Background: While observational studies have established a connection between attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and heightened risk for cardiovascular diseases (CVD), the causal relationships are not well-defined. This study is designed to examine the causality between ASD, ADHD, and CVD risk as well as investigate the mediating factors through which ADHD and ASD influence CVD. Methods and Results: Leveraging two-sample Mendelian randomization (MR) approaches and large scale GWAS summary stats, we examined underlying causal links between ASD and ADHD and the risk of CVDs. The analysis indicated that ADHD was related to an increased likelihood of developing coronary heart disease (OR [95% CI] 1.12 [1.03, 1.21], p = .008), heart failure (OR [95% CI] 1.14 [1.07, 1.22], p = 1.45 × 10⁻⁴), and large-artery stroke (OR [95% CI] 1.35 [1.09, 1.66], p = .005). In parallel, ASD showed a correlation with a greater atrial fibrillation risk (OR [95% CI] 1.09 [1.03, 1.16], p = .005] and heart failure (OR [95% CI] 1.11 [1.04, 1.19], p = .004). Additionally, we explored the mediating role of CVD risk factors through two-step MR and multivariable MR, highlighting the possible role of smoking, prescription opioid use, triglycerides, education, income, Townsend deprivation index, and obesity in the causal association of ADHD, ASD, on CVDs. Conclusion: This MR study highlights the necessity for rigorous cardiovascular surveillance and interventions to decrease adverse cardiovascular events in people with ADHD or ASD by preventing identified mediating risk factors.

Background: Depression has a significant effect on cardiovascular disease (CVD), but uncertainties persist regarding which modifiable risk factors mediate the causal effects. We aim to determine whether depression is causally linked to CVD and which modifiable risk factors play potential mediating roles. Methods: We used a two-sample Mendelian randomization (MR) approach and NHANES 2007–2018 data to estimate the effects of depression on various CVD cases and investigated 28 potential mediators of the association between depression and CVD. Results: The results of our MR analysis indicated that genetically determined depression was associated with increased risk of several CVD, including coronary heart disease (odds ratio (OR) = 1.14; 95% confidence interval (CI): 1.05,1.22), myocardial infarction (OR = 1.19; 95% CI, 1.09,1.31), atrial fibrillation (OR = 1.14; 95% CI, 1.06,1.22), and stroke (OR = 1.13; 95% CI, 1.05,1.22). However, there was no causal association between depression and heart failure. Four out of 28 cardiometabolic risk factors, including hyperlipidemia, hypertension, diabetes, and prescription opioid use, were identified as mediators of the association between depression and various CVDs. Observational association analyses from NHANES data yielded consistent results. Conclusion: Our findings demonstrated that depression has a causal detrimental effect on various CVDs. Four causal mediators (hyperlipidemia, hypertension, diabetes, and prescription opioid use) were screened to explain the causal effect. Implementing targeted management strategies for these risk factors may be warranted to mitigate the public health burden of CVD among individuals with depression.

Background: Observational studies have suggested that cereal consumption is associated with a reduced risk of cardiovascular disease (CVD). However, the potential causal relationship is not clear. We aimed to investigate the association of cereal intake and cereal type with CVD risk.Methods: Two-step Mendelian randomization (MR) analysis was performed to confirm the causal association of cereal intake and cereal type with the risk of several common CVDs. Furthermore, two-step MR analysis was used to explore the mediating effect of cardiovascular metabolic factors, and multivariable MR analysis was used to assess the impact of socioeconomic status, such as education and income, on the causal association.Results: The MR analysis indicated that genetically predicted cereal intake is associated with reduced risk of large artery stroke (LAS) (odd ratio (OR): 0.421; 95% confidence interval (CI) [0.193, 0.918]; p = 0.030), and muesli as the primary cereal intake is associated with reduced risk of coronary heart disease (CHD) (OR: 0.100; 95% CI [0.023, 0.437]; p = 0.002), myocardial infarction (MI) (OR: 0.101; 95% CI [0.020, 0.509]; p = 0.005), heart failure (OR: 0.210; 95% CI [0.064, 0.684]; p = 0.010), ischemic stroke (IS) (OR: 0.130; 95% CI [0.029, 0.591]; p = 0.008), LAS (OR: 0.017; 95% CI [0.0004, 0.737]; p = 0.034), and small-vessel stroke (OR: 0.021; 95% CI [0.001, 0.708]; p = 0.005). In contrast, genetically predicted biscuits as the primary cereal intake increased the risk of CHD (OR: 6.557; 95% CI [1.197, 36.031]; p = 0.031), and other cereals, such as cornflakes, as the primary cereal intake increased the risk of CHD (OR: 3.803; 95% CI [1.194, 12.111]; p = 0.024), MI (OR: 4.240; 95% CI [1.185, 15.174]; p = 0.026), stroke (OR: 3.154; 95% CI [1.070, 9.298]; p = 0.037), and IS (OR: 3.736; 95% CI [1.185, 11.782]; p = 0.024). Multivariable MR analysis underscored the significant role of education and income in the causal association, and two-step MR analysis indicated that body mass index, lipids, and blood glucose exerted important mediating effects in the causal association.Conclusion: The findings of our study underscore the causal beneficial influence of muesli as the primary cereal intake on CVDs. A reasonable consumption of muesli may provide primary prevention of CVDs.

