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Abstract Bilirubin is widely recognized to possess antioxidant and anti-inflammatory characteristics. However, the relationship between bilirubin and coronary artery disease (CAD) remains controversial, particularly in individuals receiving Percutaneous Coronary Intervention (PCI). Given that statins may enhance the production of heme oxygenase-1 (HO-1) and bilirubin, we investigated the long-term cardiovascular prognostic role of bilirubin levels elevated by statin use in patients undergoing PCI. Data of 6945 subjects undergoing PCI were enrolled in this study. We divided the patients into two groups based on serum total bilirubin (TB) levels detected prior to PCI. The high TB group consisted of patients with serum TB values > 8.4 μmmol/L, while the low TB group consisted of patients with serum TB values ≤ 8.4 μmmol/L. The median follow-up time was 836 days. Cox proportional hazards models were performed to evaluate the hazard ratios (HRs) and 95% confidence interval (CI) for the incidence of major adverse cardiovascular event (MACE) associated with bilirubin levels. The association between TB levels and risk of MACE was significant [adjusted HR = 0.557, 95% CI (0.59–0.96), p = 0.020). Linear analysis was performed to determine the association between preadmission usage of statin and bilirubin level. The preadmission usage of statin independently linearly increases TB [adjusted-β = 0.371, 95% CI (0.134–0.608), p = 0.002] and direct bilirubin (DB) [adjusted-β = 0.411, 95% CI (0.300–0.522), p

Abstract Mutations in the nuclear envelope (NE) protein lamin A/C (encoded by LMNA), cause a severe form of dilated cardiomyopathy (DCM) with early-onset life-threatening arrhythmias. However, molecular mechanisms underlying increased arrhythmogenesis in LMNA-related DCM (LMNA-DCM) remain largely unknown. Here we show that a frameshift mutation in LMNA causes abnormal Ca2+ handling, arrhythmias and disformed NE in LMNA-DCM patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). Mechanistically, lamin A interacts with sirtuin 1 (SIRT1) where mutant lamin A/C accelerates degradation of SIRT1, leading to mitochondrial dysfunction and oxidative stress. Elevated reactive oxygen species (ROS) then activates the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-ryanodine receptor 2 (RYR2) pathway and aggravates the accumulation of SUN1 in mutant iPSC-CMs, contributing to arrhythmias and NE deformation, respectively. Taken together, the lamin A/C deficiency-mediated ROS disorder is revealed as central to LMNA-DCM development. Manipulation of impaired SIRT1 activity and excessive oxidative stress is a potential future therapeutic strategy for LMNA-DCM.

Vascular diseases seriously threaten human life and health. Exogenous delivery of nitric oxide (NO) represents an effective approach for maintaining vascular homeostasis during pathological events. However, the overproduction of reactive oxygen species (ROS) at vascular injury sites would react with NO to produce damaging peroxynitrite (ONOO−) species and limit the therapeutic effect of NO. Hence, we design a ROS-responsive NO nanomedicine (t-PBA&NO NP) with ROS scavenging ability to solve the dilemma of NO-based therapy. t-PBA&NO NP targets NO and anti-oxidant ethyl caffeate (ECA) to the injury sites via collagen IV homing peptide. The ROS-triggered ROS depletion and ECA release potently alleviate local oxidative stress via ROS scavenging, endoplasmic reticulum and mitochondrial regulation. It subsequently maximizes vascular modulation effects of NO, without production of harmful compounds, reactive nitrogen species (RNS). Therefore, it significantly increases competitiveness of human umbilical vein endothelial cells (HUVECs) over human aortic smooth muscle cells (HASMCs) both in vitro and in vivo. The strategy proved effective in inducing faster re-endothelialization, inhibiting neointimal formation and restoring vascular homeostasis. The synergy between ROS depletion and NO therapy served as a new inspiration for the treatment of cardiovascular diseases and other ROS-associated illnesses.

The vulnerable plaques in atherosclerosis can cause severe outcome with great danger of acute cardiovascular events. Thus, timely diagnosis and treatment of vulnerable plaques in early stage can effectively benefit the clinical management of atherosclerosis. In this work, a targeting theranostic strategy on early-stage vulnerable plaques in atherosclerosis is realized by a LAID nanoplatform with X-CT and fluorescent dual-mode imaging and lipid-inflammation integrated regulation abilities. The iodinated contrast agents (ICA), phenylboronic acid modified astaxanthin and oxidized-dextran (oxDEX) jointly construct the nanoparticles loaded with the lipid-specific probe LFP. LAID indicates an active targeting to plaques along with the dual-responsive disassembly in oxidative stress and acidic microenvironment of atherosclerosis. The X-CT signals of ICA execute the location of early-stage plaques, while the LFP combines with lipid cores and realizes the recognition of vulnerable plaques. Meanwhile, the treatment based on astaxanthin is performed for restraining the progression of plaques. Transcriptome sequencing suggests that LAID can inhibit the lipid uptake and block NF-κB pathway, which synergistically demonstrates a lipid-inflammation integrated regulation to suppression the plaques growing. The in vivo investigations suggest that LAID delivers a favorable theranostics to the early-stage vulnerable plaques, which provides an impressive prospect for reducing the adverse prognosis of atherosclerosis.

Abstract Aims A therapeutic strategy for chronic heart failure (HF) is to lower resting heart rate (HR). Ivabradine is a well‐known HR‐lowering agent, but limited prospective data exist regarding its use in Chinese patients. This study aimed to evaluate the effectiveness and safety of ivabradine in Chinese patients with chronic HF. Methods and results This multicentre, single‐arm, prospective, observational study enrolled Chinese patients with chronic HF. The primary outcome was change from baseline in HR at 1 and 6 months, measured by pulse counting. Effectiveness was also evaluated using laboratory tests, the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS) and overall summary score (OSS), and New York Heart Association (NYHA) class. Treatment‐emergent adverse events (TEAEs) were assessed. A post hoc analysis examined the effectiveness and safety of ivabradine combined with an angiotensin receptor–neprilysin inhibitor (ARNI) or beta‐blocker. A total of 1003 patients were enrolled [mean age 54.4 ± 15.0 years, 773 male (77.1%), mean baseline HR 88.5 ± 11.3 b.p.m., mean blood pressure 115.7/74.4 ± 17.2/12.3 mmHg, mean left ventricular ejection fraction 30.9 ± 7.6%, NYHA Classes III and IV in 48.8% and 22.0% of patients, respectively]. HR decreased by a mean of 12.9 and 16.1 b.p.m. after 1 and 6 months, respectively (both P

Abstract Myocardial infarction (MI), a consequence of coronary artery occlusion, triggers the degradation of ferritin, resulting in elevated levels of free iron in the heart and thereby inducing ferroptosis. Targeting myocardial ferroptosis through the chelation of excess iron has therapeutic potential for MI treatment. However, iron chelation in post ischemic injury areas using conventional iron‐specific chelators is hindered by ineffective myocardial intracellular chelation, rapid clearance, and high systemic toxicity. A chitosan‐desferrioxamine nanosponge (CDNS) is designed by co‐crosslinking chitosan and deferoxamine through noncovalent gelation to address these challenges. This architecture facilitates direct iron chelation regardless of deferoxamine (DFO) release due to its sponge‐like porous hydrogel structure. Upon cellular internalization, CDNS can effectively chelate cellular iron and facilitate the efflux of captured iron, thereby inhibiting ferroptosis and associated oxidative stress and lipid peroxidation. In MI mouse models, myocardial injection of CDNS promotes sustainable retention and the suppression of ferroptosis in the infarcted heart. This intervention improves cardiac function and alleviates adverse cardiac remodeling post‐MI, leading to decreased oxidative stress and the promotion of angiogenesis due to ferroptosis inhibition by CDNS in the infarcted heart. This study reveals a nanosponge‐based nanomedicine targeting myocardial ferroptosis with efficient iron chelation and efflux, offering a promising MI treatment.

