An artificial intelligence-enabled electrocardiogram algorithm for the prediction of left atrial low-voltage areas in persistent atrial fibrillation.

OBJECTIVES: We aimed to construct an artificial intelligence-enabled electrocardiogram (ECG) algorithm that can accurately predict the presence of left atrial low-voltage areas (LVAs) in patients with persistent atrial fibrillation. METHODS: The study included 587 patients with persistent atrial fibrillation who underwent catheter ablation procedures between March 2012 and December 2023 and 942 scanned images of 12-lead ECGs obtained before the ablation procedures were performed. Artificial intelligence-based algorithms were used to construct models for predicting the presence of LVAs. The DR-FLASH and APPLE clinical scores for LVA prediction were calculated. We used a receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis to evaluate model performance. RESULTS: The data obtained from the participants were split into training (n = 469), validation (n = 58), and test sets (n = 60). LVAs were detected in 53.7% of all participants. Using ECG alone, the deep learning algorithm achieved an area under the ROC curve (AUROC) of 0.752, outperforming both the DR-FLASH score (AUROC = 0.610) and the APPLE score (AUROC = 0.510). The random forest classification model, which integrated a probabilistic deep learning model and clinical features, showed a maximum AUROC of 0.759. Moreover, the ECG-based deep learning algorithm for predicting extensive LVAs achieved an AUROC of 0.775, with a sensitivity of 0.816 and a specificity of 0.896. The random forest classification model for predicting extensive LVAs achieved an AUROC of 0.897, with a sensitivity of 0.862, and a specificity of 0.935. CONCLUSION: The deep learning model based exclusively on ECG data and the machine learning model that combined a probabilistic deep learning model and clinical features both predicted the presence of LVAs with a higher degree of accuracy than the DR-FLASH and the APPLE risk scores.

Effects of intensive blood pressure lowering in patients with diabetes: A pooled analysis of the STEP and ACCORD-BP randomized trials.

AIM: To determine whether intensive systolic blood pressure (SBP) lowering can benefit hypertensive patients with diabetes. MATERIALS AND METHODS: We performed a pooled analysis of individual patient data from two randomized trials to compare intensive and standard SBP targets in hypertensive patients with diabetes (STEP diabetes subgroup and ACCORD-BP standard glycaemic group, n = 1627 and n = 2362, respectively). We defined a modified primary outcome as a composite of stroke, major coronary artery disease (myocardial infarction and unstable angina), heart failure, and cardiovascular death. The secondary outcomes were individual components of the primary outcome and death from any cause. A Cox proportional hazards regression model was used in the main analysis. We conducted one-stage mixed-effect models and two-stage analyses as sensitivity and supplementary analyses to verify the robustness of the findings. RESULTS: A total of 3989 patients were randomized to undergo intensive (n = 1984) or standard SBP treatment (n = 2005). After a median follow-up of 3.83 years, the primary outcome occurred in 193/1984 patients in the intensive group and in 247/2005 patients in the standard group (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.64-0.93). The incidence rates for secondary outcomes were lower in the intensive group than in the standard group, but were not significantly different, except for stroke (intensive vs. standard: 32/1984 vs. 58/2005; HR 0.56, 95% CI 0.36-0.86). These results remained consistent in the additional sensitivity and supplementary analyses. CONCLUSIONS: An intensive SBP-lowering target of 110 to <130 mmHg reduces the cardiovascular outcomes compared with a standard SBP-lowering target of 130 to <150 mmHg. The findings of this study support the favourable effects of intensive SBP lowering in hypertensive patients with diabetes.

