total of 12 patients with AF who underwent both cardiac computed tomography angiography (CTA) and transesophageal echocardiography (TEE) before left atrial appendage occlusion (LAAO) were included in the study. The patients were allocated into the CR group or non-CR group based on left atrial appendage (LAA) angiography. Patient-specific models were reconstructed to evaluate time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), relative residence time (RRT), and endothelial cell activation potential (ECAP). Additionally, the incidence of thrombosis was predicted using residence time (RT) at different time-points. Results: TAWSS was lower [median (Interquartile Range) 0.27 (0.19–0.47) vs 1.35 (0.92–1.79), p

Background: This study aimed to assess the relationship between stent parameters and platelet function, as well as the platelet reactivity profiles over time in patients treated with the Xinsorb scaffold. Methods: Adenosine diphosphate-induced maximal amplitude was measured as clopidogrel on-treatment platelet reactivity using thrombelastography. High residual platelet reactivity was defined as MAADP > 47 mm. Platelet function testing was induced at baseline, discharge, and 6- and 12-month visits. Results: A total of 40 individuals undergoing Xinsorb scaffold implantation and platelet function testing were included. No adverse events were recorded during follow-up. No correlation was observed among thrombelastography indices, stent diameters, and stent coverage surface area. Significant correlation was found between MAADP and lengths of stents (Spearman rank correlation = 0.324, P =.031). Multiple logistic regression analyses demonstrated that high levels of high-density lipoprotein cholesterol was an independent protective factor for high residual platelet reactivity (odds ratio = 0.049, 95% con-fidence interval = 0.011-0.296, P =.016). No significant risk factors were identified; MAADP presented to be 20.6 [13.1-36.2] mm, 26.8 [18.2-35.0] mm, and 30.0 [19.6-33.4] mm 48 hours, 6 months, and 12 months after procedure, respectively; 12-month MAADP was sig-nificantly higher than the 48-hour MAADP (P =.026). There was no obvious trend for platelet response status over time. Conclusion: Among patients on a clopidogrel-based dual antiplatelet treatment regimen following Xinsorb scaffold implantation, stent parameters had no significant effects on platelet reactivity. The high residual platelet reactivity phenotype is relatively stable over time. High residual platelet reactivity is more likely to occur in patients with lower high-density lipoprotein cholesterol levels.

Abstract Background The management of advanced clear cell renal cell carcinoma (ccRCC) remains a major challenge in clinical practice, and the construction of more reliable prognostic prediction models and the further elucidation of key molecular mechanisms of tumor progression are topics in urgent need of in-depth investigation. Methods We used CIBERSORT to estimate the proportion of 22 tumor-infiltrating immune cell types in the TCGA-KIRC cohort. Weighted gene co-expression network analysis, least absolute shrinkage and selection operator regression analysis were used to build risk prediction models. Expression patterns and clinical significance of TRAF2 were determined through bioinformatics analysis, real-time qPCR, Western Blot, immunohistochemistry. GSEA analysis, transmission electron microscopy, 2D/3D colony formation assay, cell migration and invasion assay, and tube-formation assay were used to investigate the underlying function and mechanism of the TRAF2/M2 macrophage/autophagy axis. Results We constructed a novel prognostic prediction model based on M2 macrophage-related genes, which was identified as an accurate, independent and specific prognostic risk model for ccRCC patients. A reliable nomogram was constructed to predict 1-, 3-, and 5-year overall survival for patients with ccRCC. As one of the constituent genes of the risk model, TRAF2 was determined to be upregulated in ccRCC and associated with poor clinical prognosis. We found that TRAF2 promotes malignant progression of ccRCC by regulating macrophage polarization, migration and angiogenesis. Mechanistically, we found that TRAF2 promotes the polarization of M2 macrophages, and this chemotaxis is achieved in an autophagy-dependent pathway. Orthotopic tumor growth assay results revealed that TRAF2 plays a key role as a promotor of ccRCC growth and metastasis. Conclusions In conclusion, this risk model is highly predictive of prognostic in ccRCC patients, which is expected to promote improved treatment evaluation and comprehensive management of ccRCC. Moreover, our findings reveal that the TRAF2/M2 macrophage/autophagy axis plays a key regulatory role in the malignant progression of ccRCC, and suggest that TRAF2 is a potential novel therapeutic target for advanced ccRCC.

Pheochromocytomas (PCCs) are rare neuroendocrine tumors that originate from chromaffin cells in the adrenal gland. However, the cellular molecular characteristics and immune microenvironment of PCCs are incompletely understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on 16 tissues from 4 sporadic unclassified PCC patients and 1 hereditary PCC patient with Von Hippel-Lindau (VHL) syndrome. We found that intra-tumoral heterogeneity was less extensive than the inter-individual heterogeneity of PCCs. Further, the unclassified PCC patients were divided into two types, metabolism-type (marked by NDUFA4L2 and COX4I2) and kinase-type (marked by RET and PNMT), validated by immunohistochemical staining. Trajectory analysis of tumor evolution revealed that metabolism-type PCC cells display phenotype of consistently active metabolism and increased metastasis potential, while kinase-type PCC cells showed decreased epinephrine synthesis and neuron-like phenotypes. Cell-cell communication analysis showed activation of the annexin pathway and a strong inflammation reaction in metabolism-type PCCs and activation of FGF signaling in the kinase-type PCC. Although multispectral immunofluorescence staining showed a lack of CD8+ T cell infiltration in both metabolism-type and kinase-type PCCs, only the kinase-type PCC exhibited downregulation of HLA-I molecules that possibly regulated by RET, suggesting the potential of combined therapy with kinase inhibitors and immunotherapy for kinase-type PCCs; in contrast, the application of immunotherapy to metabolism-type PCCs (with antigen presentation ability) is likely unsuitable. Our study presents a single-cell transcriptomics-based molecular classification and microenvironment characterization of PCCs, providing clues for potential therapeutic strategies to treat PCCs.

