Risk prediction in pulmonary hypertension due to chronic heart failure: incremental prognostic value of pulmonary hemodynamics.

BACKGROUND: There is no generally accepted comprehensive risk prediction model cooperating risk factors associated with heart failure and pulmonary hemodynamics for patients with pulmonary hypertension due to left heart disease (PH-LHD). We aimed to explore outcome correlates and evaluate incremental prognostic value of pulmonary hemodynamics for risk prediction in PH-LHD. METHODS: Consecutive patients with chronic heart failure undergoing right heart catheterization were prospectively enrolled. The primary endpoint was all-cause mortality. Individual variable selection was performed by machine learning methods. Cox proportional hazards models were conducted to identify the association between variables and mortality. Incremental value of hemodynamics was evaluated based on the Seattle heart failure model (SHFM) and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) scores. RESULTS: A total of 276 PH-LHD patients were enrolled, with a median follow-up time of 34.7 months. By L1-penalized regression model and random forest approach, diastolic pressure gradient (DPG) and mixed venous oxygen saturation (SvO2) were the hemodynamic predictors most strongly associated with mortality (coefficient: 0.0255 and -0.0176, respectively), with consistent significance after adjusted for SHFM [DPG: HR 1.067, 95% CI 1.024-1.113, P = 0.022; SvO2: HR 0.969, 95% CI 0.953-0.985, P = 0.002] or MAGGIC (DPG: HR 1.069, 95% CI 1.026-1.114, P = 0.011; SvO2: HR 0.970, 95% CI 0.954-0.986, P = 0.004) scores. The inclusion of DPG and SvO2 improved risk prediction compared with using SHFM [net classification improvement (NRI): 0.468 (0.161-0.752); integrated discriminatory index (IDI): 0.092 (0.035-0.171); likelihood ratio test: P < 0.001] or MAGGIC [NRI: 0.298 (0.106-0.615); IDI: 0.084 (0.033-0.151); likelihood ratio: P < 0.001] scores alone. CONCLUSION: In PH-LHD, pulmonary hemodynamics can provide incremental prognostic value for risk prediction. CLINICAL TRIAL REGISTRATION: NCT02164526 at https://clinicaltrials.gov .

Integrated analysis of genome-wide miRNAs and targeted gene expression in esophageal squamous cell carcinoma (ESCC) and relation to prognosis.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer death worldwide and in China. We know miRNAs influence gene expression in tumorigenesis, but it is unclear how miRNAs affect gene expression or influence survival at the genome-wide level in ESCC. METHODS: We performed miRNA and mRNA expression arrays in 113 ESCC cases with tumor/normal matched tissues to identify dysregulated miRNAs, to correlate miRNA and mRNA expressions, and to relate miRNA and mRNA expression changes to survival and clinical characteristics. RESULTS: Thirty-nine miRNAs were identified whose tumor/normal tissue expression ratios showed dysregulation (28 down- and 11 up-regulated by at least two-fold with P < 1.92E-04), including several not previously reported in ESCC (miR-885-5p, miR-140-3p, miR-708, miR-639, miR-596). Expressions of 16 miRNAs were highly correlated with expressions of 195 genes (P < 8.42E-09; absolute rho values 0.51-0.64). Increased expressions of miRNA in tumor tissue for both miR-30e* and miR-124 were associated with increased survival (P < 0.05). Similarly, nine probes in eight of 818 dysregulated genes had RNA expression levels that were nominally associated with survival, including NF1, ASXL1, HSPA4, TGOLN2, BAIAP2, EZH2, CHAF1A, SUPT7L. CONCLUSIONS: Our characterization and integrated analysis of genome-wide miRNA and gene expression in ESCC provides insights into the expression of miRNAs and their relation to regulation of RNA targets in ESCC tumorigenesis, and suggest opportunities for the future development of miRs and mRNAs as biomarkers for early detection, diagnosis, and prognosis in ESCC.

Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: pooled results from two Chinese genome-wide association studies.

