胡兆
中国医学科学院阜外医院 教育部
BACKGROUND:Substantial focus has been placed on atrial fibrillation (AF) treatment and associated stroke prevention rather than preventing AF itself. We employed Mendelian randomization (MR) approach to examine the causal relationships between 50 modifiable risk factors (RFs) and AF.METHODS:Instrumental variables for genetically predicted exposures were derived from corresponding genome-wide association studies (GWASs). Summary-level statistical data for AF were obtained from a GWAS meta-analysis (discovery dataset, N = 1,030,836) and FinnGen (validation dataset, N = 208,594). Univariable and multivariable MR analyses were performed, primarily using inverse variance weighted method with a series of robust sensitivity analyses.RESULTS:Genetic predisposition to insomnia, daytime naps, apnea, smoking initiation, moderate to vigorous physical activity and obesity traits, including body mass index, waist-hip ratio, central and peripheral fat/fat-free mass, exhibited significant associations with an increased risk of AF. Coffee consumption and ApoB had suggestive increased risks. Hypertension (odds ratio (OR) 95% confidence interval (CI): 5.26 (4.42, 6.24)), heart failure (HF) (OR 95% CI, 4.77 (2.43, 9.37)) and coronary artery disease (CAD) (OR 95% CI: 1.20 (1.16, 1.24)) were strongly associated with AF, while college degree, higher education attachment and HDL levels were associated with a decreased AF risk. Reverse MR found a bidirectional relationship between genetically predicted AF and CAD, HF and ischemic stroke. Multivariable analysis further indicated that obesity-related traits, systolic blood pressure and lower HDL levels independently contributed to the development of AF.CONCLUSIONS:This study identified several lifestyles and cardiometabolic factors that might be causally related to AF, underscoring the importance of a holistic approach to AF management and prevention.
European journal of clinical investigation 2024
BACKGROUND:Autoimmune myocarditis, with increasing incidence and limited therapeutic strategies, is in urgent need to explore its underlying mechanisms and effective drugs. Pyroptosis is a programmed cell death that may contribute to the pathogenesis of myocarditis. Nonetheless, no direct evidence validated the role of pyroptosis in autoimmune myocarditis. Lupeol (Lup), a pentacyclic triterpene, possesses various biological activities such as antidiabetic properties. However, the effects of Lup on autoimmune myocarditis and pyroptosis remain unelucidated.PURPOSE:This study aimed to reveal the role of pyroptosis in autoimmune myocarditis and explore the protective effects of Lup, and its engaged mechanisms.METHODS:The experimental autoimmune myocarditis (EAM) mouse model was established by immunization with a fragment of cardiac myosin in Balb/c mice. Lup and MCC950 were administered after EAM induction. The protective effects were assessed by inflammation score, cardiac injury, chronic fibrosis, and cardiac function. Mechanistically, the effects of Lup on the M1 polarization and pyroptosis of macrophages were evaluated. Transcriptome sequencing and molecular docking were subsequently employed, and the underlying mechanisms of Lup were further explored in vitro with small interfering RNA and adenovirus.RESULTS:Administration of Lup and MCC950 alleviated EAM progression. Western blotting and immunofluorescence staining identified macrophages as the primary cells undergoing pyroptosis. Lup inhibited the expression of pyroptosis-associated proteins in macrophages during EAM in a dose-dependent manner. Furthermore, Lup suppressed pyroptosis in both bone marrow-derived macrophages (BMDMs) and THP-1-derived macrophages in vitro. In addition, Lup inhibited the M1 polarization of macrophages both in vivo and in vitro. Mechanistically, the protective effects of Lup were demonstrated via the suppression of the nuclear factor-κΒ (NF-κB) signaling pathway. Transcriptome sequencing and molecular docking revealed the potential involvement of peroxisome proliferator-associated receptor α (PPARα). Subsequently, we demonstrated that Lup activated PPARα to reduce the expression level of LACC1, thereby inhibiting the NF-κB pathway and pyroptosis.CONCLUSION:Our findings indicated the crucial role of macrophage pyroptosis in the pathogenesis of EAM. Lup ameliorated EAM by inhibiting the M1 polarization and pyroptosis of macrophages through the PPARα/LACC1/NF-κB signaling pathway. Thus, our results provided a novel therapeutic target and agent for myocarditis.
