Drug-coated balloon angioplasty with rescue stenting versus intended stenting for the treatment of patients with de novo coronary artery lesions (REC-CAGEFREE I): an open-label, randomised, non-inferiority trial.

BACKGROUND: The long-term impact of drug-coated balloon (DCB) angioplasty for the treatment of patients with de novo coronary artery lesions remains uncertain. We aimed to assess the non-inferiority of DCB angioplasty with rescue stenting to intended drug-eluting stent (DES) deployment for patients with de novo, non-complex coronary artery lesions. METHODS: REC-CAGEFREE I was an open-label, randomised, non-inferiority trial conducted at 43 sites in China. After successful lesion pre-dilatation, patients aged 18 years or older with de novo, non-complex coronary artery disease (irrespective of target vessel diameter) and an indication for percutaneous coronary intervention were randomly assigned (1:1), via a web-based centralised system with block randomisation (block size of two, four, or six) and stratified by site, to paclitaxel-coated balloon angioplasty with the option of rescue stenting due to an unsatisfactory result (DCB group) or intended deployment of second-generation thin-strut sirolimus-eluting stents (DES group). The primary outcome was the device-oriented composite endpoint (DoCE; including cardiovascular death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularisation) assessed at 24 months in the intention-to-treat (ITT) population (ie, all participants randomly assigned to treatment). Non-inferiority was established if the upper limit of the one-sided 95% CI for the absolute risk difference was smaller than 2·68%. Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT04561739. It is closed to accrual and extended follow-up is ongoing. FINDINGS: Between Feb 5, 2021, and May 1, 2022, 2272 patients were randomly assigned to the DCB group (1133 [50%]) or the DES group (1139 [50%]). Median age at the time of randomisation was 62 years (IQR 54-69), 1574 (69·3%) of 2272 were male, 698 (30·7%) were female, and all patients were of Chinese ethnicity. 106 (9·4%) of 1133 patients in the DCB group received rescue DES after unsatisfactory DCB angioplasty. As of data cutoff (May 1, 2024), median follow-up was 734 days (IQR 731-739). At 24 months, the DoCE occurred in 72 (6·4%) of 1133 patients in the DCB group and 38 (3·4%) of 1139 in the DES group, with a risk difference of 3·04% in the cumulative event rate (upper boundary of the one-sided 95% CI 4·52; pnon-inferiority=0·65; two-sided 95% CI 1·27-4·81; p=0·0008); the criterion for non-inferiority was not met. During intervention, no acute vessel closures occurred in the DCB group and one (0·1%) of 1139 patients in the DES group had acute vessel closure. Periprocedural myocardial infarction occurred in ten (0·9%) of 1133 patients in the DCB group and nine (0·8%) in the DES group. INTERPRETATION: In patients with de novo, non-complex coronary artery disease, irrespective of vessel diameter, a strategy of DCB angioplasty with rescue stenting did not achieve non-inferiority compared with the intended DES implantation in terms of the DoCE at 2 years, which indicates that DES should remain the preferred treatment for this patient population. FUNDING: Xijing Hospital and Shenqi Medical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

CircTOP1 targeted regulation of PTBP1 expression promotes the progression of coronary artery calcification.

Coronary artery calcification (CAC) is a hallmark event in the pathogenesis of cardiovascular disease, involving the phenotypic transformation of vascular smooth muscle cells (VSMC) towards an osteogenic state. Despite this understanding, the molecular mechanisms governing the VSMC osteogenic switch remain incompletely elucidated. Here, we sought to examine the potential role of circular RNA (circRNA) in the context of CAC. Through transcriptome analysis of circRNA-seq, we identified circTOP1 as a potential candidate circRNA in individuals with CAC. Furthermore, we observed that overexpression of circTOP1 exacerbated vascular calcification in a CAC model. Subsequent pull-down assays revealed an interaction between circTOP1 and PTBP1, a putative target gene of circTOP1 in the context of CAC. In both in vivo and in vitro experiments, we observed heightened expression of circTOP1 and PTBP1 in the CAC model, and noted that reducing circTOP1 expression effectively reduced calcium salt deposits and mineralized nodules in model mice. Additionally, in vitro experiments demonstrated that overexpression of PTBP1 reversed the weakening of signaling caused by silencing circTOP1, thereby exacerbating the osteogenic transition and calcification of VSMC. Collectively, our findings suggested that circTOP1 promotes CAC by modulating PTBP1 expression to mediate VSMC transdifferentiation.

