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Several observational studies indicated that atrial fibrillation might aggravate other cardiovascular diseases apart from ischaemic stroke. However, it remains to be determined whether these associations reveal independent causation. Using Mendelian randomization (MR), we systematically investigated how genetically predicted atrial fibrillation affected other cardiovascular diseases and cardiac death.Summary-level data for atrial fibrillation and other cardiovascular diseases were obtained from public genome-wide association study data. The random inverse-variance weighted method was treated as the primary analysis. Sensitivity analyses (including weighted median, MR-Egger, and multivariable MR methods) were also performed. Atrial fibrillation was significantly associated with higher risks of heart failure [odds ratio (OR): 1.24; 95% confidence interval (CI): 1.19-1.28; P 0.001], ischaemic stroke (OR: 1.21; 95% CI: 1.17-1.25; P 0.001), transient ischaemic attack (OR: 1.10; 95% CI: 1.05-1.15; P 0.001), peripheral artery diseases (OR: 1.09; 95% CI: 1.03-1.15; P = 0.002), cardiac death (OR: 1.08; 95% CI: 1.02-1.15; P = 0.008), and hypertension (OR: 1.06; 95% CI: 1.01-1.11; P = 0.010), without effects on coronary heart disease or pulmonary embolism. Associations for heart failure and ischaemic stroke remained robust to the sensitivity analyses. MR-Egger method (P 0.05) and funnel plot yielded no indication of directional pleiotropy. The leave-one-out analysis suggested that the causal associations were not driven by individual single nucleotide polymorphism.This comprehensive MR analysis verified the causal associations between atrial fibrillation and high risks of heart failure, ischaemic stroke, transient ischaemic attack, peripheral artery diseases, cardiac death, and hypertension. Interventions to reduce cardiovascular diseases beyond ischaemic stroke are warranted in patients with atrial fibrillation.

Resumo Fundamento A eficiência do manejo invasivo em pacientes mais velhos (≥75 anos) com infarto do miocárdio sem supradesnivelamento do segmento ST (IAMSSST) permanece ambígua. Objetivos Avaliar a eficiência do tratamento invasivo em pacientes idosos com IAMSSST com base em metanálise e análise sequencial de estudo (TSA). Métodos Ensaios clínicos randomizados relevantes (ECR) e estudos observacionais foram incluídos. Os resultados primários foram morte por todas as causas, infarto do miocárdio, acidente vascular cerebral e hemorragia grave. O odd ratio agrupado (OR) e o intervalo de confiança de 95% (IC) foram calculados. P

Aims The ESC/EACTS myocardial revascularization guidelines recently standardized the definition of patients at high ischemic risk (HIR). However, the ability of ESC/EACTS-HIR criteria to stratify ischemic and bleeding risk in a contemporary real-world East Asian cohort remains unexplored. Methods A total of 10,167 consecutive patients undergoing PCI from prospective Fuwai PCI Registry (January 2013 to December 2013) were reviewed. ESC/EACTS-HIR features was defined as having at least one of the eight clinical and angiographic characteristics. The primary ischemic endpoint was target vessel failure (cardiac death, target vessel myocardial infarction [MI], or target vessel revascularization [TVR]); bleeding outcome was assessed using the BARC type 2, 3, or 5 bleeding. Median follow-up was 29 months. Results Compared with non-HIR patients, HIR patients (n=5,149, 50.6%) were associated with increased risk for target vessel failure (adjusted hazard ratio [HRadjust]: 1.48 [1.25-1.74]) and patient-oriented composite outcome (HRadjust: 1.44 [1.28-1.63]), as well as cardiac death, MI, and TVR. By contrast, the risk of clinically relevant bleeding was not significantly different between the two groups. (HRadjust: 0.84 [0.66-1.06]). Greater than or equal to three implanted stents and diabetic patients with diffuse multivessel coronary disease emerged as independent predictors for long-term adverse outcomes. There was no significant interaction between high bleeding risk (HBR) status and clinical outcomes associated with ESC/EACTS-HIR criteria (all Pinteraction ＞0.05). Conclusion The ESC/EACTS-HIR features identified patients at increased risk of thrombotic events, including cardiac death, but not for clinically relevant bleeding. Importantly, HBR did not modify cardiovascular risk subsequent to patients with ESC/EACTS-HIR features, suggesting its potential clinical applicability in tailoring antithrombotic therapy.

Recent guidelines and randomized clinical trials favor the multivessel percutaneous coronary intervention (MV-PCI) strategy undertaken immediately or staged after primary PCI in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease. However, the optimal strategy of MV-PCI remains unknown.We conducted a search of PUBMED, EMBASE, Web of Science, the Cochrane database (CENTRAL), clinicaltrial.gov, and Google Scholar for studies comparing immediate versus staged MV-PCI in patients with STEMI and multivessel disease. Pooled odds ratios (OR) and 95% confidence intervals (CI) were estimated using random-effects models.Eighteen (4 randomized clinical trials) studies with 8100 patients fulfilled the inclusion criteria. Relative to staged MV-PCI, immediate MV-PCI was associated with higher short-term (within 30 days) (OR, 3.96; 95% CI, 2.07-7.59; P 0.0001) and long-term (above 6 months) mortality (OR, 2.12; 95% CI, 1.46-3.07; P 0.0001), short-term major adverse cardiovascular events (MACE)(OR, 1.99; 95% CI, 1.13-3.50; P = 0.02) and cardiac death (OR, 4.78; 95% CI, 2.17-10.53; P = 0.0001). There was a nonsignificant trend towards higher long-term MACE (OR, 1.23; 95% CI, 0.98-1.54; P = 0.07) and cardiac death (OR, 1.75; 95% CI, 0.93-3.30; P = 0.08) with immediate versus staged MV-PCI. Revascularization, myocardial infarction, and safety endpoints including stroke, major bleeding, and renal failure were similar between immediate versus staged MV-PCI. However, pooled analysis of randomized clinical trials did not show any significant differences in long-term MACE, all-cause mortality, myocardial infarction, and revascularization.Our meta-analysis suggests that among patients with STEMI and multivessel disease, staged instead of immediate MV-PCI may be the optimal revascularization strategy.

Background Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSCATV-EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSCATV-EV. Methods MSCATV-EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSCATV-EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo. Results MSCATV-EV significantly reduced the amount of CD68+ total macrophages and increased CD206+ M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group (P ATV-EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced (P ATV-EV also significantly reduced the protein and mRNA expressions of M1 markers but increased those of M2 markers in lipopolysaccharide-treated macrophages (P ATV-EV significantly attenuated while overexpression of it in MSC-EV enhanced the effect on promoting M2 polarization by suppressing downstream signal transducer and activator of transcription 1 (Stat1). Furthermore, MSCATV-EV loaded with miR-139-3p inhibitors decreased while MSC-EV loaded with miR-139-3p mimics increased the expressions of M2 markers and cardioprotective efficacy. Conclusions We uncovered a novel mechanism that MSCATV-EV remarkably facilitate cardiac repair in AMI by promoting macrophage polarization via miR-139-3p/Stat1 pathway, which has the great potential for clinical translation.

Background Data on fibrinolytic therapy use for ST-segment elevation myocardial infarction (STEMI) and long-term clinical outcomes in developing countries are limited. We aimed to investigate the management and 2-year mortality of fibrinolytic-treated patients in China. Methods A total of 19,112 patients with STEMI from 108 hospitals participated in the China Acute Myocardial Infarction registry between January 2013 and September 2014. We investigated the 2-year all-cause mortality among patients treated with fibrinolysis. Non-invasive clinical indexes were used to diagnose successful fibrinolysis or not. Results Only 1823 patients (9.5%) enrolled in the registry underwent fibrinolysis and 679 (37.2%) could be treated within 3 h after symptom onset. The overall use of rescue percutaneous coronary intervention was 8.9%. Successful fibrinolysis, which could be achieved in 1428 patients (78.3%), was related to types of fibrinolytic agents, symptom to needle time, infarction site, and Killip class. Follow-up data were available for 1745 patients (95.7%). After multivariate adjustment, successful fibrinolysis was strongly associated with a decreased risk of death compared with failed fibrinolysis at 2 years (8.5% vs. 29.0%, hazard ratio: 0.27, 95% confidence interval: 0.20–0.35). Conclusion Within a minority of STEMI patients in the CAMI registry underwent fibrinolysis, most of them could achieve successful clinical reperfusion, presenting a much benign 2-year survival outcome than those with failed fibrinolysis. Quality improvement initiatives focusing on fibrinolysis are warranted to achieve its promise fully. Trial registration: URL: https//www.clinicaltrials.gov. Unique identifier: NCT01874691. Registered 11/06/2013.

