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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.

BackgroundLimited studies have explored the association between sexual factors [age at first sexual intercourse (AFS) and lifetime number of sexual partners (LNSP)] and cardiovascular diseases (CVDs), leaving the causality inconclusive.MethodsWe performed a bi-directional Mendelian randomization (MR) study to investigate the causality between sexual factors and CVDs, including coronary artery disease, myocardial infarction, atrial fibrillation (AF), heart failure (HF), and ischemic stroke (IS). Single-nucleotide polymorphisms (SNPs) for sexual factors were extracted from the UK Biobank. Statistics for each CVD were derived from two different databases. MR estimates were calculated per outcome database and were combined through meta-analysis. Several complementary sensitivity analyses were also performed.ResultsThe primary analysis suggested that AFS was causally associated with the risk of CVDs; the odds ratios (ORs) ranged from 0.686 [95% confidence interval (CI), 0.611–0.770] for HF to 0.798 (95% CI, 0.719–0.886) for AF. However, the association between AFS and IS (OR, 0.844; 95% CI, 0.632–1.126) was not consistent in the meta-analysis after excluding SNPs related to confounders. Moreover, non-significant associations were found between LNSP and CVDs. Reverse direction MR analysis showed that CVDs were not associated with sexual factors.ConclusionsGenetic evidence suggested that AFS was causally associated with the risk of CVDs except for IS, whereas non-significant association of LNSP with CVDs was detected. Further investigation into AFS could be warranted in preventing the progression of CVDs.

Abstract Under certain conditions, cardiovascular implantable electronic devices can be directly involved in initiating and sustaining pacemaker‐mediated arrhythmias (PMA), of which repetitive reentrant ventriculoatrial synchrony (RRVAS) is the most well‐known and common type. RRVAS, also known as pacemaker‐mediated tachycardia, was commonly secondary to atrioventricular (AV) dissociation and subsequent ventriculoatrial (VA) conduction. RRVAS in a biventricular system is rare due to its less predisposition to the appearance of AV dissociation and subsequent VA conduction, but urgent in its adverse impact on cardiac resynchronization therapy (CRT), which may predispose to exacerbated heart failure. We present a rare case of recurrent PMA manifested as a right bundle branch block pattern in a patient with a CRT device. Notably, most episodes of PMA were triggered by a premature atrial contraction accompanied by the appearance of VA conduction with no prolongation of AV delay. In this study, we have demonstrated the impact of the appearance of VA conduction due to the loss of capture of right ventricular lead and its potential risk for inducing RRVAS in a CRT device.

Abstract We previously reported that ibandronate (IBAN) could improve endothelial function in spontaneously hypertensive rats. However, the mechanism by which IBAN improves endothelial function is unclear. The IBAN-induced autophagic process in vitro experiments were determined by detection of LC3, Beclin1, and P62 protein levels via western blotting. The autophagy flux was detected by confocal microscopy and transmission electron microscopy. For in vivo experiments, spontaneously hypertensive rats were orally administered with IBAN. Utilizing angiotensin II (Ang II) to stimulate the human umbilical vein endothelial cells (HUVECs) and human pulmonary microvascular endothelial cells (HPMECs) as a model of endothelial cell injury in hypertension, we found that IBAN promoted autophagy and protected cell viability in Ang II-treated-endothelial cells while these effects could be reversed by autophagy inhibitor. In terms of mechanism, IBAN treatment decreased the levels of Rac1 and mammalian target of rapamycin (mTOR) pathway. Activating either Rac1 or mTOR could reverse IBAN-induced autophagy. Furthermore, the in vivo experiments also indicated that IBAN promotes autophagy by downregulating Rac1-mTOR. Taken together, our results firstly revealed that IBAN enhances autophagy via inhibiting Rac1-mTOR signaling pathway, and thus alleviates Ang II-induced injury in endothelial cells.

Abstract 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.

BackgroundCoronavirus 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.MethodsWe 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.ResultsGenetically 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).ConclusionThis 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.

BackgroundNumerous 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).MethodsIndependent 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.ResultsWe 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.ConclusionThis 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.