Practices and outcomes of rotational atherectomy in China: The Rota China registry.

BACKGROUND: Rotational atherectomy (RA) remains an integral tool for the treatment of severe coronary calcified lesions despite emergence of newer techniques. We aimed to evaluate the contemporary clinical practices and outcomes of RA in China. METHODS: The Rota China Registry (NCT03806621) was an investigator-initiated, prospective, multicenter registry based on China Rota Elite Group. Consecutive patients treated with RA were recruited. A pre-designed, standardized protocol was recommended for the RA procedure. The primary safety endpoint was major adverse cardiovascular events (MACE: composite of cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization) at 30 days. The primary efficacy endpoint was procedural success. RESULTS: Between July 2018 and December 2020, 980 patients were enrolled at 19 sites in China. Mean patient age was 68.4 years, and 61.4% were men. Radial access was used in 79.1% patients, and 32.7% procedures were guided by intravascular imaging. A total of 22.6% procedures used more than 1 burr, and the maximal burr size was ≥1.75 mm in 24.4% cases, with burr upsizing in 19.3% cases, achieving a final burr-to-artery ratio of 0.52. Procedural success was achieved in 91.1% of patients, and the rate of 30-day and 1-year MACE was 4.9% and 8.2%, respectively. Multivariable analysis identified the total lesion length (HR 1.014, 95% CI: 1.002-1.027; p = 0.021) as predictor of 30-day MACE, and renal insufficiency (HR 1.916, 95% CI: 1.073-3.420; p = 0.028) as predictor of 1-year MACE. CONCLUSIONS: In this contemporary prospective registry in China, the use of RA was effective in achieving high procedural success rate with good short- and long-term outcomes in patients with severely calcified lesions.

Macrophages promote the transition from myocardial ischemia reperfusion injury to cardiac fibrosis in mice through GMCSF/CCL2/CCR2 and phenotype switching.

Following acute myocardial ischemia reperfusion (MIR), macrophages infiltrate damaged cardiac tissue and alter their polarization phenotype to respond to acute inflammation and chronic fibrotic remodeling. In this study we investigated the role of macrophages in post-ischemic myocardial fibrosis and explored therapeutic targets for myocardial fibrosis. Male mice were subjected to ligation of the left coronary artery for 30 min. We first detected the levels of chemokines in heart tissue that recruited immune cells infiltrating into the heart, and found that granulocyte-macrophage colony-stimulating factor (GMCSF) released by mouse cardiac microvascular endothelial cells (MCMECs) peaked at 6 h after reperfusion, and c-c motif chemokine ligand 2 (CCL2) released by GMCSF-induced macrophages peaked at 24 h after reperfusion. In co-culture of BMDMs with MCMECs, we demonstrated that GMCSF derived from MCMECs stimulated the release of CCL2 by BMDMs and effectively promoted the migration of BMDMs. We also confirmed that GMCSF promoted M1 polarization of macrophages in vitro, while GMCSF neutralizing antibodies (NTABs) blocked CCL2/CCR2 signaling. In MIR mouse heart, we showed that GMCSF activated CCL2/CCR2 signaling to promote NLRP3/caspase-1/IL-1ß-mediated and amplified inflammatory damage. Knockdown of CC chemokine receptor 2 gene (CCR2-/-), or administration of specific CCR2 inhibitor RS102895 (5 mg/kg per 12 h, i.p., one day before MIR and continuously until the end of the experiment) effectively reduced the area of myocardial infarction, and down-regulated inflammatory mediators and NLRP3/Caspase-1/IL-1ß signaling. Mass cytometry confirmed that M2 macrophages played an important role during fibrosis, while macrophage-depleted mice exhibited significantly reduced transforming growth factor-ß (Tgf-ß) levels in heart tissue after MIR. In co-culture of macrophages with fibroblasts, treatment with recombinant mouse CCL2 stimulated macrophages to release a large amount of Tgf-ß, and promoted the release of Col1α1 by fibroblasts. This effect was diminished in BMDMs from CCR2-/- mice. After knocking out or inhibiting CCR2-gene, the levels of Tgf-ß were significantly reduced, as was the level of myocardial fibrosis, and cardiac function was protected. This study confirms that the acute injury to chronic fibrosis transition after MIR in mice is mediated by GMCSF/CCL2/CCR2 signaling in macrophages through NLRP3 inflammatory cascade and the phenotype switching.