Background Patients with coronary artery disease (CAD) combined with diabetes have a higher risk of cardiovascular events, and high-sensitivity C-reactive protein (hs-CRP)-to-albumin ratio (CAR) is a novel inflammatory biomarker. However, whether the CAR can identify high-risk patients with CAD and type 2 diabetes (T2DM) remains unclear. Methods The present study was based on a prospective and observational cohort with 10,724 individuals who undergo percutaneous coronary intervention (PCI) in Fu Wai Hospital throughout the year 2013 consecutively enrolled. The primary endpoint was all-cause mortality. The secondary endpoint was cardiac mortality. CAR was calculated with the formula: hs-CRP (mg/L)/albumin (g/L). According to the optimal cut-off value of CAR for all-cause mortality, patients were divided into higher CAR (CAR-H) and lower CAR (CAR-L) groups. Results A total of 2755 patients with T2DM who underwent PCI and received dual antiplatelet therapy were finally enrolled. During a follow-up of 5 years (interquartile range: 5.0–5.1 years), 126 (4.6%) all-cause mortalities and 74 (2.7%) cardiac mortalities were recorded. In the multivariable Cox model, CAR-H was associated with a higher risk of all-cause mortality (hazard ratio [HR]: 1.634, 95% confidence interval [CI] 1.121–2.380, p = 0.011) and cardiac mortality (HR: 1.733, 95% CI 1.059–2.835, p = 0.029) compared with CAR-L. When comparing the predictive value, CAR was superior to hs-CRP for all-cause mortality (area under the curve [AUC] 0.588 vs. 0.580, p = 0.002) and cardiac mortality (AUC 0.602 vs. 0.593, p = 0.004). Conclusion In this real-world cohort study, a higher level of CAR was associated with worse 5-year outcomes among diabetic patients with PCI.

Objective The aim of the study is to assess the causal effects of cardiovascular risk factors on venous thromboembolism (VTE) and its subtypes including deep vein thrombosis (DVT) and pulmonary embolism (PE). Methods A summary-level Mendelian randomization (MR) analysis was performed by extracting data from public and large-scale genome-wide association studies for cardiovascular risk factors (hypertension, systolic blood pressure [SBP], diastolic blood pressure [DBP], total cholesterol, triglycerides, high-density lipoprotein [HDL], low-density lipoprotein [LDL], type 2 diabetes, fasting glucose, body mass index [BMI], smoking, alcohol, and physical activity), VTE, DVT, and PE to identify genetic instruments. Results BMI (per standard deviation [SD] increase; odds ratio [OR]: 1.39; 95% confidence interval [CI]: 1.25–1.54; p = 8.02 × 10−10) could increase the VTE risk, whereas SBP (per SD increase; OR: 0.99; 95% CI: 0.98–0.99; p = 0.0005) could decrease the VTE risk. For DVT, BMI (per SD increase; OR: 1.48; 95% CI: 1.28–1.72; p = 1.53 × 10−7) could increase the risk, whereas physical activity (per SD increase; OR: 0.05; 95% CI: 0.01–0.33; p = 0.0020) could decrease the risk. For PE, BMI (per SD increase; OR: 1.29; 95% CI: 1.12–1.49; p = 0.0005) could increase the risk, whereas SBP (per SD increase; OR: 0.99; 95% CI: 0.98–1.00; p = 0.0032) could decrease the risk. Suggestive evidence between smoking and higher risks of VTE and DVT was also observed. Conclusion Our study supports that BMI is a causal risk factor for VTE, DVT, and PE. SBP is a protective factor for VTE and PE. Physical activity is a protective factor for DVT. However, the effects of other cardiovascular risk factors are not identified.

Increasing evidence suggests that hypothyroidism aggravates atherosclerosis. Macrophage apoptosis plays a significant role in the development of atherosclerotic plaque. We aimed to explore the effect of thyroid hormones on macrophage apoptosis induced by oxidized low-density lipoprotein (oxLDL). Peripheral blood samples from 20 patients (normal group, hypothyroidism group, coronary artery disease [CAD] group, hypothyroidism + CAD group) were collected to perform messenger RNA microarray analysis. Bioinformatics analysis identified apoptosis and mitogen-activated protein kinase (MAPK) signaling as differentially expressed pathways between CAD and hypothyroidism + CAD group. In vitro, thyroid hormones concentration-dependently promoted cell survival and inhibited apoptosis in oxLDL-treated RAW264.7 macrophages, along with elevated extracellular signal-regulated kinases 1 and 2 (Erk1/2) phosphorylation. The STRING database showed an interaction of thyroid hormone receptor alpha1 (TRα1) and MAPK pathway. TRα1 knockdown increased cell apoptosis and decreased Erk1/2 phosphorylation. Erk1/2 inhibitor aggravated macrophage apoptosis. Moreover, thyroid hormones inhibited oxidative stress in oxLDL-treated macrophages. The study indicates that thyroid hormones concentration-dependently attenuate oxLDL-induced macrophage apoptosis through activating TRα1-Erk1/2 pathway and inhibiting oxidative stress, which implies a potential mechanism of hypothyroid-accelerated atherosclerosis.

Previous studies have shown conflicting results about the impact of moderate to vigorous physical activity on the risk of venous thromboembolism (VTE). Using Mendelian randomization, we assessed whether moderate to vigorous physical activity causally affects VTE from genetic level. Genetic instruments associated with moderate to vigorous physical activity at the genome-wide significance level (P 5×10

Junxing Lv,1 Qinghao Zhao,1 Jingang Yang,1 Xiaojin Gao,1 Xuan Zhang,1 Yunqing Ye,1 Qiuting Dong,1 Rui Fu,1 Hui Sun,1 Xinxin Yan,1 Wei Li,2 Yuejin Yang,1 Haiyan Xu1 On behalf of the China Acute Myocardial Infarction Registry Study Group1Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People’s Republic of China; 2Medical Research & Biometrics Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People’s Republic of ChinaCorrespondence: Haiyan Xu; Yuejin YangDepartment of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People’s Republic of ChinaTel +8610-88396082Email xuhaiyan@fuwaihospital.org; yangyjfw@126.comBackground: Length of stay (LOS) in patients with ST-segment elevation myocardial infarction (STEMI) is directly associated with financial pressure and medical efficiency. This study aimed to determine impact of LOS on short-term outcomes and associated factors of LOS in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (PPCI).Methods: A total of 3615 patients with STEMI after PPCI in the China Acute Myocardial Infarction registry were included in the analysis. Predictors of prolonged LOS were analyzed by multivariate logistic regression model with generalized estimating equation. The impact of LOS on 30-day clinical outcomes was assessed.Results: The median LOS was 9 (7, 12) days. Patients with a longer LOS (> 7 days) were older, more often in lower-level hospitals, had more periprocedural complications and hospitalization expense. Fourteen variables, such as weekend admission and lower-level hospitals, were identified as independent associated factors of prolonged LOS. There were no significant difference in 30-day major adverse cardiac and cerebrovascular events (MACCE), readmission, and functional status between patients with LOS≤ 7d and LOS> 7d after multivariate adjustment and propensity score matching. However, patients who discharged over one week had better medication adherence (adjusted odds ratio: 0.817, 95% confidence interval: 0.687– 0.971, P=0.022). Significant interaction was observed in medication use between gender and LOS (Pinteraction=0.038).Conclusion: Patients with STEMI undergoing PPCI experienced a relatively long LOS in China, which resulted in more medical expenses but no improvement on 30-day MACCE, readmission, and functional recovery. Poor 30-day medication adherence with short LOS reflects unsatisfying transition of management from hospital to community. More efforts are needed to reduce LOS safely and improve the efficiency of medical care.Keywords: length of stay, ST-segment elevation myocardial infarction, primary percutaneous coronary intervention, prognosis