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

Introduction Chronic kidney disease is a growing health issue, and the options of prevention and therapy remain limited. Although a number of observational studies have linked higher Lp(a) [lipoprotein(a)] levels to the kidney impairment, the causal relationship remains to be determined. The purpose of this study was to assess the causal association between Lp(a) levels and CKD.Methods We selected eight single-nucleotide polymorphisms (SNPs) significantly associated with Lp(a) levels as instrumental variables. Genome-wide association study (GWAS) from CKDGen consortium yielded the summary data information for CKD. We designed the bidirectional two-sample Mendelian randomization (MR) analyses. The estimates were computed using inverse-variance weighted (IVW), simple median, weighted median, and maximum likelihood. MR-Egger regression was used to detect pleiotropy.Results Fixed-effect IVW analysis indicated that genetically predicted Lp(a) levels were associated with CKD significantly (odds ratio, 1.039; 95% CI, 1.009–1.069; p = 0.010). The SNPs showed no pleiotropy according to result of MR-Egger test. Results from sensitivity analyses were consistent. In the inverse MR analysis, random-effect IVW method showed CKD had no causal effect on the elevated Lp(a) (odds ratio, 1.154; 95% CI, 0.845–1.576; p = 0.367).Conclusion In this bidirectional two-sample MR analysis, the causal deteriorating effects of genetically predicted plasma Lp(a) levels on the risk of CKD were identified. On the contrary, there is no evidence to support a causal effect of CKD on Lp(a) levels.

Aims: Myocardial ischemia can affect traditional right ventricular (RV) pacing parameters, but it is unclear whether coronary artery disease (CAD) impact the pacing parameters and electrophysiological characteristics of left bundle branch area pacing (LBBaP) as a physiological pacing representative. Methods: Patients who underwent coronary angiography (CAG) after/before the LBBaP procedure and underwent percutaneous coronary intervention after LBBaP procedure were divided into CAD group and Non-CAD group according to visual CAG. Pacing parameters and electrophysiological characteristics were recorded at LBBaP implantation. Multivariate logistic regression analysis was implemented to evaluate the association between CAD and higher capture threshold. Sensitivity analyses were conducted to verify result stability. Results: A total of 176 patients met inclusion criteria (115 Non-CAD patients and 61 CAD patients) with a mean age of 71.1 ± 9.0 years. Compared with the Non-CAD patients, CAD patients had the higher capture threshold (0.67 ± 0.22 V vs. 0.82 ± 0.28 V, P

Abstract Background Bioresorbable stents are designed to provide temporary mechanical support to the coronary arteries and then slowly degrade in vivo to avoid chronic inflammation. Zinc (Zn) is a promising material for bioresorbable stents; However, it can cause inflammation and neointimal formation after being implanted into blood vessels. Methods To improve biocompatibility of Zn, we first coated it with polydopamine (PDA), followed by immobilization of endothelial vascular growth factor (VEGF) onto the PDA coatings. Adhesion, proliferation, and phenotype maintenance of endothelial cells (ECs) on the coated Zn were evaluated in vitro. Then, a wire aortic implantation model in rats mimicking endovascular stent implantation in humans was used to assess vascular responses to the coated Zn wires in vivo. Thrombosis in aortas post Zn wire implantation, degradation of Zn wires in vivo, neointimal formation surrounding Zn wires, and macrophage infiltration and extracellular matrix (ECM) remodeling in the neointimas were examined. Results In vitro data showed that the PDA-coated Zn encouraged EC adhesion, spreading, proliferation, and phenotype maintenance on its surfaces. VEGF functionalization on PDA coatings further enhanced the biocompatibility of Zn to ECs. Implantation of PDA-coated Zn wires into rat aortas didn’t cause thrombosis and showed a faster blood flow than pure Zn or the Zn wires coated with VEGF alone. In addition, the PDA coating didn’t affect the degradation of Zn wires in vivo. Besides, the PDA-coated Zn wires reduced neointimal formation, increased EC coverage, decreased macrophage infiltration, and declined aggrecan accumulation in ECM. VEGF immobilization onto PDA coatings didn’t cause thrombosis and affect Zn degradation in vivo as well, and further increased the endothelization percentage as compared to PDA coating alone, thus resulting in thinner neointimas. Conclusion These results indicate that PDA coatings with VEGF immobilization would be a promising approach to functionalize Zn surfaces to increase biocompatibility, reduce inflammation, and inhibit neointimal formation after Zn implantation in vivo. Graphical Abstract

AimsStress hyperglycemia ratio (SHR), an emerging indicator of critical illness, exhibits a significant association with adverse cardiovascular outcomes. The primary aim of this research endeavor is to evaluate the association between fasting SHR and contrast-induced acute kidney injury (CI-AKI).MethodsThis cross-sectional study comprised 3,137 patients who underwent coronary angiography (CAG) or percutaneous coronary intervention (PCI). The calculation of fasting SHR involved dividing the admission fasting blood glucose by the estimated mean glucose obtained from glycosylated hemoglobin. CI-AKI was assessed based on elevated serum creatinine (Scr) levels. To investigate the relationship between fasting SHR and the proportion of SCr elevation, piecewise linear regression analysis was conducted. Modified Poisson’s regression analysis was implemented to evaluate the correlation between fasting SHR and CI-AKI. Subgroup analysis and sensitivity analysis were conducted to explore result stability.ResultsAmong the total population, 482 (15.4%) patients experienced CI-AKI. Piecewise linear regression analysis revealed significant associations between the proportion of SCr elevation and fasting SHR on both sides (≤ 0.8 and > 0.8) [β = -12.651, 95% CI (−23.281 to −2.022), P = 0.020; β = 8.274, 95% CI (4.176 to 12.372), P < 0.001]. The Modified Poisson’s regression analysis demonstrated a statistically significant correlation between both the lowest and highest levels of fasting SHR and an increased incidence of CI-AKI [(SHR < 0.7 vs. 0.7 ≤ SHR < 0.9) β = 1.828, 95% CI (1.345 to 2.486), P < 0.001; (SHR ≥ 1.3 vs. 0.7 ≤ SHR < 0.9) β = 2.896, 95% CI (2.087 to 4.019), P < 0.001], which was further validated through subgroup and sensitivity analyses.ConclusionIn populations undergoing CAG or PCI, both lowest and highest levels of fasting SHR were significantly associated with an increased occurrence of CI-AKI.

AbstractObjective: Given the psychosocial and ethical burden, patients with hypertrophic cardiomyopathy (HCMs) could benefit from the establishment of genetic probability prior to the test. This study aimed to develop a simple tool to provide genotype prediction for HCMs.Methods: A convolutional neural network (CNN) was built with the 12-lead electrocardiogram (ECG) of 124 HCMs who underwent genetic testing (GT), externally tested by predicting the genotype on another HCMs cohort (n = 54), and compared with the conventional methods (the Mayo and Toronto score). Using a third cohort of HCMs (n = 76), the role of the network in risk stratification was explored by calculating the sudden cardiac death (SCD) risk scorers (HCM risk-SCD) across the predicted genotypes. Score-CAM was employed to provide a visual explanation of the network.Results: Overall, 80 of 178 HCMs (45%) were genotype-positive. Using the 12-lead ECG as input, the network showed an area under the curve (AUC) of 0.89 (95% CI, 0.83–0.96) on the test set, outperforming the Mayo score (0.69 [95% CI, 0.65–0.78], p

