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Original Articles
The mediating role of atrial fibrillation in causal associations between risk factors and stroke: a Mendelian randomization study
Shanmei Qin, Mengmeng Wang, Dipender Gill, Zhizhong Zhang, Xinfeng Liu
Epidemiol Health. 2024;46:e2024005.   Published online December 6, 2023
DOI: https://doi.org/10.4178/epih.e2024005
  • 11,586 View
  • 110 Download
  • 1 Web of Science
  • 1 Crossref
AbstractAbstract AbstractSummary PDFSupplementary Material
Abstract
OBJECTIVES
Atrial fibrillation (AF) contributes to stroke development and progression. We aimed to quantify the mediating role of AF in the causal associations between a wide range of risk factors and stroke via a Mendelian randomization (MR) framework.
METHODS
We assessed the associations of 108 traits with stroke and its subtypes in a 2-sample univariable MR approach, then conducted a bidirectional MR analysis between these 108 traits and AF to evaluate the presence and direction of their causal associations. Finally, to further investigate the extent to which AF mediated the effects of eligible traits on stroke, we applied multivariable and 2-step MR techniques in a mediation analysis where outcomes were restricted to stroke types causally affected by AF (any stroke [AS], any ischemic stroke [AIS], and cardioembolic stroke [CES]).
RESULTS
Among 108 traits, 42 were putatively causal for at least 1 stroke type; of these 42 traits, 20 that had no bidirectional relationship with AF were retained. Finally, 33 associations of 15 eligible traits were examined in the mediation analysis. The mediation analyses for AS, AIS, and CES each included 11 eligible traits. After AF adjustment, the direct effects of all traits on CES were attenuated to null (all p>0.05), while the associations with AS and AIS persisted for most traits (AF-mediated proportion: from 6.6% [95% confidence interval, 2.7 to 0.6] to 52.0% [95% confidence interval, 39.8 to 64.3]).
CONCLUSIONS
The causal associations between all eligible traits and CES were largely mediated through AF, while most traits affected AS and AIS independently of AF.
Summary
Key Message
Previous studies have not systematically detected and quantified the mediating role of AF in causal associations between a wide range of risk factors and stroke types. This study, using several MR approaches, found that the causal associations between risk factors and stroke, and the role of AF in mediating these associations, varied across stroke types. Although AF largely mediated the trait-CES associations, most traits affected AS and AIS independently of AF, highlighting the need for accurate disease classification in clinical practice and trials.

Citations

Citations to this article as recorded by  
  • Mendelian randomization studies on ischemic stroke: a field synopsis and systematic review
    Junyi Yang, Chen Han, Yue Zhang, Shutong Tan, Qian Wu, Yumei Ma, Yuanjie Duan, Yaxin Wang, Jinke Wang, Binhui Liu, Changqing Mu, Ruixia Zhu, Xiaoqian Zhang, Jian Zhang, Xu Liu
    Journal of Translational Medicine.2025;[Epub]     CrossRef
The association between physical activity and atrial fibrillation applying the Heaviside function in survival analysis: the Multi-Ethnic Study of Atherosclerosis
Yaser Mokhayeri, Seyed Saeed Hashemi-Nazari, Mohammad Ali Mansournia, Hamid Soori, Soheila Khodakarim
Epidemiol Health. 2017;39:e2017024.   Published online June 18, 2017
DOI: https://doi.org/10.4178/epih.e2017024
  • 22,727 View
  • 205 Download
  • 6 Web of Science
  • 5 Crossref
AbstractAbstract PDF
Abstract
OBJECTIVES
Although the effect of physical activity (PA) on the incidence of atrial fibrillation (AF) has been studied, contradictory results have been reported. Such discrepancies may reflect the different effects of various types of PA upon AF, as well as gender interactions. Therefore, we aimed to evaluate the associations of PA types (total, moderate/vigorous, and intentional), as well as walking pace, with AF risk in men and women.
METHODS
Using the Multi-Ethnic Study of Atherosclerosis Typical Week Physical Activity Survey, 3 PA measures and walking pace were calculated among 6,487 men and women aged 45-84 years. The incidence of AF over approximately 11 years of followup was ascertained. The association of each PA measure and walking pace with AF incidence was estimated using multivariable Cox proportional hazard models. An extended Cox model with Heaviside functions (hv) of time was used to estimate the effects of time-varying covariates.
RESULTS
During 11 years of follow-up (49,557 person-years), 242 new AF cases occurred. The incidence rate of AF was 48.83 per 10,000 person-years. The proportional hazard (PH) assumption for total PA among women was not met; hence, we used the hv to calculate the hazard ratio. Total PA in women in the hv2 analysis was negatively associated with AF in all 3 models, although for hv1 no significant association was observed. The PH assumption for walking pace among men was not met, and none of the hv showed a statistically significant association between walking pace and AF in men.
CONCLUSIONS
These results suggest that PA is inversely associated with AF in women.
Summary

Citations

Citations to this article as recorded by  
  • Leisure-time and occupational physical activity and risk of cardiovascular disease incidence: a systematic-review and dose-response meta-analysis of prospective cohort studies
    Asma Kazemi, Sepideh Soltani, Dagfinn Aune, Elham Hosseini, Zeinab Mokhtari, Zahra Hassanzadeh, Ahmad Jayedi, Francisco Pitanga, Masoumeh Akhlaghi
    International Journal of Behavioral Nutrition and Physical Activity.2024;[Epub]     CrossRef
  • Impact of ventricular assist device use on pediatric heart transplant waitlist mortality: Analysis of the scientific registry of transplant recipients database
    Arene Butto, Lydia K. Wright, Jameson Dyal, Chad Y. Mao, Richard Garcia, William T. Mahle
    Pediatric Transplantation.2024;[Epub]     CrossRef
  • Weekly physical activity and incident atrial fibrillation in females – A dose-response meta-analysis
    Ioannis Anagnostopoulos, Maria Kousta, Charalampos Kossyvakis, Eleni Lakka, Dimitrios Vrachatis, Spyridon Deftereos, Vassilios P. Vassilikos, Georgios Giannopoulos
    International Journal of Cardiology.2023; 370: 191.     CrossRef
  • Self-Reported Walking Pace and Risk of Cardiovascular Diseases: A Two-Sample Mendelian Randomization Study
    Lu Chen, Xingang Sun, Yuxian He, Liangrong Zheng
    Frontiers in Genetics.2022;[Epub]     CrossRef
  • Sex-Specific Exposure–Effect Relationship Between Physical Activity and Incident Atrial Fibrillation in the General Population: A Dose–Response Meta-Analysis of 16 Prospective Studies
    Qin Wan, Yue Zhou, Wengen Zhu, Xiao Liu
    Frontiers in Cardiovascular Medicine.2021;[Epub]     CrossRef
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