Abstract Background Coronary microvascular dysfunction (CMD) is a strong determinant of prognosis in patients with chronic coronary syndrome (CCS). The triglyceride-glucose index (TyG index), an alternative method to evaluate insulin resistance, is positively correlated with the incidence and adverse outcomes of cardiovascular diseases. However, the relationship between the TyG index and the presence and prognosis of CMD in CCS patients has not been investigated. Therefore, we aimed to evaluate the association between the TyG index and the presence and clinical outcomes of CMD among CCS patients. Methods CCS patients who underwent coronary angiography between June 2015 to June 2019 were included. The TyG index was calculated as Ln[fasting triglycerides (mg/dL) × fasting blood glucose (mg/dL)/2]. Coronary angiography‑derived index of microvascular resistance (caIMR) was used to measure microvascular function, and CMD was defined as caIMR ≥ 25U. Patients with CMD were divided into three groups (T1, T2, and T3 groups) according to TyG tertiles. The primary endpoint was major adverse cardiac event (MACE). Results Of 430 CCS patients, 221 patients had CMD. CMD patients had significantly higher TyG index than those without CMD. Sixty-three MACE was recorded during the follow-up duration among CMD patients, and the incidence rate of MACE was higher in the T3 group compared to T1/T2 groups (39.2% vs. 20.5% vs. 25.7%; P = 0.035). Multivariable logistic regression analysis showed that the TyG index was an independent predictor of CMD (OR, 1.436; 95% CI, 1.014–2.034; P = 0.042). Compared to the T1 group, the T3 group strongly correlated with the risk of MACE in CMD patients even after adjusting for additional confounding risk factors (HR, 2.132; 95%CI, 1.066–4.261; P = 0.032). Conclusion TyG index is significantly associated with the risk of CMD, and it is an independent predictor of MACE among CMD patients with CCS. This study suggests that the TyG index has important clinical significance for the early prevention and risk stratification of CMD.

Abstract The clock synchronisation of the power system is to realise the clock synchronisation of the whole network. The clock synchronisation network is composed of the clock synchronisation systems of power grids at all levels. Dispatching agencies, power plants, and substations have their clock synchronisation systems. By using computer technology, communication technology, and network technology, combined with the topological structure of the power grid and geographic information of the geographic information system, automatically process the key index data to ensure that the distribution network project can manage the power consumption and distribution 24 h without interruption. Considering the particularity of power, the accuracy of the receiver is strictly required, and so are the positioning, speed measurement, and time accuracy. Test indicators study a set of accurate and reliable test and evaluation methods. A gross error processing method based on the k‐means algorithm is proposed. Experiments show that gross errors can be well identified and eliminated in one‐dimensional and multidimensional data. Considering that invalid data may be hidden in the test data, to improve the identification accuracy without affecting the detection of normal gross errors, based on the proposed k‐means algorithm, the number of visible satellites is added. Because the magnitude difference between the number of visible satellites and the original three‐dimensional positioning error data is relatively large, it is normalised first. The processing data is extended from three‐dimensional to four‐dimensional. The experimental simulation shows that it can not only identify invalid data but also ensure a good effect of gross error elimination, reduce possible economic losses, bring significant direct and indirect economic benefits, and verify the feasibility and promotional value of the online monitoring platform through practice.

Abstract Recent evidences have suggested that Zinc finger protein 582 (ZNF582) plays different important roles in various tumors, but its clinical role, biological function and regulatory mechanism in clear cell renal cell carcinoma (ccRCC) are still vague. Through analyzing GEO and TCGA-KIRC data and validation with local samples, we identified the low expression pattern of ZNF582 in ccRCC. Decreased ZNF582 expression is correlated with higher tumor stage and grade, distant metastasis and poor prognosis. By analyzing the DNA methylation data of ccRCC in TCGA-KIRC and using Massarray DNA methylation and demethylation analysis, we confirmed the hypermethylation status of ZNF582 in ccRCC and its negative regulation on ZNF582 expression. Using cell phenotype experiments and orthotopic kidney tumor growth models, we determined the inhibitory effect of ZNF582 overexpression on ccRCC growth and metastasis in vivo and in vitro. Mechanistically, using TMT (Tandem mass tags) quantitative proteomics test, Co-IP (Co-immunoprecipitation) and Western Blot experiments, we clarified that ZNF582 binds to TJP2 and up-regulates TJP2 protein expression. Increased TJP2 protein combines with ERK2 to promote ERK2 protein expression and suppresses the phosphorylation of ERK2, thereby inhibiting the growth and metastasis of ccRCC. In general, our findings provide the first solid theoretical rationale for targeting ZNF582/TJP2/ERK2 axis to improve ccRCC treatment.

Multisystem inflammatory syndrome adult type (MIS-A) is a rare type of post-acute COVID-19 syndrome which more frequently occurred in younger population. Here we present a 78-year-old Chinese female, the oldest case reported, diagnosed with MIS-A who had severe SARS-CoV-2 infection. She was diagnosed with severe COVID-19 and experienced an unexpected sudden hemodynamic collapse in the recovery period within three weeks. Her platelet count was sharply dropped, accompanied with sustained cardiac, kidney and liver injury. She was diagnosed with MIS-A according to criteria established by Center of Disease Control and Prevention. Though her condition was improved under administrating with high dose of methylprednisolone and intravenous immunoglobulin, methylprednisolone was unable to withdraw till two weeks as her partial pressure of oxygen/fraction of inspiration oxygen ratio and platelet count dropped on the heels of decreasing dosage. Unfortunately, the patient’s condition gradually deteriorated with the development of severe nosocomial pneumonia. We presented this rare case in order to emphasize that MIS-A could occur in the elderly and the management of this population might be more difficult as the condition of the elderly with SARS-CoV-2 infection and MIS-A might be more severe.

Abstract Background Little is known about the predictive value of soluble AXL (sAXL) in heart failure (HF). This study aimed to describe the prognostic value of plasma sAXL in patients with symptomatic HF. Methods This is a multicentre observational prospective cohort study (Registration No. NCT03727828). Plasma sAXL were measured on admission. The primary endpoint is a composite of cardiovascular mortality and HF rehospitalization. Associations between plasma sAXL levels and clinical endpoints are described using Cox regression models and Kaplan–Meier methods. Results A total of 1030 symptomatic HF patients were enrolled in the study; the mean age (65% men) was 71 ± 12 years, with a median follow‐up of 32 months (IQR: 26–41 months). The mean baseline sAXL levels were 20.03 ± 6.74 ng/mL. Plasma sAXL positively associated with NYHA classification and negatively associated with left ventricular ejection fraction (both P

Abstract Background Stress hyperglycemia ratio (SHR) is a novel biomarker of true acute hyperglycemia condition and is associated with a worse prognosis in patients with myocardial infarction (MI). However, the effects of SHR in the setting of MI with non-obstructive coronary arteries (MINOCA) have not been investigated. This study aimed to explore the association between SHR and long-term clinical outcomes among MINOCA patients. Methods A total of 410 MINOCA patients were included in the final analysis of this study. The patients were divided into three groups based on the SHR tertiles: [SHR1 group (SHR ≤ 0.73), (n = 143); SHR2 group (SHR 0.73–0.84), n = 131; and SHR3 group (SHR ≥ 0.84), n = 136]. Follow-up for major adverse cardiovascular events (MACE) was conducted on all patients. Cox regression and Kaplan–Meier curve analysis were used to evaluate the relationship between SHR and MACE. The receiver operating curve (ROC) analysis was applied to obtain the optimal cut-off value of SHR for predicting clinical MACE. Results A total of 92 patients developed MACE during the mean 34 months of follow-up. A significant increase in MACE was observed in the SHR3 group compared to the SHR1 and SHR2 groups (35.3% vs. 15.4% and 16.8%, respectively; P