Aim: The efficacy and safety of ticagrelor and clopidogrel in patients with stable coronary artery disease (SCAD) undergoing percutaneous coronary intervention (PCI) remain uncertain. Thus, this study aimed to compare the efficacy and safety of ticagrelor and clopidogrel in patients with SCAD treated with PCI. Methods: A total of 9,379 patients with SCAD undergoing PCI who received dual antiplatelet therapy (DAPT) were consecutively enrolled in two groups, namely, ticagrelor ( n =1,081) and clopidogrel ( n =8,298) groups. Major adverse cardiovascular and cerebrovascular events (MACCEs) and bleeding events according to ticagrelor or clopidogrel use were compared. Results: After propensity matching ( n =1,081 in each group), ticagrelor was associated with fewer MACCEs compared with clopidogrel (3.6% vs. 5.7%, hazard ratio [HR]=0.62, 95% confidence interval [CI] 0.41–0.93, p =0.019), and the difference between ticagrelor and clopidogrel for bleeding events was nonsignificant (4.0% vs. 3.2%, HR=1.24, 95% CI 0.79-1.93, p =0.356). On the other hand, the difference between ticagrelor and clopidogrel for net adverse clinical events was significant (4.1% vs. 6.0%, HR=0.67, 95% CI 0.46–0.98, p =0.039). In a multivariate analysis, the use of ticagrelor, number of stents, previous history of diabetes, previous history of smoking, and ACC/AHA type B2 or C lesions were considered independent predictors of MACCEs, while radial artery access, previous history of stroke, and weight ＜60kg were independent predictors of bleeding events. Conclusions Ticagrelor was associated with a lower incidence of MACCEs without an increased risk of bleeding events in patients with SCAD receiving PCI.

Background The recent randomized trials demonstrated that culprit-only percutaneous coronary intervention (CO-PCI) was superior to multivessel PCI (MV-PCI) among ST-segment elevation myocardial infarction (STEMI) patients with multivessel disease (MVD) complicated by cardiogenic shock, yet the real-world scenario remains to be determined. Methods Studies that compared CO-PCI versus MV-PCI in STEMI patients with MVD complicated by cardiogenic shock were identified by a systematic search of published articles. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated by using random-effects models. Results Eventually, 18 observational studies involving 73,528 patients were included. The results showed that CO-PCI was associated with lower risks of short-term renal failure (OR: 0.75; 95% CI: 0.64 to 0.88; I2=14.7%) and short-term stroke (OR: 0.86; 95% CI: 0.77 to 0.96; I2=0.0%) compared with immediate MV-PCI. But the risk of short-term myocardial infarction (OR: 1.12; 95% CI: 1.03 to 1.22; I2=0.0%) was increased. There was no significant difference during long-term follow-up. The results remained consistent after adding the only randomized trial. Discussion Based on real-world analyses, our meta-analysis suggested that CO-PCI decreased the risks of renal failure and stroke but increased the risk of myocardial infarction relative to immediate MV-PCI during short-term follow-up in STEMI patients with MVD complicated by cardiogenic shock. If possible in clinical practice, staged MV-PCI can be given a try to decrease the risks of renal failure and stroke associated with immediate MV-PCI and myocardial infarction associated with CO-PCI. However, the conclusions need to be confirmed by further large-scale studies.

Aims Interleukin (IL)-5 mediates the development of eosinophils (EOS) that are essential for tissue post-injury repair. It remains unknown whether IL-5 plays a role in heart repair after myocardial infarction (MI). This study aims to test whether IL-5-induced EOS population promotes the healing and repair process post-MI and to reveal the underlying mechanisms. Method and results MI was induced by permanent ligation of the left anterior descending coronary artery in wild-type C57BL/6 mice. Western blot and real-time polymerase chain reaction revealed elevated expression of IL-5 in the heart at 5 days post-MI. Immunohistostaining indicated that IL-5 was secreted mainly from macrophages and type 2 innate lymphoid cells in the setting of experimental MI. External supply of recombinant mouse IL-5 (20 min, 1 day, and 2 days after MI surgery) reduced the infarct size and increased ejection fraction and angiogenesis in the border zone. A significant expansion of EOS was detected in both the peripheral blood and infarcted myocardium after IL-5 administration. Pharmacological depletion of EOS by TRFK5 pretreatment muted the beneficial effects of IL-5 in MI mice. Mechanistic studies demonstrated that IL-5 increased the accumulation of CD206+ macrophages in infarcted myocardium at 7 days post-MI. In vitro co-culture experiments showed that EOS shifted bone marrow-derived macrophage polarization towards the CD206+ phenotypes. This activity of EOS was abolished by IL-4 neutralizing antibody, but not IL-10 or IL-13 neutralization. Western blot analyses demonstrated that EOS promoted the macrophage downstream signal transducer and activator of transcription 6 (STAT6) phosphorylation. Conclusion IL-5 facilitates the recovery of cardiac dysfunction post-MI by promoting EOS accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis. Translational perspective Accumulating evidence suggests that modulation of innate and adaptive immune responses is a promising therapeutic strategy for myocardial infarction. In this study, we demonstrate that IL-5 exerts cardioprotective effects on infarcted myocardium by promoting eosinophil accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis. Hence, regulation of cardiac IL-5 level or eosinophil count may become a therapeutic approach for post-myocardial infarction cardiac repair in humans.

Background Fibrinogen (FIB) is an independent risk factor for mortality and cardiovascular events in the general population. However, the relationship between FIB and long-term mortality among CAD patients undergoing PCI remains unclear, especially in individuals complicated with diabetes mellitus (DM) or prediabetes (Pre-DM). Methods 6,140 patients with CAD undergoing PCI were included in the study and subsequently divided into three groups according to FIB levels (FIB-L, FIB-M, FIB-H). These patients were further grouped by glycemic status [normoglycemia (NG), Pre-DM, DM]. The primary endpoint was all-cause mortality. The secondary endpoint was cardiac mortality. Results FIB was positively associated with hemoglobin A1c (HbA1c) and fasting blood glucose (FBG) in CAD patients with and without DM (P Conclusions FIB was independently associated with long-term all-cause and cardiac mortality among CAD patients undergoing PCI, especially in those with DM and Pre-DM. FIB test may help to identify high-risk individuals in this specific population.

Purpose Recent decades have been witnessing that heart failure with preserved ejection fraction (HFpEF) outweighs heart failure with reduced ejection fraction by degrees, but few drugs were proven to improve long-term clinical outcomes in patients with HFpEF. Levosimendan, a calcium sensitizing cardiotonic agent, has been found to improve decompensated heart failure clinically. However, the protective activities and underlying molecular mechanisms of levosimendan on HFpEF have not been revealed. Methods The double-hit HFpEF C57BL/6N mouse model was established, and levosimendan (3 mg/kg/week) was administered to HFpEF mice aged from 13 to 17 weeks to verify its protective effects on HFpEF. The myocardium was biochemically evaluated by western blot, immunofluorescence, flow cytometry, etc. Results After four-week administration, cardiac hypertrophy, pulmonary congestion, and exercise exhaustion were significantly alleviated. Meanwhile, junction proteins located in endothelial barrier and between cardiomyocytes were improved by levosimendan treatment. Among the gap junction channel proteins concerned, connexin 43, especially expressed on cardiomyocytes, could conduct mitochondrial protection. Furthermore, levosimendan indeed reversed mitochondrial malfunction in HFpEF mice, evidenced by increased mitofilin and decreased ROS, superoxide anion, NOX4 and cytochrome C levels. Interestingly, after levosimendan treatment, myocardium from HFpEF mice showed restricted ferroptosis, indicated by upregulated GSH/GSSG ratio, GPX4, xCT and FSP-1 expression with down-regulated intracellular ferrous ion, MDA and 4-HNE. Conclusion This study confirmed that regular long-term levosimendan administration could benefit HFpEF individuals, particularly those with metabolic syndrome, such as obesity and hypertension, by activating connexin 43-conducted mitochondrial protection and sequential ferroptosis inhibition in cardiomyocytes.