AimsStable coronary artery disease (CAD) is a prevalent comorbidity among patients requiring pacemaker implantation. This comorbidity may have an impact on the safety and prognosis of traditional right ventricular pacing (RVP). Left bundle branch area pacing (LBBaP) is a new physiological pacing modality. Our aim was to investigate the feasibility and safety of LBBaP in patients with the stable CAD.MethodsThis study included 309 patients with symptomatic bradycardia who underwent LBBaP from September 2017 to October 2021. We included 104 patients with stable CAD (CAD group) and 205 patients without CAD (non-CAD group). Additionally, 153 stable CAD patients underwent RVP, and 64 stable CAD patients underwent His-bundle pacing (HBP) were also enrolled in this study. The safety and prognosis of LBBaP was assessed by comparing pacing parameters, procedure-related complications, and clinical events.ResultsDuring a follow-up period of 17.4 ± 5.3 months, the safety assessment revealed that the overall rates of procedure-related complications were similar between the stable CAD group and the non-CAD group (7.7% vs. 3.9%). Likewise, similar rates of heart failure hospitalization (HFH) (4.8% vs. 3.4%, stable CAD vs. non-CAD) and the primary composite outcome including death due to cardiovascular disease, HFH, or the necessity for upgrading to biventricular pacing (6.7% vs. 3.9%, stable CAD vs. non-CAD), were observed. In stable CAD patients, LBBaP demonstrated lower pacing thresholds and higher R wave amplitudes when compared to HBP. Additionally, LBBaP also had significantly lower occurrences of the primary composite outcome (6.7% vs. 19.6%, P = 0.003) and HFH (4.8% vs. 13.1%, P = 0.031) than RVP in stable CAD patients, particularly among patients with the higher ventricular pacing (VP) burden (>20% and >40%).ConclusionCompared with non-CAD patients, LBBaP was found to be attainable in stable CAD patients and exhibited comparable mid-term safety and prognosis. Furthermore, in the stable CAD population, LBBaP has demonstrated more stable pacing parameters than HBP, and better prognostic outcomes compared to RVP.

Introduction The strategy for initiating antithrombotic therapy to prevent bioprosthetic valve thrombosis (BPVT) after transcatheter aortic valve replacement (TAVR) remains uncertain. There is still lacking evidence on the efficacy and safety of early 6 months usage of single-antiplatelet therapy (SAPT) or oral anticoagulant (OAC) after TAVR in patients without anticoagulant indications.Methods and analysis This is a multicentre, randomised controlled, open-label trial, and 650 patients undergoing TAVR from 13 top TAVR centres in China will be recruited. Each eligible participant will be randomly assigned to two groups (1:1 ratio) as (1) SAPT (aspirin 75–100 mg for 6 months) group or (2) OAC group (warfarin, therapeutic international normalised ratio at 1.8–2.5 for 6 months), both followed by sequential aspirin 75–100 mg for 6 months. Participants in both groups will be invited for three follow-up visits of 1, 6 and 12 months after discharge. We will use both the net clinical benefit endpoint (composite of all-cause mortality, myocardial infarction, stroke/transient ischaemic attacks, peripheral artery thrombosis, intracardiac thrombosis and major bleeding and disabling or life-threatening bleeding) and the BPVT endpoint evaluated by four-dimensional CT as our primary endpoints. P value of

Objectives: This study was aimed at comparing the “late catch-up” phenomenon between the BuMA Supreme bioresorbable polymer sirolimus-eluting stent and the XIENCE stent through serial optical coherence tomography (OCT) at within 2 months and 2 year follow-ups. Methods: A total of 49 of 75 patients from the PIONEER-II study were enrolled in a 2 year OCT follow-up study; 44 patients with 50 lesions were included in the statistical analysis. The primary endpoints were neointimal thickness and late luminal loss (LLL) after stent implantation. Results: The stenosis diameter, and minimum in-stent or in-segment diameter, did not significantly differ between the BuMA Supreme and XIENCE arms at within 2 months and 2 year follow-ups. The strut neointimal coverage and thickness were greater in the BuMA group than the XIENCE group at the 1 and 2 month follow-ups (P = 0.044 and P = 0.010, respectively) but not at the 2 year OCT follow-up. Neither early luminal loss at the within 2 months follow-up (P = 0.849) nor LLL at the 2 year OCT follow-up (P = 0.613) showed differences between device arms. No significant differences in imaging and clinical endpoints were observed between device arms at follow-up. Conclusions: The BuMA Supreme stent’s faster re-endothelization with no “late catch-up” phenomenon has potential advantages over the XIECE stent for patients with coronary artery disease and high bleeding risk because it decreases the duration of dual antiplatelet therapy.

Synthetic vascular grafts suitable for small-diameter arteries (

Aldehydes are recognized environmental toxicants that may affect lipid metabolism. For instance, acrolein has been found to increase serum triglyceride (TG) levels exclusively. However, it remains unclear whether other aldehydes are also associated with hypertriglyceridemia (HTG), and what mechanisms may be involved. This cross-sectional study analyzed data from the National Health and Nutrition Examination Survey (NHANES, 2013–2014) to identify associations between serum aldehydes, liver enzymes, and HTG. Serum aldehydes included crotonaldehyde (CRAL), propanaldehyde (3AL), butyraldehyde (4AL), pentanaldehyde (5AL), isopentanaldehyde (I5AL), and heptanaldehyde (7AL). Liver enzymes included alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT). HTG was defined as fasting TG levels ≥ 1.7 mmol/L. Aldehyde co-exposure was quantified using weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR), while mediation analysis was performed to investigate the role of liver enzymes. Among 1474 participants (mean age 38.6 years, male 50.0%), 426 were diagnosed with HTG. 4AL, 5AL, I5AL, and 7AL were shown to be positively associated with HTG (all P values

Summary: Background: Brugada syndrome (BrS) is a cardiac channelopathy that can result in sudden cardiac death (SCD). SCN5A is the most frequent gene linked to BrS, but the genotype–phenotype correlations are not completely matched. Clinical phenotypes of a particular SCN5A variant may range from asymptomatic to SCD. Here, we used comparison of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from a SCN5A mutation-positive (D356Y) BrS family with severely affected proband, asymptomatic mutation carriers (AMCs) and healthy controls to investigate this variation. Methods: 26 iPSC lines were generated from skin fibroblasts using nonintegrated Sendai virus. The generated iPSCs were differentiated into cardiomyocytes using a monolayer-based differentiation protocol. Findings: D356Y iPSC-CMs exhibited increased beat interval variability, slower depolarization, cardiac arrhythmias, defects of Na+ channel function and irregular Ca2+ signaling, when compared to controls. Importantly, the phenotype severity observed in AMC iPSC-CMs was milder than that of proband iPSC-CMs, an observation exacerbated by flecainide. Interestingly, the iPSC-CMs of the proband exhibited markedly decreased Ca2+ currents in comparison with control and AMC iPSC-CMs. CRISPR/Cas9-mediated genome editing to correct D356Y in proband iPSC-CMs effectively rescued the arrhythmic phenotype and restored Na+ and Ca2+ currents. Moreover, drug screening using established BrS iPSC-CM models demonstrated that quinidine and sotalol possessed antiarrhythmic effects in an individual-dependent manner. Clinically, venous and oral administration of calcium partially reduced the malignant arrhythmic events of the proband in mid-term follow-up. Interpretation: Patient-specific and genome-edited iPSC-CMs can recapitulate the varying phenotypic severity of BrS. Our findings suggest that preservation of the Ca2+ currents might be a compensatory mechanism to resist arrhythmogenesis in BrS AMCs. Funding: National Key R&D Program of China (2017YFA0103700), National Natural Science Foundation of China (81922006, 81870175), Natural Science Foundation of Zhejiang Province (LD21H020001, LR15H020001), National Natural Science Foundation of China (81970269), Key Research and Development Program of Zhejiang Province (2019C03022) and Natural Science Foundation of Zhejiang Province (LY16H020002).