Abstract Background The research of the sensitivity and specificity point-of-care testing (POCT) of D-dimer as a diagnostic protocol for differential diagnosis of Stanford Type A aortic syndrome (hereafter as TAAS) mimicking ST-elevated myocardial infarction (STEMI) with regular STEMI in the emergency department is limited. Methods Full medical information of 32 patients confirmed TAAS and 527 patients confirmed STEMI from January 1st, 2016 to October 1st, 2021 were retrospectively analyzed in Shanghai Tenth People’s Hospital of Tongji University. Results The baseline characteristics of two groups of patients were well-balanced post propensity score matching (PSM) analysis, and each group had 32 patients enrolled. Patients in the STEMI group had higher positive cardiac troponin I (cTNI) (0.174 ng/ml vs. 0.055 ng/ml, P = 0.008) results but lower D-dimer (0.365μg/ml vs. 31.50μg/ml, P

Abstract Background Coronary microvascular dysfunction (CMD) is common and is associated with unfavorable cardiovascular events in patients with diabetes mellitus (DM). Coronary angiography-derived index of microcirculatory resistance (caIMR) is a recently developed wire- and hyperemic agent-free method to assess CMD. We aimed to investigate the prognostic impact of CMD assessed by caIMR on clinical outcomes in patients with DM and chronic coronary syndrome (CCS). Methods CCS patients who underwent coronary angiography between June 2015 to May 2018 were included. Coronary microvascular function was measured by caIMR, and CMD was defined as caIMR ≥ 25U. The primary endpoint was major adverse cardiac events (MACE). Kaplan-Meier analysis and Cox proportional hazards models were used to assess the relationship between caIMR and the risk of MACE. Results Of 290 CCS patients, 102 patients had DM. Compared with non-diabetic patients, CMD (caIMR ≥ 25U) was higher among DM patients (57.8% vs. 38.3%; p = 0.001). During a mean 35 months follow-up, 40 MACE had occurred. Patients with caIMR ≥ 25 had a higher rate of MACE than patients with caIMR

BackgroundThe association between age at menarche and coronary heart disease has been reported, but the association between age at menarche and valvular heart disease (VHD) has not been described. We aimed to examine the association between age at menarche and VHD.MethodsBy collecting data from four medical centers of the Affiliated Hospital of Qingdao University (QUAH) from January 1, 2016, to December 31, 2020, we sampled 105,707 inpatients. The main outcome of this study was newly diagnosed VHD, which was diagnosed based on ICD-10 coding, and the exposure factor was age at menarche, which was accessed through the electronic health records. We used logistic regression model to investigate the association between age at menarche and VHD.ResultsIn this sample (mean age 55.31 ± 13.63 years), the mean age at menarche was 15. Compared with women with age at menarche 14–15 years, the odds ratio of VHD in women with age at menarche ≤13, 16–17, and ≥18 years was 0.68 (95% CI 0.57–0.81), 1.22 (95% CI 1.08–1.38), and 1.31 (95% CI 1.13–1.52), respectively (P for all

Objectives: To determine the role of MYL4 regulation of lysosomal function and its disturbance in fibrotic atrial cardiomyopathy. Background: We have previously demonstrated that the atrial-specific essential light chain protein MYL4 is required for atrial contractile, electrical, and structural integrity. MYL4 mutation/dysfunction leads to atrial fibrosis, standstill, and dysrhythmia. However, the underlying pathogenic mechanisms remain unclear. Methods and results: Rats subjected to knock-in of a pathogenic MYL4 mutant (p.E11K) developed fibrotic atrial cardiomyopathy. Proteome analysis and single-cell RNA sequencing indicate enrichment of autophagy pathways in mutant-MYL4 atrial dysfunction. Immunofluorescence and electron microscopy revealed undegraded autophagic vesicles accumulated in MYL4p.E11K rat atrium. Next, we identified that dysfunctional MYL4 protein impairs autophagy flux in vitro and in vivo. Cardiac lysosome positioning and mobility were regulated by MYL4 in cardiomyocytes, which affected lysosomal acidification and maturation of lysosomal cathepsins. We then examined the effects of MYL4 overexpression via adenoviral gene-transfer on atrial cardiomyopathy induced by MYL4 mutation: MYL4 protein overexpression attenuated atrial structural remodeling and autophagy dysfunction. Conclusions: MYL4 regulates autophagic flux in atrial cardiomyocytes via lysosomal mobility. MYL4 overexpression attenuates MYL4 p.E11K induced fibrotic atrial cardiomyopathy, while correcting autophagy and lysosomal function. These results provide a molecular basis for MYL4-mutant induced fibrotic atrial cardiomyopathy and identify a potential biological-therapy approach for the treatment of atrial fibrosis.

Introduction: Leucine-rich repetitive kinase-2 (LRRK2) is a Parkinson's disease-related gene that also participates in many inflammatory diseases. However, the functional role of LRRK2 in cardiovascular disease is not clear. Objective: In this study, we aimed to elucidate the role of LRRK2 in cardiac remodelling under pressure overload. Methods: Aortic banding surgery was performed to induce cardiac remodelling in a LRRK2 knockout mouse model. A cardiomyocyte remodelling model was established by phenylephrine (PE) stimulation in neonatal rat cardiomyocytes. Results: LRRK2 was upregulated in remodelled mouse hearts and cardiomyocytes. Cardiac hypertrophy, fibrosis and dysfunction were ameliorated in LRRK2 knockout mice. LRRK2 silencing protected against the PE-induced cardiomyocyte hypertrophic response, while LRRK2 over-expression worsened the PE-induced hypertrophic response in cardiomyocytes. Decreased autophagy was observed in remodelled cardiomyocytes, whereas LRRK2 silencing increased autophagy levels and LRRK2 overexpression reduced autophagy levels. The autophagy inhibitors 3-MA, bafilomycin and chloroquine reversed the protective effects of LRRK2 deficiency. The autophagy activator rapamycin reversed the deleterious effects of LRRK2 overexpression. We found that LRRK2 inhibited Bcl-2 phosphorylation, thus decreasing the phosphorylation of Beclin1. The protective effects of LRRK2 knockout were partly counteracted by Beclin1(+/−) in vivo and Beclin1 silencing in vitro. We also observed an interaction between LRRK2 and Rab7, an autolysosome degradation-associated protein, which caused Rab7 downregulation. Rab7 knockdown almost completely reversed LRRK2 silencing-induced protection of cardiomyocytes Conclusion: LRRK2 deficiency protected against cardiac remodelling under pressure overload by increasing Bcl-2/Beclin1 and Rab7-regulated autophagy levels in the heart.