Inter-Domain Repulsion of Dumbbell-Shaped Calmodulin during Electrospray Ionization Revealed by Molecular Dynamics Simulations.

The mechanisms whereby protein ions are released from nanodroplets at the liquid-gas interface have continued to be controversial since electrospray ionization (ESI) mass spectrometry was widely applied in biomolecular structure analysis in solution. Several viable pathways have been proposed and verified for single-domain proteins. However, the ESI mechanism of multi-domain proteins with more complicated and flexible structures remains unclear. Herein, dumbbell-shaped calmodulin was chosen as a multi-domain protein model to perform molecular dynamics simulations to investigate the structural evolution during the ESI process. For [Ca4CAM], the protein followed the classical charge residue model. As the inter-domain electrostatic repulsion increased, the droplet was found to split into two sub-droplets, while stronger-repulsive apo-calmodulin unfolded during the early evaporation stage. We designated this novel ESI mechanism as the domain repulsion model, which provides new mechanistic insights into further exploration of proteins containing more domains. Our results suggest that greater attention should be paid to the effect of domain-domain interactions on structure retention during liquid-gas interface transfer when mass spectrometry is used as the developing technique in gas phase structural biology.

Outcomes of Patients Undergoing Rotational Atherectomy with Intra-Aortic Balloon Pump Support in Patients with Multivessel Disease and Low Left Ventricular Ejection Fraction.

Background: The aim of the present study was to investigate whether intra-aortic balloon pump (IABP) support was associated with better outcomes after rotational atherectomy (RA) in patients with multivessel disease and low left ventricular ejection fraction (LVEF). Methods: Between January 2015 and December 2021, 596 consecutive patients with severely calcified coronary lesions who underwent elective RA were retrospectively enrolled. Of these, a total of 156 patients were included in this study based on the propensity score matching and divided into two groups according to elective IABP insertion (IABP group, n = 80) or no insertion (non-IABP group, n = 76) before the RA procedure. The primary endpoints were procedural success and major adverse cardiovascular events (MACE) before discharge. The secondary endpoints were mortality and readmission due to heart failure (HF) during 90-day and 180-day follow-up. Results: 77 of patients (96.3%) in the IABP group and 72 of patients (94.7%) in the non-IABP group got procedural success (p = 0.714), separately. We had not observed significant differences in periprocedural complications except for less frequent hypotension in the IABP group (p < 0.001). In-hospital MACE occurred in 7.5% of patients who received IABP support, which was significantly lower compared to the non-IABP group (p = 0.002). In addition, the cumulative incidence of readmission due to HF was also significantly lower in the IABP group during the 90-day (p < 0.001) and 180-day (p = 0.004) follow-up. However, there were no significant differences between groups regarding the incidence of all-cause mortality. Conclusions: The present study suggests the important role of IABP support in improving the outcomes of patients after RA if multivessel disease and low LVEF are anticipated. Prophylactic IABP implantation was related to a lower incidence of in-hospital MACE, and readmission due to HF within 90-day and 180-day follow-up without significant impact on the procedural success and all-cause mortality.

Rotational Atherectomy in Coronary Heart Disease Patients with Different Rotational Speed: In Hospital and Six-Month Outcomes.

Background: Rotational atherectomy (RA) is an important technique for the management of severe coronary calcification. However, optimal rotational speed is yet to be defined. Methods: A total of 372 coronary heart disease (CHD) patients were retrospectively analyzed between February 2017 and January 2022. The patients were divided into four groups based on the maximum RA speed: group 1 ( < 150,000 rpm, 76 cases), group 2 (150,000 rpm, 156 cases), group 3 (160,000 rpm, 90 cases) and group 4 ( ≥ 170,000 rpm, 50 cases). The outcomes analyzed were procedural complications, six-months major cardiovascular and cerebrovascular events (MACCE) and chronic heart failure. Results: Patients in group 4 had a higher incidence of slow flow during the RA operation (p = 0.025). There was no significant difference in other complications among the four groups, as well as six-month MACCE. After adjusting for confounding factors, increase in rotational speed led to a higher probability of slow flow (p for non-linearity = 0.131; adjusted model) and MACCE (p for non-linearity = 0.183; adjusted model). Logistic regression analysis showed that rotational speed was a predictor of slow flow during RA operation (OR = 1.25, 95% CI: 1.05~1.49, p = 0.01). Moreover, the analysis demonstrated that individuals with lower rotational speed ( < 150,000 rpm) were at 230% higher risk of vasospasm compared with a higher rotational speed (160,000 rpm) (OR = 3.3, 95% CI: 1.08~10.09, p = 0.036). Conclusions: CHD patients treated with a rotational speed of ≥ 170,000 rpm had a higher risk of slow flow after RA. Rotational speed is an independent risk factor for slow flow in CHD patients. Moreover, a rotational speed of < 150,000 rpm was associated with a higher risk of vasospasm compared with rotational speed of 160,000 rpm. There was no significant difference in six-month outcomes in comparison to elective CHD patients with different rotational speeds, and the probability of MACCE was intensified with increase in rotational speed.

