The effects of psychiatric disorders on the risk of chronic heart failure: a univariable and multivariable Mendelian randomization study.

Background: Substantial evidence suggests an association between psychiatric disorders and chronic heart failure. However, further investigation is needed to confirm the causal relationship between these psychiatric disorders and chronic heart failure. To address this, we evaluated the potential effects of five psychiatric disorders on chronic heart failure using two-sample Mendelian Randomization (MR). Methods: We selected single nucleotide polymorphisms (SNPs) associated with chronic heart failure and five psychiatric disorders (Attention-Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Major Depression, Bipolar Disorder and Schizophrenia (SCZ)). Univariable (UVMR) and multivariable two-sample Mendelian Randomization (MVMR) were employed to assess causality between these conditions. Ever smoked and alcohol consumption were controlled for mediating effects in the multivariable MR. The inverse variance weighting (IVW) and Wald ratio estimator methods served as the primary analytical methods for estimating potential causal effects. MR-Egger and weighted median analyses were also conducted to validate the results. Sensitivity analyses included the funnel plot, leave-one-out, and MR-Egger intercept tests. Additionally, potential mediators were investigated through risk factor analyses. Results: Genetically predicted heart failure was significantly associated with ADHD (odds ratio (OR), 1.12; 95% CI, 1.04-1.20; p = 0.001), ASD (OR, 1.29; 95% CI, 1.07-1.56; p = 0.008), bipolar disorder (OR, 0.89; 95% CI, 0.83-0.96; p = 0.001), major depression (OR, 1.15; 95% CI, 1.03-1.29; p = 0.015), SCZ (OR, 1.04; 95% CI, 1.00-1.07; p = 0.024). Several risk factors for heart failure are implicated in the above cause-and-effect relationship, including ever smoked and alcohol consumption. Conclusion: Our study demonstrated ADHD, ASD, SCZ and major depression may have a causal relationship with an increased risk of heart failure. In contrast, bipolar disorder was associated with a reduced risk of heart failure, which could potentially be mediated by ever smoked and alcohol consumption. Therefore, prevention strategies for heart failure should also incorporate mental health considerations, and vice versa.

Clinical Profile and Prognosis of Hereditary Transthyretin Amyloid Cardiomyopathy: A Single-Center Study in South China.

Background: Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is a genotypically heterogeneous disorder with a poor prognosis. There is limited literature describing the variants responsible for ATTRv in areas outside the United State, the United Kingdom and Europe. This study was performed to describe the clinical characteristics and genotypic profiles of this disease in South China. Methods: This was a single-center retrospective study that evaluated 29 patients with a confirmed diagnosis of hereditary transthyretin amyloid cardiomyopathy enrolled from January 2016 to November 2021. Results: 93.1% patients were male and the median age of symptom onset was 53 (46, 62.5) years old. The initial manifestations of ATTR-CM were cardiovascular symptoms (55.2%), neuropathy (41.4%) and vitreous opacity (3.4%). Phenotypes at diagnosis were mixed (82.8%), predominant cardiac (6.9%), neurological (6.9%) and ophthalmic (3.4%). Poor R-wave progression (41%), pseudo-infarct (31%) and low-voltage (31%) patterns were common findings on electrocardiogram. Unexplained increased wall thickness was observed in all 29 patients, with mean septal and posterior wall thicknesses of 14.25 ± 6.26 mm and 15.34 ± 2.84 mm, respectively. Diastolic dysfunction was also seen in all 29 patients, and 17 (58%) had a restrictive fill pattern at diagnosis. Nine different missense mutations of the TTR gene were found in 29 patients from 23 families, with c.349G>T (p.Ala117Ser) the most common mutation. The median survival time after diagnosis was 47.6 (95% CI 37.9-57.4) months, with 1, 3 and 5-year survival rates of 91.2%, 74% and 38% respectively. Patients with advanced heart failure (National Amyloidosis Staging stage II/III) had worse survival than stage I [Breslow (Generalized Wilcoxon), χ2 = 4.693, P = 0.03)]. Conclusions: ATTR amyloidosis genotypes and phenotypes are highly heterogeneous. Advanced heart failure predicts a poor prognosis. Understanding the different clinical profiles of ATTR cardiac amyloidosis with different genotype is important to its early recognition.

The Effectiveness and Safety of Tripterygium wilfordii Hook. F Extracts in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

Objective: To conduct a meta-analysis of the effectiveness and safety of Tripterygium wilfordii Hook. F (TwHF) extracts for the treatment of rheumatoid arthritis (RA). Methods: A systematic literature search was conducted in PubMed, EMBASE, Cochrane, Medline, CNKI, SinoMed and WanFang Library till 12 July 2017. All included studies were analyzed with the use of the Review Manager 5.2 software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol. Results: Fourteen randomized controlled trials (RCTs) were identified. TwHF extracts provided a statistically significant improvement in grip strength (GS), swelling joint count (SJC) and morning stiffness (MS) compared with placebo (P < 0.001). The meta-analysis showed significant differences between TwHF extract-treated group and the DMARDs group in GS, MS, C-reactive protein (CRP), and tender joint count (TJC) (P < 0.05), aside from ESR and SJC (P > 0.05). The pooled results also displayed significant differences between the combination of TwHF extracts with DMARDs and the DMARDs alone group in ESR, CRP, SJC, and TJC (P ≤ 0.05). For the safety analysis, two trials favored TwHF extract-treatment and one trial favored non-TWHF extract-treatment in AEs (P < 0.05). Eleven trials showed no statistically significant differences between TwHF extract-treated group and the DMARDs group (P > 0.05). Conclusions: The findings of this systematic review with meta-analysis indicate that TwHF extracts provides statistically significant and clinically important improvement in RA symptoms and has an acceptable safety profile.