Heart rate variability (HRV) is an important marker for assessing the balance of the autonomic nervous system and clinical prognosis, because it can be non-invasively and easily measured, and the results are accurate and valuable. HRV is widely applied in cardiovascular disease fields. Exercise training is an important part of cardiac rehabilitation. Personalized sports rehabilitation therapy can effectively prevent the emergence of cardiovascular diseases, decrease the risk of recurrent cardiovascular events, and ameliorate dysfunction, as well as limitations in life, work, and social participation, caused by adverse cardiovascular events. However, sports rehabilitation can have drawbacks, in that improper training can cause injury, excessive fatigue, or even harmful cardiovascular events. To support future applications, this article reviews recent applications of HRV in sports rehabilitation for cardiovascular diseases.

Background: Various electrocardiographic (ECG) abnormalities are associated with the severity of pulmonary thromboembolism (PTE). The utility of evaluating the clot burden of PTE based on ECG findings alone has yet to be thoroughly investigated in Chinese patients. The aim of this study was therefore to use ECG signs to establish novel models for quantitative and localization analysis of clot burden in patients with acute PTE. Methods: Acute PTE patients from three centers were enrolled between 2015 and 2019 in a retrospective cohort study (NCT03802929). We analyzed the 12-lead ECGs at admission and studied computed tomography pulmonary angiography (CTPA) features to obtain the Qanadli score of clot burden and location of thrombus. Novel risk prediction models were developed and validated using derivation and external validation cohorts, respectively. Results: A total of 341 acute PTE patients were screened, of whom 246 (72.1%) were from Shanghai Tenth People’s Hospital, 71 (20.8%) were from Shanghai Pulmonary Hospital and 24 (7.0%) were from Qidong People’s Hospital. In the derivation cohort, predictors included in the final models were congestive heart failure, chronic obstructive pulmonary disease, hypertension, coronary heart disease, atrial fibrillation and ECG abnormalities. The CHARIS (COPD/CHF/CHD, HTN, Atrial arrhythmias/AF, RBBB/RAD, Inverted T wave and S1Q3T3/ Sinus tachycardia) I model was established for quantitatively assessing Qanadli score. It had moderate discrimination in both the derivation cohort (concordance index (c-index) of 0.720, 95% CI 0.655–0.780) and the validation cohort (c-index of 0.663, 95% CI 0.559–0.757). The CHARIS II model was used to predict the probability of trunk obstruction. It showed similar discrimination in the derivation cohort (c-index of 0.753, 95% CI 0.691–0.811) and in the validation cohort (c-index of 0.741, 95% CI 0.641–0.827). Calibration curves and Hosmer-Lemeshow test confirmed the accuracy of the risk prediction equations in the external validation dataset. Decision curve analysis showed the CHARIS I and CHARIS II algorithms had positive net benefits in both the derivation and validation cohorts. Conclusions: From quantitative and localization perspectives, the CHARIS algorithms can identify acute PTE patients with heavy thrombus burdens prior to imaging diagnosis. Clinical Trial Registration: NCT03802929, https://www.clinicaltrials.gov/study/NCT03802929.

Abstract Getah virus (GETV), a member of the genus alphavirus, is a mosquito-borne pathogen that can cause pyrexia and reproductive losses in animals. Although antibodies to GETV have been found in over 10% of healthy people, there are no reports of clinical symptoms associated with GETV. The biological and pathological properties of GETV are largely unknown and antiviral or vaccine treatments against GETV are still unavailable due to a lack of knowledge of the structure of the GETV virion. Here, we present the structure of infective GETV at a resolution of 2.8 Å with the atomic models of the capsid protein and the envelope glycoproteins E1 and E2. We have identified numerous glycosylation and S-acylation sites in E1 and E2. The surface-exposed glycans indicate a possible impact on viral immune evasion and host cell invasion. The S-acylation sites might be involved in stabilizing the transmembrane assembly of E1 and E2. In addition, a cholesterol and a phospholipid molecule are observed in a transmembrane hydrophobic pocket, together with two more cholesterols surrounding the pocket. The cholesterol and phospholipid stabilize the hydrophobic pocket in the viral envelope membrane. The structural information will assist structure-based antiviral and vaccine screening, design, and optimization.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial pneumonia. Lung cancer, mainly non-small cell lung cancer (NSCLC), is a complication of idiopathic pulmonary fibrosis. IPF is also an independent risk factor of lung cancer. Some studies have shown that the complement system can promote the progression of interstitial pulmonary fibrosis. In addition, C1q has also demonstrated to exert a tumor-promoting effect in many tumors. However, the role of C1q in idiopathic pulmonary fibrosis and lung cancer still remain unclear. Methods We selected common differentially expressed genes in IPF and non-small cell lung cancer using datasets from GEO, and investigated common hub gene. The hub genes were validated in IPF by establishing mouse model of IPF and using another four datasets from the GEO. Multiple databases were analyzed including those of Kaplan–Meier Plotter, Tumor Immune Estimation Resource (TIMER2.0) and the Human Protein Atlas (HPA) for NSCLC. Results In this study, 37 common DEGs were identified in IPF and NSCLC including 32 up-regulated genes and 5 down-regulated genes, and C1q was identified as common hub gene. The methylation status of C1q decreased and the expression levels of C1q increased in both lung cancer and idiopathic pulmonary fibrosis. The prognosis of non-small cell lung cancer and IPF patients with high levels of C1q is poor. Conclusions These results show that C1q participates in pulmonary fibrosis and non-small cell lung cancer, and may be a potential diagnostic / prognostic biomarker or a therapeutic target.