It is well established that lipoprotein(a)[Lp(a)] and low-density lipoprotein cholesterol (LDL-C) play a vital role in atherosclerosis. We investigated the prevalence and prognostic implications of increased Lp(a) in patients undergoing percutaneous coronary intervention (PCI) according to different LDL-C concentrations.A total of 9,190 patients with CAD after PCI were consecutively enrolled in the study and subsequently divided into three groups according to baseline LDL-C at cut-off of 70 and 100 mg/dl. Increased Lp(a) was defined as30 mg/dl. The primary endpoint was all-cause death. Second endpoint was cardiac death. Cox regression, Kaplan-Meier and Sensitivity analysis were performed.During an average of 5.0 y of follow-up, 354 (3.9%) patients experienced all-cause death with 213(2.3%) of whom from cardiac death. Increased Lp(a) was present in 25.7%, 34.2%, and 40.6% across the LDL-C70, 70-100 and≧100 mg/dl groups, respectively. After multivariate adjustment, Lp(a) elevation remained significantly associated with 5-y all-cause death (adjusted HR, 1.243; 95% CI 1.001-1.544; p = 0.048) in the total cohort and only in those with LDL-C ≥ 100 mg/dl (adjusted HR, 1.642; 95% CI 1.139-2.367; p = 0.008) when analyzed within each LDL-C category. Consistently with the results of associations between Lp(a) and cardiac death (adjusted HR, 1.534; 95% CI 1.164-2.021; p = 0.002 for total cohort and adjusted HR, 2.404; 95% CI 1.439-3.872; p0.001 for LDL-C ≥ 100 mg/dl). And this relationship holds after adjusting for LDL-Ccorr additionally. These findings are confirmed again in sensitivity analyses that excluded patients with Lp(a) concentrations in the top or the bottom 5%.We confirmed that increased Lp(a) was associated with increased risk of long-term outcomes, and such an association was modified by the baseline LDL-C concentrations. Screening of high Lp(a) in individuals with elevations of LDL-C may enables risk stratification for poor prognosis.

Background Total occlusion is the most severe coronary lesion, indicating heavy ischemic burden and poor prognosis. The lipid profile is central to the development of atherosclerotic coronary lesions. Evidence on the optimal lipid measure to be monitored and managed in patients with established coronary artery disease (CAD) is inconclusive. Methods Total cholesterol (TC), total triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), nonhigh-density lipoprotein cholesterol (non-HDL-c), lipoprotein (a) [Lp(a)], apolipoprotein B (apoB), non-HDL-c/HDL-c, and apoB/apoA-1 were analyzed in quintiles and as continuous variables. The associations of lipid measures with total occlusion were tested using logistic regression models, visualized with restricted cubic splines, and compared by areas under the receiver operating characteristic curves (AUROC). Discordance analysis was performed when apoB/apoA-1 and non-HDL-c/HDL-c were not in concordance. Results The prospective cohort study included 10,003 patients (mean age: 58 years; women: 22.96%), with 1879 patients having total occlusion. The risks of total occlusion significantly increased with quintiles of Lp(a), non-HDL-c/HDL-c, and apoB/apoA-1 (all p for trend p p Conclusion ApoB/apoA-1 confers better predictive power for total occlusion than non-HDL-c/HDL-c and single lipid measures in established CAD patients.

Background: Patients with diabetes mellitus (DM) are considered to increase the risk of thrombosis and bleeding. However, whether DM is an independent risk factor for events in patients anticoagulated with bivalirudin during elective percutaneous coronary intervention (PCI) is not clear. Methods: Patients anticoagulated with bivalirudin during elective PCI from January 2017 to August 2018 in 3 centers were enrolled. The primary endpoint of thrombotic events was major adverse cardiac and cerebrovascular events (MACCE, including all-cause death, myocardial infarction, ischemic revascularization, stent thrombosis, and stroke); the primary endpoint of bleeding events was Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding. Results: 1152 patients were finally enrolled. After one-year follow-up, 89 (7.7%) MACCE and 21 (1.8%) BARC 2, 3 or 5 bleeding occurred. Multivariate Cox regression analysis showed DM was not an independent risk factor for MACCE (hazard ratio [HR]: 1.029, 95% confidence interval [CI]: 0.674-1.573, P = .893), but peripheral artery disease (PAD) history (HR: 2.200, 95%CI: 1.290-3.751, P = .004) was an independent risk factor for MACCE. DM was not an independent risk factor for BARC 2, 3 or 5 bleeding (HR: 0.732, 95%CI: 0.293-1.831, P = .505), but PAD history (HR: 3.029, 95%CI: 1.102-8.332, P = .032) and low hemoglobin level (HR = 0.972, 95%CI: 0.947-0.998, P = .036) were independent risk factors for BARC 2, 3 or 5 bleeding. Conclusions: DM was not an independent risk factor for one-year thrombotic and bleeding events in patients anticoagulated with bivalirudin during elective PCI. More attention should be paid to PAD history and hemoglobin level to identify high-risk patients.

To assess the predictive value of stress hyperglycemia ratio (SHR) for long-term mortality after acute myocardial infarction (AMI) in patients with and without diabetes.We evaluated 6892 patients with AMI from the prospective, nationwide, multicentre China Acute Myocardial Infarction registry, of which 2820 had diabetes, and the remaining 4072 were nondiabetic patients. Patients were divided into high SHR and low SHR groups according to the optimal cutoff values of SHR to predict long-term mortality for diabetic and nondiabetic patients, respectively. The primary endpoint was all-cause mortality at 2 years.The optimal cutoff values of SHR for predicting 2-year mortality were 1.20 and 1.08 for the diabetic and nondiabetic population, respectively. Overall, patients with high SHR were significantly associated with higher all-cause mortality compared with those with low SHR, in both diabetic patients (18.5% vs. 9.7%; hazard ratio [HR] 2.01, 95% confidence interval 1.63-2.49) and nondiabetic patients (12.0% vs. 6.4%; HR 1.95, 95%CI 1.57-2.41). After the potential confounders were adjusted, high SHR was significantly associated with higher risks of long-term mortality in both diabetic (adjusted HR 1.73, 95%CI 1.39-2.15) and nondiabetic (adjusted HR 1.63, 95%CI 1.30-2.03) patients. Moreover, adding SHR to the original model led to a slight albeit significant improvement in C-statistic, net reclassification, and integrated discrimination regardless of diabetic status.This study demonstrated a strong positive association between SHR and long-term mortality in patients with AMI with and without diabetes, suggesting that SHR should be considered a useful marker for risk stratification in these patients.ClinicalTrials.gov NCT01874691.

Objectives: To compare short and long-term prognosis of patients with ST-segment elevation myocardial infarction (STEMI) caused by de novo lesions or nonacute stent thrombosis treated by primary PCI.Background: The incidence of acute stent thrombosis has decreased significantly, however, with the extension of postoperative time, patients still have a possibility of developing nonacute stent thrombosis.Methods: A total of 8069 STEMI patients who undergoing primary PCI from the China Acute Myocardial Infarction Registry (CAMI) were enrolled and divided into a nonacute stent thrombosis group and a de novo lesion group according to angiographic thrombosis findings. Propensity score matching (1∶2) according to baseline risk factors was performed between the two groups. The primary outcome was the incidence of all-cause mortality in the hospital and at the 1-year and 2-year follow-ups. The secondary outcome was the incidence of all major adverse cardiovascular events (MACEs) in the hospital and at follow-ups.Results: A total of 121 STEMI patients(96 males) with nonacute stent thrombosis and 7948 STEMI patients(6473 males) with de novo lesions were enrolled. After propensity score matching, 121 patients were enrolled in the nonacute stent thrombosis group and 242 patients in the de novo lesion group. The incidences of recurrent MI (4.7% vs. 0.9%, P=0.039) and MACEs (14.8% vs. 7.4% at the 1-year follow-up, P=0.034; 18.0% vs. 9.1% at the 2-year follow-up, P=0.020) was higher in the nonacute stent thrombosis group. Multivariate Cox regression analysis showed that advanced age, female sex, history of diabetes, chronic renal insufficiency and low preoperative EF were independent risk factors for all-cause death at 2 years. Stent thrombosis was an independent risk factor for MACEs at the 1- and 2-year follow-ups but not for all-cause death.Conclusions: The nonacute stent thrombosis group had a higher incidence of recurrent MI and MACEs at follow-up than the de novo lesion group. Nonacute stent thrombosis was an independent risk factor for all MACEs, but not mortality, at the 1-year and 2-year follow-ups.Trial registration: CAMI, NCT01874691, Registered 11/06/2013, https://clinicaltrials.gov/ct2/show/NCT01874691?term=01874691&draw=2&rank=1