MicroRNA-181a, -146a and -146b in spleen CD4+ T lymphocytes play proinflammatory roles in a murine model of asthma.

CD4+ T lymphocytes can be primarily polarized to differentiate into Th2 cells, and are heavily involved in the Th2 inflammation of asthma. Little is known about the correlation between microRNAs and Th2 inflammation in asthma, therefore we explore the roles of five microRNAs (microRNA-181a, -155, -150, -146a and -146b) in Th2 inflammation of asthma by tracking their expression levels in splenic CD4+ T lymphocytes under different conditions. Using quantitative real-time polymerase chain reaction (qPCR), the dynamic changes of these microRNAs in murine models of acute asthma (i.e. the OVA group) were analyzed, in comparison to a control group. The effects of dexamethasone on the miRNA expression levels were also investigated. The results showed that the expression levels of microRNA-181a, -150, -146a and -146b were higher in the OVA group compared to the control group in the beginning of the disease, and after 5days dropped to control group levels because there was no new airway challenge. Moreover, the miRNA-146a expression was down-regulated by treatment with dexamethasone. MicroRNA-181a had a positive linear correlation with the numbers of inflammatory cells (i.e. the numbers of total cells or of the eosinophils in the BALF) by Spearman correlation analysis, so did miRNA-146a and miRNA-146b. These observations suggest that microRNA-181a, -146a and -146b are proinflammatory factors in asthma, and that down-regulation of miRNA-146a may partially account for the anti-inflammatory effect of dexamethasone.

[Effect of STAT5 gene silencing on the proliferation of T lymphocytes in a mouse model of asthma].

OBJECTIVE: To study the effect of silencing STAT5 gene on the proliferation of T lymphocytes in a mouse model of asthma. METHODS: Spleen T-lymphocytes of normal and asthmatic mice were selected by immunomagnetic beads, and the STAT5a/b genes of these T-lymphocytes were silenced by siRNA. The mRNA of STAT5a/b was detected by fluorescence quantitative PCR, and the protein by Western blot. The proliferation rates of T-lymphocytes was evaluated by CCK-8, and the cell cycle and the cell apoptosis was measured by flow cytometry. RESULTS: (1) Significant inflammatory cell infiltration was present in asthmatic mouse airways, as compared to the normal control mice. (2) The STAT5a/b mRNA expression of the asthmatic group was significantly higher compared with the normal control group. (3) Compared to the blank control group, the mRNA expression of STAT5a/b was reduced in the siRNA-specific intervention (T: 35.014 vs 14.553, P < 0.01). The protein expression of STAT5a/b was also reduced after siRNA-specific intervention (T: -10.958 vs -14.706, P < 0.01). The proliferation rates of T lymphocytes was reduced after siRNA-specific intervention (T: 8.692 vs 10.540, P < 0.01), and the number of T-lymphocytes in proliferative phase was all significantly reduced after siRNA-specific intervention (T: 6.975 vs -5.567, P < 0.05). The apoptosis rates of T lymphocytes were significantly increased after siRNA-specific intervention (T: -6.404 vs -6.038, P < 0.05). CONCLUSION: RNA interference specifically reduced the expression of STAT5a/b, inhibited the proliferation of T lymphocytes, and promoted the apoptosis of T lymphocytes in a mouse model of asthma.

shRNA targeting ß1-integrin suppressed proliferative aspects and migratory properties of airway smooth muscle cells.

Dysfunction of airway smooth muscle (ASM) is an essential feature of airway remodeling in chronic asthma. However, the precise mechanisms of this pathological process have not been well studied. In previous study, we found that ß1-integrin, which was dramatically upregulated in ASM cells in an asthmatic mouse model, was associated with the cell proliferation. In this study, we employed short hairpin RNA (shRNA) targeting ß1-integrin to assess the effect of down-regulation of this receptor on the proliferative aspects and migratory properties of ASM cells in vitro. The cells were treated with shRNA expression vectors directed against ß1-integrin, control vectors that included the blank control, empty vector without shRNA, and mismatched shRNA, respectively. The mRNA and protein expressions of ß1-integrin were determined by real-time PCR and Western blotting. Cell proliferation was measured by BrdU ELISA and cell cycle by fluorescence-activated cell sorter. Cell apoptosis was detected by Annexin V-PE/7-AAD staining. Cell migration assays were evaluated by transwell assay and expression of IL-6 and IL-8 by ELISA. The results revealed that shRNA targeting ß1-integrin significantly decreased the mRNA and protein expressions of ß1-integrin, enhanced the proportion of cells in G0/G1 phase, decreased the proportion in S phase, promoted cell apoptosis, inhibited cell proliferation, migration, IL-6 and IL-8 secretion in vitro. In conclusion, the overexpression of ß1-integrin in ASM cells is essential for airway dysfunction development because it promotes proliferative aspects and migratory properties of ASM cells. Importantly, shRNA targeting ß1-integrin may provide a new approach to preventing airway remodeling in chronic asthma.