Genetic deletion of CMG2 exacerbates systemic-to-pulmonary shunt-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) secondary to congenital heart disease (CHD-PAH) with systemic-to-pulmonary shunt (SPS) is characterized by proliferative vascular remodeling. Capillary morphogenesis gene-2 (CMG2) plays a key role in cell proliferation and apoptosis. This study aimed to determine the role of CMG2 in the pathogenesis of SPS-induced PAH. CMG2 levels were significantly downregulated in pulmonary arterioles from patients with Eisenmenger syndrome and rats with SPS-induced PAH. CMG2 was highly expressed in several cells including human pulmonary arterial smooth muscle cells (HPASMCs). CMG2-/- rats exhibited more severe PAH and pulmonary vascular remodeling than wild-type rats when exposed to SPS for 8 weeks. Overexpression of CMG2 significantly inhibited proliferation and promoted apoptosis of HPASMCs, while knockdown of CMG2 promoted cell proliferation and inhibited cell apoptosis. Next-generation sequencing and subsequent validation results suggested that PI3K-AKT was the most prominent signaling pathway regulated by differentially expressed genes (DEGs) in CMG2-/- rat lungs. Our work identified a novel role for CMG2 in SPS-induced PAH based on the findings that CMG2 deficiency exacerbates SPS-induced vascular remodeling in the development of PAH, indicating that CMG2 might act as a potential target for the treatment of CHD-PAH.

The association between visceral adiposity index and leukocyte telomere length in adults: results from National Health and Nutrition Examination Survey.

BACKGROUND: Leukocyte telomere length (LTL) is a robust marker of biological aging, which is associated with obesity. Recently, the visceral adiposity index (VAI) has been proposed as an indicator of adipose distribution and function. OBJECTIVE: To evaluated the association between VAI and LTL in adult Americans. METHODS: There were 3193 participants in U.S. National Health and Nutrition Examination Surveys (1999-2002) included in this analysis. LTL was measured using quantitative PCR (qPCR) and expressed as telomere to single-gene copy ratio (T/S ratio). We performed multiple logistic regression models to explore the association between VAI and LTL by adjusting for potential confounders. RESULTS: Among all participants, VAI was associated with the shorter LTL (ß: - 14.81, 95% CI - 22.28 to - 7.34, p < 0.001). There were significant differences of LTL in VAI tertiles (p < 0.001). Participants in the higher VAI tertile had the shorter LTL (1.26 ≤ VAI < 2.46: ß = - 130.16, 95% CI [ - 183.44, - 76.87]; VAI ≥ 2.46: ß = - 216.12, 95% CI [ - 216.12, - 81.42], p for trend: < 0.001) comparing with the lower VAI tertile. We also found a non-linear relationship between VAI and LTL. VAI was negatively correlated with LTL when VAI was less than 2.84. CONCLUSIONS: The present study demonstrates that VAI is independently associated with telomere length. A higher VAI is associated with shorter LTL. The results suggest that VAI may provide prediction for LTL and account for accelerating the biological aging.

Facilitating Catalytic Purification of Auto-Exhaust Carbon Particles via the Fe2O3{113} Facet-dependent Effect in Pt/Fe2O3 Catalysts.

The purification efficiency of auto-exhaust carbon particles in the catalytic aftertreatment system of vehicle exhaust is strongly dependent on the interface nanostructure between the noble metal component and oxide supports. Herein, we have elaborately synthesized the catalysts (Pt/Fe2O3-R) of Pt nanoparticles decorated on the hexagonal bipyramid α-Fe2O3 nanocrystals with co-exposed twelve {113} and six {104} facets. The area ratios (R) of co-exposed {113} to {104} facets in α-Fe2O3 nanocrystals were adjusted by the fluoride ion concentration in the hydrothermal method. The strong Pt-Fe2O3{113} facet interaction boosts the formation of coordination unsaturated ferric sites for enhancing adsorption/activation of O2 and NO. Pt/Fe2O3-R catalysts exhibited the Fe2O3{113} facet-dependent performance during catalytic purification of soot particles in the presence of H2O. Among the catalysts, the Pt/Fe2O3-19 catalyst exhibits the highest catalytic activities (T50 = 365 °C, TOF = 0.13 h-1), the lowest apparent activation energy (69 kJ mol-1), and excellent catalytic stability during soot purification. Combined with the results of characterizations and density functional theory calculations, the catalytic mechanism is proposed: the active sites located at the Pt-Fe2O3{113} interface can boost the key step of NO oxidation to NO2. The crystal facet engineering is an effective strategy to obtain efficient catalysts for soot purification in practical applications.