BackgroundAcute coronary syndrome (ACS) is the most time-sensitive acute cardiac event that requires rapid dispatching and response. The medical priority dispatch system (MPDS), one of the most extensively used types of emergency dispatch systems, is hypothesized to provide better-quality prehospital emergency treatment. However, few studies have revealed the impact of MPDS use on the process of ACS care. ObjectiveThis study aimed to investigate whether the use of MPDS was associated with higher prehospital diagnosis accuracy and shorter prehospital delay for patients with ACS transferred by an emergency medical service (EMS), using a national database in China. MethodsThis retrospective analysis was based on an integrated database of China’s MPDS and hospital registry. From January 1, 2016, to December 31, 2020, EMS-treated ACS cases were divided into before MPDS and after MPDS groups in accordance with the MPDS launch time at each EMS center. The primary outcomes included diagnosis consistency between hospital admission and discharge, and prehospital delay. Multivariable logistic regression and propensity score–matching analysis were performed to compare outcomes between the 2 groups for total ACS and subtypes. ResultsA total of 9806 ACS cases (3561 before MPDS and 6245 after MPDS) treated by 43 EMS centers were included. The overall diagnosis consistency of the after MPDS group (Cohen κ=0.918, P

Summary: Background: Acute aortic dissection (AAD) is a life-threatening cardiovascular emergency with high mortality, so identifying modifiable risk factors of AAD is of great public health significance. The associations of non-optimal temperature and temperature variability with AAD onset and the disease burden have not been fully understood. Methods: We conducted a time-stratified case-crossover study using a nationwide registry dataset from 1,868 hospitals in 313 Chinese cities. Conditional logistic regression and distributed lag models were used to investigate associations of temperature and temperature changes between neighboring days (TCN) with the hourly AAD onset and calculate the attributable fractions. We also evaluated the heterogeneity of the associations. Findings: A total of 40,270 eligible AAD cases were included. The exposure-response curves for temperature and TCN with AAD onset risk were both inverse and approximately linear. The risks were present on the concurrent hour (for temperature) or day (for TCN) and lasted for almost 1 day. The cumulative relative risks of AAD were 1.027 and 1.026 per 1°C lower temperature and temperature decline between neighboring days, respectively. The associations were significant during the non-heating period, but were not present during the heating period in cities with central heating. 23.13% of AAD cases nationwide were attributable to low temperature and 1.58% were attributable to temperature decline from the previous day. Interpretation: This is the largest nationwide study demonstrating robust associations of low temperature and temperature decline with AAD onset. We, for the first time, calculated the corresponding disease burden and further showed that central heating may be a modifier for temperature-related AAD risk and burden. Funding: This work was supported by the National Natural Science Foundation of China (92043301 and 92143301), Shanghai International Science and Technology Partnership Project (No. 21230780200), the Medical Research Council-UK (MR/R013349/1), and the Natural Environment Research Council UK (NE/R009384/1).

Background Left atrial appendage (LAA) closure (LAAC) could prevent stroke in patients with atrial fibrillation. However, LAAC may impair the compliance of the left atrium and result in poor prognosis. This study aimed to comparatively evaluate the prognosis of LAAC among patients with different sizes of LAA orifice. Methods and Results Three hundred two consecutive patients who underwent successful LAAC were included and divided into 4 groups based on LAA orifice size that was measured using transesophageal echocardiography. Clinical outcomes including thromboembolic events, major cardiocerebrovascular adverse events, and acute heart failure (AHF) were compared among 4 quartile groups and between propensity‐score matched groups of large and small LAAs. Through follow‐up of 39.6±8.4 months, survival of thromboembolic events was similar. Survival of major cardiocerebrovascular adverse events was significantly lower in the group with the largest LAA orifice (log‐rank P

BackgroundThe relative contributions of each component of body composition to blood pressure (BP) remain unclear.ObjectiveWe aimed to comprehensively investigate the impact of body composition and fat distribution on BP and quantify their relative contributions to BP in a large cohort with young and middle-aged adults.Methods14,412 participants with available data on whole-body DXA measurement from the National Health and Nutrition Examination Survey were included. Multiple stepwise linear regressions of BP on components of body composition and fat distribution were built. Then, relative importance analysis was performed to quantify the contributions of each component to BP.ResultsThe median age of participants was 36 years and there were 50.7% women. Linear regression with mutual adjustment showed that total fat mass, total muscle mass, and trunk fat mass significantly and positively associated with BP; however, arm and leg fat mass significantly and negatively associated with BP. In men, after further adjusted for potential covariates, SBP were significantly determined by trunk fat mass (β = 0.33, P < 0.001), leg fat mass (β = − 0.12, P < 0.001), and total muscle mass (β = 0.10, P < 0.001); and DBP were significantly determined by trunk fat mass (β = 0.52, P < 0.001), leg fat mass (β = −0.15, P < 0.001), arm fat mass (β = −0.23, P < 0.001), and total muscle mass (β = 0.06, P < 0.001). Similar results were observed in women. Relative importance analysis showed that trunk fat mass was the major contributor (38–61%) to both SBP and DBP; meanwhile, total muscle mass also made relatively great contribution (35–43%) to SBP.ConclusionBoth fat mass and muscle mass independently associated with and substantially contributed to SBP in both men and women. After full adjustment, trunk fat mass positively associated with both SBP and DBP, and was the most dominant contributor to BP; however, leg fat mass negatively associated with both SBP and DBP.

BackgroundAlthough the implant success rate of left atrial appendage closure (LAAC) has increased and complications have decreased over time, there are still anatomically and technically complicated cases where novel LAA occluders may simplify the procedure and thus might potentially improve the clinical outcome.ObjectivesThis study aimed to assess the safety and efficacy of the newly designed device with isogenous barbs in LAAC.MethodsEight centers in China participated in this prospective study from July 2016 to April 2018. Peri- and post-procedural safety and efficacy were evaluated through scheduled follow-ups and transesophageal echocardiography (TEE).ResultsA total of 175 patients with a mean age of 68.4 ± 9.2 years old, a mean CHA2DS2-VASc score of 4.7 ± 1.8, and a mean HAS-BLED score of 3.2 ± 1.3, were included. The device was successfully implanted in 173 patients (98.9%). The device size ranged from 18 to 34 mm. Clinically relevant pericardial effusion (PEF) in the perioperative period, occurred in 3 patients (1.7%). TEE follow-up was available in 167 (96.5%) patients at 12-month. During follow-up, 9 patients suffered serious adverse event: 4 death (2.3%), 1 ischemic stroke (0.6%), and 2 gastro-intestinal bleeding (1.2%) and 2 device-related thrombus (DRT) (1.2%). Estimated annual thromboembolism rate reduced by 90% and estimated annual major bleeding rate reduced by 81% after LAAC with the newly designed device.ConclusionThe newly designed device with isogenous barbs for LAAC could be performed effectively with a low incidence of adverse events and a high incidence of anatomic closure.