Phytomedicine : international journal of phytotherapy and phytopharmacology 2024
BACKGROUND:Life-threatening ventricular arrhythmias (LTVAs) are main causes of sudden cardiac arrest and are highly associated with an increased risk of mortality. A prediction model that enables early identification of the high-risk individuals is still lacking.OBJECTIVE:We aimed to build machine learning (ML)-based models to predict in-hospital mortality in patients with LTVA.METHODS:A total of 3140 patients with LTVA were randomly divided into training (n=2512, 80%) and internal validation (n=628, 20%) sets. Moreover, data of 2851 patients from another database were collected as the external validation set. The primary output was the probability of in-hospital mortality. The discriminatory ability was evaluated by the area under the receiver operating characteristic curve (AUC). The prediction performances of 5 ML algorithms were compared with 2 conventional scoring systems, namely, the simplified acute physiology score (SAPS-II) and the logistic organ dysfunction system (LODS).RESULTS:The prediction performance of the 5 ML algorithms significantly outperformed the traditional models in predicting in-hospital mortality. CatBoost showed the highest AUC of 90.5% (95% CI 87.5%-93.5%), followed by LightGBM with an AUC of 90.1% (95% CI 86.8%-93.4%). Conversely, the predictive values of SAPS-II and LODS were unsatisfactory, with AUCs of 78.0% (95% CI 71.7%-84.3%) and 74.9% (95% CI 67.2%-82.6%), respectively. The superiority of ML-based models was also shown in the external validation set.CONCLUSIONS:ML-based models could improve the predictive values of in-hospital mortality prediction for patients with LTVA compared with traditional scoring systems.
Journal of medical Internet research 2023
BACKGROUND:High-sensitivity C-reaction protein (hsCRP), a biomarker of residual inflammatory risk, has been demonstrated with poor cardiovascular outcomes. We aimed to investigate the prognostic value of hsCRP in patients undergoing percutaneous coronary intervention (PCI) with or without diabetes mellitus (DM).METHODS:In this large-scale, prospective cohort study, we enrolled 8050 consecutive patients who underwent PCI for coronary artery stenosis. All subjects were stratified as high hsCRP (> 3 mg/L) and low hsCRP (≤ 3 mg/L) and were divided into four groups (hsCRP-L/non-DM, hsCRP-H/non-DM, hsCRP-L/DM, hsCRP-H/DM). The primary endpoint of the study was major adverse cardiovascular events (MACEs), including all-cause mortality, myocardial infarction, stroke, and unplanned vessel revascularization, evaluated at a 3 year follow-up.RESULTS:After 35.7 months (interquartile range: 33.2 to 36.0 months) of median follow-up time, 674 patients suffered from MACEs. We found elevated hsCRP was highly associated with an increased risk of MACEs in both diabetic (hazard ratio [HR] = 1.68, 95% confidence interval CI 1.29-2.19, P < 0.001) and non-diabetic patients (HR = 1.31, 95% CI: 1.05-1.62, P = 0.007) after adjustment for other confounding factors. Kaplan-Meier survival analysis showed the highest incidence of MACEs in hsCRP-H/DM (P < 0.001). In addition, the results of the restricted cubic spline analysis suggested a positive linear relationship between hsCRP and MACEs.CONCLUSION:Elevated hsCRP is an independent risk factors of MACEs in patients undergoing PCI irrespective of glycemic metabolism status.
Cardiovascular diabetology 2023
BACKGROUND:Renal denervation (RDN) is a promising treatment based on catheter intervention for patients with refractory hypertension. However, the effect in patients with isolated systolic hypertension (ISH) remains controversial. The aim of this meta-analysis was to determine the blood pressure lowing effect of RDN in patients with ISH compared with combined systolic/diastolic hypertension (CH) patients.METHODS:PubMed, Embase, Cochrane and ClinicalTrials.gov were searched for prospective clinical studies that included RDN. The outcomes of interest were the change of 24-hour ambulatory systolic blood pressure (SBP) from baseline. We used the fixed effects model to calculate weighted mean difference (WMD) with 95% confidence interval (CI).RESULTS:Six trials were included, with 1405 participants, including 597 patients with ISH and 808 patients with CH. Mean follow-up was five months. The reduction of 24-hour ambulatory SBP was significantly greater for the CH patients than the ISH patients (WMD = 3.89, 95% CI: 2.32-5.45, P < 0.0001). RDN also showed a greater reduction in office SBP in the CH patients compared to the ISH patients (WMD = 10.24, 95% CI: 4.24-15.74, P = 0.0003). And the effect was independent of age, length of follow-up, and ablation device.CONCLUSIONS:RDN provides superior blood pressure control in the CH patients compared with the ISH patients, and the CH patients may be the best suitable population for which RDN is indicated.