Pharmacological Inhibition of P-Rex1/Rac1 Axis Blocked Angiotensin II-Induced Cardiac Fibrosis.

PURPOSE: Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor-1 (P-Rex1), as one of the members of Rac-GEFs, has been proven to play a critical role in cancer progression and metastasis. Nonetheless, its role in cardiac fibrosis remains elusive. In the present study, we aimed to investigate whether and how the P-Rex1 mediates AngII-induced cardiac fibrosis. METHOD: A cardiac fibrosis mouse model was established by chronic AngII perfusion. The heart structure, function, pathological changes of myocardial tissues, oxidative stress, and cardiac fibrotic protein expression were determined in an AngII induced mouse model. To provide a molecular mechanism for P-Rex1 involvement in cardiac fibrosis, a specific inhibitor or siRNA was used to block P-Rex1, and target the relationship between Rac1-GTPase and its downstream effector. RESULTS: Blocking P-Rex1 showed down-regulation of its downstream effectors such as the profibrotic transcriptional regulator Paks, ERK1/2, and ROS generation. Intervention treatment with P-Rex1 inhibitor 1A-116 ameliorated AngII-induced abnormalities in heart structure and function. Moreover, pharmacological inhibition of the P-Rex1/Rac1 axis showed a protective effect in AngII-induced cardiac fibrosis through the down-regulation of collagen1, CTGF, and α-SMA expression. CONCLUSION: Our findings demonstrated for the first time that P-Rex1 was an essential signaling mediator in CFs activation and subsequent cardiac fibrosis, and 1A-116 could be a potential pharmacological development drug.

The contribution of genotype-guided selection of P2Y12 inhibitor on prognosis in ACS /CCS patients undergoing percutaneous coronary intervention: a retrospective cohort study.

PURPOSE: We aimed to explore the contribution of genotype-guided selection of P2Y12 inhibitors on prognosis in Chinese patients with acute coronary syndromes (ACS) or chronic coronary syndromes (CCS) undergoing percutaneous coronary intervention (PCI). METHODS: Totally, 2063 patients were included. They were divided into empiric treatment group (n = 1025) and individualized treatment group (n = 1038) depending on whether taken CYP2C19 genetic testing. The incidences of clinical endpoint events were compared in two groups at 1-year follow-up. The effective endpoint events were major adverse cardiovascular events (MACEs), including all-cause mortality, in-stent restenosis, nonfatal myocardial infarction, nonfatal stroke and severe recurrent ischemia. Meanwhile, the safe endpoint was bleeding events defined by the Bleeding Academic Research Consortium (BARC) criteria. RESULTS: Finally, 66.83% patients were diagnosed with ACS and 33.17% patients were diagnosed with CCS in empiric group. 68.11% patients were diagnosed with ACS and 31.89% patients were diagnosed with CCS in individualized group. At 1-year follow-up, individualized group showed lower MACEs rate than empiric group (19.61% vs. 10.69%, HR: 1.915; 95% CI: 1.534 to 2.392; P < 0.0001, log-rank test; adjusted HR: 1.983; 95% CI: 1.573 to 2.501; P = 0.000, cox proportional hazards regression models), while bleeding events were significantly less common in empiric group than in individualized group (7.32% vs. 10.40%, HR: 0.693; 95% CI: 0.519 to 0.926; P = 0.0132, log-rank test; adjusted HR: 0.695; 95% CI: 0.518 to 0.933; P = 0.016, cox proportional hazards regression models). It was mainly manifested in BARC class 1 bleeding, which did not warrant the interruption of antiplatelet therapy (ITA). Further, subgroup analyses illustrated that no significant difference existed in cumulative MACEs-free survival rate between all treatment arms of individualized group (P = 0.6579 by log-rank test), and CYP2C19 intermediate metabolizer (IM) genetype appeared to be significantly associated with bleeding events for patients treated with ticagrelor (clopidogrel vs. ticagrelor: 6.80% vs. 14.88%; adjusted HR:0.440; 95% CI: 0.246 to 0.787; adjusted P = 0.006). CONCLUSIONS: Genotype-guided selection of P2Y12 inhibitor made a very positive contribution on the prognosis in Chinese ACS/CCS patients undergoing PCI. Instead of intensifying antiplatelet strategies, conventional-dose clopidogrel could be recommended as P2Y12 inhibitor after weighing MACEs and bleeding events in CYP2C19 IM patients.

