A Mendelian randomization study to assess the genetic liability of gastroesophageal reflux disease for cardiovascular diseases and risk factors.

Observational studies have reported that gastroesophageal reflux disease (GERD) is a risk factor for cardiovascular diseases (CVD); however, the causal inferences between them remain unknown. We conducted a Mendelian randomization (MR) study to estimate the causal associations between GERD and 10 CVD outcomes, as well as 14 cardiovascular risk factors. We used summary statistics from genome-wide association studies for GERD and the FinnGen consortium for CVD. We further investigated whether GERD correlated with cardiovascular risk factors and performed multivariable MR and mediation analyses to estimate the mediating effects of these risk factors on GERD-CVD progression. Sensitivity analyses and replication analyses were also performed. Our results indicated that GERD was positively associated with seven CVD outcomes with odds ratios of 1.26 [95% confidence interval (CI), 1.15, 1.37] for coronary artery disease, 1.41 (95% CI, 1.28, 1.57) for myocardial infarction, 1.34 (95% CI, 1.19, 1.51) for atrial fibrillation, 1.34 (95% CI, 1.21, 1.50) for heart failure, 1.30 (95% CI, 1.18, 1.43) for any stroke, 1.19 (95% CI, 1.06, 1.34) for ischemic stroke and 1.29 (95% CI, 1.16, 1.44) for venous thromboembolism. Furthermore, GERD was associated with nine cardiovascular risk factors and major depressive disorder demonstrated significant mediation effects on the causal pathway linking GERD and any stroke. This study demonstrates that GERD is associated with seven CVD outcomes and nine cardiovascular risk factors. Importantly, GERD treatment may help prevent common CVD events.

Resveratrol protects against doxorubicin-induced cardiotoxicity by attenuating ferroptosis through modulating the MAPK signaling pathway.

Doxorubicin (Dox) is a widely used antitumor agent with dose-dependent and cumulative cardiotoxic effects. Resveratrol (Res) is a natural non-flavonoid polyphenol that can potentially provide cardiovascular benefits. We aimed to estimate the protective effect of Res on Dox-induced cardiotoxicity (DIC) and explore whether it was related to attenuating ferroptosis. We established DIC models in C57BL/6 J mice, H9C2 cardiomyoblasts, and neonatal rat cardiomyocytes (NRCMs). We further treated H9C2 cells with RSL3, a ferroptosis agonist, to investigate whether Res exerted protective effects through inhibiting ferroptosis. Ferrostatin-1 (Fer-1) was applied to suppress ferroptosis. Dox treatment caused cardiac dysfunction and resulted in apparent ferroptotic damage in cardiac tissue, involving increased iron accumulation, glutathione depletion, increased expression of ferroptosis-related proteins, and decreased expression of glutathione peroxidase 4, which were alleviated by Fer-1 and Res administration. These findings were also confirmed in Dox-treated H9C2 cells and NRCMs, with Fer-1 and Res effectively attenuating Dox-induced cytotoxicity and ferroptosis. Furthermore, Res protected H9C2 cells from RSL3-induced ferroptotic cell death, and the protective effect was similar to that of Fer-1. Both Dox and RSL3 treatment increased the phosphorylation levels of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinases; however, these changes were hindered by Res. This study demonstrates that Res effectively alleviates DIC by suppressing ferroptosis possibly through modulating the MAPK signaling pathway. Our results highlight that targeting ferroptosis can be a potential cardioprotective strategy for DIC.

High expression of VTA1 is an adverse prognostic factor in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a common pathological type of non-small cell lung cancer; identifying preferable biomarkers has become one of the current challenges. Given that VTA1 has been reported associated with tumor progression in various human solid cancers but rarely reported in LUAD, herein, RNA sequencing data from TCGA and GTEx were obtained for analysis of VTA1 expression and differentially expressed gene (DEG). Furthermore, functional enrichment analysis of VTA1-related DEGs was performed by GO/KEGG, GSEA, immune cell infiltration analysis, and protein-protein interaction (PPI) network. In addition, the clinical significance of VTA1 in LUAD was figured out by Kaplan-Meier Cox regression and prognostic nomogram model. R package was used to analyze incorporated studies. As a result, VTA1 was highly expressed in various malignancies, including LUAD, compared with normal samples. Moreover, high expression of VTA1 was associated with poor prognosis in 533 LUAD samples, as well as T stage T2&T3&T4, N stage N1&N2&N3, M stage M1, pathologic stage II&III&IV, and residual tumor R1&R2, et al. (P < 0.05). High VTA1 was an independent prognostic factor in Cox regression analysis; Age and cytogenetics risk were included in the nomogram prognostic model. Furthermore, a total of 4232 DEGs were identified between the high- and the low-expression group, of which 736 genes were up-regulated and 3496 genes were down-regulated. Collectively, high expression of VTA1 is a potential biomarker for adverse outcomes in LUAD. The DEGs and pathways recognized in the study provide a preliminary grasp of the underlying molecular mechanisms of LUAD carcinogenesis and progression.