Circulating Connective Tissue Growth Factor Is Associated with Diastolic Dysfunction in Patients with Diastolic Heart Failure.

BACKGROUND: Connective tissue growth factor (CTGF) and transforming growth factor ß1 (TGF-ß1) are emerging biomarkers for tissue fibrosis. The aim of this study was to investigate the association between circulating CTGF, TGF-ß1 levels and cardiac diastolic dysfunction in patients with diastolic heart failure (DHF). METHODS: Admitted subjects were screened for heart failure and those with left ventricular (LV) ejection fraction <45% were excluded. Diastolic dysfunction was defined as functional abnormalities that exist during LV relaxation and filling by echocardiographic criteria. Totally 114 patients with DHF and 72 controls were enrolled. Plasma levels of CTGF, TGF-ß1, and B-type natriuretic peptide (BNP) were determined. RESULTS: The plasma CTGF and TGF-ß1 levels increased significantly in patients with DHF. Circulating CTGF and TGF-ß1 levels were correlated with echocardiographic parameter E/e' and diastolic dysfunction grading in DHF patients. In multivariate logistic analysis, CTGF was significantly associated with diastolic dysfunction (odds ratio: 1.027, p < 0.001). Plasma CTGF (AUC: 0.770 ± 0.036, p < 0.001) and CTGF/BNP (AUC: 0.839 ± 0.036, p < 0.001) showed good predictive power to the diagnosis of DHF. CONCLUSIONS: This finding suggested CTGF could be involved in the pathophysiology of diastolic heart failure and CTGF/BNP might have auxiliary diagnostic value on diastolic heart failure.

Correlation between clinic, cumulative, 24h-ambulatory systolic blood pressure, and chronic kidney damage in Chinese elderly.

The aim of this study was to investigate whether clinic, cumulative, and 24h ambulatory systolic blood pressure (SBP) was associated with chronic kidney damage, defind as estimated glomerular filtration rate (eGFR) <60 ml/(min·1.73 m2) and/or microalbuminuria ≥30 mg/L, and, if so, which measurement of SBP is more associated with chronic kidney damage in Chinese elderly. A total of 1207 participants older than 60 years old were included in the final analysis. Clinical blood pressure, cumulative blood pressure exposure was calculated and ambulatory 24h blood pressure was assessed. Multiple logistic regression analysis showed that the clinic (p < .001), cumulative (p = .033), 24h average (p < .001), daytime (p = .001) and nighttime SBP (p = .001) were respectively associated with lower eGFR, and cumulative (p = .008), 24 average (p < .001), daytime (p < .001), and nighttime SBP (p < .001) were the risk factors of microalbuminuria. The degree of correlation were strongest between 24h average SBP and chronic kidney damage (odds ratio, 1.78; 95% confidence interval, 1.46-2.15; p < .001), clinic SBP and eGFR (odds ratio, 1.57; 95% confidence interval, 1.13-2.17; p = .007), nighttime SBP and microalbuminuria (odds ratio, 1.45; 95% confidence interval, 1.05-2.00; p = .024). The likelihood ratio test demonstrated that the introduction of 24h average SBP will improve the goodness of fit of the clinic SBP model(p < .05), while the introduction of cumulative SBP exposure has no such effect(p > .05). Cumulative SBP exposure seems inferior to other measurement in indentifying chronic kidney damage, including decreased GFR and microalbuminuria.

MicroRNA-181c targets Bcl-2 and regulates mitochondrial morphology in myocardial cells.