Abstract Aims We performed a Mendelian randomization (MR) study to elucidate the associations of ever smoking, lifelong smoking duration, and smoking cessation with heart failure (HF) risk. Methods and results We extracted genetic variants associated with smoking initiation, age at initiation of regular smoking, cigarettes per day, and smoking cessation from the genome‐wide association study and Sequencing Consortium of Alcohol and Nicotine use (1.2 million individuals), as well as a composite lifetime smoking index from the UK Biobank (462 690 individuals). The associations between smoking phenotypes and HF were explored in the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium (47 309 cases; 930 014 controls) employing inverse variance‐weighted meta‐analysis and multivariable MR. The mediation effects of coronary artery disease and atrial fibrillation on smoking–HF risk were explored using mediation analysis. The odds ratios (ORs) for HF were 1.28 [95% confidence interval (CI), 1.22–1.36; P = 1.5 × 10−18] for ever regular smokers compared with never smokers and 1.25 (95% CI, 1.09–1.44; P = 1.6 × 10−3) for current smokers vs. former smokers. Genetic liability to smoking more cigarettes per day (OR, 1.37; 95% CI, 1.20–1.58; P = 6.4 × 10−6) and a higher composite lifetime smoking index (OR, 1.49; 95% CI, 1.31–1.70; P = 2.5 × 10−9) were associated with a higher risk of HF. The results were robust and consistent in all sensitivity analyses and multivariable MR after adjusting for HF risk factors, and their associations were independent of coronary artery disease and atrial fibrillation. Conclusions Genetic liability to ever smoking and a higher lifetime smoking burden are associated with a higher risk of HF.

Background and Aims: Epidemiological studies have suggested positive associations between asthma and the risk of cardiovascular diseases (CVDs). However, causality remains inconclusive. We aim to explore the causal associations between asthma and CVDs risk using the Mendelian Randomization (MR) approach.Methods: We obtained summary-level data for eight CVDs [including atrial fibrillation (AF), coronary artery disease (CAD), heart failure (HF), stroke, ischemic stroke, large artery stroke, small vessel stroke, and cardioembolic stroke] from several large genome-wide association studies (GWASs) and the FinnGen consortium. Nine lead single-nucleotide polymorphisms associated with asthma (p < 5 × 10−8) were identified from the GWAS conducted by the Trans-National Asthma Genetic Consortium. MR analyses were performed using the inverse variance weighted method, supplemented by the weighted median and MR-Egger methods.Results: Inverse variance weighted method showed suggestive effects of genetically determined asthma on AF (odds ratio (OR), 1.08; 95% confidence interval (CI), 1.02, 1.14; p = 0.009) and HF (OR, 1.05; 95% CI, 1.01, 1.09; p = 0.029). We found no causal associations between asthma and other CVDs. No horizontal pleiotropy was observed.Conclusion: This MR study provides genetic evidence suggesting a causal association between asthma and the risk of AF and HF, although not at the level of significance after multiple testing correction. Programs aimed at treating asthma among asthmatics might help prevent the adverse health effects inflicted by CVDs.

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.

Background and AimsObservational epidemiological studies have suggested that atopic dermatitis (AD) was associated with an increased risk of cardiovascular diseases (CVDs). However, causality remains to be established. In the present study, Mendelian randomization (MR) analyses were used to evaluate whether AD and CVDs are causally associated.MethodsThis study was based on summary statistics of genome-wide association studies (GWASs) for a set of cardiovascular outcomes including heart failure (HF), coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), stroke, and stroke subtypes. A total of 19 independent single nucleotide polymorphisms associated with AD were identified at a genome-wide significance threshold (P < 5 × 10−8) based on a large GWAS meta-analysis. MR estimates were pooled using the inverse variance weighted method. Complementary analyses further evaluated the robustness of the results.ResultsGenetically determined AD was causally associated with HF [odds ratio (OR), 1.07; 95% confidence interval (CI), 1.03–1.10; P = 1.11 × 10−4]. However, there was no causal association between AD and the risk of AF, CAD, MI, stroke, and stroke subtypes. Complementary analyses returned similar results. No horizontal pleiotropy was found.ConclusionThis MR study provided evidence to support that AD exerted an effect contributing to HF. No significant associations were found for other cardiovascular outcomes. The study suggested that prevention and early diagnosis of AD may help prevent HF. Improved awareness of these associations is warranted for better management of CVDs in the future.