Journal of geriatric cardiology : JGC 2023
BACKGROUND:The stress hyperglycemia ratio (SHR) has demonstrated a noteworthy association with unfavorable cardiovascular clinical outcomes and heightened in-hospital mortality. Nonetheless, this relationship in critically ill patients remains uncertain. This study aims to elucidate the correlation between SHR and patient prognosis within the critical care setting.METHODS:A total of 8978 patients admitted in intensive care unit (ICU) were included in this study. We categorized SHR into uniform groups and assessed its relationship with mortality using logistic or Cox regression analysis. Additionally, we employed the restricted cubic spline (RCS) analysis method to further evaluate the correlation between SHR as a continuous variable and mortality. The outcomes of interest in this study were in-hospital and 1-year all-cause mortality.RESULTS:In this investigation, a total of 825 (9.2%) patients experienced in-hospital mortality, while 3,130 (34.9%) individuals died within the 1-year follow-up period. After adjusting for confounding variables, we identified a U-shaped correlation between SHR and both in-hospital and 1-year mortality. Specifically, within the SHR range of 0.75-0.99, the incidence of adverse events was minimized. For each 0.25 increase in the SHR level within this range, the risk of in-hospital mortality rose by 1.34-fold (odds ratio [OR]: 1.34, 95% CI: 1.25-1.44), while a 0.25 decrease in SHR within 0.75-0.99 range increased risk by 1.38-fold (OR: 1.38, 95% CI: 1.10-1.75).CONCLUSION:There was a U-shaped association between SHR and short- and long-term mortality in critical ill patients, and the inflection point of SHR for poor prognosis was identified at an SHR value of 0.96.
Cardiovascular diabetology 2023
BACKGROUND AND AIMS:Non-alcoholic fatty liver disease (NAFLD) is prevalent in hypertensive people, but the causal effect remains unclear. We employed Mendelian randomization (MR) approach to assess the causality between NAFLD and different blood pressure (BP) parameters.METHOD AND RESULTS:Instrumental variables for genetically predicted NAFLD, including chronically elevated serum alanine aminotransferase levels (cALT) and imaging and biopsy-confirmed NAFLD, were obtained from a genome-wide association study (N = 164,197). Multiple MR methods were implemented, including Inverse variance weighted, MR-Egger, Maximum likelihood, Weighted median, Simple median, Penalised weighted median, MR-RAPS, and cML-MA. Outliers were detected using MR-PRESSO, and pleiotropy was assessed using MR-Egger intercept and Phenoscanner. Heterogeneity was quantified using Cochran's Q and Rucker's Q' tests. Potential shared risk factors were analyzed to reveal the mediating effect. A higher genetic predisposition to cALT was causally associated with an increased risk of elevated BP levels, resulting in 0.65 mmHg (95% CI, 0.42-0.87), 0.38 mmHg (95% CI, 0.25-0.50) and 0.33 mmHg (95% CI, 0.22-0.44) higher for systolic BP, diastolic BP and pulse pressure, respectively. When more stringent criteria were used, imaging and biopsy-confirmed NAFLD showed a 1.12 mmHg (95% CI, 0.94-1.30) increase in SBP and a 0.55 mmHg (95% CI, 0.39-0.70) increase in DBP. Risk factor and mediation analyses suggested type 2 diabetes and fasting insulin levels might mediate the causal relationship between NAFLD and BP.CONCLUSION:The two-sample MR analyses showed robust causal effects of genetically predicted NAFLD on 3 different BP indices. The shared genetic profile between NAFLD and BP may suggest important therapeutic targets and early interventions for cardiometabolic risk factors.