OBJECTIVE: Although several genome-wide association studies (GWAS) of non-cardia gastric cancer have been published, more novel association signals could be exploited by combining individual studies together, which will further elucidate the genetic susceptibility of non-cardia gastric cancer. DESIGN: We conducted a meta-analysis of two published Chinese GWAS studies (2031 non-cardia gastric cancer cases and 4970 cancer-free controls) and followed by genotyping of additional 3564 cases and 4637 controls in two stages. RESULTS: The overall meta-analysis revealed two new association signals. The first was a novel locus at 5q14.3 and marked by rs7712641 (per-allele OR=0.84, 95% CI 0.80 to 0.88; p=1.21×10-11). This single-nucleotide polymorphism (SNP) marker maps to the intron of the long non-coding RNA, lnc-POLR3G-4 (XLOC_004464), which we observed has lower expression in non-cardia gastric tumour compared with matched normal tissue (Pwilcoxon signed-rank=7.20×10-4). We also identified a new signal at the 1q22 locus, rs80142782 (per-allele OR=0.62; 95% CI 0.56 to 0.69; p=1.71×10-19), which was independent of the previously reported SNP at the same locus, rs4072037 (per-allele OR=0.74; 95% CI 0.69 to 0.79; p=6.28×10-17). Analysis of the new SNP conditioned on the known SNP showed that the new SNP remained genome-wide significant (Pconditional=3.47×10-8). Interestingly, rs80142782 has a minor allele frequency of 0.05 in East Asians but is monomorphic in both European and African populations. CONCLUSION: These findings add new evidence for inherited genetic susceptibility to non-cardia gastric cancer and provide further clues to its aetiology in the Han Chinese population.

Gastric microbiota features associated with cancer risk factors and clinical outcomes: A pilot study in gastric cardia cancer patients from Shanxi, China.

Little is known about the link between gastric microbiota and the epidemiology of gastric cancer. In order to determine the epidemiologic and clinical relevance of gastric microbiota, we used 16 S ribosomal RNA gene sequencing analysis to characterize the composition and structure of the gastric microbial community of 80 paired samples (non-malignant and matched tumor tissues) from gastric cardia adenocarcinoma (GCA) patients in Shanxi, China. We also used PICRUSt to predict microbial functional profiles. Compared to patients without family history of upper gastrointestinal (UGI) cancer in the non-malignant gastric tissue microbiota, patients with family history of UGI cancer had higher Helicobacter pylori (Hp) relative abundance (median: 0.83 vs. 0.38, p = 0.01) and lower alpha diversity (median observed species: 51 vs. 85, p = 0.01). Patients with higher (vs. lower) tumor grade had higher Hp relative abundance (0.73 vs. 0.18, p = 0.03), lower alpha diversity (observed species, 66 vs. 89, p = 0.01), altered beta diversity (weighted UniFrac, p = 0.002) and significant alterations in relative abundance of five KEGG functional modules in non-malignant gastric tissue microbiota. Patients without metastases had higher relative abundance of Lactobacillales than patients with metastases (0.05 vs. 0.01, p = 0.04) in non-malignant gastric tissue microbiota. These associations were observed in non-malignant tissues but not in tumor tissues. In conclusion, this study showed a link of gastric microbiota to a major gastric cancer risk factor and clinical features in GCA patients from Shanxi, China. Studies with both healthy controls and gastric cardia and noncardia cancer cases across different populations are needed to further examine the association between gastric cancer and the microbiota.

Immune Cell Repertoire and Their Mediators in Patients with Acute Myocardial Infarction or Stable Angina Pectoris.

Background: To evaluate the natural innate and adaptive immunity through gene expression and cytology levels in peripheral blood mononuclear cells in patients with acute myocardial infarction (AMI), stable angina pectoris (SAP) and controls. Methods: 210 patients with AMI, 210 with SAP, and 250 clinical controls were recruited. Whole human genome microarray analysis was performed in 20 randomly chosen subjects per group were examined to detect the expressions of complement markers, natural killer cells, T cells and B cells. The quantity of these cells and related cytokines as well as immunoglobulin levels were measured in all subjects. Results: In AMI group, the mRNA expressions of late complement component, markers of natural killer cells, CD3+, CD8+ T cells and B cells were down-regulated, while those of early complement component and CD4+T cells were up-regulated (p<0.05). In both AMI and SAP patients, the quantity of natural killer cells, CD3+, CD8+ T cells, B cells, IgM and IgG were significantly lower than those of the controls. CD4+ T cells, CH50, C3, C4, IL-2, IL-4, IL-6 and IFN-γ were significantly higher (p<0.05). Conclusions: In AMI patients, both of gene expressions related to complement, natural killer cells, CD3+, CD8+ T cells, B cells and the quantity of these immune cells decreased while cell number reduced in SAP patients. Immune function in both AMI and SAP patients decreased especially in AMI patients with declined gene and protein levels. To improve the immune system is a potential target for medical interventions and prevention in AMI.