Abstract Mesenchymal stem cell‐derived extracellular vesicle (MSC‐EV) is shown to promote cardiac repair, however, it still falls short in initiating myocardia proliferation restart. In this regard, ROS‐induced DNA damage and responses are the culprit of cellcycle arrest. Here, this work constructs a hybrid cell‐derived extracellular vesicle that is composed of MSC and macrophage membranes and encompasses MitoN, a ROS scavenger, to boost the healing of the heart. The MitoN, a NAD(P)H mimic, could target the mitochondrial to eliminate the ROS resuming the arrested cell cycle. The hybrid extracellular vesicle (N@MEV) could respond to the inflammatory signals generated during myocardial injury and thus enable superior targeting and enrichment to the location of the damage. L‐arginine, which could be catalyzed by NOS and ROS into NO and SO provide a driving force, is immobilized within the vesicle (NA@MEV) to further enhance the N@MEV's potential to penetrate the cardiac stroma. In combination with multiple mechanisms, NA@MEV increased heart function 1.3‐fold EF% versus MSC‐EV in mouse myocardial injury model. A more in‐depth mechanistic study found that the NA@MEV could modulate M2 macrophage; promote angiogenesis; reduce DNA damage and response, and thereby restart cardiomyocyte proliferation. Thus, this combined therapy shows synthetic effects in heart repair and regeneration.

Abstract Background Nutritional risk is prevalent in various diseases, but its association with contrast-induced acute kidney injury (CI-AKI) remains unclear. This study aimed to explore this association in patients undergoing coronary angiography (CAG). Methods In this retrospective cross-sectional study, 4386 patients undergoing CAG were enrolled. Nutritional risks were estimated by nutritional risk screening 2002 (NRS-2002), controlling nutritional status (CONUT), prognostic nutritional index (PNI), and geriatric nutritional risk index (GNRI), respectively. CI-AKI was determined by the elevation of serum creatinine (Scr). Multivariable logistic regression analyses and receiver operator characteristic (ROC) analyses were conducted. Subgroup analyses were performed according to age (

Abstract Background The proliferation ability and autophagy level of pulmonary artery endothelial cells (PAECs) play an important role in promoting the development of pulmonary artery hypertension (PAH), and there is still no effective treatment for PAH. Farnesyl diphosphate synthase (FDPS) is a key enzyme in the mevalonate pathway. The intermediate metabolites of this pathway are closely related to the activity of autophagy-associated small G proteins, including Ras-related C3 botulinum toxin substrate 1 (Rac1). Studies have shown that the mevalonate pathway affects the activation levels of different small G proteins, autophagy signaling pathways, vascular endothelial function, and so on. However, the exact relationship between them is still unclear in PAH. Method In vitro, western blotting and mRFP-GFP-LC3 puncta formation assays were used to observe the expression of FDPS and the level of autophagy in PAECs treated with monocrotaline pyrrole (MCTP). In addition, cell proliferation and migration assays were used to assess the effect of FDPS on endothelial function, and Rac1 activity assays were used to evaluate the effect of Rac1 activation on PAEC autophagy via the PI3K/AKT/mTOR signaling pathway. In vivo, the right heart catheterization method, hematoxylin and eosin (H&E) staining and western blotting were used to determine the effect of FDPS on PAEC autophagy and monocrotaline (MCT)-induced PAH. Results We show that the expression of FDPS is increased in the PAH module in vitro and in vivo, concomitant with the induction of autophagy and the activation of Rac1. Our data demonstrate that inhibition of FDPS ameliorates endothelial function and decreases MCT-induced autophagy levels. Mechanistically, we found that FDPS promotes autophagy, Rac1 activity and endothelial disfunction through the PI3K/AKT/mTOR signaling pathway. Conclusion Our study suggests that FDPS contributes to active small G protein-induced autophagy during MCT-induced PAH, which may serve as a potential therapeutic target against PAH.

BackgroundElevated low-density lipoprotein cholesterol (LDL-C) is an established risk factor for atherosclerotic cardiovascular disease (ASCVD). However, low adherence to medication and lifestyle management has limited the benefits of lowering lipid levels. Cognitive behavioral therapy (CBT) has been proposed as a promising solution. ObjectiveThis trial aimed to evaluate the efficacy of mobile-based CBT interventions in lowering LDL-C levels in patients with ASCVD. MethodsThis multicenter, prospective, randomized controlled trial enrolled 300 patients with ASCVD, who were randomly assigned to the mobile-based CBT intervention group and the control group in a ratio of 1:1. The intervention group received CBT for ASCVD lifestyle interventions delivered by WeChat MiniApp: “CBT ASCVD.” The control group only received routine health education during each follow-up. The linear regression and logistic regression analyses were used to determine the effects of a mobile-based CBT intervention on LDL-C, triglyceride, C-reactive protein, the score of General Self-Efficacy Scale (GSE), quality of life index (QL-index), and LDL-C up-to-standard rate (

Abstract As an emerging pacing technique, left bundle branch area pacing (LBBAP) has served as a physiological pacing modality that overcomes the limitations of His bundle pacing (HBP) or right ventricular pacing. Three patients with terminal heart failure who were waiting for heart transplantation and met the indications of pacemaker implantations received LBBAP. Symptoms were relieved and stabilized and eventually received heart transplantation. Diseased hearts from the recipients were dissected post‐transplantation, and the direct visual of pacing lead locations in the interventricular septum were evaluated, and the histopathological examination around the lead was conducted for the first time in human. As a result, we found that the locations of LBBAP leads were matched with fluoroscopic views during the procedure and Masson's staining showed extensive fibrosis occur around the lead but did not result in high thresholds.

Abstract Aging is a major risk for developing cardiac and skeletal muscle dysfunction, yet the underlying mechanism remains elusive. Here we demonstrated that the mitochondria-associated endoplasmic reticulum membranes (MAMs) in the rat heart and skeletal muscle were disrupted during aging. Using quantitative morphological analysis, we showed that the mitochondria-endoplasmic reticulum contacts (MERCs) were reduced by half over the lifespan with an early onset of accelerated thickening in the clefts. The ultrastructural changes were further validated by proteomic profiling of the MAM fractions. A combination of subcellular fractionation and quantitative mass spectrometry identified 1306 MAM-enriched proteins in both heart and skeletal muscle, with a catalog of proteins dysregulated with aging. Functional mapping of the MAM proteome suggested several aging signatures to be closely associated with the ER-mitochondria crosstalk, including local metabolic rewiring, calcium homeostasis imbalance, and impaired organelle dynamics and autophagy. Moreover, we identified a subset of highly interconnected proteins in an ER-mitochondria organization network, which were consistently down-regulated with aging. These decreased proteins, including VDAC1, SAMM50, MTX1 and MIC60, were considered as potential contributors to the age-related MAM dysfunction. This study highlights the perturbation in MAM integrity during the striated muscle aging process, and provides a framework for understanding aging biology from the perspective of organelle interactions.

BackgroundPrevious observational studies have shown an association between smoking and coronary artery disease (CAD) in patients with diabetes. Whether this association reflects causality remains unestablished. This study aimed to explore the causal effect of smoking on CAD in patients with diabetes.MethodsGenetic signatures for smoking were extracted from a large genome-wide association study (GWAS), consisted of up to 1.2 million participants. Four smoking phenotypes were included: smoking initiation, cigarettes per day, age at initiation of regular smoking, and smoking cessation. Genetic associations with CAD in patients with diabetes were extracted from another GWAS, which included 15,666 participants (3,968 CAD cases and 11,696 controls). The analyses were performed using the univariable and multivariable Mendelian randomization (MR) method.ResultsMR analysis revealed that smoking initiation was positively related to CAD risk in patients with diabetes (OR = 1.322, 95% CI = 1.114 – 1.568, P = 0.001), but this association was attenuated when adjusted for cardiovascular risk factors (OR = 1.212, 95% CI = 1.008 – 1.457, P = 0.041). Age at initiation of regular smoking was negatively related to CAD in patients with diabetes (OR = 0.214, 95% CI = 0.070 – 0.656, P = 0.007), but this association became insignificant when adjusted for cardiovascular risk factors.ConclusionsThis study supported the effect of smoking initiation on the risk of CAD in patients with diabetes.