Background Bone marrow cells (BMCs), especially mesenchymal stem cells (MSCs), have shown attractive application prospects in acute myocardial infarction (AMI). However, the weak efficacy becomes their main limitation in clinical translation. Based on the anti-inflammation and anti-apoptosis effects of a Chinese medicine-Tongxinluo (TXL), we aimed to explore the effects of TXL-pretreated MSCs (MSCsTXL) in enhancing cardiac repair and further investigated the underlying mechanism. Methods MSCsTXL or MSCs and the derived exosomes (MSCsTXL-exo or MSCs-exo) were collected and injected into the infarct zone of rat hearts. In vivo, the anti-apoptotic and anti-inflammation effects, and cardiac functional and histological recovery were evaluated. In vitro, the apoptosis was evaluated by western blotting and flow cytometry. miRNA sequencing was utilized to identify the significant differentially expressed miRNAs between MSCsTXL-exo and MSCs-exo, and the miRNA mimics and inhibitors were applied to explore the specific mechanism. Results Compared to MSCs, MSCsTXL enhanced cardiac repair with reduced cardiomyocytes apoptosis and inflammation at the early stage of AMI and significantly improved left ventricular ejection fraction (LVEF) with reduced infarct size in an exosome-dependent way. Similarly, MSCsTXL-exo exerted superior therapeutic effects in anti-apoptosis and anti-inflammation, as well as improving LVEF and reducing infarct size compared to MSCs-exo. Further exosomal miRNA analysis demonstrated that miR-146a-5p was the candidate effector of the superior effects of MSCsTXL-exo. Besides, miR-146a-5p targeted and decreased IRAK1, which inhibited the nuclear translocation of NF-κB p65 thus protecting H9C2 cells from hypoxia injury. Conclusions This study suggested that MSCsTXL markedly facilitated cardiac repair via a new mechanism of the exosomal transfer of miR-146a-5p targeting IRAK1/NF-κB p65 pathway, which has great potential for clinical translation.

Aims This analysis presents the final five-year results of the I-LOVE-IT 2 trial, a non-inferiority study comparing a biodegradable polymer (BP) sirolimus-eluting stent (SES) with a durable polymer (DP) SES in patients with coronary artery disease. Methods and results Overall, 2,737 Chinese patients eligible for coronary stenting were treated with BP-SES or DP-SES in a 2:1 ratio. Patients who were randomised to the BP-SES group were additionally re-randomised to receive either six-month or 12-month dual antiplatelet therapy (DAPT) in a 1:1 ratio. The primary endpoint was 12-month target lesion failure (TLF: cardiac death, target vessel myocardial infarction (MI), or clinically indicated target lesion revascularisation). At five years, the overall follow-up rate was 90.8%, and the cumulative incidence of TLF as the primary endpoint was similar between BP-SES and DP-SES (hazard ratio [HR] 1.01, 95% confidence interval [CI]: 0.79 to 1.28), as was that for the patient-oriented composite endpoint (PoCE: all-cause death, all MI and any revascularisation) (HR 1.03, 95% CI: 0.86 to 1.23), or definite/probable stent thrombosis (ST) (HR 0.91, 95% CI: 0.70 to 1.77). Cumulative events were also similar between the six-month DAPT and 12-month DAPT groups after BP-SES implantation. Conclusions I-LOVE-IT 2 showed that the five-year safety and efficacy of BP-SES and DP-SES were similar, as were those between six months and 12 months of DAPT after BP-SES implantation.

Aims. This study sought to report the 10-year clinical outcomes of patients who underwent unprotected left main (LM) percutaneous coronary intervention (PCI) in a large centre. Methods and Results. A total of 913 consecutive patients who underwent unprotected LM PCI from January 2004 to December 2008 at Fu Wai Hospital were retrospectively analysed; the mean age was 60.0 ± 10.9 years, females accounted for 22% of patients, diabetes was present in 27.7% of patients, and an LM bifurcation lesion occurred in 82.9% of patients. During the median follow-up of 9.7 years, major adverse cardiac or cerebrovascular events (MACCEs) occurred in 25.6% (234) of patients, and the rates of all-cause death, myocardial infarction, and stroke were 14.9%, 11.0%, and 7.1%, respectively. Cardiac death occurred in only 7.9% of patients. The estimated event rate was 41.9% for death/myocardial infarction/any revascularization and 45.9% for death/MI/stroke/any revascularization. Definite/probable stent thrombosis occurred in 4.3% (39) of patients. According to the subgroup analysis, IVUS-guided PCI was associated with less long-term MACCEs. Further multivariate analysis identified that age and LVEF

The secreted factors from cardiac microvascular endothelial cells (CMECs) regulate the physiological activity of adjacent tissues and could be modulated by myocardial ischemia/reperfusion injury (MIRI). How this paracrine function of CMECs is regulated by MIRI and resveratrol remains to be elucidated. CMECs pretreated with/ without resveratrol were subjected to hypoxia/reoxygenation (H/R). Apoptosis was measured by flowcytometry. Protein antibody arrays were performed to find the alteration of cytokine secreted by CMECs. The Gene Ontology analysis was applied to interpret the function of modulated factors. We revealed resveratrol inhibited apoptosis of CMECs dose-dependently after H/R and reached its peak effect at the concentration of 100 μM. 29 factors were significantly changed by H/R, and resveratrol at 100 μM changed 98 types of factors compared with the H/R group. Among these factors, eight were increased by H/R and then were decreased by resveratrol. Eleven were attenuated by H/R and further decreased by resveratrol. Insulin-like growth factor binding protein-1 was upregulated by H/R and it was further increased by resveratrol. The altered factors were involved in cell proliferation, cell growth, cell motility, chemotaxis, angiogenesis and vasculogenesis. The study suggests that resveratrol inhibits the apoptosis and modulates the paracrine function of CMECs under ischemia/reperfusion condition.

To determine whether late percutaneous coronary intervention (PCI) of an infarct-related artery12 h after ST-segment elevation myocardial infarction onset is beneficial, patients were included from the prospective, nationwide, multicenter China Acute Myocardial Infarction registry. The number of patients who underwent PCI or received drug therapy alone was 4791 and 1149, respectively. Hazard ratio (HR) and associated 95% confidence interval (CI) were calculated. Compared with drug therapy, PCI was associated with lower incidences of 2-year major adverse cardiac and cerebrovascular events (MACCE; 6.43 vs 20.19%; HR, .27; 95% CI, .23-.32; P.001), all-cause death (4.13 vs 15.74%; HR, .24; 95% CI, .20-.30; P.001), myocardial infarction (1.73 vs 3.31%; HR, .49; 95% CI, .33-.72; P = .0003), stroke (1.02 vs 2.00%; HR, .47; 95% CI, .28-.77; P = .0026), and revascularization (10.96 vs 27.56%; HR, .32; 95% CI, .26-.39; P.001). Subgroup analysis consistently indicated that PCI was superior to drug therapy. Moreover, the left ventricular ejection fraction in the PCI group was increased after 2-year follow-up, whereas there was no significant increase in the drug therapy group. In conclusion, late PCI is common in Chinese clinical practice, and it is associated with significant improvements in cardiac function and survival compared with drug therapy alone.

Background: The appropriate duration of dual antiplatelet therapy (DAPT) and risk-benefit ratio for long-term DAPT in patients with left main (LM) disease undergoing percutaneous coronary intervention remains uncertain. Methods: Four thousand five hundred sixty-one consecutive patients with stenting of LM disease at a single center from January 2004 to December 2016 were enrolled. Decision to discontinue or remain on DAPT after 12 months was left to an individualized decision-making based on treating physicians by weighing the patient’s risks of ischemia versus bleeding and considering patient preference. The primary outcome was a composite of death, myocardial infarction, stent thrombosis, or stroke at 3 years. Key safety outcome was 3-year rate of Bleeding Academic Research Consortium 2, 3, or 5 bleeding. Results: Of 3865 patients free of ischemic and bleeding events at 12 months, 1727 (44.7%) remained on DAPT (mostly clopidogrel based [97.7%]) beyond 12 months after LM percutaneous coronary intervention. DAPT>12-month versus ≤12-month DAPT was associated with a significant reduced risk of 3-year primary outcome (2.6% versus 4.6%; adjusted hazard ratio: 0.59 [95% CI, 0.41–0.84]). The same trend was found for other ischemic end points: death (0.9% versus 3.0%; P log-rank P log-rank =0.001), myocardial infarction (0.8% versus 1.9%; P log-rank =0.005), and stent thrombosis (0.4% versus 1.1%; P log-rank =0.017). The key safety end point was not significantly different between 2 regimens (1.8% versus 1.6%; adjusted hazard ratio: 1.07 [95% CI, 0.65–1.74]). The effect of DAPT>12 month on primary and key safety outcomes was consistent across clinical presentations, high bleeding risk, P2Y 12 inhibitor, and LM bifurcation percutaneous coronary intervention approach. Conclusions: In a large cohort of patients free from clinical events during the first year after LM percutaneous coronary intervention and at low apparent future bleeding risk, an individualized patient-tailored approach to longer duration (>12 month) of DAPT with aspirin plus a P2Y 12 inhibitor (mostly clopidogrel) improved both composite and individual efficacy outcomes by reducing ischemic risk, without a concomitant increase in clinically relevant bleeding.