Genetically predicted visceral adipose tissue and risk of nine non-tumour gastrointestinal diseases: evidence from a Mendelian randomization study.

BACKGROUND: Numerous studies have linked visceral adipose tissue (VAT) to gastrointestinal diseases. However, it remains unclear whether these associations reflect causal relationships. METHODS: We used a two-sample Mendelian randomization (MR) approach to elucidate the causal effect of VAT on nine non-tumour gastrointestinal diseases. The inverse-variance weighted method was used to perform the MR analyses. Complementary and multivariable MR analyses were performed to confirm the results. RESULTS: Genetically predicted higher VAT was associated with an increased risk of gastro-oesophageal reflux disease (GORD) (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.09-1.34; P = 3.06 × 10-4), duodenal ulcer (DU) (OR, 1.40; 95% CI, 1.10-1.77; P = 0.005), cholelithiasis (OR, 1.75; 95% CI, 1.53-2.00; P = 1.14 × 10-16), and non-alcoholic fatty liver disease (NAFLD) (OR, 2.68; 95% CI, 1.87-3.82; P = 6.26 × 10-8). There were suggestive associations between VAT and gastric ulcer (GU) (OR, 1.22; 95% CI, 1.01-1.48; P = 0.035) and acute pancreatitis (AP) (OR, 1.26; 95% CI, 1.05-1.52; P = 0.013). However, there was little evidence to support the associations between VAT and inflammatory bowel disease, irritable bowel syndrome, or chronic pancreatitis. The associations with GORD, GU, and NAFLD remained in the multivariable MR analyses with adjustment for body mass index (BMI). CONCLUSIONS: This study provided evidence in support of causal associations between VAT and GORD, GU, DU, cholelithiasis, AP, and NAFLD. Moreover, the associations between GORD, GU, and NAFLD were independent of the effect of BMI.

Elevated HMGB1 and sRAGE levels in cerebrospinal fluid of aneurysmal subarachnoid hemorrhage patients.

BACKGROUND: Neuroinflammation after aneurysmal subarachnoid hemorrhage (aSAH) leads to poor outcome of patients. High mobility group box 1 (HMGB1) contributes to inflammation through binding to receptors for advanced glycation end-products (RAGE) in various diseases. We aimed to determine the production of these two factors after aSAH and their relationship with clinical features. METHODS: HMGB1 and soluble RAGE (sRAGE) levels in cerebrospinal fluid (CSF) of aSAH patients and controls were measured, and their temporal courses were observed. The correlation between early concentrations (days 1-3) and clinical symptoms assessed by disease severity scores, neuroinflammation estimated by CSF IL-6 levels, as well as prognosis evidenced by delayed cerebral ischemia (DCI) and 6-month adverse outcome was investigated. Finally, combined analysis of early levels for predicting prognosis was confirmed. RESULTS: CSF HMGB1 and sRAGE levels were higher in aSAH patients than in controls (P < 0.05), and the levels decreased from higher early to lower over time. Their early concentrations were positively associated with disease severity scores, IL-6 levels, DCI and 6-month poor outcome (P < 0.05). HMGB1 ≥ 6045.5 pg/ml (OR = 14.291, P = 0.046) and sRAGE ≥ 572.0 pg/ml (OR = 13.988, P = 0.043) emerged as independent predictors for DCI, while HMGB1 ≥ 5163.2 pg/ml (OR = 7.483, P = 0.043) and sRAGE ≥ 537.3 pg/ml (OR = 12.653, P = 0.042) were predictors for 6-month poor outcome. Combined analysis of them improved predictive values of adverse prognosis. CONCLUSION: CSF HMGB1 and sRAGE levels of aSAH patients were increased early and then varied dynamically, which might act as potential biomarkers for poor outcome, especially when co-analyzed.