Apoptosis is an important mechanism for the development of heart failure. Mitochondria are central to the execution of apoptosis in the intrinsic pathway. The main regulator of mitochondrial pathway of apoptosis is Bcl-2 family which includes pro- and anti-apoptotic proteins. MicroRNAs are small noncoding RNA molecules that regulate gene expression by inhibiting mRNA translation and/or inducing mRNA degradation. It has been proposed that microRNAs play critical roles in the cardiovascular physiology and pathogenesis of cardiovascular diseases. Our previous study has found that microRNA-181c, a miRNA expressed in the myocardial cells, plays an important role in the development of heart failure. With bioinformatics analysis, we predicted that miR-181c could target the 3' untranslated region of Bcl-2, one of the anti-apoptotic members of the Bcl-2 family. Thus, we have suggested that miR-181c was involved in regulation of Bcl-2. In this study, we investigated this hypothesis using the Dual-Luciferase Reporter Assay System. Cultured myocardial cells were transfected with the mimic or inhibitor of miR-181c. We found that the level of miR-181c was inversely correlated with the Bcl-2 protein level and that transfection of myocardial cells with the mimic or inhibitor of miR-181c resulted in significant changes in the levels of caspases, Bcl-2 and cytochrome C in these cells. The increased level of Bcl-2 caused by the decrease in miR-181c protected mitochondrial morphology from the tumour necrosis factor alpha-induced apoptosis.

Clinical Application of Induced Pluripotent Stem Cells in Cardiovascular Medicine.

Induced pluripotent stem cells (iPSCs) are generated by reprogramming human somatic cells through the overexpression of four transcription factors: Oct4, Sox2, Klf4 and c-Myc. iPSCs are capable of indefinite self-renewal, and they can differentiate into almost any type of cell in the body. These cells therefore offer a highly valuable therapeutic strategy for tissue repair and regeneration. Recent experimental and preclinical research has revealed their potential for cardiovascular disease diagnosis, drug screening and cellular replacement therapy. Nevertheless, significant challenges remain in terms of the development and clinical application of human iPSCs. Here, we review current progress in research related to patient-specific iPSCs for ex vivo modeling of cardiovascular disorders and drug screening, and explore the potential of human iPSCs for use in the field of cardiovascular regenerative medicine.

Vascular endothelial function of patients with stable coronary artery disease.

OBJECTIVES: To evaluate vascular endothelial function and contributing factors in coronary heart disease (CHD) patients. METHODS: One hundred twenty six CHD outpatients were randomly recruited. Reactive hyperemia index (RHI) <1.67 indicates endothelial dysfunction. Correlation between RHI and different biochemical parameters was evaluated. RESULTS: RHI in patients receiving statins treatment was significantly higher than patients without statins treatment (P<0.05). RHI in patients with more than 3 risk factors for CHD was also markedly lower than that in patients with ≤2 risk factors (P<0.05). Patients with lesions at several branches of coronary artery had a markedly lower RHI when compared with those with coronary lesions at a single branch (P<0.05). For patients without statins treatment, RHI increased significantly after statins treatment for 1 month (P=0.01). In patients with endothelial dysfunction, FBG, HbA1C, hs-CRP and Hcy were significantly higher than those in patients with normal endothelial function (P<0.05 for all). Smokers with CHD had a remarkably lower RHI when compared with non-smokers (P<0.05). CONCLUSIONS: Smoking, FBG, HbA1C, Hcy and hs-CRP are significantly associated with endothelial dysfunction. Endothelial dysfunction is also related to the numbers of risk factors for CHD, degree of coronary lesions and statins. Statins treatment may significantly improve the endothelial function of CHD patients.

[Concentration of plasma vascular endothelial growth factor and related factors in patients with unstable angina pectoris].

OBJECTIVE: To observe plasma vascular endothelial growth factor(VEGF) levels and related factors in patients with unstable angina pectoris(UAP). METHODS: A total of 108 consecutive patients with chest pain hospitalized in our department from October to December 2014 were included. They were divided into UAP (n=78) and non-CHD group (n=30) by the result of coronary angiography(CAG). Coronary artery lesion was assessed according to the Gensini score, serum lipids, homocysteine(Hcy) levels and other biochemical indicators were also determined. The peripheral arterial tonometry was evaluated by reactive hyperemia index(RHI) measured by Endo-PAT2000 Noninvasive Diagnostic System.The level of plasma VEGF was detected in patients with unstable angina pectoris. Multiple linear regression analysis was used to analyze the correlations between VEGF and various related factors. RESULTS: Percent of male gender, triglyceride (TG) and Hcy levels were significantly higher in UAP group than in no-CHD group(all P<0.05). VEGF values was significantly higher ((102.1 ± 55.7)ng/L vs.(80.9 ± 38.1)ng/L, P<0.05), while RHI was significantly lower (1.53 ± 0.27 vs.1.65 ± 0.32, P<0.05) in UAP group than in no-CHD group. Multiple linear regression analysis showed that VEGF value was significantly correlated with degree of coronary artery stenosis, Gensini score and RHI (ß=38.03, P<0.01; ß=0.51, P<0.01; ß=-69.30, P=0.03; respectively). CONCLUSION: VEGF levels are significantly increased in patients with unstable angina pectoris, and VEGF level is significantly associated with the degree of coronary artery stenosis, Gensini score and RHI. V EGF level might serve as a new biochemical indicator for coronary artery lesion in patients with UAP.

