Uncovering non-clinical risk factors through mendelian randomization

A new study identifying 56 non-clinical risk factors associated with sudden cardiac arrest (SCA), spanning lifestyle, physical measures, psychosocial factors, socioeconomic status, and the local environment, offers compelling evidence that improving these unfavorable profiles could prevent up to 63% of SCA cases. The article appearing in the Canadian Journal of Cardiology, published by Elsevier, provides new insights into how lifestyle and environmental factors can contribute to SCA prevention.

SCA is a global public health challenge with profound physical and psychosocial consequences for the individuals affected, along with far-reaching impacts on families, friends, and entire communities. Its high fatality rate and unpredictability make it a leading cause of death worldwide. In Canada, an estimated 60,000 SCAs occur annually. A reliable and practical approach to mitigate the burden of SCA entails investigating the long-term, modifiable risk factors and subsequently formulating preventive measures. However, significant knowledge gaps regarding SCA prevention persist.

Lead investigator and first author of the article "Modifiable Risk Factors and Attributable Burden of Cardiac Arrest: An Exposome-wide and Mendelian Randomization Analysis" Huihuan Luo, PhD, School of Public Health, Key Lab of Public Health Safety of the Ministry of Education, and NHC Key Lab of Health Technology Assessment, Fudan University, Shanghai, China, explains, "All previous studies investigating the risk factors of SCA were hypothesis-driven and focused on a limited number of candidate exposure factors grounded in prior knowledge or theoretical frameworks. We conducted an exposome-wide association study, which examines the relationship between a wide range of environmental exposures and health outcomes using UK Biobank data, followed by Mendelian randomization to assess causal relationships. The study found significant associations between various modifiable factors and SCA, with lifestyle changes being the most impactful in preventing cases."

Eliminating the worst 1/3 of all risk domains (conservative elimination), 40% of SCA cases could be prevented according to the study, rising to 63% SCA prevention if the worst 2/3 of all risk factors were eliminated (thorough elimination). Lifestyle habits appeared to contribute the most to SCA prevention, accounting for 13% and 18% of SCA cases under conservative and thorough elimination, respectively.

To our knowledge, this is the first study that comprehensively investigated the associations between non-clinical modifiable risk factors and SCA incidence. We were surprised by the large proportion (40%–63%) of SCA cases that could be prevented by improving unfavorable profiles."

Renjie Chen, PhD, Department of Environmental Health, School of Public Health, Fudan University

Researchers found that factors such as higher consumption of champagne/white wine and increased fruit intake, along with maintaining a positive mood, weight management, blood pressure control, and improved education, may serve as important protective factors.

The authors of the accompanying editorial "Transitioning from Reaction to Prevention in Sudden Cardiac Arrest: Causal Clues and Caveats from Mendelian Randomization Studies" Nicholas Grubic, MSc, Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, ON, Canada, and Dakota Gustafson, PhD, Department of Emergency Medicine and Department of Epidemiology, Faculty of Medicine, Queen's University, Kingston, ON, Canada, say, "One of the study's most intriguing findings is the cardioprotective effect associated with champagne and white wine consumption, questioning long-held assumptions about the specificity of red wine's cardioprotective properties. Research on the underlying mechanisms remains unclear, but these findings reinforce the idea that the benefits of moderate alcohol consumption may be more complex than previously assumed."

Surprisingly, computer use showed an inverse relationship with SCA risk, seemingly contradicting sedentary behavior risks. Dr. Luo explains, "While our initial analysis showed that correlation, we strongly suspect this reflects underlying socioeconomic or occupational differences between groups, not a direct protective effect from screen time. This is a common challenge in observational studies. By using advanced methods like Mendelian Randomization, we were able to dig deeper and filter out some of that 'noise.' The results from those more rigorous analyses didn't show the same protective link, which strengthens our confidence in identifying the other, more clearly modifiable factors as the key targets for prevention."

Mr. Grubic and Dr. Gustafson conclude, "To achieve dramatic reductions in the immense burden SCA places on the health system, this narrative must extend beyond acute intervention to a broader, population-wide strategy that prioritizes primary prevention. While shifting from responding to SCA to actively preventing its occurrence may seem straightforward, it is far more complex in practice. The multifactorial nature of these events – often influenced by a combination of genetic predispositions, underlying cardiovascular conditions, environmental triggers, and lifestyle factors – poses significant challenges for healthcare professionals and policymakers. Identifying modifiable factors linked to SCA is crucial for informing the development of high-quality public health messaging and interventions, especially in resource-limited environments."