No causal association between plasma homocysteine levels and atrial fibrillation: A Mendelian randomization study.

BACKGROUND AND AIMS: Although several studies have shown an association between plasma homocysteine (Hcy) levels and atrial fibrillation (AF), the causality remains unclear. We undertook a Mendelian randomization (MR) study to investigate the causal association between Hcy and AF. METHODS AND RESULTS: Single-nucleotide polymorphisms (SNPs) which genome-wide significantly associated with plasma Hcy levels were obtained from a genome-wide meta-analysis (N = 44 147). MR analyses including the random-effect inverse variance-weighted (IVW) meta-analysis, weighted median analysis, and MR-Egger regression were used to estimate the associations between the selected SNPs and AF based on a meta-analysis of genome-wide association study for AF (N = 588 190). The MR analyses revealed no causal role of genetically elevated plasma Hcy levels with AF risk (random-effect IVW, odds ratio per 1 SD increase in Hcy levels = 0.972, 95% confidence interval = 0.919 to 1.027, P = 0.308). The results were consistent with the weighted median method, MR-Egger and the analysis after excluding the pleiotropic SNPs. No heterogeneity and directional pleiotropy were observed in sensitivity analyses. CONCLUSION: The findings suggested that plasma Hcy levels were not causally associated with AF.

Haematoma scavenging in intracerebral haemorrhage: from mechanisms to the clinic.

The products of erythrocyte lyses, haemoglobin (Hb) and haem, are recognized as neurotoxins and the main contributors to delayed cerebral oedema and tissue damage after intracerebral haemorrhage (ICH). Finding a means to efficiently promote absorption of the haemolytic products (Hb and haem) around the bleeding area in the brain through stimulating the function of the body's own garbage cleaning system is a novel clinical challenge and critical for functional recovery after ICH. In this review, available information of the brain injury mechanisms underlying ICH and endogenous haematoma scavenging system is provided. Meanwhile, potential intervention strategies are discussed. Intracerebral blood itself has 'toxic' effects beyond its volume effect after ICH. Haptoglobin-Hb-CD163 as well as haemopexin-haem-LRP1 is believed to be the most important endogenous scavenging pathway which participates in blood components resolution following ICH. PPARγ-Nrf2 activates the aforementioned clearance pathway and then accelerates haematoma clearance. Meanwhile, the scavenger receptors as novel targets for therapeutic interventions to treat ICH are also highlighted.

Early elevated levels of soluble triggering receptor expressed on myeloid cells-1 in subarachnoid hemorrhage patients.

Early brain injury (EBI) contributes to poor prognosis of subarachnoid hemorrhage (SAH). This study aimed to clarify whether triggering receptor expressed on myeloid cells-1 (TREM-1) was implicated in the inflammatory mechanisms of EBI. The cerebrospinal fluid (CSF) levels of soluble TREM-1 (sTREM-1), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) as well as plasma levels of white blood cells (WBC) count and C-reactive protein in 17 SAH patients at early stage (within the EBI period) and 9 volunteers were observed. Also World Federation of Neurosurgical Societies (WFNS) scale of SAH patients was calculated on admission. Compared to controls, increased CSF levels of sTREM-1 (t = 5.66, P < 0.001), TNF-α (t = 5.41, P < 0.001) and IL-6 (t = 2.98, P = 0.007) as well as elevated plasma WBC counts (t = 7.61, P < 0.001) and C-reactive protein levels (t = 3.91, P = 0.001) were found in SAH patients. Considering the increased WBC counts in SAH group, covariate analysis was also performed when comparing patients' sTREM-1 levels with respect to controls and no obvious difference was found (F = 0.982, P = 0.332). For SAH group, early CSF concentrations of sTREM-1 were correlated with those of both TNF-α (r = 0.582, P = 0.014) and IL-6 (r = 0.593, P = 0.012). Also the CSF sTREM-1 levels were positively correlated with WBC counts (r = 0.629, P = 0.007) and C-reactive protein levels (r = 0.804, P < 0.001) as well as WFNS scale (r = 0.835, P < 0.001). This study showed an early increased sTREM-1 CSF level in SAH patients, which correlated with inflammation intensity post-SAH and clinical severity, indicating that TREM-1 may participate in the inflammatory mechanisms of EBI.