Downregulation of microRNA-19b contributes to angiotensin II-induced overexpression of connective tissue growth factor in cardiomyocytes.

OBJECTIVES: The present study was designed to decipher the molecular mechanisms underlying angiotensin (Ang) II-induced overexpression of connective tissue growth factor (CTGF) in cultured cardiomyocytes. METHODS: Cardiomyocytes isolated from 1- to 3-day-old neonatal rats were cultured and treated with 100 nM Ang II with or without pretreatment with 10 nM telmisartan, an Ang II type 1 receptor antagonist. The role of microRNA (miR)-19b in the regulation of Ang II-induced CTGF expression was evaluated in cultured cardiomyocytes with quantitative real-time reverse transcription polymerase chain reaction and Western blot analysis. RESULTS: We provide several lines of evidence to show that miR-19b contributes to the Ang II-induced overexpression of CTGF in cultured cardiomyocytes. Firstly, administration of Ang II decreased the level of miR-19b dramatically (p < 0.05 vs. control), which was abolished by telmisartan. Secondly, Ang II increased the level of CTGF significantly (p < 0.05 vs. control), which was also prevented by pretreatment with telmisartan. Thirdly, overexpression of miR-19b decreased CTGF levels (p < 0.05 vs. control). Finally, transfection of miR-19b into cardiomyocytes prevented the upregulation of CTGF induced by Ang II. CONCLUSION: Downregulation of miR-19b contributes to Ang II-induced overexpression of CTGF in cultured cardiomyocytes.

Association of the visceral adiposity index with arterial stiffness in elderly Chinese population.

BACKGROUND: The visceral adiposity index (VAI) is a new marker of adipose dysfunction and related with cardiometabolic risk. The aim of this study is to investigate the association of VAI with arterial stiffness in elderly Chinese population. METHODS: A total of 1,707 elderly individuals over 60 years of age were recruited for this cross-sectional study. We measured body composition, anthropometrics, blood pressure, and lipid parameters. The arterial stiffness was measured by brachial-ankle pulse wave velocity (baPWV) and defined as baPWV ≥ 1400 cm/s. VAI‬ was calculated based on body mass index, waist circumference, triglyceride and high-density lipoprotein cholesterol. Multivariable regression analysis was performed to evaluate the association between VAI and baPWV. RESULTS: There were significant differences in VAI tertiles between low-baPWV and high-baPWV group (p = 0.008). Univariate analysis demonstrated that age, history of hypertension, SBP, DBP, total cholesterol, fasting glucose, the higher VAI tertiles were correlated with the existence of high-baPWV (p < 0.05). Participants in the higher VAI tertiles had higher OR (1.0 ≤ VAI < 1.74: OR= 2.89, 95% CI [1.44, 5.80]; VAI ≥ 1.75: OR = 4.23, 95% CI [1.45, 12.37], p for trend: 0.004) comparing with the lowest VAI tertile. Non-linear relationship was detected between VAI and baPWV. VAI was positively correlated with baPWV when VAI < 2.10. CONCLUSIONS: This study demonstrates that VAI is independently associated with the risk of arterial stiffness in elderly population.

Circulating exosomal lncRNAs in patients with chronic coronary syndromes.