Proteomic Analysis of Serum Proteins from Patients with Severe Coronary Artery Calcification.

Background: Proteomic studies investigating novel molecular markers of coronary artery calcification (CAC) are scarce.This study compared the protein expression in the serum of patients with severe CAC and non-CAC. Methods: The serum from 30 patients with severe CAC and 30 matched-controls were screened by data-independent acquisition(DIA)-based proteomic technology. Bioinformatics analysis tools were used to analyze the underlying molecular mechanisms of the differentially expressed proteins. Candidate proteins were further validated by an enzyme-linked immunosorbent assay (ELISA) in an independent cohort. A receiver operating characteristic (ROC) curve was used to estimate the diagnostic power of the candidate proteins. Results: Among the 110 identified proteins, the expression of 81 was significantly upregulated, whereas 29 proteins were downregulated (fold change ≥ 1.5; p < 0.05) between patients with and without CAC. Bioinformatics analysis indicated that the differential proteins are involved in complement and coagulation cascades, platelet activation, regulation of actin cytoskeleton, or glycolysis/gluconeogenesis pathways. Further verification showed that serum levels of complement C5 (C5), fibrinogen gamma (FGG), pyruvate kinase isoform M2 (PKM2), and tropomyosin 4 (TPM4) were consistent with the proteomic findings, which could allow discrimination between CAC and non-CAC patients. Conclusions: This study revealed that high serum levels of serum C5, FGG, PKM2, and TPM4 proteins were linked to severe CAC. These proteins may be developed as biomarkers to predict coronary calcification.

Effects of imbalance of lipid metabolism through NF-KB pathway on atherosclerosis and vascular aging in rats.

Cardiovascular diseases have become a mainstream disease by intensifying the country's population aging. The purpose of this article is to explore the specific effect and mechanism of lipid metabolism imbalance through the NF-KB pathway on atherosclerosis and vascular aging in rats. Twenty healthy adult rats were randomly divided into two groups, control in the observation group and the observation group. The rats in the observation group were fed a high-fat diet to imbalance the lipid metabolism of the rats. Immunohistochemistry and transmission electron microscope detectors were used to observe the NF-KB pathway in rats and study atherosclerosis-specific conditions of sclerosis and vascular aging. The results show that the imbalance of lipid metabolism through the NF-KB pathway can increase the rate of apoptosis in rat blood vessels by 24% and the proliferation rate by 18%. The number of vascular endothelial cell damage increased by 33%, which promoted atherosclerosis in rats and increased the rate of vascular aging in rats by 27%.

Role of NLRP3 Inflammasome in Myocardial Ischemia-Reperfusion Injury and Ventricular Remodeling.

Reperfusion therapy is the optimal therapy for acute myocardial infarction (AMI), but acute inflammatory injury and chronic heart failure (HF) after myocardial ischemia and reperfusion (MI/R) remain the leading cause of death after AMI. Pyroptosis, a newly discovered form of cell death, has been proven to play a significant role in the acute reperfusion process and the subsequent chronic process of ventricular remodeling. Current research shows that multiple stimuli activate the pyroptotic signaling pathway and contribute to cell death and nonbacterial inflammation after MI/R. These stimuli promote the assembly of the nucleotide-binding and oligomerization-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome by activating NLRP3. The mature NLRP3 inflammasome cleaves procaspase-1 to active caspase-1, which leads to mature processing of interleukin (IL)-18, IL-1ß, and gasdermin D (GSDMD) protein. That eventually results in cell lysis and generation of nonbacterial inflammation. The present review summarizes the mechanism of NLRP3 inflammasome activation after MI/R and discusses the role that NLRP3-mediated pyroptosis plays in the pathophysiology of MI/R injury and ventricular remodeling. We also discuss potential mechanisms and targeted therapy for which there is evidence supporting treatment of ischemic heart disease.