BackgroundAdipokine chemerin was proven to be associated with coronary artery disease (CAD), but its prognostic implications in CAD remain unclear.MethodsThis study consists of two parts, one is a basic study and the other is a clinical cohort study. First, we investigated the differential expression of six adipokines in the atherosclerotic mice model compared to mice with milder degrees of atherosclerosis and mice without atherosclerosis using microarray data. We then examined the potential of chemerin as a diagnostic and prognostic indicator in a CAD cohort. A total of 152 patients were enrolled in our study, including 77 patients with angiographically proven CAD and 75 control subjects without cardiovascular disease. Plasma adipokine chemerin levels were measured in all patients, and major adverse cardiovascular events (MACEs) were followed up, including ischemic stroke, non-fatal myocardial infarction, revascularization, and cardiovascular death.ResultsIn the aortas of atherosclerotic mice, chemerin expression was up-regulated compared to control mice. The plasma chemerin levels of CAD patients were higher than those of non-CAD patients (128.93 ± 37.06 vs. 109.85 ± 27.47 mmol/L, respectively, P < 0.001). High chemerin levels were an independent predictor of CAD (β = 2.702, 95% CI, 1.344–5.431, P = 0.001). We followed up with patients for a median duration of 5.5 years (3.9–5.6). The Kaplan–Meier curves showed that patients in the high chemerin group had a significantly higher risk of MACEs than the low chemerin group in patients with CAD (log-rank P = 0.003), not with non-CAD (Log-rank P = 0.120). Furthermore, Cox multivariate analysis revealed that high chemerin levels were an independent predictor of MACEs (HR 2.267; 95% CI, 1.139–4.515; P = 0.020). Finally, the cellular study showed that chemerin is predominantly expressed in PBMC-derived macrophages.ConclusionPlasma chemerin levels were increased in the CAD patients, and a high chemerin level increased the risk of MACEs in CAD patients.

Summary: Background: The associations of ambient temperature with acute myocardial infarction (AMI) have seldom been examined based on the time of symptom onset. Methods: We conducted a time-stratified case-crossover study among 1,046,773 eligible AMI patients from 2,093 hospitals in 324 Chinese cities from January 1, 2015 to June 30, 2021, after excluding those transferred from other hospitals or having not reported the time of symptom onset. Hourly exposure to ambient temperature was calculated as multiple moving 24-h averages (days) before hourly onset of AMI symptoms. Conditional logistic regression and distributed lag non-linear models with a duration of 0–21 days were used to estimate the cumulative associations of non-optimum temperature with AMI onset and the corresponding disease burden nationally. Subgroup analyses by region and period were conducted. Specifically, cities with and without centralized heating system were classified into heating and non-heating regions, respectively. The whole year in heating region was divided into heating and non-heating periods based on the duration of centralized heating in each city. Findings: Almost monotonically increasing risks were observed for both overall AMI and its two subtypes when ambient temperature declined. The effects of extremely low temperature occurred immediately on the concurrent day, and lasted up to almost 3 weeks. The excess risks of AMI onset associated with non-optimum ambient temperatures were observed during the whole year in the non-heating region and non-heating period in the heating region, but not during heating period. Specifically, odds ratios of AMI onset associated with extremely low temperature cumulated over 0–21 days were 1.24 (95% CI: 1.13–1.37), 1.46 (95% CI: 1.20–1.76), and 1.62 (95% CI: 1.46–1.81) in the heating region during non-heating period, in the non-heating region during winter and non-winter period, respectively. The heat effects on AMI onset were very modest and transient. Totally, 13.26% of AMI cases could be attributable to non-optimum temperatures nationally. The burden of AMI attributable to non-optimum temperature was much smaller in heating region than in non-heating region. Somewhat stronger effects were observed in females and patients aged older than 65. Interpretation: This nationwide study provided robust evidence that non-optimum ambient temperature may significantly trigger AMI onset, and for the first time estimated the disease burden after accounting for spatial and seasonal heterogeneity. Centralized heating might substantially mitigate AMI burden due to non-optimum temperature. Funding: Shanghai International Science and Technology Partnership Project, National Natural Science Foundation of China, Talent Training Program of Zhongshan Hospital, Fudan University.

ObjectiveCoronary microvascular dysfunction (CMD) may associate with adverse cardiovascular events in obese patients. Coronary angiography-derived index of microcirculatory resistance (caIMR) is proposed as a less-invasive and pressure-wire-free index to assess CMD. We aimed to investigate the impact of coronary microvascular function assessed by caIMR in patients with overweight and chronic coronary syndrome (CCS).MethodsCCS patients who underwent coronary angiography between 2015 to 2018 were included. Overweight was defined as BMI≥24.0kg/m². Impaired coronary microvascular function was defined as caIMR≥25U. The patients were classified according to BMI and caIMR. The primary endpoint was major adverse cardiac events (MACE). Kaplan-Meier and Cox regression analyses evaluated the association between caIMR and MACE.ResultsTwo hundred and eighty-two CCS patients were enrolled. Among these, 169 (59.93%) were overweight. Impaired coronary microvascular function was higher in overweight patients than in patients with normal weight (49.70% vs. 38.05%; P=0.035). During 35 months of follow-up, 33 MACE had occurred. Among the total CCS population, MACE was higher in patients with high caIMR than in low caIMR (18.11% vs. 6.45%, P=0.003). In subgroups analysis, MACE was higher in overweight patients with high caIMR than low caIMR (20.24% vs. 7.06%, P=0.014), while there were no significant differences in normal-weight patients. Multivariate Cox analysis demonstrated that caIMR≥25 was independently associated with MACE in overweight patients (HR, 2.87; 95% CI, 1.12-7.30; P=0.027) but not in the normal-weight patients. In addition, caIMR showed a significant predictive value for adverse outcomes in overweight patients and provided an incremental prediction when added to a prediction model with BMI.ConclusionsImpaired coronary microvascular function assessed by caIMR was common and is an independent predictor of MACE in overweight patients with CCS.

BackgroundThe high prevalence of cardiovascular diseases globally causes a great social burden and much individual suffering. The effective recognition of high-risk subjects is critical for primary prevention in the general population. In the elderly cohort, anthropometric measurements may have different prognostic values. Our study aimed to find convincing anthropometric measures to supplement conventional risk factors for major adverse cardiovascular events (MACEs) in the elderly cohort.Materials and MethodsA total of 1,576 elderly participants (44.5% male, aged 72.0 ± 6.0 years) recruited into the Northern Shanghai Study (2014–2015) were followed up between 2016 and 2017. Following the standard guideline for cardiovascular risk evaluation, all conventional cardiovascular risk factors were assessed. The body measures were made up of body weight, body height, hip circumference, waist circumference, and middle-upper arm circumference (MUAC). Organ damage (OD) markers for cardiac, vascular, and renal diseases will be evaluated by the standardized methods.ResultsAfter the average 571 (±135) days of follow-up, a total of 90 MACEs (5.7%) occurred, i.e., 13 non-fatal myocardial infarction, 68 non-fatal stroke, and 9 cardiovascular deaths. Univariable COX survival analysis revealed that only MUAC could validly predict MACEs among anthropometric characters [adjusted hazard ratio (HR) 0.89; 95% confidence interval (CI) 0.82–0.96]. In Kaplan-Meier analysis, the group of high MUAC showed the lowest MACE risk (log-rank p = 0.01). Based on OD analysis, MUAC was independently linked to higher risk of left ventricular hypertrophy (LVH) in women and left ventricular diastolic dysfunction (LVDD) in both men and women. In adjusted COX analysis, only MUAC indicated statistical significance, but all other anthropometric parameters such as BMI, waist circumference, and waist-to-hip ratio (WHR) did not indicate significance. The higher level of MUAC remained a protective factor in fully adjusted models (HR: 0.73; 95% CI: 0.59–0.91), with p-values markedly significant in men (HR: 0.69; 95% CI: 0.49–0.97) and marginally significant in women (HR: 0.0.77; 95% CI: 0.59–1.01). After considering all factors (i.e., cardiovascular risk factors, MUAC, BMI, and WHR), the fully adjusted COX regression analysis demonstrated that the increased MUAC level was linked to decreased MACE risk in both men (HR: 0.57; 95% CI: 0.37–0.88) and women (aHR: 0.64; 95% CI: 0.46–0.93).ConclusionDespite being associated with a higher rate of cardiac damage, higher MUAC independently and significantly conferred protection against the MACE, in the elderly cohort.