Introduction: The concept of chronic coronary syndrome (CCS) was first presented at the European Society of Cardiology Meeting in 2019. However, the roles of exosomal lncRNAs in CCS remain largely unclear. Material and methods: A case-control study was performed with a total of 218 participants (137 males and 81 females), including 15 CCS patients and 15 controls for sequencing profiles, 20 CCS patients and 20 controls for the first validation, and 100 CCS patients and 48 controls for the second validation. Exosomes were isolated from the plasma of CCS patients and controls, and exosomal lncRNAs were identified by sequencing profiles and verified twice by qRT-PCR analysis. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of exosomal lncRNAs for CCS patients. Results: A total of 152 significantly differentially expressed lncRNAs with over two-fold changes were detected in plasma exosomes of CCS patients, including 90 upregulated and 62 downregulated lncRNAs. Importantly, 6 upregulated lncRNAs with the top fold changes were selected for validations. Exosomal lncRNAs ENST00000424615.2 and ENST00000560769.1 were significantly elevated in CCS patients in both validations compared with controls. The areas under the ROC of lncRNAs ENST00000424615.2 and ENST00000560769.1 were 0.654 and 0.722, respectively. Additionally, exosomal lncRNA ENST00000560769.1 was significantly higher in the CCS patients with more diseased vessels (p = 0.028). Conclusions: Exosomal lncRNA ENST00000424615.2 and ENST00000560769.1 were identified as novel diagnosis biomarkers for patients with CCS. Moreover, exosomal lncRNA ENST00000560769.1 was significantly higher in the CCS patients with more diseased vessels, and might be associated with a poor prognosis.

Plasma levels of bone morphogenic protein-4 are downregulated in elderly hypertensive patients with heart failure with preserved ejection fraction.

OBJECTIVE: This study aimed to evaluate the association between plasma bone morphogenic protein-4 (BMP-4) levels and heart failure (HF) with preserved ejection fraction (HFpEF) or mildly reduced ejection fraction (HFmrEF) in elderly hypertensive patients. METHODS: A total of 222 hypertensive individuals meeting the inclusion criteria were enrolled from October 2021 to July 2022. Data were collected including clinical characteristics, laboratory tests and echocardiogram measurements. Plasma BMP-4 levels were tested using enzyme-linked immunosorbent assay analysis. RESULTS: Among 222 elderly hypertensive patients, 149 were without HF, 59 had HFpEF, and 14 had HFmrEF. Plasma BMP-4 levels were strikingly downregulated in hypertensive patients with HFpEF/HFmrEF [median (25th, 75th percentile): 15.89 (7.69, 23.12) pg/mL vs. 19.67 (10.60, 33.04) pg/mL; P = 0.002]. After univariate and multivariate logistic regression analysis, the risk of HFpEF/HFmrEF was declined in the 4th quartile BMP-4 group when compared with the 1st quartile BMP-4 group (odds ratio, 0.20, 95% confidence interval (CI), 0.04 to 1.00; P = 0.050, P for trend = 0.025). Receiver operating characteristic curve analysis revealed that BMP-4 ≤ 28.5 pg/mL exhibited a sensitivity of 95.9% and a specificity of 28.2% in HFpEF/HFmrEF diagnosis. Furthermore, the area under the curve (AUC) was 0.619 (95% CI:0.540-0.698, P < 0.001). The corresponding AUC for brain natriuretic peptide (BNP) was 0.781 (95% CI: 0.710-0.852), P < 0.001. Adding BMP-4 to BNP increased the AUC to 0.790 (95% CI: 0.724-0.856), vs. BMP-4, P < 0.001; vs. BNP, P = 0.730, respectively. CONCLUSIONS: Plasma BMP-4 levels are downregulated in elderly hypertensive patients with HFpEF. BMP-4 is a promising biomarker for diagnosing HFpEF/HFmrEF during hypertension.

A single site ruthenium catalyst for robust soot oxidation without platinum or palladium.