Abstract This retrospective study aimed to explore the relationships between electrolytes and osmotic pressure homeostasis with contrast-associated acute kidney injury (CA-AKI) risk in patients with percutaneous coronary intervention or coronary angiography. We totally enrolled 4386 hospitalized patients, who were categorized into five groups based on the predetermined cutoff values of electrolytes and osmotic pressure. CA-AKI was defined as an increase in serum creatine by 0.5 mg/dL (44.2 mol/L) or a 25% increase of the highest level post-operation compared to baseline. Multivariable logistic analysis was used to examine the association of CA-AKI incidence with electrolytes and osmotic pressure levels. Piecewise linear regression models and restricted cubic spline analysis were further utilized to determine the nonlinear relationship. The results showed U-shaped relationships between sodium, chloride, magnesium, and osmotic pressure levels and CA-AKI incidence. The lowest incidence was observed in the categories of 139–141.9 mmol/L, 107.0–109.9 mmol/L, 0.91–1.07 mmol/L, and 290.0–299.9 mOsm/kg, respectively. J-shaped associations were observed for potassium and phosphate levels and CA-AKI incidence, with the lowest incidence in the categories of 3.50–4.09 mmol/L and 0.96–1.28 mmol/L, respectively. A negative correlation was observed between calcium level and CA-AKI incidence, with the lowest CA-AKI risk in the category of ≥ 2.58 mmol/L. In conclusion, abnormally higher or lower sodium, chloride, magnesium, phosphate, and osmotic pressure levels on admission were associated with increased risks of CA-AKI. While for potassium and calcium, the status of hyperkalemia and hypocalcemia on admission showed more susceptibility for CA-AKI.

Layered double hydroxides (LDH) are ideal for charge storage, however, the sluggish reaction dynamics are obstacle to their development. Here, triggered by mismatching integration of Mn sites, the authors configure wrinkled Mn/NiCo-LDH with strains and defects, where promoted mass & charge transport behaviors are realized.

Abstract Background The unique mechanism of diabetic atherosclerosis has been a central research focus. Previous literature has reported that the inflammatory response mediated by dendritic cells (DCs) plays a vital role in the progression of atherosclerosis. The objective of the study was to explore the role of DCs in diabetes mellitus complicated by atherosclerosis. Methods ApoE−/− mice and bone marrow-derived DCs were used for in vivo and in vitro experiments, respectively. Masson’s staining and Oil-red-O staining were performed for atherosclerotic lesion assessment. The content of macrophages and DCs in plaque was visualized by immunohistochemistry. The expression of CD83 and CD86 were detected by flow cytometry. The fluctuations in the RNA levels of cytokines, chemokines, chemokine receptors and adhesions were analyzed by quantitative RT-PCR. The concentrations of IFN-γ and TNF-α were calculated using ELISA kits and the proteins were detected using western blot. Coimmunoprecipitation was used to detect protein–protein interactions. Results Compared with the ApoE−/− group, the volume of atherosclerotic plaques in the aortic root of diabetic ApoE−/− mice was significantly increased, numbers of macrophages and DCs were increased, and the collagen content in plaques decreased. The expression of CD83 and CD86 were significantly upregulated in splenic CD11c+ DCs derived from mice with hyperglycemia. Increased secretion of cytokines, chemokines, chemokine receptors, intercellular cell adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) also were observed. The stimulation of advanced glycation end products plus oxidized low-density lipoprotein, in cultured BMDCs, further activated toll-like receptor 4, protein kinase C and receptor of AGEs, and induced immune maturation of DCs through the RAGE-TLR4-PKCβ1 signaling pathway that was bound together by intrinsic structures on the cell membrane. Administering LY333531 significantly increased the body weight of diabetic ApoE−/− mice, inhibited the immune maturation of spleen DCs, and reduced atherosclerotic plaques in diabetic ApoE−/− mice. Furthermore, the number of DCs and macrophages in atherosclerotic plaques was significantly reduced in the LY333531 group, and the collagen content was increased. Conclusions Diabetes mellitus aggravates chronic inflammation, and promotes atherosclerotic plaques in conjunction with hyperlipidemia, which at least in part through inducing the immune maturation of DCs, and its possible mechanism of action is through the RAGE-TLR4-pPKCβ1 signaling pathway.

Abstract Myocardial ischemia reperfusion (I/R) injury is a complex process with intense inflammatory response and cardiomyocyte apoptosis. As a decoy receptor of IL-1β, Interleukin-1 receptor type 2 (IL-1R2) inhibits IL-1β signaling. However, its role in I/R injury remains unknown. Here we found that the serum levels of IL-1R2 were significantly increased in patients with acute myocardial infarction (AMI) following interventional therapy. Similarly, after myocardial I/R surgery, IL-1R2 expression was significantly increased in heart of wild-type mice. In addition, IL-1R2-deficient mice heart showed enlarged infarct size, increased cardiomyocyte apoptosis together with reduced cardiac systolic function. Following exposure to hypoxia and reoxygenation (H/R), neonatal rat ventricular myocytes (NRVM) significantly increased IL-1R2 expression relying on NF-κB activation. Consistently, IL-1R2-deficient mice increased immune cells infiltrating into heart after surgery, which was relevant with cardiac damage. Additionally, IL-1R2 overexpression in cardiomyocyte protected cardiomyocyte against apoptosis through reducing the IL-17RA expression both in vivo and in vitro. Our results indicate that IL-1R2 protects cardiomyocytes from apoptosis, which provides a therapeutic approach to turn down myocardial I/R injury.

Abstract Background To investigate the causal association between serum 25-hydroxyvitamin D (25OHD), calcium (Ca), and parathyroid hormone (PTH) levels and the risk of coronary artery disease (CAD) in patients with diabetes using a Mendelian randomization approach. Methods Genetic signatures associated with serum 25OHD, Ca, and PTH levels were extracted from recently published genome-wide association study (GWAS), including 79,366, 39,400, 29,155 individuals, respectively. Genetic association estimates for CAD in patients with diabetes were obtained from a GWAS of 15,666 individuals with diabetes (3,968 CAD cases, 11,696 controls). The inverse-variance-weighted method was employed for the primary analysis, and other robust methods were applied for sensitivity analyses. Results Six, seven and five single nucleotide polymorphisms were identified as instrumental variables for serum 25OHD, Ca and PTH levels, respectively. There was no significant association between genetically predicted serum 25OHD levels and the risk of CAD in patients with diabetes (odds ratio (OR) = 1.04, 95% confidence interval (CI): 0.58 - 1.87, P = 0.888). Similarly, genetically predicted serum Ca (OR = 1.83, 95% CI: 0.62 – 5.35, P = 0.273) and PTH levels (OR = 1.27, 95% CI: 0.67 – 2.44, P = 0.464) were not significantly associated with the risk of CAD in patients with diabetes. These findings were robust in sensitivity analyses. Conclusions/interpretation Serum 25OHD, Ca and PTH levels may not be causally associated with the risk of CAD in patients with diabetes.