Incidence and survival of lacunar infarction in a southern Chinese population: A 7-year prospective study.

OBJECTIVE: Little attention has been paid to the epidemiological characteristics of lacunar infarction (LAC) in China before. This study aimed to examine the incidence and survival of LAC in a southern Chinese population. METHODS: From 2004-2010 in Changsha, two communities with a registered population of ∼100 000 were selected and data from first-ever ischaemic stroke (IS) cases were prospectively collected. Then the epidemiological characteristics of LAC and non-LAC were evaluated. RESULTS: During the study period, the age-standardized incidence increased at an annual rate of 0.7% (p < 0.001) for LAC and 2.0% (p < 0.001) for non-LAC. The mean annual age-standardized incidence of LAC and non-LAC was 28.2/100 000 and 45.0/100 000, respectively. Compared with non-LAC patients, the prevalence of hypertension, diabetes and hyperlipidemia was significantly higher in patients with LAC (p < 0.05). Although the 30-day fatality rate was significantly lower in patients with LAC than non-LAC (0.5% vs. 14.9%, p < 0.001), there was no significant difference in survival between the two groups (96.7% vs. 95.2%, p = 0.203) after excluding the patients who died within 1 year of stroke onset. CONCLUSION: LAC is a common stroke sub-type in southern China and the long-term prognosis is not benign.

Radiofrequency ablation using the ThermoCool SmartTouch Catheter guided by ablation index versus antiarrhythmic drugs in atrial fibrillation treatment in China: a cost-consequence analysis.

Aim: To evaluate the costs and consequences of two front-line atrial fibrillation (AF) treatments from Chinese healthcare system perspective: radiofrequency catheter ablation (RFCA) using ThermoCool SmartTouch Catheter guided by Ablation Index (STAI), in comparison to antiarrhythmic drugs (AADs). Patients & methods: We simulated clinical and economic consequences for AF patients initially receiving STAI or AADs using a short-term decision tree model leading to a 10-year long-term Markov model. The model projected both clinical consequences and costs associated with, among others, AF, heart failure (HF), strokes, and deaths due to AF or AF related complications. Data informing the models included combination of a local real-world study and published clinical studies. Results: STAI was advantageous versus AADs on all 4 main clinical outcomes evaluated; AF: 25.83% lower (12.84% vs 38.67%), HF: 2.22% lower (1.33% vs 3.55%), stroke or post stroke: 1.82% lower (10.00% vs 11.82%) and deaths due to AF or AF related complications: 0.64% lower (4.11% vs 4.75%). The average total cost per patient in STAI group was ¥16,682 lower (¥123,124 vs ¥139,806). The one-way sensitivity analysis indicated that the difference in total cost was most sensitive to annual AF recurrence probability in AADs-treated patients. Probabilistic sensitivity analysis indicated a 98.5% probability that RFCA treatment would result in cost savings by the end of the 10th year. Conclusion: Radiofrequency catheter ablation using SmartTouch catheter guided by Ablation Index was superior to AADs as the first-line AF treatment in Chinese setting with better clinical outcomes and at lower costs over a 10-year time horizon.

Public and professional education on urgent therapy for acute ischemic stroke: a community-based intervention in Changsha.

Excessive delay of presentation for stroke in China is reported. In this study, an intervention trial was conducted to promote urgent therapy for acute ischemic stroke. Two communities in Changsha were selected as either intervention or control community from November 2007 to December 2011. Public and professional education was regularly implemented in the intervention community. Publics' knowledge about early identification and urgent therapy of ischemic stroke was surveyed before and after intervention in the two communities. During the intervention period, first-ever ischemic stroke cases occurring in the intervention community (intervention group) and that in the control community (control group) were collected and followed for 90 days. After intervention, the publics' knowledge levels in the intervention community improved significantly. Intervention group' average presentation time was shorter than control group (8.3 ± 5.8 vs. 10.5 ± 6.5 h, P = 0.018). Percentage of presentation time within 3 h (48.0 %), the rate of ambulance use (59.0 %), and thrombolytic therapy (9.3 %) in the intervention group was all obviously higher than that in the control group (21.5, 41.3, and 4.5, respectively). When admitted, the intervention group had lower mean systolic blood pressure (160.8 ± 26.7 vs. 164.7 ± 26.8 mmHg, P = 0.000) than control group. Survivors in the intervention group were more likely to be in higher Barthel index scoring groups than that in the control group at day 90 [(75, 50-100) vs. (65, 35-90), P = 0.035]. Public and professional education may promote prompt presentation and urgent therapy for ischemic stroke, which may be helpful for patients' prognosis.