Integrative genomics analysis of genes with biallelic loss and its relation to the expression of mRNA and micro-RNA in esophageal squamous cell carcinoma.

BACKGROUND: Genomic instability plays an important role in human cancers. We previously characterized genomic instability in esophageal squamous cell carcinomas (ESCC) in terms of loss of heterozygosity (LOH) and copy number (CN) changes in tumors. In the current study we focus on biallelic loss and its relation to expression of mRNA and miRNA in ESCC using results from 500 K SNP, mRNA, and miRNA arrays in 30 cases from a high-risk region of China. RESULTS: (i) Biallelic loss was uncommon but when it occurred it exhibited a consistent pattern: only 77 genes (<0.5%) showed biallelic loss in at least 10% of ESCC samples, but nearly all of these genes were concentrated on just four chromosomal arms (i.e., 42 genes on 3p, 14 genes on 9p, 10 genes on 5q, and seven genes on 4p). (ii) Biallelic loss was associated with lower mRNA expression: 52 of the 77 genes also had RNA expression data, and 41 (79%) showed lower expression levels in cases with biallelic loss compared to those without. (iii) The relation of biallelic loss to miRNA expression was less clear but appeared to favor higher miRNA levels: of 60 miRNA-target gene pairs, 34 pairs (57%) had higher miRNA expression with biallelic loss than without, while 26 pairs (43%) had lower miRNA expression. (iv) Finally, the effect of biallelic loss on the relation between miRNA and mRNA expression was complex. Biallelic loss was most commonly associated with a pattern of elevated miRNA and reduced mRNA (43%), but a pattern of both reduced miRNA and mRNA was also common (35%). CONCLUSION: Our results indicate that biallelic loss in ESCC is uncommon, but when it occurs it is localized to a few specific chromosome regions and is associated with reduced mRNA expression of affected genes. The effect of biallelic loss on miRNA expression and on the relation between miRNA and mRNA expressions was complex.

Association between circulating levels of sex steroid hormones and Barrett's esophagus in men: a case-control analysis.

BACKGROUND & AIMS: Esophageal adenocarcinoma is believed to result from the progression of gastroesophageal reflux disease to erosive esophagitis and re-epithelialization of the esophagus with a columnar cell population termed Barrett's esophagus (BE). Men develop BE and esophageal adenocarcinoma more frequently than women, yet little is known about the mechanisms of this difference. We assessed whether sex steroid hormones were associated with BE in a male population. METHODS: We analyzed data from the Barrett's Esophagus Early Detection Case Control Study, based at the Walter Reed National Military Medical Center. Blood samples were collected from 174 men with BE and 213 men without BE (controls, based on endoscopic analysis); 13 sex steroid hormones were measured by mass spectrometry and sex hormone binding globulin was measured by enzyme-linked immunosorbent assay. We also calculated free estradiol, free testosterone, and free dihydrotestosterone (DHT). We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age, race, smoking status, alcohol consumption, body mass index, heartburn, regurgitation, and gastroesophageal symptom score (excluding heartburn and regurgitation). RESULTS: Levels of free testosterone and free DHT were associated positively with BE risk; patients in the highest quartile for these hormones were most likely to have BE (free testosterone: OR, 5.36; 95% CI, 2.21-13.03; P = .0002; free DHT: OR, 4.25; 95% CI, 1.87-9.66; P = .001). Level of estrone sulfate was associated inversely with BE risk (P for trend = .02). No other hormone was associated with BE risk. Relationships were not modified by age or BMI. CONCLUSIONS: In an analysis of men, levels of free testosterone and free DHT were significantly associated with BE.

Increased Expressions of Integrin Subunit ß1, ß2 and ß3 in Patients with Acute Infection.