Abstract Background The causality between the use of alcohol and cigarettes and atrial fibrillation (AF) remains controversial. We conducted a Mendelian randomization (MR) study to evaluate the association of genetic variants related to tobacco and alcohol use with AF. Methods Single nucleotide polymorphisms (SNPs) related to smoking initiation (N = 374), age at initiation of regular smoking (N = 10), cigarettes per day (N = 55), and smoking cessation (N = 24) were derived from a genome-wide association studies (GWAS) of tobacco use (N = 1.2 million individuals). SNPs related to heavy alcohol use (N = 6) were derived from a GWAS of UK biobank (N = 125,249 individuals). The genetically matching instrumented variables were obtained from the GWAS of AF (N = 588,190 individuals). The estimates between tobacco and alcohol use and AF were combined by inverse-variance weighted (IVW), simple median, weighted median, MR-robust adjusted profile score method, MR-PRESSO, and multivariable MR. Results A total of 65,446 AF patients and 522,744 referents were included. In the IVW analysis, the odds ratio per one-unit increase of smoking initiation was 1.11 (95% CI, 1.06–1.16; P = 3.35 × 10−6) for AF. Genetically predicted age at initiation of regular smoking, cigarettes per day and smoking cessation were not associated with AF. The IVW estimate showed that heavy alcohol consumption increased AF risk (OR, 1.11; 95% CI, 1.04–1.18; P = 0.001). The results were consistent in complementary analyses and multivariable MR. Conclusion Our MR study indicated that regular smoking was associated with increased risk of AF, no matter the age at initiation of regular smoking, or the number of cigarettes smoked per day. Genetically predicted heavy alcohol consumption increased the risk of AF.

Abstract A woman with a dual‐chamber pacemaker was examined for recurrent chest discomfort and palpitations at our hospital. The Holter monitor test recorded recurrent episodes of a sudden increase in pacing rate from 60 to 105 bpm, which corresponded to the symptoms. Orthodromic pacemaker‐mediated arrhythmia (OPMA), caused by ventricular lead dislodgement and atrial far‐field sensing, caused the recurrent episodes of a sudden change in pacing rate. The occurrence of OPMA may represent a rare but noteworthy pacemaker problem. To our knowledge, our study reports the first case of PMA that only occurs, and is maintained, in the DDI mode.

BackgroundSeveral 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.MethodsA 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.ResultsIn 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.ConclusionEvidence 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.

Background and Aims: Coffee consumption has been suggested to increase the risk of migraine. However, causality remains inconclusive. In the present study, we performed a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between coffee consumption and migraine.Methods: We obtained nine single-nucleotide polymorphisms (SNPs) associated with coffee consumption at genome-wide significance (p < 5 × 10−8) from a large genome-wide association study (GWAS) based on the UK Biobank study (included 375,833 individuals). Summary-level data for any migraine (AM) and its subtypes (migraine with aura (MA) and migraine without aura (MO)) were obtained from the largest available GWAS of migraine conducted by the International Headache Genetics Consortium (IHGC) (included 59,674 cases and 316,078 controls). MR estimates were pooled using fixed-effect inverse-variance weighted (IVW) as the main method. Sensitivity analyses were further performed using weighted median, MR-Egger, and MR-PRESSO to assess the robustness of our findings.Results: Genetically-predicted 50% increase of coffee consumption was not causally associated with the risk of AM (odds ratio (OR), 0.97; 95% confidence interval (CI), 0.83–1.14; p = 0.71), MA (OR, 0.81; 95%CI, 0.58, 1.12; p = 0.19), or MO (OR, 0.97; 95%CI, 0.72, 1.30; p = 0.83) in the fixed-effect IVW methods. Sensitivity analyses returned similar results. No directional pleiotropy was found.Conclusion: This MR study does not support a causal relationship between genetically predicted coffee consumption and the risk of migraine. Coffee consumption is likely not a trigger nor a prevention strategy for migraine headaches.

Abstract Background Chymase is the major angiotensin II (Ang II)-forming enzyme in cardiovascular tissue, with an important role in atrial remodeling. This study aimed to examine the association between chymase 1 gene (CMA1) polymorphisms and atrial fibrillation (AF) in a Chinese Han population. Methods This case-control study enrolled 126 patients with lone AF and 120 age- and sex-matched healthy controls, all from a Chinese Han population. Five CMA1 polymorphisms were genotyped. Results The CMA1 polymorphism rs1800875 (G-1903A) was associated with AF. The frequency of the GG genotype was significantly higher in AF patients compared with controls (p = 0.009). Haplotype analysis further demonstrated an increased risk of AF associated with the rs1800875-G haplotype (Hap8 TGTTG, odds ratio (OR) = 1.668, 95% CI 1.132–2.458, p = 0.009), and a decreased risk for the rs1800875-A haplotype (Hap5 TATTG, OR = 0.178, 95% CI 0.042–0.749, p = 0.008). Conclusions CMA1 polymorphisms may be associated with AF, and the rs1800875 GG genotype might be a susceptibility factor for AF in the Chinese Han population.