Self-Reported Walking Pace and Risk of Cardiovascular Diseases: A Two-Sample Mendelian Randomization Study.

Background: In observational studies, the self-reported walking pace has been associated with the risk of cardiovascular diseases (CVD). However, whether those associations indicate causal links remains unclear. We performed two-sample Mendelian randomization (MR) analyses to evaluate the causal effect of walking pace on several CVD outcomes, including atrial fibrillation (AF), heart failure (HF), any stroke, ischemic stroke (IS), and IS subtypes. Methods: Genetic variants associated with self-reported walking pace were selected as instrumental variables (IVs) from the latest genome-wide association studies (GWAS). Summary-level data for outcomes were obtained from the corresponding GWAS and the FinnGen consortium. The random-effects inverse variance weighted (IVW) method was used as the main MR analysis, supplemented by replication analyses using data from the FinnGen. To explore the effect of pleiotropy due to adiposity-related traits, we further conducted MR analyses by excluding the adiposity-related IVs and regression-based multivariable MR adjusting for body mass index (BMI). Results: The MR results indicated significant inverse associations of self-reported walking pace with risks of AF [odds ratio (OR), 0.577; 95% confidence interval (CI), 0.442, 0.755; p = 5.87 × 10-5], HF (OR, 0.307; 95% CI, 0.229, 0.413; p = 5.31 × 10-15), any stroke (OR, 0.540; 95% CI, 0.388, 0.752; p = 2.63 × 10-4) and IS (OR, 0.604; 95% CI, 0.427, 0.853; p = 0.004) and suggestive inverse association of self-reported walking pace with cardioembolic stroke (CES) (OR, 0.492; 95% CI, 0.259, 0.934; p = 0.030). Similar results were replicated in the FinnGen consortium and persisted in the meta-analysis. However, there was no causality between walking pace and large artery stroke (OR, 0.676; 95% CI, 0.319, 1.434; p = 0.308) or small vessel stroke (OR, 0.603; 95% CI, 0.270, 1.349; p = 0.218). When excluding adiposity-related IVs and adjusting for BMI, the associations for HF and any stroke did not change substantially, whereas the associations for AF, IS, and CES were weakened. Conclusion: Our findings suggested that genetically predicted increasing walking pace exerted beneficial effects on AF, HF, any stroke, IS, and CES. Adiposity might partially mediate the effect of walking pace on AF, IS, and CES.

Circulating α-Klotho Levels in Relation to Cardiovascular Diseases: A Mendelian Randomization Study.

Background: Several studies have reported a protective role of circulating α-Klotho on cardiovascular diseases (CVD); however, the causality remains unclear. We aim to elucidate whether genetically predicted circulating α-Klotho levels were causally associated with the risk of coronary artery disease (CAD), atrial fibrillation (AF), heart failure (HF), stroke, ischemic stroke (IS), and IS subtypes. Methods: A two-sample Mendelian randomization (MR) study was designed, with 5 single-nucleotide polymorphisms associated with circulating α-Klotho levels utilized as instrumental variables. MR estimates on each CVD outcome derived from the fixed-effects inverse-variance weighted (IVW) approach in different data sources were combined by the fixed-effects meta-analysis approach, complemented by several sensitivity analyses including the simple median, the weighed median, MR-Egger regression, and MR-pleiotropy residual sum and outlier. Results: In the meta-analysis combining different data sources, suggestive inverse causal association of circulating α-Klotho concentrations with CAD [Odds ratio (OR), 0.97; 95% confidence interval (CI), 0.94, 1.00; P = 0.044] and significant inverse association of circulating α-Klotho concentrations with AF (OR, 0.96; 95% CI, 0.93, 0.99; P = 0.005) was observed. However, there was no causal association of α-Klotho with HF, any stroke, IS, or IS subtypes neither in different data sources nor in the meta-analysis. Complementary sensitivity analyses showed consistent and robust results in general. Conclusion: Evidence was found for a protective effect of circulating α-Klotho on the prevention of AF risk. However, no significant causal association between genetically predicted circulating α-Klotho levels and risk of CAD, HF, stroke, IS, or IS subtypes was found.