Triglyceride to High-Density Lipoprotein Ratio can predict coronary artery calcification.

Objectives: We assessed the TG/HDL-C ratio as a predictor for the presence of coronary artery calcifications (CACs). Methods: We collected demographic characteristics (age and gender), physical examination (height, weight, BMI, SBP, DBP), comorbidities, medication use, and laboratory variables Triglyceride to High-Density Lipoprotein (TG, HDL-C, TG/HDL-C, UA, TBG, 25-OH-VitD3); and we used coronary angiography to determine the presence of CACs. We performed univariate and multivariate analyses to evaluate the correlation between the TG/HDL-C ratio and CACs and established a predictive model. Results: CAC was present in 121 patients (25.80%). The levels of TG and TG/HDL-C ratio in the CAC group were higher than those in the non-CAC group, while the level of HDL-C in the CAC group was lower than that in the non-CAC group. The univariate analysis showed that the TG/HDL-C ratio was associated with CAC (OR, 0.021; 95% CI, 0.008 to 0.052; P<0.001), and the multivariate analysis indicated that the ratio was an independent risk factor for CAC (OR, 4.088; 95% CI, 2.787-5.996; P<0.001). Using the ratio to establish a prediction model, the area under the ROC curve was 0.814 (95% CI, 0.775-0.853; P<0.001), suggesting that the TG/HDL-C ratio has a high diagnostic efficiency. The diagnostic threshold was 1.037, and the corresponding sensitivity and specificity were 89.3% and 60.5%, respectively. Conclusion: The Triglyceride to High-Density Lipoprotein TG/HDL-C ratio is an independent risk factor for CAC with good diagnostic efficacy.

Factors Associated with the Prognosis of Patients with Acute Myocardial Infarction and Cardiogenic Shock.

BACKGROUND Patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) usually have high mortality. This study aimed to identify factors related to the short-term survival of patients with AMI and CS treated by percutaneous coronary intervention (PCI) under intra-aortic balloon pump (IABP) support. MATERIAL AND METHODS This retrospective study included consecutive patients with AMI and CS treated with PCI under IABP support. Clinical characteristics, including the infarct-related artery, lesion number, aspiration catheter usage, conventional or delayed stenting, and thrombolysis in myocardial infarction (TIMI) flow grade before and after PCI, were collected. Patients were followed up postoperatively for 30 days. Multivariate logistic regression was used to identify factors associated with the 30-day mortality. RESULTS There were marked differences between the nonsurvival group (n=49) and the survival group (n=92) in the no-reflow after surgery (49.0% vs 14.1%, P<0.001), postoperative TIMI grade 3 flow (65.3% vs 91.3%, P<0.001), and delayed stent implantation (18.4% vs 37.0%, P=0.022). Factors associated with 30-day mortality were postoperative TIMI grade 3 flow (odds ratio [OR]: 0.227; 95% confidence interval [CI]: 0.076-0.678; P=0.008), delayed stent implantation (OR: 0.371; 95% CI: 0.139-0.988; P=0.047), and intraoperative no-reflow (OR: 2.737; 95% CI: 1.084-6.911; P=0.033). CONCLUSIONS For patients with AMI complicated by CS treated with emergent PCI under IABP support, prevention of no-reflow during surgery by delayed stent implantation can reduce postoperative 30-day mortality in selected cases.

Multicentre, randomized comparison of two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: the DEFINITION II trial.