The quest for efficient non-Pt/Pd catalysts has proved to be a formidable challenge for auto-exhaust purification. Herein, we present an approach to construct a robust catalyst by embedding single-atom Ru sites onto the surface of CeO2 through a gas bubbling-assisted membrane deposition method. The formed single-atom Ru sites, which occupy surface lattice sites of CeO2, can improve activation efficiency for NO and O2. Remarkably, the Ru1/CeO2 catalyst exhibits exceptional catalytic performance and stability during auto-exhaust carbon particle oxidation (soot), rivaling commercial Pt-based catalysts. The turnover frequency (0.218 h-1) is a nine-fold increase relative to the Ru nanoparticle catalyst. We further show that the strong interfacial charge transfer within the atomically dispersed Ru active site greatly enhances the rate-determining step of NO oxidation, resulting in a substantial reduction of the apparent activation energy during soot oxidation. The single-atom Ru catalyst represents a step toward reducing dependence on Pt/Pd-based catalysts.

Predictive value of CTRP3 for the disease recurrence of atrial fibrillation patients after radiofrequency ablation.

OBJECTIVE: To explore the expression of plasma CTRP3 in patients with non-valvular paroxysmal atrial fibrillation after radiofrequency ablation and its predictive value for disease recurrence. METHODS: In this retrospective study, the patients in the Heart Center of Beijing Chaoyang Hospital from June 2016 to November 2017 were collected. According to the guidelines for diagnosis and treatment of atrial fibrillation 2016, patients diagnosed with paroxysmal atrial fibrillation were selected as the study subjects. All patients with successful radiofrequency ablation of atrial fibrillation were followed up by telephone or outpatient service at 1, 3, 6 and 12 months after radiofrequency ablation, respectively. Recurrence of atrial fibrillation was defined as a duration of rapid atrial arrhythmia ≥30 seconds confirmed by electrocardiogram or 24-hour ambulatory electrocardiogram 3 months after radiofrequency ablation. According to the follow-up results, the patients were divided into a recurrent group and non-recurrent group. The level of CTRP3 was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Analysis of clinical baseline data showed significant differences between the recurrent group and the non-recurrent group in age, systolic blood pressure, diastolic blood pressure, EGFR, thyroid stimulating hormone level, platelet count, high-sensitivity C-reactive protein, NT proBNP, left atrial anterior posterior diameter, left atrial upper and lower diameter and CTRP3 (P < 0.05). The univariate logistic regression showed that older age (or = 1.08, P < 0.001), increased diastolic blood pressure (OR = 1.051, P = 0.002), cardiac dysfunction (OR = 2.594, P = 0.01), high-sensitivity C-reactive protein (OR = 1.134, P = 0.008) and NT proBNP (OR = 1.000, P = 0.005), increased anterior posterior diameter of left atrium (OR = 1.158, P < 0.001), increased upper and lower diameter of left atrium (OR = 1.133, P < 0.001), thrombocytopenia (OR = -0.008, P < 0.027) and CTRP3 (OR = 1.007, P = 0.006) were the risk factors for the recurrence of atrial fibrillation after radiofrequency ablation. Moreover, the multivariate logistic regression analysis demonstrated that CTRP3 (or = 1.032, P = 0.005) was an independent predictor of recurrence. CONCLUSION: The plasma concentration of CTRP3 increased significantly in patients with recurrent atrial fibrillation after radiofrequency ablation. Moreover, CTRP3 was a predictor of recurrence after radiofrequency ablation in patients with atrial fibrillation.

Vital Roles of Gremlin-1 in Pulmonary Arterial Hypertension Induced by Systemic-to-Pulmonary Shunts.

Background Heterozygous mutation in BMP (bone morphogenetic protein) receptor 2 is rare, but BMP cascade suppression is common in congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH); however, the underling mechanism of BMP cascade suppression independent of BMP receptor 2 mutation is unknown. Methods and Results Pulmonary hypertensive status observed in CHD-PAH was surgically reproduced in rats. Gremlin-1 expression was increased, but BMP cascade was suppressed, in lungs from CHD-PAH patients and shunted rats, whereas shunt correction retarded these trends in rats. Immunostaining demonstrated increased gremlin-1 was mainly in the endothelium and media of remodeled pulmonary arteries. However, mechanical stretch time- and amplitude-dependently stimulated gremlin-1 secretion and suppressed BMP cascade in distal pulmonary arterial smooth muscle cells from healthy rats. Under static condition, gremlin-1 significantly promoted the proliferation and inhibited the apoptosis of distal pulmonary arterial smooth muscle cells from healthy rats via BMP cascade. Furthermore, plasma gremlin-1 closely correlated with hemodynamic parameters in CHD-PAH patients and shunted rats. Conclusions Serving as an endogenous antagonist of BMP cascade, the increase of gremlin-1 in CHD-PAH may present a reasonable mechanism explanation for BMP cascade suppression independent of BMP receptor 2 mutation.