No causal effect of tea consumption on cardiovascular diseases: A two-sample Mendelian randomization study.

Background: Numerous studies have been conducted to investigate the relationship between tea consumption and the risk of cardiovascular diseases (CVD); however, no conclusive results have been achieved. We conducted a Mendelian randomization (MR) study to elucidate the causal associations between tea consumption and several CVD outcomes, including coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF). Methods: Independent single-nucleotide polymorphisms (SNPs) genome-wide significantly associated with tea consumption were used as instrumental variables (IVs). Summary statistics for CVD outcomes were obtained from the corresponding genetic consortia and the FinnGen consortium. The inverse-variance weighted (IVW) method was the primary analytical method, and MR estimates from different data sources were combined using fixed-effects meta-analysis. Supplementary MR analyses, including the weighted median, MR-Egger, and the MR pleiotropy residual sum and outlier methods, were conducted to evaluate the robustness of the results. Further MR analyses were repeated by including more genetic variants at a higher P-value threshold. Results: We found that genetically predicted tea consumption was not causally associated with any CVD outcomes in the IVW method using data from large genetic consortia [CAD: odds ratio (OR) = 1.00, 95% confidence interval (CI), 0.91, 1.10, P = 0.997; MI: OR = 0.98, 95% CI, 0.90, 1.08, P = 0.751; AF: OR = 0.97, 95% CI, 0.92, 1.03, P = 0.350; HF: OR = 0.96, 95% CI, 0.88, 1.05, P = 0.401] or the FinnGen consortium (CAD: OR = 1.06, 95% CI, 0.96, 1.17, P = 0.225; MI: OR = 1.01, 95% CI, 0.89, 1.15, P = 0.882; AF: OR = 1.00, 95% CI, 0.88, 1.14, P = 0.994; HF: OR = 0.96, 95% CI, 0.88, 1.04, P = 0.362). The results were robust and consistent across meta-analysis, supplementary MR analyses, and analyses with more IVs included. Conclusion: This MR study revealed no causal association between tea consumption and four CVD outcomes, suggesting that tea consumption may not be beneficial for the primary prevention of CVD.

Obstructive sleep apnea and atrial fibrillation: insights from a bidirectional Mendelian randomization study.

BACKGROUND: Observational studies have suggested that obstructive sleep apnea (OSA) is in relation to atrial fibrillation (AF); however, these studies might be confounded and whether the relationship is causal remains unclear. We conducted a bidirectional Mendelian randomization (MR) study to clarify the causal inference between OSA and AF. METHODS: Genetic instruments for OSA and AF were obtained from genome-wide association studies. The fixed-effects inverse-variance weighted (IVW) method was used as the main method, supplemented by several sensitivity analyses. For replication, another AF dataset was used to validate the causal effect of OSA on AF. Furthermore, multivariable MR analyses were performed to obtain direct estimates adjusting for potential confounders. RESULTS: Genetic liability to OSA was found to be significantly associated with a higher AF risk in the fixed-effects IVW method [odds ratio (OR) 1.210; 95% CI 1.119-1.307; P = 1.51 × 10-6]. The results were consistent in MR sensitivity analyses as well as in replication analyses, and the significance remained after adjusting for potential confounders. In the reverse MR analyses, there was no causal effect of AF on OSA. CONCLUSIONS: Our study strengthened the causal evidence of genetically predicted OSA with a higher AF risk. Early screening and appropriate management of OSA might show anti-arrhythmic benefits.

Cardiac Troponin I and Risk of Stroke: A Mendelian Randomization Study.