Abstract Background Emerging evidence confirms that lncRNAs (long non-coding RNAs) are potential biomarkers that play vital roles in tumors. ZNF582-AS1 is a novel lncRNA that serves as a potential prognostic marker of cancers. However, the specific clinical significance and molecular mechanism of ZNF582-AS1 in ccRCC (clear cell renal cell carcinoma) are unclear. Methods Expression level and clinical significance of ZNF582-AS1 were determined by TCGA-KIRC data and qRT-PCR results of 62 ccRCCs. DNA methylation status of ZNF582-AS1 promoter was examined by MSP, MassARRAY methylation and demethylation analysis. Gain-of-function experiments were conducted to investigate the biological roles of ZNF582-AS1 in the phenotype of ccRCC. The subcellular localization of ZNF582-AS1 was detected by RNA FISH. iTRAQ, RNA pull-down and RIP-qRT-PCR were used to identify the downstream targets of ZNF582-AS1. rRNA MeRIP-seq and MeRIP-qRT-PCR were utilized to examine the N(6)-methyladenosine modification status. Western blot and immunohistochemistry assays were used to determine the protein expression level. Results ZNF582-AS1 was downregulated in ccRCC, and decreased ZNF582-AS1 expression was significantly correlated with advanced tumor stage, higher pathological stage, distant metastasis and poor prognosis. Decreased ZNF582-AS1 expression was caused by DNA methylation at the CpG islands within its promoter. ZNF582-AS1 overexpression inhibited cell proliferative, migratory and invasive ability, and increased cell apoptotic rate in vitro and in vivo. Mechanistically, we found that ZNF582-AS1 overexpression suppressed the N(6)-methyladenosine modification of MT-RNR1 by reducing rRNA adenine N(6)-methyltransferase A8K0B9 protein level, resulting in the decrease of MT-RNR1 expression, followed by the inhibition of MT-CO2 protein expression. Furthermore, MT-RNR1 overexpression reversed the decreased MT-CO2 expression and phenotype inhibition of ccRCC induced by increased ZNF582-AS1 expression. Conclusions This study demonstrates for the first time that ZNF582-AS1 functions as a tumor suppressor gene in ccRCC and ZNF582-AS1 may serve as a potential biomarker and therapeutic target of ccRCC.

Background: Rotational atherectomy (RA) is the major tool used to treat severely calcified lesions in patients with coronary artery disease (CAD). The relationship between coronary microvascular dysfunction and RA remains unknown. Therefore, we attempted to explore the predictive implications of the coronary angiography-derived index of microcirculatory resistance (angio-IMR) in CAD patients undergoing RA. Methods: This retrospective study included 118 patients with severe coronary calcification who underwent a successful RA from January 2018 to June 2021. The angio-IMR was calculated based on computed flow and pressure dynamic principles to assess coronary microcirculatory function. Follow-up was performed on all patients for major adverse cardiovascular events (MACEs), including all-cause death, non-fatal myocardial infarction, target vessel revascularization (TVR), and stroke. Results: The mean angio-IMR for all patients was 25.58 ± 7.93. Patients were stratified the groups based on a mean angio-IMR of 25, fifty-four (45.8%) patients had angio-IMR ≥25. The logistic regression analysis showed that angiography-derived fractional flow reserve was significantly associated with coronary microvascular dysfunction. After median follow-up of 21.7 (15.1–24.0) months, MACEs occurred in 30.6%, including 12.5% all-cause deaths, 6.4% non-fatal myocardial infarction, 14.5% TVR, and 0.9% stroke. Kaplan-Meier analysis demonstrated that patients with angio-IMR ≥25 had greater cumulative MACEs (41.6%) and TVR (20.7%) than patients with preserved angio-IMR. COX regression analysis indicated that angio-IMR ≥25 and reduced left ventricular ejection fraction were independent predictors of MACEs. In addition, angio-IMR ≥25 and lowered minimum luminal area independently predicted TVR occurrence. Conclusions: In CAD patients undergoing RA, angio-IMR ≥25 was an independent and significant predictor of MACEs and TVR. Clinical Trial Registration: NCT05435898.

Background/aim: This study was aimed at evaluating 5-year effectiveness and safety in participants after XIENCE PRIME Everolimus Elution Coronary Stent System (EECSS) implantation. Materials and methods: From December 2013 to May 2014, 108 patients (127 lesions) were treated with the XIENCE PRIME EECSS. The entire follow-up included annual assessments for 5 years after treatment or until one of the clinical endpoints was reached. We evaluated the 5-year clinical outcomes with Kaplan-Meier analysis and the Cox regression model. Results: Nearly three-quarters of the participants were men (76.8%), and the average age was 65.6 ± 10.8 years. Bifurcation lesions accounted for 96.1% (122 lesions), and left main lesions accounted for 3.9% (five lesions), with a total count of 127 lesions. The cumulative rate of major adverse cardiac events was as follows: 1 year, 1.9%; 2 year, 4.0%; and 5 year, 10.0%. No definite or probable stent thrombosis was observed, and the rate of target lesion failure was only 3.3% over 5 years. The cumulative rate of major bleeding eventually increased to only 4.4%. Conclusions: The 5-year clinical outcomes were favorable in patients treated with XIENCE PRIME EECSS, and the incidence of stent thrombosis and target lesion failure was relatively low. The incidence of major bleeding gradually increased but remained moderate.