With the development of stem cell therapy in translational research and regenerative medicine, bone marrow mesenchymal stem cells (BM-MSCs), as a kind of pluripotent stem cells, are favored for their instant availability and proven safety. It has been reported that transplantation of BM-MSCs is of great benefit to repairing injured tissues in various diseases, which might be related to modulating the immune and inflammatory responses via paracrine mechanisms. Extracellular vesicles (EVs), featuring a double-layer lipid membrane structure, are considered to be the main mediators of the paracrine effects of stem cells. Recognized for their crucial roles in cell communication and epigenetic regulation, EVs have already been applied in vivo for immunotherapy. However, similar to its maternal cells, most of the studies on the efficacy of transplantation of EVs still remain at the level of small animals, which is not enough to provide essential evidence for clinical translation. Here, we use density-gradient centrifugation to isolate bone marrow cells (BMC) from porcine bone marrow at first, and get porcine BM-MSCs (pBM-MSCs) by cell culture subsequently, identified by the results of observation under the microscope, induced differentiation assay, and flow cytometry. Furthermore, we isolate EVs derived from pBM-MSCs in cell supernatant by ultracentrifugation, proved by the techniques of transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting successfully. Overall, pBM-MSCs and their derived EVs can be isolated and identified effectively by the following protocols, which might be widely used in pre-clinical studies on the transplantation efficacy of BM-MSCs and their derived EVs.

In patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI), the effects of high-sensitivity C-reactive protein (hsCRP) on Lipoprotein(a) (Lp(a))-associated cardiovascular risk remains unclear. This study aimed to investigate the independent and combined association of Lp(a) and hsCRP with cardiovascular events in this specific population.A total of 10,424 patients with measurements of both Lp(a) and hsCRP were included in this prospective cohort study. Cox proportional hazards models and Kaplan-Meier analysis were performed to evaluate the relationship between Lp(a), hsCRP and adverse cardiac and cerebrovascular events (MACCE; all-cause death, myocardial infarction, ischemic stroke and revascularization).During 5 years of follow-up, 2140 (20.5%) MACCE occurred. Elevated Lp(a) and hsCRP levels were associated with increased risks of MACCE (p0.05). Notably, there might be a significant interaction between Lp(a) and hsCRP (P for interaction = 0.019). In the setting of hsCRP≥2 mg/L, significant higher risk of MACCE was observed with Lp(a) 15-29.9 mg/dL (HR: 1.18; 95% CI 1.01-1.39) and Lp(a) ≥30 mg/dL (HR: 1.20; 95% CI 1.04-1.39), whereas such association was attenuated when hsCRP was2 mg/L with Lp(a) 15-29.9 mg/dL (HR: 0.94; 95% CI 0.80-1.10) and Lp(a) ≥30 mg/dL (HR: 1.12; 95% CI 0.98-1.28). Moreover, when Lp(a) and hsCRP were combined for risk stratification, patients with dual elevation of these two biomarkers had a significant higher risk of MACCE compared with the reference group (Lp(a) 15 mg/dL and hsCRp2 mg/L) (p0.05).In patients with CAD undergoing PCI, high Lp(a) level was associated with worse outcomes, and this association might be stronger in those with elevated hsCRP concomitantly. Evaluation of Lp(a) and hsCRP together may help identify high-risk individuals for targeted intervention in clinical utility.

The clinical relevance of coronary artery ectasia (CAE) is poorly understood. We investigated the prevalence, potential predictors, and prognostic significance of CAE in patients with atherosclerotic coronary artery disease. Consecutive patients undergoing percutaneous coronary intervention (PCI) from January 2016 to December 2018 were included and followed up for 1 year. CAE was diagnosed as an abnormal dilation >1.5-fold the diameter of adjacent normal segments on angiography. A total of 590 patients with CAE were identified from 36 790 patients undergoing PCI (overall rate of CAE: 1.6%). In multivariate analysis, variables including body mass index >30 kg/m2 (risk ratio, RR: 2.413, P = .018), ever-smoking (RR: 1.669, P < .001), hypertension (RR: 1.221, P = .025), acute myocardial infarction at admission (RR: 1.343, P = .004), no diabetes (RR: .810, P = .023), previous myocardial infarction (RR: 1.545, P < .001), no left main disease (RR: .632, P = .008) and multiple-vessel disease (RR: 1.326, P = .001), increased C-reactive protein (RR: 1.006, P = .012) were predictors of CAE. The incidence of adverse cardiovascular outcomes did not differ significantly between patients with or without CAE ( P = .203). CAE is not uncommon among patients undergoing PCI in this cohort study. The presence of CAE vs its absence had no significant impact on 1-year clinical outcomes after PCI.

Background Moderate/severe coronary artery calcification (CAC) predicts worse clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). However, to date most studies have been modest in size and with limited follow-up. We aimed to assess the association between calcification severity and long-term clinical outcomes in a large cohort undergoing PCI.Methods and Results:In total, 10,068 consecutive patients who underwent PCI at Fuwai Hospital were enrolled in this prospective observational study. Patients were categorized as none/mild or moderate/severe CAC according to the severity of the target lesion by visual assessment of coronary angiography. Major adverse cardiovascular events (MACE), a composite event of death, myocardial infarction and revascularization, at 5 years were assessed. None/mild CAC was observed in 8,229 (81.7%) patients, and moderate/severe CAC was observed in 1,839 (18.3%) patients. Patients with moderate/severe CAC had a significantly higher rate of 5-year unplanned revascularization (15.2% vs. 13.2%, P=0.022) and MACE (20.7% vs. 17.9%, P=0.005). After propensity score matching, the moderate/severe CAC group still had a higher rate of 5-year unplanned revascularization (15.2% vs. 12.6%, P=0.019). Cox regression analysis using clinically significant variables revealed moderate/severe calcification was independently associated with higher risk of 2-year unplanned target vessel revascularization (hazard ratio (HR)=1.287, 95% confidence interval (CI): 1.036-1.600, P=0.023) and MACE (HR=1.242, 95% CI: 1.039-1.484, P=0.017), but not 5-year unplanned revascularization and MACE. Conclusions In patients undergoing PCI, moderate/severe coronary calcification increases the risk of long-term MACE.

Background Risk stratification of patients with non-ST-segment elevation myocardial infarction (NSTEMI) is important in terms of treatment strategy selection. Current efforts have focused on short-term risk prediction after discharge, but we aimed to establish a risk score to predict the 24-month mortality risk in survivors of NSTEMI.Methods and Results:A total of 5,509 patients diagnosed with NSTEMI between January 2013 and September 2014 were included. Primary endpoint was all-cause death at 24 months. A multivariable Cox regression model was used to establish a practical risk score based on independent risk factors of death. The risk score included 9 variables: age, body mass index, left ventricular ejection fraction, reperfusion therapy during hospitalization, Killip classification, prescription of diuretics at discharge, heart rate, and hemoglobin and creatinine levels. The C-statistics for the risk model were 0.83 (95% confidence interval [CI]: 0.81-0.85) and 0.83 (95% CI: 0.79-0.86) in the development and validation cohorts, respectively. Mortality risk increased significantly across groups: 1.34% in the low-risk group (score: 0-58), 5.40% in intermediate group (score: 59-93), and 23.87% in high-risk group (score: ≥94). Conclusions The current study established and validated a practical risk score based on 9 variables to predict 24-month mortality risk in patients who survive NSTEMI. This score could help identify patients who are at high risk for future adverse events who may benefit from good adherence to guideline-recommended secondary prevention treatment.