BackgroundCaffeine is widely consumed not only in coffee but also in soft drinks and tea. However, the long-term health effects of caffeine are still controversial, especially in people with high cardiovascular risk such as elderly patients with hypertension.MethodsThis study analyzed data from the National Health and Nutrition Examination Survey 2003–2018. Caffeine intake was calculated by two 24-h dietary recall interviews. Complex sampling-weighted multivariable Cox proportional hazards models were used to compare the hazard ratios (HRs) of all-cause and cardiovascular mortality in elderly hypertensive patients with different caffeine intake (

BackgroundPhysical activity and sedentary behavior are independently related to the risk of cardiovascular disease. Physical activity is recognized as having a protective effect, while being sedentary seems to be adverse. Nonetheless, the interactions between physical activity and sedentary behavior and the combined effect on the prognosis of heart failure patients remain unclear.Methods and resultsThis cohort study included 886 heart failure patients from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. Physical activity and sedentary behavior were assessed by the NHANES questionnaires. The all-caused deaths of enrolled subjects were identified from National Death Index (NDI) database. During a median follow-up of 51 months, 321 (36.2%) deaths from any causes occurred. Multivariable Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence interval (CI) for the all-cause mortality in heart failure patients associated with physical activity and sedentary behavior. Physical activity was independently associated with lower mortality [HR = 0.51, 95% CI (0.38-0.68), p < 0.001] and sedentary behavior was associated with adverse prognosis [HR = 1.79, 95% CI (1.41–2.28), p < 0.001]. Kaplan–Meier survival curve showed that physical activity appeared to attenuate the negative consequences of SB, while sedentary behavior increased the all-cause mortality, particularly those without physical activity.ConclusionPhysical activity has a protective effect on HF patients’ prognosis, particularly those with sedentary behavior. Sedentary behavior independently exhibited a negative association in populations without physical activity, while it does not increase mortality in those with moderate physical activity.

Objective While greater body mass index (BMI) is associated with increased risk of developing atrial fibrillation (AF), the impact of BMI on outcomes in newly diagnosed AF is unclear. We examine the influence of BMI on outcomes and whether this is modified by sex and evaluate the effect of non-vitamin K oral anticoagulants (NOACs) in patients with high BMI.Methods GARFIELD-AF is a prospective registry of 52 057 newly diagnosed AF patients. The study population comprised 40 482 participants: 703 underweight (BMI

BackgroundTo evaluate the safety and efficacy of hybutimibe plus atorvastatin for lipid control in hypercholesterolemia patients with atherosclerotic cardiovascular disease risk equivalent.MethodsIn this double-blind phase III study, we 1:1 randomly assigned 255 hypercholesterolemia patients with atherosclerotic cardiovascular disease to receive hybutimibe plus atorvastatin or placebo plus atorvastatin. The primary endpoint was the rate of change of plasma low-density lipoprotein-cholesterol (LDL-C) level at 12 weeks from baseline. The secondary endpoints were plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), non-HDL-C, apoprotein (Apo) B, and 2-, 4-, 8-, and 12-week Apo A1 levels change rate and rates of change of plasma LDL-C levels at 2, 4, and 8 weeks from baseline.ResultsFrom April 2016 to January 2018, 128 in the hybutimibe plus atorvastatin group and 125 in the atorvastatin group were included in modified intention-to-treat (mITT) analysis. After 12 weeks of treatment, LDL-C level changed from 2.61 mmol/L (±0.30) at baseline to 2.18 mmol/L (±0.45) in the hybutimibe plus atorvastatin group and from 2.58 (±0.31) mmol/L to 2.40 (± 0.46) mmol/L in the atorvastatin group (P < 0.0001), in mITT. The change rate in the hybutimibe plus atorvastatin group was significantly higher than that in the atorvastatin group (P < 0.0001); the estimated mean rates of change were −16.39 (95% confidence interval: −19.04, −13.74) and −6.75 (−9.48, −4.02), respectively. Consistently, in per-protocol set (PPS) analysis, the rate of change of LDL-C in the hybutimibe plus atorvastatin group was significantly higher than that in atorvastatin group. Significant decreases in the change rates of non-HDL-C, TC, and Apo B at 2, 4, 8, and 12 weeks (all P < 0.05) were observed for hybutimibe plus atorvastatin, while the differences were not significant for HDL-C, TG, and Apo-A1 (all P > 0.05). During the study period, no additional side effects were reported.ConclusionsHybutimibe combined with atorvastatin resulted in significant improvements in LDL-C, non-HDL-C, TC, and Apo B compared with atorvastatin alone. The safety and tolerability were also acceptable, although additional benefits of hybutimibe plus atorvastatin were not observed compared with atorvastatin alone in HDL-C, TG, and Apo-A1.

The alarming mortality and morbidity rate of myocardial infarction (MI) is becoming an important impetus in the development of early diagnosis and appropriate therapeutic approaches, which are critical for saving patients’ lives and improving post-infarction prognosis. Despite several advances that have been made in the treatment of MI, current strategies are still far from satisfactory. Nanomaterials devote considerable contribution to tackling the drawbacks of conventional therapy of MI by improving the homeostasis in the cardiac microenvironment via targeting, immune modulation, and repairment. This review emphasizes the strategies of nanomaterials-based MI treatment, including cardiac targeting drug delivery, immune-modulation strategy, antioxidants and antiapoptosis strategy, nanomaterials-mediated stem cell therapy, and cardiac tissue engineering. Furthermore, nanomaterials-based diagnosis strategies for MI was presented in term of nanomaterials-based immunoassay and nano-enhanced cardiac imaging. Taken together, although nanomaterials-based strategies for the therapeutics and diagnosis of MI are both promising and challenging, such a strategy still explores the immense potential in the development of the next generation of MI treatment.

BackgroundAcute exacerbation of chronic heart failure contributes to substantial increases in major adverse cardiovascular events (MACE). The study developed a risk score to evaluate the severity of heart failure which was related to the risk of MACE.MethodsThis single-center retrospective observational study included 5,777 patients with heart failure. A credible random split-sample method was used to divide data into training and validation dataset (split ratio = 0.7:0.3). Least absolute shrinkage and selection operator (Lasso) logistic regression was applied to select predictors and develop the risk score to predict the severity category of heart failure. Receiver operating characteristic (ROC) curves, and calibration curves were used to assess the model’s discrimination and accuracy.ResultsBody-mass index (BMI), ejection fraction (EF), serum creatinine, hemoglobin, C-reactive protein (CRP), and neutrophil lymphocyte ratio (NLR) were identified as predictors and assembled into the risk score (P < 0.05), which showed good discrimination with AUC in the training dataset (0.770, 95% CI:0.746–0.794) and validation dataset (0.756, 95% CI:0.717–0.795) and was well calibrated in both datasets (all P > 0.05). As the severity of heart failure worsened according to risk score, the incidence of MACE, length of hospital stay, and treatment cost increased (P < 0.001).ConclusionA risk score incorporating BMI, EF, serum creatinine, hemoglobin, CRP, and NLR, was developed and validated. It effectively evaluated individuals’ severity classification of heart failure, closely related to MACE.

Background: The hemoglobin glycation index (HGI) quantifies interindividual variation in glycation and is positively associated with cardiovascular diseases. However, the association between HGI and contrast-induced acute kidney injury (CI-AKI) remains unclear. Therefore, this study aimed to assess the association of HGI with CI-AKI.Methods: In this observational study, a total of 3,142 patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) were included. The HGI was calculated as the difference between the measured glycated hemoglobin (HbA1c) and predicted HbA1c. CI-AKI was defined as an increase of either 25% or 0.5 mg/dl (44.2 μmol/L) in the serum creatinine (SCr) level within 72 h following the exposure to contrast medium. Piecewise linear regression analysis was conducted to testify the association of HGI with the proportion of SCr elevation. Modified Poisson’s regression analysis was performed to determine the association between HGI and CI-AKI. Exploratory analysis was also performed according to the stratification of HbA1c levels.Results: Among 3,142 patients, the average age was 66.9 years and 483 of them (15.4%) suffered CI-AKI. Piecewise linear regression analysis demonstrated the linear association of HGI with the proportion of SCr elevation on both positive and negative sides of HGI [HGI

