Association between plasma proteome and pulmonary heart disease: A two-stage Mendelian randomization analysis.

Pulmonary heart disease (PHD) involves altered structure and function of the right ventricle caused by an abnormal respiratory system that causes pulmonary hypertension. However, the association between changes in plasma proteomics and PHD remains unclear. Hence, we aimed to identify causal associations between genetically predicted plasma protein levels and PHD. Mendelian randomization was performed to test the target proteins associated with PHD. Summary statistics for the human plasma proteome and pulmonary heart disease were acquired from the UK Biobank (6038 cases and 426 977 controls) and the FinnGen study (6753 cases and 302 401 controls). Publicly available pQTLs datasets for human plasma proteins were obtained from a largescale genome-wide association study in the INTERVAL study. The results were validated using a case-control cohort. We first enrolled 3622 plasma proteins with conditionally independent genetic variants; three proteins (histo-blood group ABO system transferase, activating signal cointegration 1 complex subunit 1, and calcium/calmodulin-dependent protein kinase I [CAMK1]) were significantly associated with the risk of pulmonary heart disease in the UK Biobank cohort. Only CAMK1 was successfully replicated (odds ratio: 1.1056, 95% confidence interval: 1.019-1.095, p = 0.0029) in the FinnGen population. In addition, the level of CAMK1 in 40 patients with PHD was significantly higher (p = 0.023) than that in the control group. This work proposes that CAMK1 is associated with PHD, underscoring the importance of the calcium signaling pathway in the pathophysiology to improve therapies for PHD.

Association of monocyte to HDL cholesterol ratio and a composite risk score with left ventricular aneurysm formation in patients with acute ST-segment elevation myocardial infarction.

BACKGROUND: Left ventricular aneurysm (LVA) is an important complication of acute myocardial infarction. This study aimed to investigate the potential predictive value of the monocyte count to high-density lipoprotein cholesterol ratio (MHR) and a composite risk score in determining the formation of LVA in patients with acute ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention. METHODS: We recruited 1005 consecutive patients with STEMI. Multivariable logistic regression analysis was conducted identify the independent risk factors for LVA formation. Predictive power of MHR and composite risk score for LVA formation were assessed using receiver operating characteristic curve analysis. RESULTS: The MHR was significantly higher among patients with LVA compared to those without LVA [6.6 (3.8-10.8) vs. 4.6 (3.3-6.3), P  < 0.001]. Univariable logistic regression analysis revealed that MHR (OR = 3.866, 95% CI = 2.677-5.582, P  < 0.001) was associated with the risk of LVA formation. The predictive value of MHR remained significant even after multivariate logistic regression analysis [odds ratio (OR) = 4.801, 95% confidence interval (CI) = 2.672-8.629, P  < 0.001]. The discriminant power of MHR for LVA is 0.712, which is superior to both monocyte ( C statistic = 0.553) and high-density lipoprotein cholesterol ( C statistic = 0.654). The composite risk score including MHR, gender, LVEF, hemoglobin, lymphocyte and left anterior descending artery as the culprit vessel could significantly increase the predictive ability ( C statistic = 0.920). CONCLUSION: A higher MHR could effectively identify individuals at high risk of LVA formation, especially when combined with gender, LVEF, hemoglobin, lymphocyte and left anterior descending artery as the culprit vessel.

Serum apolipoprotein B to apolipoprotein A-I ratio predicts mortality in patients with heart failure.