PURPOSE: Cardiac troponin I (cTnI) is a well-established biomarker for stroke prediction, especially in patients with heart diseases. However, the causal effect of circulating cTnI on stroke remains unclear. METHODS: We employed Mendelian Randomization (MR) analysis to determine the associations between genetically predicted circulating cTnI levels and stroke and its subtypes. Summary-level data for exposure and outcomes were generated from different genome-wide association studies. Single-nucleotide polymorphisms (SNPs) associated with circulating cTnI at genome-wide significance level (P < 5 × 10-8) were employed as instrumental variables (IVs). We used fixed-effect inverse-variance weighted (IVW) as the main method for pooling MR estimates. Sensitivity analyses and multivariable MR analyses were carried out to assess the robustness of the results. RESULTS: Using the fixed-effects IVW method, we found that genetically elevated plasma cTnI levels may have a causal effect on the risk of cardioembolic stroke (CES) (odds ratio (OR), 1.58; 95% confidence interval (CI), 1.17-2.13; P = 0.003). Additional analyses including multiplicative random-effects (mre) IVW, weighted median, MR-Egger and MR-PRESSO yielded similar results, but with broader CIs that span 1.0. The total effect of cTnI on CES was attenuated by adjusting for the effect of atrial fibrillation (OR,1.26; 95% CI, 0.76-2.11; P = 0.371) and smoking (OR,1.53; 95% CI, 0.87-2.66; P = 0.137). In addition, we found no causal effect of cTnI on the risk of any stroke and other stroke subtypes, including any ischemic stroke, large artery stroke, cardioembolic stroke, small vessel stroke, and intracerebral hemorrhage. These results were consistent across sensitivity analyses. CONCLUSION: This study provides little evidence that increased serum cTnI levels lead to a higher risk of stroke.

Visceral adipose tissue and risk of COVID-19 susceptibility, hospitalization, and severity: A Mendelian randomization study.

Background: Coronavirus Disease 2019 (COVID-19) has rapidly evolved as a global pandemic. Observational studies found that visceral adipose tissue (VAT) increased the likelihood of worse clinical outcomes in COVID-19 patients. Whereas, whether VAT is causally associated with the susceptibility, hospitalization, or severity of COVID-19 remains unconfirmed. We aimed to investigate the causal associations between VAT and susceptibility, hospitalization, and severity of COVID-19. Methods: We applied a two-sample Mendelian randomization (MR) study to infer causal associations between VAT and COVID-19 outcomes. Single-nucleotide polymorphisms significantly associated with VAT were derived from a large-scale genome-wide association study. The random-effects inverse-variance weighted method was used as the main MR approach, complemented by three other MR methods. Additional sensitivity analyses were also performed. Results: Genetically predicted higher VAT mass was causally associated with higher risks of COVID-19 susceptibility [odds ratios (ORs) = 1.13; 95% confidence interval (CI), 1.09-1.17; P = 4.37 × 10-12], hospitalization (OR = 1.51; 95% CI = 1.38-1.65; P = 4.14 × 10-20), and severity (OR = 1.58; 95% CI = 1.38-1.82; P = 7.34 × 10-11). Conclusion: This study provided genetic evidence that higher VAT mass was causally associated with higher risks of susceptibility, hospitalization, and severity of COVID-19. VAT can be a useful tool for risk assessment in the general population and COVID-19 patients, as well as an important prevention target.

Aerobic Glycolysis Induced by mTOR/HIF-1α Promotes Early Brain Injury After Subarachnoid Hemorrhage via Activating M1 Microglia.

M1 microglial activation is crucial for the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH), and there is growing evidence that glucose metabolism is frequently involved in microglial activation. However, the molecular mechanism of glycolysis and its role in M1 microglial activation in the context of EBI are not yet fully understood. In this study, firstly, the relationship between aerobic glycolysis and M1 microglial activation as well as SAH-induced EBI was researched in vivo. Then, intervention on mammalian target of rapamycin (mTOR) was performed to investigate the effects on glycolysis-dependent M1 microglial activation and EBI and its relationship with hypoxia-inducible factor-1α (HIF-1α) in vivo. Next, Hif-1α was inhibited to analyze its role in aerobic glycolysis, M1 microglial activation, and EBI in vivo. Lastly, both in vivo and in vitro, mTOR inhibition and Hif-1α enhancement were administered simultaneously, and the combined effects were further confirmed again. The results showed that aerobic glycolysis and M1 microglial polarization were increased after SAH, and glycolytic inhibition could attenuate M1 microglial activation and EBI. Inhibition of mTOR reduced glycolysis-dependent M1 microglial polarization and EBI severity by down-regulating HIF-1α expression, while enhancement had the opposite effects. Blockading HIF-1α had the similar effects as suppressing mTOR, while HIF-1α agonist worked against mTOR antagonist when administered simultaneously. In conclusion, the present study showed new evidence that aerobic glycolysis induced by mTOR/HIF-1α might promote EBI after SAH by activating M1 microglia. This finding provided new insights for the treatment of EBI.