OBJECTIVE: Our previous studies have shown that integrin subunits ß1, ß2 and ß3 were the core proteins of venous thrombi and potential useful biomarker of venous thromboembolism (VTE). Patients with acute infection have a high risk of VTE. In this study we explored that is there any relevance between core proteins and acute infection. METHODS: A total of 230 patients (112 females) with clinically proven acute infection in the emergency unit were recruited into this study, meanwhile 230 patients without acute infection matched in sex and age were recruited as control group. Flow cytometry was done to measure the expressions of blood integrin ß1, ß2, ß3 and cellular immunity (CD3, CD4, CD8, CD4/CD8, CD16CD56 and CD19). The association degree between increased core proteins and acute infection was analyzed by calculating the relative risk (RR). RESULTS: The expression of integrin ß1, ß2 and ß3 was markedly increased in patients with acute infection (P=0.000, 0.000 and 0.015, respectively). The relative risk ratio (RR) of increased integrin ß1, ß2 and ß3 in acute infection patients was 1.424 (95%CI: 1.156-1.755, P=0.001), 1.535 (95%CI: 1.263-1.865, P=0.000) and 1.20 (95%CI: 0.947-1.521, P=0.148), respectively. Combined integrin ß1, ß2 and ß3 analysis showed that the relative risk ratio (RR) of increased in patients with acute infection was 2.962 (95%CI: 1.621-5.410, P=0.001), and this relative risk (RR) rise to 3.176 (95%CI: 1.730-5.829, P=0.000) in patients with respiratory tract infection (RTI). CONCLUSION: As the core proteins of venous thrombi, integrinß1, ß2 and ß3 were markedly increased expression in patients with acute infection, which maybe explain the increased risk of VTE in acute infection patients. A weakened immune system could be the basic condition of VTE occurrence.

Efficiency and safety of pulmonary rehabilitation in acute exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: Pulmonary rehabilitation (PR) is able to improve dyspnea, endurance capacity, and health-related quality of life in chronic obstructive pulmonary disease (COPD) patients, but it is rarely used in China. This study aimed to assess the effectiveness and safety of PR after exacerbation of COPD. MATERIAL AND METHODS: Patients admitted to hospital due to an exacerbation of COPD were randomized to receive either PR or routine care (control group). The PR program was performed from the second day of admission until discharge. The pre-post changes in 6-minute walk distance (6MWD), self-reported quality of life (QOL) assessed by CAT score and CRQ-SAS score, and activity of daily life assessed by ADL-D score were determined. The perceived end-effort dyspnea (Borg scale) was measured throughout the study. RESULTS: A total of 101 patients were enrolled, of whom 7 withdrew after randomization, and 94 completed this study. There were 66 patients in the PR group and 28 in the control group. The 6MWD, resting SpO2, and exercise Borg dyspnea score were significantly improved in the PR group. In addition, the PR group had greater improvement in the total CRQ-SAS score and had a lower CAT score. Significant improvements were also found in the ADL-D and BODE index in the PR group. No adverse events were recorded during exercise. CONCLUSIONS: Our study provides evidence that it is safe and feasible to apply an early PR in patients with acute exacerbation of COPD.

Genetic variants in fas signaling pathway genes and risk of gastric cancer.

Populations in north central China are at high risk for gastric cancers (GC), and altered FAS-mediated cell signaling and/or apoptosis may contribute to this risk. We examined the association of 554 single nucleotide polymorphisms (SNPs) in 53 Fas signaling-related genes using a pathway-based approach in 1758 GC cases (1126 gastric cardia adenocarcinomas (GCA) and 632 gastric noncardia adenocarcinomas (GNCA)), and 2111 controls from a genome-wide association study (GWAS) of GC in ethnic Chinese. SNP associations with risk of overall GC, GCA and GNCA were evaluated using unconditional logistic regressions controlling for age, sex and study. Gene- and pathway-based associations were tested using the adaptive rank-truncated product (ARTP) method. Statistical significance was evaluated empirically by permutation. Significant pathway-based associations were observed for Fas signaling with risk of overall GC (p = 5.5E-04) and GCA (p = 6.3E-03), but not GNCA (p= 8.1E-02). Among examined genes in the Fas signaling pathway, MAP2K4, FAF1, MAPK8, CASP10, CASP8, CFLAR, MAP2K1, CAP8AP2, PAK2 and IKBKB were associated with risk of GC (nominal p < 0.05), and FAF1 and MAPK8 were significantly associated with risk of both GCA and GNCA (nominal p< 0.05). Our examination of genetic variation in the Fas signaling pathway is consistent with an association of altered Fas signaling and/or apoptosis with risk of GC. As one of the first attempts to investigate a pathway-level association, our results suggest that these genes and the Fas signaling pathway warrant further evaluation in relation to GC risk in other populations.

Internet abusers associate with a depressive state but not a depressive trait.