AIMS: Apolipoproteins have been reported to be involved in many cardiovascular diseases. The aim of our study was to investigate the prognostic value of apolipoprotein B (ApoB) to apolipoprotein A-I (ApoA-I) ratio (ApoB/ApoA-I) in patients with heart failure (HF). METHODS AND RESULTS: We randomly assigned 2400 HF patients into the training cohort (n = 1400) and the validation cohort (n = 1000). Using a receiver operating characteristic curve, we identified the optimal cut-off value of the ApoB/ApoA-I in the training cohort as 0.69, which was further validated in the validation cohort. A propensity score matching (PSM) analysis was conducted to eliminate the imbalance in the baseline characteristics of the high and low ApoB/ApoA-I group. A total of 2242 HF patients were generated in the PSM cohort. We also validated our results with an independent cohort (n = 838). Univariate and multivariate analyses were conducted to explore the independent prognostic value of ApoB/ApoA-I in the training cohort (n = 1400), the validation cohort (n = 1000), the PSM cohort (n = 2242), and the independent cohort (n = 838). Patients with high ApoB/ApoA-I ratio had significantly poorer prognosis compared with those with low ApoB/ApoA-I ratio in the training cohort, the validation cohort, the PSM cohort, and the independent cohort (P < 0.05). Multivariate analysis indicated that the ApoB/ApoA-I was an independent prognostic factor for HF in the training cohort [hazard ratio (HR) = 1.637, 95% confidence interval (CI) = 1.201-2.231, P = 0.002], the validation cohort (HR = 1.54, 95% CI = 1.051-2.257, P = 0.027), the PSM cohort (HR = 1.645, 95% CI = 1.273-2.125, P < 0.001), and the independent cohort (HR = 1.987, 95% CI = 1.251-3.155, P = 0.004). CONCLUSIONS: Serum ApoB/ApoA-I ratio is an independent predictor for the prognosis of HF patients.

Association between serum albumin to serum creatinine ratio and mortality risk in patients with heart failure.

The aim of this study was to investigate the association between serum albumin to serum creatinine ratio (sACR) and the prognosis of heart failure (HF). In this single-center prospective cohort study, a total of 2625 patients with HF were enrolled between March 2012 and June 2017. All patients were divided into three groups according to the tertiles of sACR. Of 2625 patients, the mean age was 57.0 ± 14.3 years. During a median follow-up time of 23 months, 666 end point events occurred. Prognosis analysis indicated that the lowest sACR was significantly associated with higher mortality risk of HF (hazard ratio [HR] = 1.920, 95% confidence interval [CI] = 1.585-2.326, p < 0.001) when compared with the highest tertile. After adjusting for covariates including age, gender, diabetes, systolic blood pressure (SBP), diastolic blood pressure, heart rate, total cholesterol, triglycerides, HDL-C, LDL-C, white blood cell count, hemoglobin, glycosylated hemoglobin, and ß-blocker use, the HRs for mortality risk of HF was 1.513 (95% CI = 1.070-2.139, p = 0.019). Subgroup analysis indicated that the mortality risk of HF statistically significantly reduced with the rise in sACR in patients with no ß-blocker use, patients with serum creatine less than 97 µmol/L. However, stratification by age, sex, history of hypertension, diabetes, and smoking, level of glycosylated hemoglobin, and albumin have no obvious effect on the association between sACR and the prognosis of HF. Additionally, patients with lower sACR displayed reduced left ventricular ejection fraction and increased left ventricular end-diastolic diameter. The discriminant power of sACR alone and in combination with age, gender, SBP, heart rate, and glycosylated hemoglobin were excellent with C statistic of 0.655 and 0.889, respectively. Lower sACR was an independent risk factor for mortality risk of HF.

Association between MMP2 gene polymorphisms and dilated cardiomyopathy in a Chinese Han population.