Nutrition, metabolism, and cardiovascular diseases : NMCD 2023
BACKGROUND:Female patients are underrepresented in randomized controlled clinical trials and registries of ventricular arrhythmia (VA). Personalized prevention and therapies require an understanding of sex differences in risk factors and prognosis of VA.OBJECTIVE:We aimed to assess sex differences in the incidence, risk factors, and mortality of VA in congestive heart failure (HF) patients.METHODS:This study included 10,889 patients (mean [SD] age, 73.8 [13.4] years; 5917 [53.8%] male) with congestive HF, of which 1555 (14.3%) patients developed VA during hospitalization. VA incidence, potential risk factors, and in-hospital mortality were evaluated in both sexes.RESULTS:Men were more strongly associated with incident VA compared with women (odds ratio [OR]: 2.006, 95% CI: 1.790-2.248, p < 0.001). Thirteen potential predictors, which accounted for 91.0% of the risk of VA in men and 88.2% in women, were included in this study. There were significant interactions by sex in the association between incident VA, atrial fibrillation (AF) (relative risk ratio = 0.730, 95% CI: 0.571-0.933, interaction p = 0.012), and non-ischemic cardiomyopathy (NICM) (relative risk ratio = 1.391, 95% CI: 1.029-1.872, interaction p = 0.030). Congestive HF patients developed with VA had an approximately 1.5-fold risk of in-hospital mortality, which was not affected by sex.CONCLUSIONS:In congestive HF patients, incident VA was an independent risk factor of in-hospital mortality, and male sex was strongly associated with an increased risk of VA. Awareness of sex differences in the association of AF and NICM with VA may enhance therapeutic decisions, thus improving their clinical outcomes.
International journal of cardiology 2023
BACKGROUND:Observational studies have suggested a close association between atrial fibrillation (AF) and heart failure (HF), yet the causal effect remains uncertain. In this study, we employed a bidirectional Mendelian randomization analysis to investigate the causal effect of one disease on the other.METHODS:Genetic instrumental variables were obtained from large-scale summary-level genome-wide association studies of AF (n = 1,030,836) and HF(n = 1,665,481), respectively. Two-sample Mendelian randomization was conducted to establish causal inferences. Inverse-variance weighted (IVW) was the primary estimate, while additional analyses including MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), MR-Egger, and Weighted median were performed to validate robustness and identify pleiotropy.RESULTS:After accounting for confounding variables, MR analysis suggested a potential causal relationship between AF and HF. An augmented genetic predisposition to atrial fibrillation was associated with an elevated risk of heart failure (odds ratio (OR) = 1.18, 95% confidence interval (CI):1.14-1.22). Likewise, genetically determined heart failure also increased the risk of heart failure (OR = 1.44, 95%CI:1.23-1.68). The robustness of the findings was corroborated through MR sensitivity analyses, and the causal estimates remained consistent when the instrument P-value threshold was tightened.CONCLUSIONS:Our bidirectional Mendelian randomization study supports a reciprocal causal relationship between AF and HF. The shared genetic profile of these conditions may provide crucial insights into potential therapeutic targets for the prevention and progression of both disorders. These findings underscore the necessity for further investigation into the underlying molecular mechanisms linking AF and HF, as well as the potential for personalized treatment strategies grounded in genetic profiling.
BMC medical genomics 2023
Backgrounds:Decreased urine output (UO) is associated with adverse outcomes in certain patients, but this effect in patients admitted for cardiovascular diseases is still unproven. Moreover, the relationship between increased UO and prognosis is also unclear.Objective:To investigate the relationship between decreased or increased UO and outcomes in patients with the cardiovascular intensive care unit (CICU).Methods:This study was a retrospective cohort analysis based on the medical information mart for intensive care III (MIMIC-III) database. The patients' data were extracted from the Beth Israel Deaconess Medical Center (Boston, MA) between 2001 and 2012. With the initial 24-h UO range from 0.5 to 1.0 ml/kg/h as the reference, participants were divided into the several groups. The primary outcome was 30-day mortality. The secondary outcomes were 90-day mortality, ICU mortality, hospital mortality, use of mechanical ventilation (MV), and vasopressor agents in the first 24-h of ICU. The association between UO and mortality was assessed by multivariable logistic regression.Results:A total of 13,279 patients admitted to CICU were included. Low UO (< 0.5 ml/kg/h) was strongly associated with 30-day mortality (unadjusted OR = 3.993, 95% CI: 3.447-4.625, p < 0.001), and very high UO (≥ 2.0 ml/kg/h) was also a significantly risk factor for 30-day mortality (Unadjusted OR = 2.069, 95% CI: 1.701-2.516, p < 0.001) compared with the reference. The same effects also were shown in the multivariable logistic regression, adjusted by age, gender, vital signs, common comorbidities, and use of diuretics, with an adjusted OR of 2.023 (95% CI: 1.693-2.417, p < 0.001) for low UO and 1.771 (95% CI: 1.389-2.256, p < 0.001) for very high UO. Moreover, both decreased UO and increased UO were risk factors for 90-day mortality, ICU mortality, hospital mortality, use of MV and vasopressor agents.Conclusion:The decreased and increased UO both were significantly associated with short-term mortality, the relationship between UO and mortality was U-shape rather than linear.
Frontiers in cardiovascular medicine 2022