The efficacy and safety of ticagrelor and clopidogrel in East Asian patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) remains uncertain. The purpose of this study was to compare the efficacy and safety of ticagrelor and clopidogrel in East Asian patients with CAD treated with PCI.A total of 12383 patients with CAD undergoing PCI who received dual antiplatelet therapy (DAPT) were consecutively enrolled in the ticagrelor group (After propensity matching (Ticagrelor was associated with a lower incidence of MACCEs and an increased risk of TIMI bleeding events in East Asian patients with CAD receiving PCI.

Background and aims Circulating monocytes have been proven to be critical mediators in the propagation and progression of atherosclerosis and myocardial infarction. The present study was designed to characterise a new transmembrane protein—NFAT activating protein with ITAM motif 1 (NFAM1)—on monocytes and uncover the potential effects and underlying mechanisms in coronary artery disease. Methods Monocytes from a population of four controls, five stable coronary artery disease patients and five acute coronary syndrome patients were isolated for RNA sequencing. A potential monocyte biomarker molecule was discovered and then validated with a cohort of 79 controls, 70 stable coronary artery disease patients and 183 acute coronary syndrome patients. A stable cell line was generated as an in vitro model to determine chemotaxis migration and chemokine receptor expression. Results NFAM1 was identified through RNA sequencing analysis. The validation results confirmed that NFAM1 expression on monocytes was significantly increased by coronary artery disease status. A higher expression level of NFAM1 on classical and intermediate monocytes was observed compared with that on nonclassical monocytes. As shown in the in vitro cell model, knockdown of NFAM1 significantly attenuated chemotactic migration of monocytes by downregulating chemokine receptor expression and the p38 MAPK signalling pathway. Multivariable regression analysis of a group of 16 individuals suggested that NFAM1 was positively correlated with CCR2 expression. Conclusions The present study reported for the first time that distinctive alterations of NFAM1 expression on monocytes may correlate with atherosclerosis pathobiology and serve as a potential monocyte biomarker and therapeutic target for coronary artery disease.

The benefits and harms of dual antiplatelet therapy (DAPT) continuation with aspirin and clopidogrel beyond 1 year after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation for high ischemic or bleeding risk patients remain unclear. All consecutive patients undergoing PCI were prospectively included in the Fuwai PCI Registry from January 2013 to December 2013. We evaluated 7521 patients who were at high risk for thrombotic or hemorrhagic complications and were events free at 1 year after the index procedure. "TWILIGHT-like" patients with high risk of bleeding or ischemic events were defined by clinical and angiographic criteria. The primary ischemic outcome was major adverse cardiac and cerebrovascular events [MACCE] (a composite of all-cause death, myocardial infarction, or stroke). Median follow-up duration was 2.4 years. The risk of MACCE was significantly lower in DAPT1-year group (n = 5252) than DAPT≤1-year group (n = 2269) (1.5% vs. 3.8%; hazard ratio [HR]: 0.37; 95% confidence interval [CI]: 0.27-0.50

Objective Atherosclerosis is a chronic inflammatory process characterized by the accumulation and formation of lipid-rich plaques within the layers of the arterial wall. Although numerous studies have reported the underlying pathogenesis, no data-based studies have been conducted to analyze the potential genes and immune cells infiltration in the different stages of atherosclerosis via bioinformatics analysis. Methods In this study, we downloaded GSE100927 and GSE28829 from NCBI-GEO database. Gene ontology and pathway enrichment were performed via the DAVID database. The protein interaction network was constructed via STRING. Enriched hub genes were analyzed by the Cytoscape software. The evaluation of the infiltrating immune cells in the dataset samples was performed by the CIBERSORT algorithm. Results We identified 114 common upregulated differentially expressed genes and 22 common downregulated differentially expressed genes. (adjust p value Conclusions These results may reveal the underlying correlations between genes and immune cells in atherosclerosis, which enable us to investigate the novel insights for the development of treatments and drugs.

Objectives The aim of this study was to determine whether an active side branch protection (SB-P) strategy is superior to the conventional strategy in reducing side branch (SB) occlusion in high-risk bifurcation treatment. Background Accurate prediction of SB occlusion after main vessel stenting followed by the use of specific strategies to prevent occlusion would be beneficial during bifurcation intervention. Methods Eligible patients who had a bifurcation lesions with high risk for occlusion as determined using the validated V-RESOLVE (Visual Estimation for Risk Prediction of Side Branch Occlusion in Coronary Bifurcation Intervention) score were randomized to an active SB-P strategy group (elective 2-stent strategy for large SBs and jailed balloon technique for small SBs) or a conventional strategy group (provisional stenting for large SBs and jailed wire technique for small SBs) in a 1:1 ratio stratified by SB vessel size. The primary endpoint of SB occlusion was defined as an angiography core laboratory–assessed decrease in TIMI (Thrombolysis In Myocardial Infarction) flow grade or absence of flow in the SB immediately after full apposition of the main vessel stent to the vessel wall. Results A total of 335 subjects at 16 sites were randomized to the SB-P group (n = 168) and conventional group (n = 167). Patients in the SB-P versus conventional strategy group had a significantly lower rate of SB occlusion (7.7% [13 of 168] vs. 18.0% [30 of 167]; risk difference: –9.1%; 95% confidence interval: −13.1% to −1.8%; p = 0.006), driven mainly by the difference in the small SB subgroup (jailed balloon technique vs. jailed wire technique: 8.1% vs. 18.5%; p = 0.01). Conclusions An active SB-P strategy is superior to a conventional strategy in reducing SB occlusion when treating high-risk bifurcation lesions. (Conventional Versus Intentional Strategy in Patients With High Risk Prediction of Side Branch Occlusion in Coronary Bifurcation Intervention [CIT-RESOLVE]; NCT02644434)

Background/Aim. The relation between complex percutaneous coronary intervention (PCI), high bleeding risk (HBR), and adverse events after coronary artery implantation of drug-eluting stents has been incompletely characterized. This study sought to investigate the ischemic and bleeding events after complex PCI including stratification according to HBR estimated by PARIS bleeding risk score. Methods. Between January 2013 and December 2013, 10,167 consecutive patients undergoing PCI were prospectively enrolled in Fuwai PCI Registry. Complex PCI was defined when having at least one of the following characteristics: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, treatment of chronic total occlusion, unprotected left main PCI, in-stent restenosis target lesion, and severely calcified lesion. The primary ischemic endpoint was major adverse cardiovascular events (MACE) (composite of cardiac death, myocardial infarction, definite/probable stent thrombosis, and target lesion revascularization), and primary bleeding endpoint was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. Results. The median duration of follow-up was 29 months. In adjusted Cox regression analysis, patients having complex PCI procedures experienced higher risks of MACE (hazard ratio (HR): 1.63, 95% confidence interval (CI): 1.38–1.92; P<0.001), compared with noncomplex PCI. In contrast, the risk of clinically relevant bleeding was statistically similar between the 2 groups (HR: 0.86 [0.66–1.11]; P=0.238). There was no statistical interaction between HBR (PARIS bleeding score ≥8 or Pinteraction=0.388) and clinically relevant bleeding (adjusted Pinteraction=0.279). Conclusions. Patients who had undergone complex PCI resulted in substantially more ischemic events, without an increase in clinically relevant bleeding risk, and these associations did not seem to be modified by HBR status. More intensified antiplatelet therapy may be beneficial for patients with complex percutaneous coronary revascularization procedures.