AIMS: Dilated cardiomyopathy (DCM) belongs to the common types of cardiomyopathies. The pathogenesis remains unclear despite the fact that various genes have been found associated with DCM. MMP2 is a zinc-dependent and calcium-containing secreted endoproteinases, which could cleave a broad spectrum of substrates including extracellular matrix components and cytokines. It has proved to play an important role in the cardiovascular diseases. This study aimed to investigate the potential role of MMP2 gene polymorphisms in DCM susceptibility and prognosis in a Chinese Han population. METHODS AND RESULTS: A total of 600 idiopathic DCM patients and 700 healthy controls were enrolled. Patients with contact information were followed up for a median period of 28 months. Three tagged single nucleotide polymorphisms (rs243865, rs2285052, and rs2285053) in the promoter of MMP2 gene were genotyped. A series of function analysis were conducted to illuminate the underlying mechanism. The frequency of rs243865-C allele was increased in DCM patients when compared with healthy controls (P = 0.001). Genotypic frequencies of rs243865 were associated with the susceptibility of DCM in the codominant, dominant, and overdominant models (P < 0.05). Besides, rs243865-C allele presented a correlation with the poor prognosis of DCM patients in both dominant (HR = 2.0, 95% confidence interval [CI] = 1.14-3.57, P = 0.017) and additive (HR = 1.85, 95% CI = 1.09-3.13, P = 0.02) model. The statistical significance remained after adjustment for sex, age, hypertension, diabetes, hyperlipidaemia, and smoking status. There were significant differences in left ventricular end-diastolic diameter and left ventricular ejection fraction between rs243865-CC and CT genotypes. Functional analysis indicated that rs243865-C allele increased luciferase activity and the mRNA expression level of MMP2 by facilitating ZNF354C binding. CONCLUSIONS: Our study suggested that MMP2 gene polymorphisms were associated with DCM susceptibility and prognosis in the Chinese Han population.

An eleven autophagy-related genes-based prognostic signature for endometrial carcinoma.

BACKGROUND: Endometrial cancer (EC) is a common malignant tumor in women with increasing mortality. The prognosis of EC is highly heterogeneous which needs more effective biomarkers for clinical decision. Here, we reported the effect of autophagy-related genes (ARGs) on the prognosis of EC. METHODS: The expression data of EC tissues and adjacent non-tumor samples were available from the TCGA dataset and 232 autophagy-related genes were from The Human Autophagy Database. A prognostic ARGs risk model was further constructed by using LASSO-Cox regression, and its prognostic and predictive value were evaluated by nomogram. Further functional analysis was conducted to reveal a significant signaling pathway. RESULTS: A total of 45 differentially expressed ARGs were obtained, including 18 upregulated and 27 downregulated genes. Eleven ARGs (BID, CAPN2, CDKN2A, DLC1, GRID2, IFNG, MYC, NRG3, P4HB, PTK6, and TP73) were finally selected to build ARGs risk. This signature could well distinguish between the high- and low-risk patients (survival analysis: P = 1.18E-10; AUC: 0.733 at 1 year, 0.795 at 3 years, and 0.823 at 5 years). Furthermore, a nomogram was plotting to predict the possibility of overall survival and suggested good value for clinical utility. CONCLUSION: We established an eleven-ARG signature, which was probably effective in the prognostic prediction of patients with EC.

Common variants in Neuraminidases genes contribute to predisposition to and progression of chronic heart failure.

Introduction The role of neuraminidases in cardiovascular disease has recently gained increasing attention. However, the association between neuraminidase gene polymorphisms and heart failure (HF) has not yet been investigated. Methods and Results Genotyping of nine single nucleotide polymorphisms (SNPs) in the NEU2/NEU3/NEU4 genes was performed in 610 HF patients and 600 healthy controls from the Southwest Han Chinese population using TaqMan SNP Genotyping Assay. Individuals carrying the A allele of rs11545301 had decreased risk of HF (additive model: OR=0.704, 95% CI=0.511-0.97; P = 0.032). While the C allele of rs2293763 increased the risk of HF in recessive model (OR=1.486, 95% CI=1.095-2.012; P = 0.011). Rs2233384, rs2233394 and rs2293763 were significantly associated with the mortality risk of HF in dominant model, both with and without adjustment for conventional risk factors (HR= 0.686, 95% CI= 0.52-0.906, P = 0.008 for rs2233384; HR= 1.357, 95% CI= 1.035-1.78, P = 0.027 for rs2233384 and HR= 0.76, 95% CI= 0.592-0.975; P = 0.031 for rs2293763). Conclusion Our findings demonstrated the association between a series of variants in NEU2/NEU4 genes and the risk or prognosis of HF in Han Chinese Population. These data suggested an important role of NEU2 and NEU4 in the pathogenesis of HF.

Transcriptomic and Metabolomic Changes Triggered by Fusarium solani in Common Bean (Phaseolus vulgaris L.).