Abstract Background Obstruction of coronary microcirculation can lead to myocardial ischemia and poor prognosis. Salvianolate exerts cardiovascular protection at cellular levels. However, no studies have confirmed the effect of salvianolate on stable coronary heart disease (CHD) with high fractional flow reserve (FFR) and myocardial microcirculatory disturbances. Methods/design This study will enroll 78 patients who have stable coronary disease with 50 to 70% stenosis in major coronary arteries and whose FFR > 0.80 and index of microcirculatory resistance (IMR) > 25. Patients will be randomly divided into the salvianolate group or the placebo group. After above evaluations, salvianolate 200 mg will be intravenously dripped immediately for the next 30 min and subsequent 7 days in the salvianolate group, and matching 0.9% normal saline will be arranged in the placebo group. IMR will be reevaluated in immediate phase after first 30 min of salvianolate or placebo treatment. The primary end point will be the IMR change in this phase, and the secondary end points will be the total ischemic burden assessed by the Seattle angina scale, quality of life scale, Holter electrocardiography, and 6-min walk test after 7 days before discharge. Discussion This study will firstly clarify the improvement effect of salvianolate on coronary microcirculation and provide an effective treatment method for stable CHD patients with high FFR and myocardial microcirculatory disturbance. Trial registration Chinese Clinical Trial Registry ChiCTR1800018772 . Registered on 9 October 2018 and updated on 2 March 2020

Vertical graphene (VG) combines the excellent properties of conventional graphene with a unique vertical nanosheet structure, and has shown tremendous promise in the field of electronics and composites. However, its complex surface morphology brings great difficulties to micro-nano fabrication, especially regarding photolithography induced nanosheet collapse and remaining chemical residues. Here, we demonstrate an innovative method for directly growing patterned VG on a SiO2/Si substrate. A patterned Cr film was deposited on the substrate as a barrier layer. The VG was synthesized by PECVD on both the patterned Cr film and the exposed SiO2/Si substrate. During the cooling process, the patterned Cr film covered by VG naturally peeled off from the substrate due to the thermal stress mismatch, while the VG directly grown on the SiO2/Si substrate was remained. The temperature-dependent thermal stress distribution in each layer was analyzed using finite element simulations, and the separation mechanism of the Cr film from the substrate was explained. This method avoids the contamination and damage caused by the VG photolithography process. Our work is expected to provide a convenient and reliable solution for the manufacture of VG-based electronic devices.

BackgroundIdentifying high-risk patients for contrast-associated acute kidney injury (CA-AKI) helps to take early preventive interventions. The current study aimed to establish and validate an online pre-procedural nomogram for CA-AKI in patients undergoing coronary angiography (CAG).MethodsIn this retrospective dataset, 4,295 patients undergoing CAG were enrolled and randomized into the training or testing dataset with a split ratio of 8:2. Optimal predictors for CA-AKI were determined by Least Absolute Shrinkage and Selection Operator (LASSO) and Random Forest (RF) algorithm. Nomogram was developed and deployed online. The discrimination and accuracy of the nomogram were evaluated by receiver operating characteristic (ROC) and calibration analysis, respectively. Clinical usefulness was estimated by decision curve analysis (DCA) and clinical impact curve (CIC).ResultsA total of 755 patients (17.1%) was diagnosed with CA-AKI. 7 pre-procedural predictors were identified and integrated into the nomogram, including age, gender, hemoglobin, N-terminal of the prohormone brain natriuretic peptide, neutrophil-to-lymphocyte ratio, cardiac troponin I, and loop diuretics use. The ROC analyses showed that the nomogram had a good discrimination performance for CA-AKI in the training dataset (area under the curve, AUC = 0.766, 95%CI [0.737 to 0.794]) and testing dataset (AUC = 0.737, 95%CI [0.693 to 0.780]). The nomogram was also well-calibrated in both the training dataset (P = 0.965) and the testing dataset (P = 0.789). Good clinical usefulness was identified by DCA and CIC. Finally, this model was deployed in a web server for public use (https://duanbin-li.shinyapps.io/DynNomapp/).ConclusionAn easy-to-use pre-procedural nomogram for predicting CA-AKI was established and validated in patients undergoing CAG, which was also deployed online.

Background and AimsSystemic immune-inflammation index (SII) is an emerging indicator and correlated to the incidence of cardiovascular diseases. This study aimed to explore the association between SII and contrast-induced acute kidney injury (CI-AKI).MethodsIn this retrospective cross-sectional study, 4,381 subjects undergoing coronary angiography (CAG) were included. SII is defined as neutrophil count × platelet count/lymphocyte count. CI-AKI was determined by the elevation of serum creatinine (Scr). Multivariable linear and logistic regression analysis were used to determine the relationship of SII with Scr and CI-AKI, respectively. Receiver operator characteristic (ROC) analysis, structural equation model analysis, and subgroup analysis were also performed.ResultsOverall, 786 (17.9%) patients suffered CI-AKI after the intravascular contrast administration. The subjects were 67.1 ± 10.8 years wold, with a mean SII of 5.72 × 1011/L. Multivariable linear regression analysis showed that SII linearly increased with the proportion of Scr elevation (β [95% confidence interval, CI] = 0.315 [0.206 to 0.424], P < 0.001). Multivariable logistic regression analysis demonstrated that higher SII was associated with an increased incidence of CI-AKI ([≥12 vs.

To assess the diagnostic performance of fractional flow reserve (FFR) derived from coronary computed tomography angiography (CTA) (CT-FFR) obtained by a new computational fluid dynamics (CFD) algorithm to detect ischemia, using FFR as a reference, and analyze the characteristics of “gray zone” and misdiagnosed lesions. This prospective multicenter clinical trial (NCT03692936, https://clinicaltrials.gov/) analyzed 317 patients with coronary stenosis between 30 and 90% in 366 vessels from five centers undergoing CTA and FFR between November 2018 and March 2020. CT-FFR were obtained from a CFD algorithm (Heartcentury Co., Ltd., Beijing, China). Diagnostic performance of CT-FFR and CTA in detecting ischemia was assessed. Coronary atherosclerosis characteristics of gray zone and misdiagnosed lesions were analyzed. Per-vessel sensitivity, specificity and accuracy for CT-FFR and CTA were 89.9, 87.8, 88.8% and 89.3, 35.5, 60.4%, respectively. Accuracy of CT-FFR was 80.0% in gray zone lesions. In gray zone lesions, lumen area and diameter were significantly larger than lesions with FFR < 0.76 (both p < 0.001), lesion length, non-calcified and calcified plaque volume were all significantly higher than non-ischemic lesions (all p < 0.05). In gray zone lesions, Agatston score (OR = 1.009, p = 0.044) was the risk factor of false negative results of CT-FFR. In non-ischemia lesions, coronary stenosis >50% (OR = 2.684, p = 0.03) was the risk factor of false positive results. Lumen area (OR = 0.567, p = 0.02) and diameter (OR = 0.296, p = 0.03) had a significant negative effect on the risk of false positive results of CT-FFR. In conclusion, CT-FFR based on the new parameter-optimized CFD model provides better diagnostic performance for lesion-specific ischemia than CTA. For gray zone lesions, stenosis degree was less than those with FFR < 0.76, and plaque load was heavier than non-ischemic lesions.

BackgroundDespite coronary re-vascularization, the common complications of acute myocardial infarction (AMI), cardiac remodeling, and heart failure (HF), is increasing globally. Sacubitril valsartan (SV), an angiotensin receptor-neprilysin inhibitor (ARNI), has been previously demonstrated to improve HF. We further hypothesize that ultra-early SV treatment is also effective in preventing cardiac remodeling for patients with AMI following primary percutaneous coronary intervention (PCI).MethodsThe Assessment of ultra-early administration of Sacubitril Valsartan to improve cardiac remodeling in patients with Acute Myocardial Infarction following primary PCI (ASV-AMI) trial is a prospective, multicenter, randomized controlled trial in China planning to enroll at least 1,942 eligible patients from 10 centers. After successful primary PCI of culprit artery within 24 h, AMI patients are randomized to 2 h group or 3–7 days group with SV treatment. The major endpoints are echocardiographic measurement, cardiothoracic ratio, and N-Terminal pro-B-Type Natriuretic Peptide (NT pro-BNP) at baseline, 1, 3, 6, and 12 months. The secondary endpoints included MACE (cardiac arrest, cardiogenic death, myocardial infarction, and target vessel re-vascularization), in-/out-patient HF, EuroQol Five Dimensions Questionnaire (EQ-5D), and Kansas City Cardiomyopathy Questionnaire (KCCQ).DiscussionThe ASV-AMI trial is the first clinical trial of ultra-early administration of SV in the treatment of post-PCI AMI, adding more clinical evidence. Early application of SV to prevent cardiac remodeling in AMI patient is a major focus of this trial.Clinical Trial RegistrationTrial registration Chinese Clinical Trial Registry (http://www.chictr.org.cn; ChiCTR2100051979). Registered on 11 October 2021.