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-β in fibroblasts and attenuated tachypacing-induced oxidative stress including reactive oxygen species (ROS), Tgf-β, 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.

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.

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Background Observational studies have indicated that depression is associated with coronary artery disease (CAD) and myocardial infarction. Nevertheless, causal associations between depression and cardiovascular diseases remain controversial. Hence, we conducted a Mendelian randomization and mediation analysis to evaluate the associations of depression‐related genetic variants with CAD and myocardial infarction. Methods and Results Summary statistics from genome‐wide association studies of depression (807 553 individuals), and CAD (60 801 cases, including 43 676 with myocardial infarction, and 123 504 controls) were used. We pooled Mendelian randomization estimates using a fixed‐effects inverse‐variance weighted meta‐analysis and multivariable Mendelian randomization. The mediation effects of potential cardiovascular risk factors on depression‐CAD and myocardial infarction risk were investigated by using mediation analysis. We also explored the relationship of genetic liability to depression with heart failure, atrial fibrillation, and ischemic stroke. Genetic liability to depression was associated with higher CAD (odds ratio [OR], 1.14; 95% CI, 1.06–1.24; P=1.0×10−3) and myocardial infarction (OR, 1.21; 95% CI, 1.11–1.33; P=4.8×10−5) risks. Results were consistent in all sensitivity analyses. Type 2 diabetes mellitus and smoking demonstrated significant mediation effects. Furthermore, our Mendelian randomization analyses revealed that the genetic liability to depression was associated with higher risks of heart failure and small vessel stroke. Conclusions Genetic liability to depression is associated with higher CAD and myocardial infarction risks, partly mediated by type 2 diabetes mellitus and smoking. The potential preventive value of depression treatment on cardiovascular diseases should be investigated in the future.

Transient potential receptor vanilloid 1 (TRPV1) channels, which are expressed on sensory neurons, elicit cardioprotective effects during ischemia reperfusion injury by stimulating the release of neuropeptides, namely calcitonin gene-related peptide (CGRP) and substance P (SP). Recent studies show that TRPV1 channels are also expressed on cardiomyocytes and can exacerbate air pollutant-induced apoptosis. However, whether these channels present on cardiomyocytes directly modulate cell death and survival pathways during hypoxia/reoxygenation (H/R) injury remains unclear. In the present study, we investigated the role of TRPV1 in H/R induced apoptosis of H9C2 cardiomyocytes. We demonstrated that TRPV1 was indeed expressed in H9C2 cells, and activated by H/R injury. Although neuropeptide release caused by TRPV1 activation on sensory neurons elicits a cardioprotective effect, we found that capsaicin (CAP; a TRPV1 agonist) treatment of H9C2 cells paradoxically enhanced the level of apoptosis by increasing intracellular calcium and mitochondrial superoxide levels, attenuating mitochondrial membrane potential, and inhibiting mitochondrial biogenesis (measured by the expression of ATP synthase β). In contrast, treatment of cells with capsazepine (CPZ; a TRPV1 antagonist) or TRPV1 siRNA attenuated H/R induced-apoptosis. Furthermore, CAP and CPZ treatment revealed a similar effect on cell viability and mitochondrial superoxide production in primary cardiomyocytes. Finally, using both CGRP8–37 (a CGRP receptor antagonist) and RP67580 (a SP receptor antagonist) to exclude the confounding effects of neuropeptides, we confirmed aforementioned detrimental effects as TRPV1−/− mouse hearts exhibited improved cardiac function during ischemia/reperfusion. In summary, direct activation of TRPV1 in myocytes exacerbates H/R-induced apoptosis, likely through calcium overload and associated mitochondrial dysfunction. Our study provides a novel understanding of the role of myocyte TRPV1 channels in ischemia/reperfusion injury that sharply contrasts with its known extracardiac neuronal effects.