Objectives. We aim to evaluate long-term outcomes after left main coronary artery (LMCA) percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS). Background. PCI of the LMCA has been an acceptable revascularization strategy in stable coronary artery disease. However, limited studies on long-term clinical outcomes of LMCA PCI in ACS patients are available. Methods. A total of 6429 consecutive patients with ACS undergoing PCI in Fuwai Hospital in 2013 were enrolled. Patients are divided into LMCA group and Non-LMCA group according to whether the target lesion was located in LMCA. Prognosis impact on 2-year major adverse cardiovascular and cerebrovascular events (MACCE) is analyzed. Results. 155 (2.4%) patients had target lesion in LMCA, while 6274 (97.6%) patients belong to the non-LMCA group. Compared with non-LMCA patients, LMCA patients have generally more comorbidities and worse baseline conditions. Two-year follow-up reveals that LMCA patients have significantly higher rate of cardiac death (2.6% vs. 0.7%, p=0.034), myocardial infarction (7.1% vs. 1.8%, p<0.001), in-stent thrombosis (4.5% vs. 0.8%, p<0.001), and stroke (7.1% vs. 6.4%, p=0.025). After adjusting for confounding factors, LMCA remains independently associated with higher 2-year myocardial infarction rate (HR = 2.585, 95% CI = 1.243–5.347, p=0.011). Conclusion. LMCA-targeted PCI is an independent risk factor for 2-year myocardial infarction in ACS patients.

The association between lipoprotein(a) [Lp(a)] levels and the risk of cardiovascular disease is of great interest but still controversial. This study sought to investigate the impact of Lp(a) on coronary severity and long-term outcomes of patients who undergo percutaneous coronary intervention (PCI).A total of 6714 consecutive patients who received PCI were enrolled to analyze the association between Lp(a) and coronary severity and major adverse cardiovascular and cerebrovascular events (MACCE). Patients were divided into tertiles according to Lp(a) levels on admission. Coronary severity was evaluated by SYNTAX scoring system. The MACCE included recurrent myocardial infarction, unplanned target vessel revascularization, stent thrombosis, ischemic stroke and all-cause mortality. Significantly, Lp(a) levels were positively associated with coronary severity (p 0.001). Multivariate logistic regression analyses showed Lp(a) was an independent predictor of intermediate to high SYNTAX score. During an average of 874 days follow-up, 755 patients presented with MACCE (11.25%) were reported. The incidence rates of MACCE, all-cause mortality, cardiac death, target vessel revascularization, recurrent myocardial infarction, stent thrombosis, stroke and bleeding were not statistically different among the Lp(a) tertile groups. Furthermore, both Kaplan-Meier and Cox regression analyses found no relationship between Lp(a) and cardiovascular outcomes (p 0.05).Lp(a) is an independent predictor of the prevalence of more complex coronary artery lesions (SYNTAX score ≥ 23) in patients with PCI. In addition, our study has shown that Lp(a) has no relationship with long-term cardiovascular outcomes in Chinese patients with PCI.

Rationale: The crosstalk between cardiac microvascular endothelial cells (CMECs) and cardiomyocytes (CMs) has emerged as a key component in the development of, and protection against, cardiac diseases. For example, activation of endothelial nitric oxide synthase (eNOS) in CMECs, by therapeutic strategies such as ischemic preconditioning, plays a critical role in the protection against myocardial ischemia/reperfusion (I/R) injury. However, much less is known about the signals produced by CMs that are able to regulate CMEC biology. Here we uncovered one such mechanism using Tongxinluo (TXL), a traditional Chinese medicine, that alleviates myocardial ischemia/reperfusion (I/R) injury by activating CMEC eNOS. The aim of our study is to identify the signals produced by CMs that can regulate CMEC biology during I/R. Methods: Ex vivo, in vivo, and in vitro settings of ischemia-reperfusion were used in our study, with the protective signaling pathways activated in CMECs identified using genetic inhibition (p70s6k1 siRNA, miR-145-5p mimics, etc.), chemical inhibitors (the eNOS inhibitor, L-NNA, and the small extracellular vesicles (sEVs) inhibitor, GW4869) and Western blot analyses. TritonX-100 at a dose of 0.125% was utilized to inactivate the eNOS activity in endothelium to investigate the role of CMEC-derived eNOS in TXL-induced cardioprotection. Results: We found that while CMEC-derived eNOS activity was required for the cardioprotection of TXL, activation of eNOS in CMECs by TXL did not occur directly. Instead, eNOS activation in CMECs required a crosstalk between CMs and CMECs through the uptake of CM-derived sEVs. We further demonstrate that TXL induced CM-sEVs contain increased levels of Long Intergenic Non-Protein Coding RNA, Regulator Of Reprogramming (Linc-ROR). Upon uptake into CMECs, linc-ROR downregulates its target miR-145-5p leading to activation of the eNOS pathway by facilitating the expression of p70s6k1 in these cells. The activation of CMEC-derived eNOS works to increase survival in both the CMECs and the CMs themselves. Conclusions: These data uncover a mechanism by which the crosstalk between CMs and CMECs leads to the increased survival of the heart after I/R injury and point to a new therapeutic target for the blunting of myocardial I/R injury.

Inflammation plays a pivotal role in coronary artery disease (CAD). Few data from large-size studies are available on the association of high-sensitivity C-reactive protein (hs-CRP) and severity of CAD. Our aim was to investigate their relationship as well as their impact on long-term outcomes in patients undergoing percutaneous coronary intervention.In 2013, 10,020 patients were consecutively included. Patients were divided into three groups based on hs-CRP on admission: 0-3mg/L (n=6978, 69.6%), 3.01-10mg/L (n=1997, 19.9%),10mg/L (n=1045, 10.4%). Disease severity was determined by SYNTAX score (SS). Their differences were assessed in SS and major adverse cardiovascular events (MACEs, including all-cause death, myocardial infarction, revascularization, and in-stent thrombosis) among groups.The mean follow-up period was 874 days. Patients with elevated hs-CRP were older, had more risk factors such as hypertension, cerebrovascular disease, chronic obstructive pulmonary disease, and cigarette smoking. Multivariate regression analysis showed that hs-CRP10mg/L (OR 1.49, 95% confidence interval 1.21-1.84, p0.001), age, previous myocardial infarction, serum creatinine, and left ventricular ejection fraction were independent predictors of intermediate-high SS (22). Subgroup analysis indicated that the relation between hs-CRP and SS was also consistent in acute coronary syndrome and its subtypes. Although elevated hs-CRP was positively associated with increased rates of MACEs (11.0% versus 12.1% versus 14.3%, p=0.006), death (1.0% versus 1.3% versus 3.0%, p0.001), and revascularization (8.6% versus 10.4% versus 10.0%, p=0.032), it did not show any prognostic effect for adverse outcomes in multivariate regression analyses (all adjusted p0.05). While SS22 remained independently predictive of MACEs and revascularization after adjusting confounders, the risks of which were increased by 56% and 68%, respectively.Serum hs-CRP could be a useful biomarker for indicating CAD severity and could aid in risk stratification.

ObjectiveJailed balloon technique (JBT) is an active side branch (SB) protection strategy and is considered to be superior to the jailed wire technique (JWT) in reducing SB occlusion. However, no randomized trials have proved that. We aim to investigate whether JBT could decrease the SB occlusion rate.MethodsConventional versus Intentional straTegy in patients with high Risk prEdiction of Side branch OccLusion in coronary bifurcation interVEntion (CIT-RESOLVE) (NCT02644434, registered on December 31, 2015) (https://clinicaltrials.gov) is a randomized trial that assessed the effects of different strategies on SB occlusion rate in patients with a high risk of SB occlusion. The present subgroup analysis enrolled bifurcation lesions (2 mm ≤ reference vessel diameter of SB < 2.5 mm) with Visual estimation for Risk prEdiction of Side branch OccLusion in coronary bifurcation intervention (V-RESOLVE) score ≥ 12 points. The primary endpoint is SB occlusion. One-year clinical events were compared.ResultsA total of 284 subjects at 16 sites were randomly assigned to the JBT group (n = 143) or the JWT group (n = 141). The rate of SB occlusion (9.1 vs. 19.9%, p = 0.02) and periprocedural myocardial infarction (defined by WHO, 7 vs. 14.9%, p = 0.03) is significantly lower in the JBT group than in the JWT group. The JBT and JWT groups showed no significant differences in cardiac death (0.7 vs. 0.7%, p = 1), myocardial infarction (MI, 6.3 vs. 7.1%, p = 0.79), target lesion revascularization (TLR, 1.4 vs. 2.1%, p = 0.68), and major cardiac adverse events (MACE, a composite of all-cause death, MI, or TLR, 8.4 vs. 10.6%, p = 0.52) during a 1-year follow-up.ConclusionIn patients with a high risk of SB occlusion (V-RESOLVE score ≥ 12 points), JBT is superior to JWT in reducing SB occlusion. However, no significant differences were detected in 1-year MACE.