MicroRNA-122 aggravates angiotensin II-mediated apoptosis and autophagy imbalance in rat aortic adventitial fibroblasts via the modulation of SIRT6-elabela-ACE2 signaling.

Abnormal aortic adventitial fibroblasts (AFs) play essential roles in the development of vascular remodeling and disorders. Previous studies revealed that microRNA-122 (miR-122) levels were elevated in the aortic adventitia of hypertensive rats with vascular injury. Here, we aim to evaluate the biological effects and underlying mechanisms of miR-122 in rat AFs. Exposure to angiotensin II (ATII) in rat AFs resulted in decreased levels of sirtuin 6 (SIRT6), elabela (ELA), and angiotensin-converting enzyme 2 (ACE2). Additionally, stimulation with ATII contributed to a decline in autophagic flux and obvious increases in cellular migration, oxidative stress, and apoptosis, which were exacerbated by the transfection of miR-122-5p mimic but were rescued by miR-122-5p inhibitor, exogenous replenishment of ELA, and recombinant adeno-associated virus expressing SIRT6 (rAAV-SIRT6), respectively. Moreover, stimulation with miR-122-5p mimic led to a marked reduction in the levels of SIRT6 and ELA in rat AFs, which were elevated by stimulation with rAAV-SIRT6. Furthermore, miR-122-5p inhibitor-mediated pro-autophagic, anti-oxidant and anti-apoptotic effects in rat AFs were partially suppressed by 3-methyladenine, SIRT6 small interfering RNA (siRNA) and ELA siRNA, which were linked with the downregulation in the protein levels of LC3-II, beclin-1, and ACE2 and the upregulation of p62 expression and bax/bcl-2 ratio. Our findings indicated that miR-122-5p inhibition prevented ATII-mediated loss of autophagy, and the promotion of apoptosis and oxidative stress via activating the SIRT6-ELA-ACE2 signaling. MiR-122-5p may be a novel predictive biomarker of adventitial injury, and targeting the SIRT6-ELA-ACE2 signaling may have the potential therapeutic importance of controlling vascular remodeling and disorders.

p38/JNK Is Required for the Proliferation and Phenotype Changes of Vascular Smooth Muscle Cells Induced by L3MBTL4 in Essential Hypertension.

AIM: Hypertension is a complicated disorder with multifactorial etiology and high heritability. Our previous work has identified L3MBTL4 as a novel susceptibility gene for the development of essential hypertension, accompanied with activation of p38/JNK. Yet, little evidence has been reported whether p38/JNK contributed directly to L3MBTL4-induced vascular remodeling and exploring the potential mechanism of L3MBTL4 in vascular smooth muscle cells (VSMCs). METHODS: We evaluated the contribution of L3MBTL4 on proliferation, migration, and phenotype changes of VSMCs and further explored the critical role of p38 and JNK signaling pathway underlying. RESULTS: In L3MBTL4 transgenic rats, we found that the elevated blood pressure, increased left ventricular hypertrophy, and thickened vascular media layer were significantly relieved by both p38 and JNK inhibitors. Meanwhile, increased cell proliferation, advanced cell cycle progression, greater migratory capability, and synthetic phenotype were observed in L3MBTL4 overexpressed VSMCs, which could be blocked by either p38 or JNK inhibitor. CONCLUSIONS: Our findings pinpointed that p38 and JNK were required for the proliferation and phenotype changes of VSMCs induced by L3MBTL4 in hypertension. These novel findings yield new insights into the genetic and biological basis of hypertension and are fundamental for further studies to explore the intervention strategies targeting L3MBTL4 and p38/JNK to counteract the progression of hypertension.