AIM: The present study investigated three issues: (i) whether Internet abusers display a depressive state without a depressive trait; (ii) which symptoms are shared between Internet abuse and depression; and (iii) which personality characteristics were shown in Internet abusers. METHODS: Ninety-nine male and 58 female participants aged 18-24 years were screened with the Chen Internet Addiction Scale. After screening, subjects were separated into the high- (n = 73) and low-risk (n = 84) Internet abuser groups. Participants were respectively administered the Chinese version of the Beck Depression Inventory-II to assess a depressive state and the Minnesota Multiphasic Personality Inventory-2 to assess a depressive trait. RESULTS: The present results showed that high-risk Internet abusers exhibited a stronger depressive state than low-risk Internet abusers in the Beck Depression Inventory-II. However, high-risk Internet abusers didnot show a depressive trait in the Minnesota Multiphasic Personality Inventory-2 compared to low-risk Internet abusers. Therefore, high-risk Internet abuse participants exhibited a depressive state without a depressive trait. CONCLUSIONS: In a comparison of the symptoms of depression and Internet abuse, it was found that high-risk Internet abuse participants shared some common behavioral mechanisms with depression, including the psychiatric symptoms of loss of interest, aggressive behavior, depressive mood, and guilty feelings. High-risk Internet abuse participants may be more susceptible to a temporal depressive state but not a permanent depressive trait. The present findings have clinical implications for the prevention and treatment of Internet abuse.

Enzyme and Pathway Engineering for Improved Betanin Production in Saccharomyces cerevisiae.

Betanin is a water-soluble red-violet pigment belonging to the betacyanins family. It has become more and more attractive for its natural food colorant properties and health benefits. However, the commercial production of betanin, typically extracted from red beetroot, faces economic and sustainability challenges. Microbial heterologous production therefore offers a promising alternative. Here, we performed combinatorial engineering of plant P450 enzymes and precursor metabolisms to improve the de novo production of betanin in Saccharomyces cerevisiae. Semirational design by computer simulation and molecular docking was used to improve the catalytic activity of CYP76AD. Alanine substitution and site-directed saturation mutants were screened, with a combination mutant showing an approximately 7-fold increase in betanin titer compared to the wild type. Subsequently, betanin production was improved by enhancing the l-tyrosine pathway flux and UDP-glucose supply. Finally, after optimization of the fermentation process, the engineered strain BEW10 produced 134.1 mg/L of betanin from sucrose, achieving the highest reported titer of betanin in a shake flask by microbes. This work shows the P450 enzyme and metabolic engineering strategies for the efficient microbial production of natural complex products.

Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma.

In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single-nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations.

Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population.

The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P = 6.37 × 10(-4)), but not with GC (P = 0.20). The most significant gene in ESCC was CHEK2 (P = 2.00 × 10(-6)) and in GC was CLK2 (P = 3.02 × 10(-4)). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.

Consistency evaluation of exercise target heart rate determined by resting heart rate and anaerobic threshold in chronic heart failure patients.