Abstract Background Postoperative atrial fibrillation (POAF) is one of the most common complications of esophagectomy, which may extend the inpatient hospital stay. Minimally invasive esophagectomy (MIE) has been increasingly used in clinical practice; however, its POAF risk and short-term mortality remain unclear. This study aimed to examine the POAF risk and in-hospital mortality rate between patients receiving MIE and open esophagectomy (OE). Methods Esophageal cancer patients who underwent MIE or OE from a retrospective cohort study were evaluated. A multivariate logistic regression model was built to assess the associations between esophagectomy (MIE vs. OE) and various outcomes (POAF, in-hospital mortality). Covariates included age, sex, body mass index, neoadjuvant therapy, tumor stage, surgery incision type, comorbidities, cardia conditions, peri-operative medication, and complications. Results Of the 484 patients with esophageal cancer, 63 received MIE. A total of 53 patients developed POAF. Compared to patients receiving OE, MIE patients had 81% reduced odds of POAF (adjusted odds ratio [aOR] 0.185, 95% CI 0.039–0.887, P = 0.035). No statistically significant association was found for in-hospital mortality (aOR 0.709, 95% CI 0.114–4.409, P = 0.712). Conclusions MIE is associated with a lower risk of POAF, compared to traditional surgery. No significant short-term survival benefit was found for MIE.

Abstract Left bundle branch pacing was associated with narrower QRS in patients with pacemaker indications. LBBP guided by ICE improves the accuracy of LBBP, facilitates the lead localization, minimizes complications, and above all reduces radiation exposure time.

Abstract Background Atherosclerosis is associated with chronic inflammation and lipid metabolism. The neutrophil to lymphocyte ratio (NLR) as an indicator of inflammation has been confirmed to be associated with cardiovascular disease prognosis. However, few studies have explored the effects of blood lipid variability on NLR. The aim of this study was to explore the relationship between variability in blood lipid levels and NLR. Methods The association between variability in blood lipids and NLR was assessed with both univariate and multivariate linear regression. Multivariate linear regression was also performed for a subgroup analysis. Results The variability of high-density lipoprotein cholesterol (HDL-C) (regression coefficients [β] 4.008, standard error (SE) 0.503, P-value

Objective: To investigate the effects of advanced glycation end products (AGEs) on the proliferation and apoptosis of cardiac microvascular endothelial cells (CMECs) in rats and their underlying signaling pathway. Methods: CMECs were isolated from Sprague–Dawley rats. We first examined the effects of AGEs on the proliferation and apoptosis of CMECs and then tested whether protein kinase C (PKC) β blockers could counteract the effects of AGEs. The PKC agonists phorbol 12-myristate 13-acetate (PMA) and PKCβ blockers were also used to verify whether PKC could act independently on CMECs. The receptor for AGEs (RAGE)–small interfering RNA (siRNA) transfection was used to verify the effect of AGEs on PKC. Following the above steps, we explained whether AGEs regulated the CMEC proliferation and early apoptosis through the PKCβ signaling pathway. Proliferation of CMECs was detected using the Cell Counting Kit-8 (CCK-8) assay, and early apoptosis was determined using the Annexin V- Fluorescein Isothiocyanate (FITC)/propidium iodide (PI) double staining. Expression of proliferation and apoptosis-related proteins and PKC phosphorylation were determined by western blotting analysis. Cell cycle distributions were assayed using a BD FACSCalibur cell-sorting system. Results: AGEs facilitated the proliferation of CMECs, upregulated phosphorylated extracellular signal regulated kinase (p-ERK), and accelerated the entry of cells from G1 phase to the S+G2/M phase, which was consistent with the upregulated cyclin D1 by AGEs. AGEs inhibited early apoptosis of CMECs by increasing the expression of survivin and decreasing the expression of cleaved-caspase3. All these effects can be reversed by PKCβ1/2inhibitors. In addition, AGE upregulated the RAGE expression and phosphorylation of PKCβ1/2 in CMECs, while the inhibition of RAGE reversed the phosphorylation, as well as the effects of AGEs on proliferation and apoptosis in CMECs. Conclusion: The study indicated that AGEs facilitated the proliferation and reduced early apoptosis of CMECs via the PKCβ signaling pathway.

Abstract Background Ticagrelor and clopidogrel, P2Y12 receptor antagonists, can prevent thrombotic events and are used to treat cardiovascular diseases such as acute coronary syndrome and chronic obstructive pulmonary disease, in which inflammation is involved. Moreover, NF-B is the central regulator of inflammation. Thus, we suspected that ticagrelor and clopidogrel are involved in the regulation of the NF-ΚB signaling pathway. Methods After human umbilical vein endothelial cells (HUVECs) were cultured with ticagrelor or clopidogrel and given lipopolysaccharide (LPS) and CD14, the mRNA levels of related inflammatory factors, the protein level and subcellular localization of molecules in the NF-ΚB signaling pathway, cell viability, apoptosis and the cell cycle, cell migration, and vascular formation were detected using quantitative polymerase chain reaction (qPCR), western blotting and immunofluorescence assay, CCK-8, flow cytometry, transwell assay, and matrigel, respectively. All data was expressed as the mean ± S.D. The statistical significance of data was assessed by an unpaired two-tailed t-test. Results Ticagrelor and clopidogrel can inhibit the degradation of IKBα and phosphorylation of p65, prevent p65 from entering the nucleus, reduce the production of TNFα, IL-1, IL-8, IL-6 and IL-2, and alleviate the decrease in cell viability, cell migration and angiogenesis, the changes of cell cycle and apoptosis induced by LPS. Conclusions Ticagrelor and clopidogrel alleviate cellular dysfunction through suppressing NF-ΚB signaling pathway.

Abstract Background Conventional pharmacologic therapies aim to reduce fluid overload in advanced heart failure (HF) represented by intravenous (IV) loop diuretics (LDs) have sometimes not so efficacious and been reported to have side effects such as unpredictable removal of water and sodium and electrolyte disturbance. It is not certain whether early ultrafiltration (UF) is effective than LDs in relieving edema. Given the weakness of evidence for early UF in patients with fluid overload, recommendations of UF in guidelines is considered as second-line therapy only for patients with refractory congestion, who failed to respond to LD-based strategies. Methods The early continuous ultrafiltration in Chinese patients with congestive heart failure (EUC-CHF) trial is an open-label, registry-based, prospective study, recruiting patients with severe acute decompensated HF who are hospitalized for HF worsening due to overt fluid overload 24 h from hospital admission. Forty patients will be enrolled to two treatment groups (n = 20 for each group). The primary outcomes are the changes of weight loss and dyspnea severity score after treatment, as well as the occurrence of clinically overt major bleeding. Discussion EUC-CHF trial was primarily designed to evaluate the efficacy and safety of early UF in patients with acute decompensated HF to reduce volume overload and improve clinical outcome. The trial aims to determine if early UF in acute HF is superior to IV LDs in clinical parameter improvement without adverse events and prevents rehospitalization up to 30 days. Also the trial is expected to establish a scoring system based on Chinese population to guide early UF treatment in appropriate patients. EUC-CHF is one of the first controlled trials tailored to determine the benefit of UF with 24 h from hospital admission. Trial registration www.chictr.org.cn, ChiCTR1800019556. Registered on 18 November 2018.