AIM: The present study aimed to assess the benefits of two-stent techniques for patients with DEFINITION criteria-defined complex coronary bifurcation lesions. METHODS AND RESULTS: In total, 653 patients with complex bifurcation lesions at 49 international centres were randomly assigned to undergo the systematic two-stent technique (two-stent group) or provisional stenting (provisional group). The primary endpoint was the composite of target lesion failure (TLF) at the 1-year follow-up, including cardiac death, target vessel myocardial infarction (TVMI), and clinically driven target lesion revascularization (TLR). The safety endpoint was definite or probable stent thrombosis. At the 1-year follow-up, TLF occurred in 37 (11.4%) and 20 (6.1%) patients in the provisional and two-stent groups, respectively [77.8%: double-kissing crush; hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.30-0.90; P = 0.019], largely driven by increased TVMI (7.1%, HR 0.43, 95% CI 0.20-0.90; P = 0.025) and clinically driven TLR (5.5%, HR 0.43, 95% CI 0.19-1.00; P = 0.049) in the provisional group. At the 1 year after indexed procedures, the incidence of cardiac death was 2.5% in the provisional group, non-significant to 2.1% in the two-stent group (HR 0.86, 95% CI 0.31-2.37; P = 0.772). CONCLUSION: For DEFINITION criteria-defined complex coronary bifurcation lesions, the systematic two-stent approach was associated with a significant improvement in clinical outcomes compared with the provisional stenting approach. Further study is urgently warranted to identify the mechanisms contributing to the increased rate of TVMI after provisional stenting. STUDY REGISTRATION: http://www.clinicaltrials.com; Identifier: NCT02284750.

Long noncoding RNA MALAT1 enhances the apoptosis of cardiomyocytes through autophagy modulation.

Induction of autophagy promotes cardiomyocyte survival and confers a cardioprotective effect on acute myocardial infarction (AMI). Our previous study showed that knockdown of long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) attenuated myocardial apoptosis in mouse AMI. Herein, this study further investigated whether the mechanisms by which MALAT1 enhanced cardiomyocyte apoptosis involved the autophagy regulation. To address this, cardiomyocytes were isolated from neonatal mice and then stimulated with hypoxia/reoxygenation (H/R) injury to mimic AMI. The cell apoptosis was evaluated using TUNEL staining and Western blot analysis of apoptosis-related proteins. The autophagy level was assessed using GFP-LC3 immunofluorescence and Western blot analysis of autophagy-related proteins. The results showed that H/R injury increased MALAT1 expression. Furthermore, MALAT1 overexpression significantly enhanced apoptosis and regulated autophagy of cardiomyocytes, whereas MALAT1 knockdown exerted the opposite effect. Moreover, rapamycin (an autophagy activator) effectively attenuated the MALAT1-mediated enhancement of cardiomyocyte apoptosis. Overall, our findings demonstrated that the increased MALAT1 expression induced by H/R injury enhances cardiomyocyte apoptosis, at least in part, through autophagy modulation.

Exosomes derived from regulatory T cells ameliorate acute myocardial infarction by promoting macrophage M2 polarization.

Acute myocardial infarction (AMI) is a serious ischemic heart disease. Regulatory T cells (Tregs) participate in AMI. This article aims to investigate the mechanism of action of Tregs in AMI. We constructed AMI mouse model. Then, AMI mouse and mouse macrophages (RAW264.7) were treated with Tregs or Treg-derived exosomes. The cardiac function of mice was detected. Triphenyl-tetrazolium chloride and TdT-mediated dUTP nick-end labeling staining were performed to detect the myocardial infarct size or apoptosis. The proportions of macrophages were analyzed by flow cytometry. Enzyme linked immunosorbent assay and quantitative real-time PCR was performed to estimate the levels of cytokines and genes. We found that Tregs ameliorated cardiac function, reduced myocardial infarct size and inhibited apoptosis of myocardial cells in AMI mice. Moreover, Treg-derived exosomes reduced myocardial infarct size and repressed apoptosis of myocardial cells in AMI mice. Furthermore, Treg-derived exosomes suppressed the expression of M1 macrophage markers, and promoted the expression of M2 macrophage markers in myocardial tissues of AMI mice and RAW264.7 cells. In conclusion, our work demonstrates that exosomes derived from Tregs ameliorate AMI by promoting macrophage M2 polarization. Thus, Tregs may be an essential cell for AMI treatment.

Circ-HIPK2 Accelerates Cell Apoptosis and Autophagy in Myocardial Oxidative Injury by Sponging miR-485-5p and Targeting ATG101.