PURPOSE: To evaluate the consistency on the target heart rate for exercise determined by simple target heart rate (sTHR) based on resting heart rate (HRrest) and heart rate at anaerobic threshold (HRAT) in cardiopulmonary exercise test (CPET) for patients with chronic heart failure. METHODS: This is a retrospective cohort study, in which CHF patients who underwent CPET in Tongji Hospital Cardiac Rehabilitation Center Affiliated to Tongji University from March 2007 to December 2018 were enrolled. The clinical data of the patients from the electronic medical record system, HRrest and HRAT measured by CPET were collected. Patients were further divided into subgroups according to gender, age (<60 years group and ≥ 60 years group), with or without beta-blocker therapy and subgroup of heart failure (heart failure with reduced, mid-range and preserved ejection fraction). The sTHR (HRrest plus 10, 15, 20, 25 and 30 bpm) and HRAT were all calculated in each patient. Paired t-test was used for the difference between the two methods, correlation analysis was shown by pearson analysis and intraclass correlation coefficient (ICC) was calculated for consistency test. RESULTS: A total of 547 CHF patients were enrolled, including 447 males (81.7%), aged 63 (56,69) years, with BMI of 25.2 (23.5,26.4) kg/m2 and LVEF of 45.0 (36.0, 52.0) %. The target heart rate determined by HRAT method was (93.59 ± 13.95) bpm, and its counterpart determined by HRrest plus 20 bpm (HRrest+20) was (93.16 ± 7.69) bpm. There was no significant difference between the two methods (P>0.05). However, it was statistically different between HRrest plus 10, 15, 25, 30 bpm and HRAT respectively (P<0.001). And HRrest+20 was positively correlated with HRAT (r = 0.418, P<0.001). Therefore, HRrest+20 below was regarded as sTHR. The ICC of the consistency test between sTHR and HRAT was 0.523,95%CI 0.435-0.596 (P < 0.001) in all patients (n = 547). In patients with beta-blocker therapy (n = 464), the ICC of sTHR and HRAT consistency test was 0.534,95%CI 0.441-0.612, P < 0.001; The ICC of the consistency test between sTHR and HRAT of patients without beta-blocker therapy (n = 83) was 0.407,95%CI 0.083-0.616, P < 0.05. In the sinus rhythm group (n = 466), the ICC of sTHR and HRAT consistency test was 0.527,95%CI 0.433-0.606, P < 0.001; The ICC of the consistency test between sTHR and HRAT of atrial fibrillation patients in group (n = 81) was 0.482,95%CI 0.195-0.667, P < 0.05.The ICC of the consistency test between sTHR and HRAT was 0.501,95%CI 0.338-0.623 (P < 0.001) in patients under 60 years old (n = 195); The ICC of the consistency test between sTHR and HRAT in patients ≥60 years old (n = 352) was 0.533,95%CI 0.424-0.621, P < 0.001. In the male group (n = 447), the ICC of sTHR and HRAT consistency test was 0.577,95%CI 0.491-0.649, P < 0.001; The ICC of the consistency test between sTHR and HRAT of female patients in group (n = 100) was 0.344,95%CI 0.025-0.559, P < 0.05. The ICC of sTHR and HRAT consistency test in HFrEF group (n = 170) was 0.395,95%CI 0.181-0.553, P < 0.01; The ICC values of the consistency test between sTHR and HRAT was 0.543, 95%CI 0.405-0.649 (P < 0.001) in patients with HFmrEF (n = 222); In HFpEF group (n = 155), the ICC of sTHR and HRAT consistency test was 0.620,95%CI 0.478-0.723, P < 0.001. CONCLUSION: The exercise target heart rate calculated by HRrest is consistent with that determined by HRAT in patients with CHF. For primary hospitals without CPET, exercise prescription equivalent to AT intensity for patients with CHF can be determined by HRrest. However, the target heart rate calculated by HRrest can't replace that determined by HRAT in this patient cohort completely.

Symptomatic venous thromboembolism is a disease related to infection and immune dysfunction.

The characteristics of human genomics and cellular immune function between clinically symptomatic venous thromboembolism (VTE) and controls were systematically compared to explore the immunologic pathogenesis of VTE. Microarray assay showed the mRNA expressions of genes related to non-specific cellarer immune and cytokines were significantly down-regulated. Abnormal expressions of CD3+, CD4+, CD8+, NK marker CD16+56+, CD19 and aberrant CD4+/CD8+ ratio were detected in 54 among 56 patients. In PE patients, microarray assay revealed the imbalance in the expressions of genes related to the immune system. The expressions of genes related to non-specific immune cells and cytokines were markedly up-regulated and those associated with cellular immune were dramatically down-regulated. In VTE patients, cytological examination indicated the functions of NK cells were significantly compromised, and the antigen recognition and killing function of T cells markedly decreased. The consistence between genomic and cytological examination suggests the symptomatic VTE is closely associated with the infection and immune dysfunction.

Analysis on the pathogenesis of symptomatic pulmonary embolism with human genomics.

BACKGROUND: In the present study, the whole human genome oligo microarray was employed to investigate the gene expression profile in symptomatic pulmonary embolism (PE). METHODS: Twenty patients with PE and 20 age and gender matched patients without PE as controls were enrolled into the present study in the same period. The diagnosis of PE was based on the clinical manifestations and findings on imaging examinations. Acute arterial and/or venous thrombosis was excluded in controls. The whole human genome oligo microarray was employed for detection. Statistical analysis was performed with t test following analysis of very small samples of repeated measurements and Gene Ontology (GO) analysis. RESULTS: Genomic data showed no damage to vascular endothelial cells in PE patients. Genomic data only found increased mRNA expression of a small amount of coagulation factors in PE patients. In the PE group, anticoagulant proteins, Fibrinolytic system and proteins related to platelet functions only played partial roles in the pathogenesis of PE. In addition, the mRNA expressions of a fraction of adhesion molecules were markedly up-regulated. Gene Ontology analysis showed the genes with down-regulated expressions mainly explain the compromised T cell immunity. Symptomatic VTE patients have compromised T cell immunity. CONCLUSION: The damage to vascular endothelial cells is not necessary in the pathogenesis of VTE, and only a fraction of factors involved in the shared coagulation cascade are activated. Genomic results may provide a new clue for clinical diagnosis, treatment and prevention of VTE.