Aims: Observational studies have suggested that anaemia is associated with an increased risk of heart failure (HF). But the potential causal association is not clear. We aimed to investigate the association between anaemia and HF risk. Methods and results: A Mendelian randomization (MR) analysis was performed to confirm the causal association of anaemia with the risk of HF and left ventricular structure and function. Furthermore, a reverse-direction MR analyses was conducted to assess the causal effect of HF on anaemia. The MR analysis indicated that genetically predicted anaemia is associated with the increased risk of HF (meta: odd ratio (OR) = 1.12; 95% confidence interval (CI) [1.04, 1.20]; P = 0.002), and left ventricular mass index (β = 1.051; 95% CI [0.384, 1.718]; P = 0.002), left ventricular mass (β = 2.063; 95% CI [0.578, 3.547]; P = 0.006), left atrial minimum volume (β = 0.076; 95% CI [0.008, 0.143]; P = 0.028), and left atrial maximum volume (β = 0.090; 95% CI [0.023, 0.157]; P = 0.009). In the reverse-direction MR analyses, we found that genetic susceptibility to HF was significantly associated with the increased risk of anaemia (meta: OR = 1.40; 95% CI [1.24, 1.59]; P = 1.79 × 10−7). Conclusions: This MR study supports the genetic evidence that there is bidirectional causality between anaemia and the risk of HF as well as anaemia may cause left ventricular hypertrophy and enlargement of the left atrium. Considering the adverse causal effects between the two diseases, more attention should be paid to the prevention and treatment of anaemia in patients with HF.

Background: Old drugs for new indications in the novel coronavirus disease of 2019 (COVID-19) pandemic have raised concerns regarding cardiotoxicity, especially the development of drug-induced QT prolongation. The acute blocking of the cardiac hERG potassium channel is conventionally thought to be the primary mechanism of QT prolongation induced by COVID-19 drugs fluvoxamine (FLV) and lopinavir (LPV). The chronic impact of these medications on the hERG expression has yet to be determined.Methods: To investigate the effect of long-term incubation of FLV and LPV on the hERG channel, we used electrophysiological assays and molecular experiments, such as Western blot, RT-qPCR, and immunofluorescence, in HEK-293 cells stably expressing hERG and human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs).Results: Compared to the acute effects, chronic incubation for FLV and LPV generated much lower half-maximal inhibitory concentration (IC50) values, along with a left-shifted activation curve and retarded channel activation. Inconsistent with the reduction in current, we unexpectedly found that the chronic effects of drugs promoted the maturation of hERG proteins, accompanied by the high expression of Hsp70 and low expression of Hsp90. Targeting Hsp70 using siRNA was able to reverse the effects of these drugs on hERG proteins. In addition, FLV and LPV resulted in a significant reduction of APD90 and triggered the early after-depolarizations (EADs), as well as inhibited the protein level of the L-type voltage–operated calcium channel (L-VOCC) in hiPSC-CMs.Conclusion: Chronic incubation with FLV and LPV produced more severe channel-blocking effects and contributed to altered channel gating and shortened action potential duration by inhibiting hERG and Cav1.2.

Aims: Numerous observational studies have reported an association between calcific aortic valve stenosis (CAVS) and an increased risk of other cardiovascular diseases (CVDs). However, the potential causal association is uncertain. Methods and results: A bidirectional Mendelian randomization (MR) analysis was performed to confirm the causal association between CAVS and the risk of seven common CVDs. The meta-analysis was used to estimate the combined causal effect with multiple MR results. The MR analysis indicated that genetically predicted CAVS is associated with the increased risk of heart failure (odds ratio [OR] = 1.064; 95% confidence interval [CI] [1.008, 1.123]; P = 0.025), large-artery stroke (OR = 1.256; 95% CI [1.112, 1.418]; P < 0.001), cardioembolic stroke (OR = 1.228; 95% CI [1.117, 1.349]; P < 0.001) and atrial fibrillation (OR = 1.100; 95% CI [1.061, 1.140]; P < 0.001) without heterogeneity and pleiotropy. Genetically predicted hypertension (FinnGen: OR = 1.170; 95% CI [1.055, 1.297]; P = 0.003 and UK Biobank: OR = 2.456; 95% CI: 1.571, 3.840; P = 8.16 × 10−5) increased the risk of CAVS. Conclusions: This comprehensive MR study revealed the causal relationship between genetically predicted CAVS and the increased risk of various CVDs and the causal relationship between hypertension and CAVS risk. Given the harmful causal impact of CAVS on adverse cardiovascular events, it is crucial to prioritize the prevention and management of CVD in individuals with CAVS. Blood pressure management is an effective preventive intervention.