Comparison with previous research
Our research findings indicate that patients with CMDs are at an increased risk of developing AF, which is consistent with previous research. A close association between CAD and AF has been demonstrated in previous research on specific CMDs.8 Data indicates that 5.7% of acute coronary syndrome patients develop AF during hospitalisation,20 while this percentage rises to 28% in acute myocardial infarction patients who concurrently experience reduced left ventricular ejection fraction.21 A bidirectional Mendelian randomisation study also demonstrated that CAD elevated AF risk by 11%–14%.22 Research also suggests a correlation between diabetes and an increased AF risk.23 24 A 2011 meta-analysis, which encompassed seven prospective cohort studies and four case-control studies, revealed that patients with diabetes exhibit a 40% increased risk of developing AF compared with those without diabetes.25 New genetic evidence supporting a causal relationship between type 2 diabetes and AF was collected in another Mendelian randomisation investigation.26 The link between AF and stroke has been confirmed by numerous studies.27–29 Interestingly, the probability of new-onset AF also increases following a haemorrhagic stroke.30 Additionally, hypertension is identified as the most significant risk factor for AF occurrence. The Atherosclerosis Risk in Communities study revealed that 21.6% of AF cases could be attributed to hypertension.31 The aforementioned studies all indicate that a history of specific CMD is a risk factor for new-onset AF. Nevertheless, there is currently no research examining whether the coexistence of multiple CMDs results in an additive increase in AF risk.
Cardiometabolic multimorbidity is currently afflicting approximately 10 million adults in the USA and Europe.32 33 The cumulative effects of cardiometabolic multimorbidity on a series of adverse outcomes have been examined.14 34 Patients with two CMDs have a threefold increased risk of mortality in comparison to those without CMDs, and this risk rises to nearly sevenfold for those with three conditions.14 A cohort study reported that patients with cardiometabolic comorbidities possess a 73% increased risk of cognitive decline and an 86% elevated risk of dementia compared with patients without CMDs. Additionally, patients with three CMDs experienced cognitive decline and the onset of dementia 3.7 and 4.2 years earlier, respectively.16 We assessed the correlation between the number of CMDs and the risk of AF in light of the increasing prevalence of cardiometabolic multi-morbidity. We found that an increase in the number of CMDs has a significant dose-dependent cumulative effect on AF risk. We associated the presence of adverse effects of concurrent CMDs with the occurrence of AF, aligning with the recent concept that AF is also a chronic disease based on cardiometabolic factors.35 36 According to a recent multi-centre prospective cohort study among COVID-19 patients, the incidence of arrhythmias increased in tandem with the number of CMDs.37 In summary, our results emphasise the necessity for early screening and AF prevention in patients with concurrent CMDs.
The observed accumulative association between the risk of AF and the coexistence of various CMDs in this study can be accounted for by a variety of mechanisms. First, CMDs and AF are associated with similar risk factors, including smoking, excessive alcohol consumption, sedentary lifestyle and obesity.38 Second, CMDs are frequently observed in conjunction with chronic inflammation, alterations in neurohumoral regulation and cardiac structural remodelling.39 40 These factors may lead to alterations in cardiac ion channels, atrial fibrosis and remodelling of cardiac electrical activity, thereby accelerating AF progression.41 Additionally, psychosocial factors are significant modulators in AF development.42 Patients with CMDs are usually affected by the chronic disease course, diminished physical function and economic burdens,43 44 which negatively impact psychosocial factors and may accumulate with the cardiometabolic multimorbidity.45
Furthermore, in the age- and gender-stratified subgroup analyses, we noted a more pronounced dose-response effect linked to CMDs in females and younger individuals (<65 years). The association between the number of CMDs and AF is inconsistent among different subgroups, which may be attributed to the unique characteristics of specific subgroups. For instance, the AF risk is inherently higher in males and older subgroups,46 47 potentially diluting the influence of CMDs, thereby resulting in a relatively stronger correlation in females and younger subgroups. The presence of a greater number of CMDs in younger individuals may suggest a less healthy lifestyle, a worse prognosis, a heavier economic burden and greater psychosocial stress, all of which could increase the risk of AF. Ningjian Wang et al also reported that most cardiometabolic factors and clinical comorbidities demonstrate significant interactions with age, and this association is generally more pronounced in younger populations.48 As the results of subgroup analyses are provisional, additional research is required to validate the potential differences related to age and sex.
The cumulative impact of CMDs on AF is the primary finding of this investigation. The results indicate that patients with cardiometabolic multimorbidity, especially females and younger individuals, possess a higher risk of developing AF. Our research highlights the importance of screening for AF and early prevention in patients with CMDs, particularly in those with multiple comorbidities. Given the poor clinical prognosis linked to AF and cardiometabolic multimorbidity, as well as their combined presence,14 38 49 it is imperative to implement a comprehensive biopsychosocial management strategy when diagnosing individuals with CMDs.50 Chronic health issues and multimorbidity are becoming more prevalent as a result of the longer average lifespan and increased health awareness. Emphasis on cumulative effects can help us implement preventive and therapeutic measures in advance.
Strengths and limitations
Our research exhibits multiple advantages. First, we employed the extensive population data from the UK Biobank to conduct a prospective cohort analysis. This enabled us to stratify the number of CMDs within an adequately large sample and confirm the cumulative effects that may result from the coexistence of multiple diseases. Second, paroxysmal AF is frequently challenging to identify during medical appointments or self-monitoring. Our results indicate that the frequency of monitoring or screening should be increased in the presence of multiple CMDs, particularly among females and younger individuals. Third, we enhanced the definition of CMDs by incorporating diagnostic, medication and surgical information from self-reported medical histories, as well as diagnostic and surgical information from health-related records of hospitalised patients. This approach decreased the misclassification of patients with CMDs.
However, our study has several limitations. First, the participants in the UK Biobank are predominantly Caucasian, and there is evidence indicating that the incidence of AF is higher among Caucasians compared with other ethnic groups.51 This restricts the generalisability of our findings to populations of other ethnicities and countries. Second, the maximum age of participants at recruitment in the UK Biobank was approximately 73 years, which may underestimate AF risk in individuals over the age of 65. Third, the potential for misclassification and biased results exists due to the fact that paroxysmal AF can be asymptomatic, which could have resulted in the omission of certain AF cases. Fourth, as this was an observational study, we cannot entirely rule out the possibility of residual confounding bias and reverse causality despite having adjusted for diverse confounding factors such as demographics, lifestyle and other clinical histories and conducted a series of sensitivity analyses. Lastly, we did not classify the specific types of AF, and there are numerous causes of secondary AF. Consequently, excluding all participants with common causes of secondary AF proved challenging. Although sensitivity analyses were performed after excluding participants with several common causes, the potential for overestimating the relationship between CMDs and the risk of AF remains.
Overall, the coexistence of multiple CMDs demonstrates a dose-dependent and cumulative relationship with increased AF risk. This correlation is more pronounced in individuals aged <65 years and females.