Myocardial injury has been deemed as a major cause of heart diseases including myocarditis and coronary heart disease, which have brought multiple mortalities globally. Long non-coding RNAs (lncRNAs) are widely recognized in diverse diseases. However, the role of circular RNA HIPK2 (circ-HIPK2) remains unclear in myocardial injury induced by H2O2. We attempted to investigate the probable role of circ-HIPK2 in myocardial injury induced by H2O2. This study discovered that the treatment of H2O2 inhibited cell proliferation but boosted cell apoptosis and autophagy. ATG101 was upregulated in primary mouse neonatal cardiomyocytes under H2O2 treatment. ATG101 knockdown promoted proliferation and limited apoptosis by attenuating autophagy in H2O2-injured mouse neonatal cardiomyocytes. Furthermore, miR-485-5p was validated to combine with ATG101 and circ-HIPK2, and circ-HIPK2 positively regulated ATG101 expression by sponging miR-485-5p. At last, silenced circ-HIPK2 mediated the promotion of cell proliferation, and repression of cell apoptosis was restored by ATG101 amplification. In a word, circ-HIPK2 facilitates autophagy to accelerate cell apoptosis and cell death in H2O2-caused myocardial oxidative injury through the miR-485-5p/ATG101 pathway, indicating a novel therapeutic target point for patients with myocardial injury.

Ideal cardiovascular health metrics and the risk of non-alcoholic fatty liver disease: A cross-sectional study in northern China.

BACKGROUND AND PURPOSE: The components of ideal cardiovascular health (CVH) metrics have been shown to be associated with non-alcoholic fatty liver disease (NAFLD). The present study aimed to determine the association between ideal CVH metrics and NAFLD. METHODS: A total of 10,511 participants (47.26% men) aged 18 to 92 years were selected from the Jidong and Kailuan communities. Ideal CVH was based on 7 ideal CVH metrics: smoking, body mass index (BMI), physical activity, diet, total cholesterol, blood pressure and fasting blood glucose. NAFLD was determined by abdominal ultrasonography. All participants underwent questionnaire assessments and clinical and laboratory examinations. Logistic regression models were used to analyse the relationship of CVH metrics and the number of ideal CVH metrics with NAFLD. RESULTS: The prevalence rates of NAFLD by CVH summary score quartiles were 64.38% (2,015/3,130), 50.16% (786/1,567), 33.28% (1,194/3,588) and 20.89% (465/2,226). Participants in the highest quartile showed a lower odds ratio (OR) than those in the lowest quartile (fully adjusted OR: 0.17, 95% CI: 0.17-0.20, P < 0.001). Similar results were observed in subjects stratified by sex and age (45 years). The ORs were progressively decreased with an increased number of ideal CVH metrics (all P < 0.001). CONCLUSIONS: NAFLD was significantly associated with both the summary score of CVH metrics and the number of ideal CVH metrics. The combined evaluation of ideal CVH may contribute to the prevention of NAFLD.

Long non-coding RNA MALAT1 enhances the apoptosis of cardiomyocytes through autophagy inhibition by regulating TSC2-mTOR signaling.

BACKGROUND: Our previous study showed that knockdown of long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) attenuated myocardial apoptosis in mouse acute myocardial infarction (AMI). This study aims to explore whether MALAT1 enhanced cardiomyocyte apoptosis via autophagy regulation and the underlying mechanisms of MALAT1 regulating autophagy. METHODS: Cardiomyocytes were isolated from neonatal mice and then stimulated with hypoxia/reoxygenation (H/R) injury to mimic AMI. The autophagy level was assessed using GFP-LC3 immunofluorescence and western blot analysis of autophagy-related proteins. RNA pull-down and RNA immunoprecipitation (RIP) was performed to analyze the binding of MALAT1 and EZH2. Chromatin immunoprecipitation (ChIP) assay was performed to analyze the binding of TSC2 promoter and EZH2. The cell apoptosis was evaluated using TUNEL staining and western blot analysis of apoptosis-related proteins. RESULTS: H/R injury increased MALAT1 expression in cardiomyocytes. Furthermore, MALAT1 overexpression inhibited, whereas MALAT1 knockdown enhanced the autophagy of cardiomyocytes. Moreover, MALAT1 overexpression recruited EZH2 to TSC2 promoter regions to elevate H3K27me3 and epigenetically inhibited TSC2 transcription. Importantly, TSC2 overexpression suppressed mTOR signaling and then activated the autophagy. Further results showed that MALAT1 inhibited proliferation and enhanced apoptosis of cardiomyocytes through inhibiting TSC2 and autophagy. CONCLUSION: These findings demonstrate that the increased MALAT1 expression induced by H/R injury enhances cardiomyocyte apoptosis through autophagy inhibition by regulating TSC2-mTOR signaling.