[The expression of T cell immune-related gene mRNAs in peripheral blood mononuclear cells from patients with venous thromboembolism].

OBJECTIVE: To explore the role of T cell-mediated immunity in the pathogenesis of venous thromboembolism (VTE) by analyzing the differential expression of T cell immune-related gene mRNAs peripheral blood mononuclear cells (PBMCs) between VTE patients and controls with GeneChip Human Genome. METHODS: Human cDNA microarray analysis was employed in PBMCs from 20 VTE patients and 20 hypertensive controls, and random variant model (RVM) corrected t-test was used for statistical analysis of differential gene expression. RESULTS: Six mRNA stripes including CD(247), CD(3D), CD(3G), Granzyme A (GzmA), Granzyme B (GzmB) and Zeta-chain-associated protein kinase 70 (ZAP70) were found to be associated with T cell-mediated immunity. Significant down-regulation of these six mRNAs was found in the VTE group compared with the controls (15.3050 ± 0.6346 vs 15.8053 ± 0.5567, 13.7878 ± 0.7731 vs 14.3820 ± 0.4857, 13.3299 ± 0.9104 vs 14.1246 ± 0.6011, 14.8893 ± 0.8675 vs 15.5305 ± 0.4624, 15.9113 ± 0.8123 vs 16.4553 ± 0.5055, 14.3652 ± 0.7717 vs 14.3652 ± 0.7717; all P values < 0.05). CONCLUSIONS: T cells' function including antigen recognition, signal transduction and cytotoxicity was impaired in VTE patients. T cell-mediated immunity dysfunction probably plays an important role in the pathogenesis of VTE.

[The expression of interferon associated genes mRNA in patients with pulmonary embolism].

OBJECTIVE: To investigate the gene expression difference of IFN and their receptors in peripheral blood mononuclear cells (PBMC) of pulmonary embolism (PE) patients. METHODS: Twenty cases of PE patients and twenty sex and age matched controls were recruited into the study. Human cDNA microarray analysis was used to detect the gene expression difference of IFN associated genes between the two groups, and random variance model corrected t test was used to analyze the statistical data. RESULTS: In comparison with the control group, mRNA expression of type I IFN, including IFNα(5) mRNA, IFNα(6) mRNA, IFNα(8) mRNA, IFNα(14) mRNA, IFNκ mRNA, IFNω(1) mRNA, IFNε(1) mRNA in PBMC of PE patients were down-regulated (P < 0.05). There was no significant difference in gene expression of type I IFN receptors IFNαR(1) and IFNαR(2) between the PE and control groups (P > 0.05). In comparison with the control group, mRNA expression of IFNγ gene was down-regulated (P < 0.05). The mRNA expression of IFNγR(1) and IFNγR(2) genes were upregulated compared with the control (P > 0.05). CONCLUSION: mRNA expression of type I and type II IFN in PE are significantly down-regulated, but not the IFN receptors. Reduced immune function may play an important role in the PE patients who are susceptible to virus, intracellular bacteria and parasites.

The High Expression of Adhering and Circulating Integrin Serves as a Diagnostic Marker in Venous Thromboembolism.

Objective: To investigate the diagnostic value of circulating integrins ß1, 2, and 3 in venous thrombosis (VTE). Materials and Methods: A total of 474 VTE patients and 306 patients with nonhigh risk for VTE as the control group were studied. Levels of adhering integrins ß1, 2, and 3 were detected by flow cytometry. Levels of circulating integrins ß1, 2, and 3 in serum were measured by enzyme-linked immunosorbent assay. Results: We found that integrins ß1, 2, and 3 were expressed highly both in serum and on the surface of leukocytes and platelets in venous thromboembolism. The levels of circulating integrins ß1, 2, and 3 are positively correlated with adhering integrins. It showed excellent clinical diagnostic performance of circulating integrins ß1, 2, and 3 in venous thromboembolism. Conclusions: Integrin subunit ß can be used as a diagnostic marker with high sensitivity and specificity for venous thromboembolism.