Abstract Aims Elevated heart rate (HR) in heart failure (HF) is associated with worse outcomes, particularly in acute HF (AHF). HR reduction with ivabradine reduces cardiovascular events in HF patients with reduced ejection fraction. The present trial aimed to test the hypothesis that the early HR reduction using ivabradine improves clinical outcomes in patients with AHF. Methods and results SHIFT‐AHF is a prospective, multi‐centre, double‐blind, randomized, placebo‐controlled trial to evaluate the efficacy and safety of ivabradine when adding to standard therapy in AHF patients (SHIFT‐AHF). The trial will include 674 AHF patients with left ventricular ejection fraction

Introduction Telemedicine and blood pressure (BP) self-monitoring conduces to management of hypertension. Recent hypertension guidelines highly recommended single pill combination (SPC) for the initial treatment of essential hypertension. Based on this fact, an SPC-based telemedicine titration regimen with BP self-monitoring could be a better way in managing hypertension. This trial aims to elucidate whether telemedicine combined with BP self-monitoring is superior to self-monitoring alone during hypertension management.Methods and analysis This study will be a multicentred, open-labelled, randomised controlled trial. A minimum sample of 358 hypertensive patients with uncontrolled BP from four centres will be included. The intervention group will include BP self-monitoring and tele-monitoring plus a free SPC-based telemedicine titration therapy for 6 months, they will be recommended to take BP measurements at least once every 7 days, in the meantime, researchers will call to give a consultation on lifestyle or titration advice once a fortnight. The control group will be required to self-monitor BP at the same time interval as intervention group, without any therapy change. Primary outcome of the trial will be the difference in systolic blood pressure at 6-month follow-up between intervention and control group, adjusted for baseline variables. Secondary outcomes such as BP control rate, major adverse cardiovascular events, medication adherence, quality of life will be investigated.Ethics and dissemination Ethics approval was granted by Ethical Committee of Shanghai Tenth People’s Hospital (SHSY-IEC-4.1/20-194/01). The results will be disseminated in peer-reviewed literature, and to policy-makers and healthcare partners.Trial registration number ChiCTR2000037217.

Background: The association of four-limb systolic blood pressure differences (SBPDs) including inter-arm (IASBPD), inter-leg (ILSBPD) and ankle-brachial index (ABI) with cardiovascular risk factors and target organ changes (TOCs) remains controversial. This study aims at investigating the association of those parameters with cardiovascular risk factors and TOCs in an elderly Chinese population. Methods: A total of 1528 subjects derived from the Northern Shanghai Study were studied. Four-limb BPs were simultaneously measured by VP-1000 device. Cardiovascular risk factors and TOCs including parameters of left ventricular structure and function, carotid intima-media thickness, carotid-femoral pulse-wave velocity (CF-PWV), estimated glomerular filtration rate (eGFR) and urinary albumin/creatinine ratio, were evaluated with standardized methods. Results: ABI significantly associated age (β = −0.004, p < .01), female gender (β = 0.02, p < .01), body mass index (β = −0.004, p < .01), smoking (β = −0.04, p < .01), high-density lipoprotein (β = 0.04, p < .01), low-density lipoprotein (β = −0.01, p = .01) and diabetes mellitus (β = −0.02, p < .01), while the fourth root of IASBPD significantly associated with body mass index (β = 0.03, p < .01), high-density lipoprotein (β = −0.10, p = .02) and brachial SBP (β = 0.003, p < .01); the fourth root of ILSBPD significantly associated with high-density lipoprotein (β = −0.12, p < .01) and diabetes mellitus (β = 0.09, p = .01). IASBPD, ILSBPD, and ABI all significantly associated with CF-PWV and eGFR (all p < .05) in either unadjusted or adjusted models, but not with other TOCs. Conclusion: Four-limb SBPDs, namely ABI, IASBPD, and ILSBPD, bore various burdens of cardiovascular risk factors and significantly and independently associated with CF-PWV and eGFR.

Abstract Background The optimal duration of oral anticoagulant therapy for patients with venous thromboembolism (VTE) remains highly uncertain in clinical practice. It is essential to accurately assess the effect of anticoagulant therapy in reducing recurrent VTE against the risk of inducing major bleeding. Methods Randomized controlled trials were identified by searching PubMed, Web of Science, Embase, and the Cochrane library, reporting rates of recurrent VTE and major bleeding in patients taking Vitamin K Antagonists (VKA) with VTE and comparing different durations. Results Eleven RCTs with 3109 participants utilizing varied durations were included in the meta-analysis. Longer VKA therapy was associated with significantly lower rates of VTE recurrence compared with shorter duration of VKA therapy (OR 0.75, 95%CI 0.57–0.99), with significant difference noted in major bleeding risk (OR 2.31, 95%CI 1.17–4.56). During anticoagulation duration, patients treated by 6-month VKA had higher risk of major bleeding compared with 3-month VKA regimen (OR 33.45, 95%CI 2.00–559.67). Conclusions Regimen longer than 6 months did not show statistical elevation of major bleeding risk. VKA treatment strongly reduces the risk of recurrent VTE during anticoagulation therapy. The absolute risk of recurrent VTE declines over time while the risk for major bleeding after 6 months’ treatment did not demonstrate a continuous significant increase with extended duration of VKA therapy.

As a nonspecific antagonist of the adenosine A2A receptor (A2AR), caffeine enhances learning and improves memory impairment. Simultaneously, the consumption of caffeine correlates with a feeling of anxiety. The hippocampus is functionally differentiated along its dorsal/ventral axis and plays a crucial role both in memory and anxiety. Whether caffeine exerts its regulation by inhibiting A2ARs in different subregions of the hippocampus is still unknown. In the present study, we found that after chronic intake of drinking water containing caffeine (1 g/L, 3 weeks), mice exhibited aggravated anxiety-like behavior and enhanced memory function. Tissue-specific, functional disruption of dorsal hippocampal A2ARs by the CRE-LoxP system prevented the memory-enhancing effect of caffeine, while selective disruption of ventral hippocampal A2ARs blocked the impact of caffeine on anxiety. These results, together with the enhanced memory of dorsal hippocampus A2AR knockout mice and greater anxiety-like behavior of ventral hippocampus A2AR knockout mice without caffeine, indicates a dissociation between the roles of ventral and dorsal hippocampal A2A receptors in caffeine’s effects on anxiety-like and memory-related behavioral measures, respectively. Furthermore, optogenetic activation of dorsal or ventral hippocampal A2ARs reversed the behavioral alterations caused by drinking caffeine, leading to impaired memory or decreased anxiety-like behaviors, respectively. Taken together, our findings suggest that the memory- and anxiety-enhancing effects of caffeine are related to the differential effects of inhibiting A2ARs in the dorsal and ventral hippocampus, respectively.