Common bean (Phaseolus vulgaris L.) is a major legume and is frequently attacked by fungal pathogens, including Fusarium solani f. sp. phaseoli (FSP), which cause Fusarium root rot. FSP substantially reduces common bean yields across the world, including China, but little is known about how common bean plants defend themselves against this fungal pathogen. In the current study, we combined next-generation RNA sequencing and metabolomics techniques to investigate the changes in gene expression and metabolomic processes in common bean infected with FSP. There were 29,722 differentially regulated genes and 300 differentially regulated metabolites between control and infected plants. The combined omics approach revealed that FSP is perceived by PAMP-triggered immunity and effector-triggered immunity. Infected seedlings showed that common bean responded by cell wall modification, ROS generation, and a synergistic hormone-driven defense response. Further analysis showed that FSP induced energy metabolism, nitrogen mobilization, accumulation of sugars, and arginine and proline metabolism. Importantly, metabolic pathways were most significantly enriched, which resulted in increased levels of metabolites that were involved in the plant defense response. A correspondence between the transcript pattern and metabolite profile was observed in the discussed pathways. The combined omics approach enhances our understanding of the less explored pathosystem and will provide clues for the development of common bean cultivars' resistant to FSP.

Immediate and short-term effects of transcatheter device closure of large atrial septal defect in senior people.

OBJECTIVES: We sought to evaluate the safety and efficacy in improving cardiac function and functional capacity with device closure of large atrial septal defects (ASD) in senior adults. BACKGROUND: Atrial septal defect accounts for about 10% of all congenital heart disease. It still remains unclear whether large ASD closure in senior people should be performed or not. Hence we aim to prospectively assess the safety and clinical status of senior patients after transcatheter closure in large ASD. PATIENTS AND INTERVENTIONS: This was a prospective study of all patients aged over 50 years who underwent device closure of a secundum large ASD between January 2013 and January 2018. Investigations including brain natriuretic peptide level, electrocardiography, chest X-ray, transthoracic echocardiogram, transesophageal echocardiogram, and 6-minute walk test were performed before and at 2 days and 4 weeks and 6 months after the procedure. RESULTS: Twenty patients (median age 68 years, 10 women) had transcatheter device closure of large ASD successfully. Median ASD size was 32 mm (range 30-39 mm). Median pulmonary artery pressure was 58 mm Hg (range 47-67 mm Hg). At 6 months, there was a significant change in right atrium size (P < .001) and right ventricle size (P < .01) and left ventricle size (P < .001) and also pulmonary artery pressure (P < .0001), New York Heart Association functional class improved (P = .03) in 19 patients and also significant improvement in 6-minute walk test distance (P < .001). There were no major complications. CONCLUSIONS: Our data showed that large ASD closure at senior people results in satisfactory cardiac remodeling and cardiac function improvement.

The relationship between visfatin and HOMA-IR in hypertensive patients, and the effect of antihypertensive drugs on visfatin and HOMA-IR in hypertensive patients with insulin resistance.

OBJECTIVE: To investigate the correlation between serum visfatin and insulin resistance (IR) in non-diabetic essential hypertensive (EH) patients with and without IR, and to evaluate the effect of antihypertensive treatment on serum visfatin and IR in these patients. METHODS: A total of 81 non-diabetic EH patients, including 54 with IR and 27 without IR, were enrolled. After two weeks wash-out, patients with IR were randomly assigned to telmisartan (group T) or amlodipine (group A) for 6 months. Blood samples were taken before and after treatment for measurement of routine biochemical parameters, visfatin and insulin resistance (measured by HOMA-IR). RESULTS: Visfatin was independently correlated with HOMA-IR (r=0.845, P=0.000). After 6 months of treatment, both drugs lowered HOMA-IR, more significantly so in group T than group A (P=0.010). Serum visfatin levels increased in group T but decreased in group A. CONCLUSION: Serum visfatin levels were higher in non-diabetic EH patients with IR compared with those without IR. Visfatin is independently correlated with HOMA-IR. Telmisartan lowers HOMA-IR to a greater extent than amlodipine. Interestingly, serum visfatin increased with telmisartan yet decreased with amlodipine treatment.