Fibroblast Growth Factor 21 Protects Against Atrial Remodeling via Reducing Oxidative Stress.

Aim: The structural and electrical changes in the atrium, also known as atrial remodeling, are the main characteristics of atrial fibrillation (AF). Fibroblast growth factor 21 (Fgf21) is an important endocrine factor, which has been shown to play an important role in cardiovascular diseases. However, the effects of Fgf21 on atrial remodeling have not been addressed yet. The purpose of the present study is to evaluate the effects of Fgf21 on atrial remodeling. Methods and Results: Adult mice were treated with Ang II, and randomly administrated with or without Fgf21 for 2 weeks. The susceptibility to AF was assessed by electrical stimulation and optical mapping techniques. Here, we found that Fgf21 administration attenuated the inducibility of atrial fibrillation/atrial tachycardia (AF/AT), improved epicardial conduction velocity in the mice atria. Mechanistically, Fgf21 protected against atrial fibrosis and reduced oxidative stress of the atria. Consistently, in vitro study also demonstrated that Fgf21 blocked the upregulation of collagen by Tgf-ß in fibroblasts and attenuated tachypacing-induced oxidative stress including reactive oxygen species (ROS), Tgf-ß, and ox-CaMKII in atrial myocytes. We further found that Fgf21 attenuated oxidative stress by inducing antioxidant genes, such as SOD2 and UCP3. Fgf21 also improved tachypacing-induced myofibril degradation, downregulation of L-type calcium channel, and upregulation of p-RyR2, which implicated protective effects of Fgf21 on structural and electrical remodeling in the atria. Moreover, Nrf2 was identified as a downstream of Fgf21 and partly mediated Fgf21-induced antioxidant gene expression in atrial myocytes. Conclusion: Fgf21 administration effectively suppressed atrial remodeling by reducing oxidative stress, which provides a novel therapeutic insight for AF.

Association of Autism Spectrum Disorder, Neuroticism, and Subjective Well-Being With Cardiovascular Diseases: A Two-Sample Mendelian Randomization Study.

Background: Previous observational studies have reported an association between psychiatric traits and cardiovascular diseases (CVDs). In this two-sample Mendelian randomization (MR) study, we aimed to investigate the causality between psychiatric traits and CVDs. Methods: Single-nucleotide polymorphisms (SNPs) associated with autism spectrum disorder (ASD), neuroticism, and subjective well-being at genome-wide significance (P < 1 × 10-8) were identified from genome-wide association studies. Summary-level data of the outcomes, including coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF), were obtained from several largest datasets. The inverse-variance weighted (IVW) method was used as our main analyses to conduct this MR study. Sensitivity analyses included the weighted median, the MR-robust adjusted profile score (MR-RAPS), and the MR pleiotropy residual sum and outlier (MR-PRESSO) method. Repeated MR analyses using a more relaxed threshold (P < 1 × 10-6) for instruments selection and multivariable MR analyses were also applied to evaluate the robustness of results. Results: The MR analyses showed that genetic predisposition to ASD was associated with a higher risk of AF [odds ratio (OR), 1.109; 95% confidence interval (CI), 1.023-1.201; P = 0.011] and HF (OR, 1.138; 95% CI, 1.036-1.251; P = 0.007). Neuroticism was casually associated with an increased risk of AF (OR, 1.201; 95% CI, 1.037-1.392; P = 0.015), whereas subjective well-being had a protective effect on HF (OR, 0.732; 95% CI, 0.574-0.933; P = 0.012). No other causal association between psychiatric traits and CVDs was observed. Consistent results were obtained in sensitivity analyses. Conclusion: This study provided evidence of causal associations of ASD with a higher risk of AF and HF. Besides, neuroticism was casually associated with an increased risk of AF, and subjective well-being was associated with a decreased risk of HF.