To the best of our knowledge, this is the first study to report the cumulative burden of MetS and its components on the risk of AF in a large nationwide population-based cohort study. We demonstrated several principal findings, which are as follows: (1) the cumulative burden of MetS during the four health examinations had a linear correlation with the risk of AF; (2) the cumulative burden of each MetS component showed a positive association with the risk of AF; (3) among the five metabolic components, elevated blood pressure had the greatest increase in AF risk, whereas impaired glucose intolerance had the lowest impact; (4) the cumulative number of total MetS components showed an incremental association with the risk of AF; and (5) temporal trends in MetS burden showed a different effect on the risk of AF.
Both MetS and AF confer a high burden of cardiovascular morbidity and mortality, and the association between MetS and AF has been reported in various studies [10, 11, 19, 20]. Compelling evidence supports that MetS itself is associated with the development of AF, and the presence of an increasing number of MetS components predisposes individuals to a higher risk of AF [11, 19, 21, 22]. However, these studies analyzed the number of MetS components at a single point. In contrast to previous studies, we have investigated the influence of temporal accumulation of MetS by combining four serial health examinations collectively. While participants diagnosed with MetS once had an 18% increased risk of AF compared to that in non-MetS participants, those diagnosed with MetS repeatedly at four times of measurement had a 72% higher risk of AF. Notably, the risk of AF increased by 3.1-fold as the number of fulfilled MetS components increased to a total of 20 counts during consecutive health examinations. This finding is noticeable because it implicates that the risk of AF development is different among patients with metabolic derangements depending on the past and upcoming metabolic burden. Given the proportional increase in AF risk according to the degree of metabolic burden integrating temporal changes, it is plausible to infer that the risk of AF would be higher in those diagnosed with MetS more than four times during their health examination checkups.
Regarding the relationship between elevated TG and the risk of AF, there were controversial reports [11, 19, 21, 23, 24]. The Niigata Preventive Medicine Study and post-hoc analysis from the ARIC study reported that hypertriglyceridemia was not related to incident AF [11, 19]. In addition, a recent study reported no association between elevated TG levels and the risk of AF . However, the Multi-Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study (FHS) reported that hypertriglyceridemia was associated with a higher risk of AF . In our study, meeting the criteria of elevated TG once or twice during 4 times of health screening examinations seems insignificantly or minimally associated with the risk of AF. Nonetheless, the association became evident as elevated TG levels were repeatedly checked, whereby the risk of AF was as high as 27% if hypertriglyceridemia was repeatedly confirmed through the entire health examinations of the study period, even after adjusting for potential confounders and other MetS components. Elevated TG is reported to be associated with endothelial dysfunction and the presence of microvascular disease [25, 26], which could be an early manifestation of atherosclerosis. Moreover, it is related to an increased risk of recurrent coronary artery disease , as well as insulin resistance, and is known to increase blood glucose levels . Although the exact mechanism of the development of AF is not known, the pro-atherogenic property of elevated TG might play a role in AF development.
Along with hypertriglyceridemia, other metabolic components and MetS itself could be linked to a higher risk of AF by several pathophysiological mechanisms. Mechanical alterations including an increase in atrial size and ventricular hypertrophy due to MetS, obesity, hypertension, and low HDL-C may contribute to the development of AF [13, 29–32]. Moreover, elevated levels of inflammation and oxidative stress have been proposed in the pathogenesis of both MetS and AF; indeed, HDL-C exerts anti-inflammatory and anti-oxidative activities that promote vascular health; hence, low HDL-C levels are related to a proinflammatory milieu [33, 34]. These metabolic changes may predispose patients with MetS or individual metabolic components to AF development.
The International Diabetes Federation (IDF) estimates that approximately 25% of the world's population, which corresponds to over a billion people, is affected by MetS despite the fact that the prevalence varies widely according to age, ethnicity, and sex of the population studied [35, 36]. Considering that AF is strongly associated with cardiovascular diseases such as stroke, heart failure, myocardial infarction, dementia, and increased mortality [3, 37], exploring the pragmatic association between metabolic derangements and AF along with the understanding of potential subsequent diseases is important to address the public health care burden of AF and AF-related complications. Our large study population with a mean age at mid-forties, much younger than that reported in previous studies [11, 19, 20], thereby representing the most active group socioeconomically, contributing to emphasize the awareness of the group harboring the risk of AF and the early initiation of prevention strategies. Importantly, we ascertained that even meeting one or two components of MetS over time is sufficient to increase the risk of AF, and thus, it would be crucial to make a concerted effort to minimize the metabolic derangements.
Even within the participants who presented the same cumulative number of total MetS components in the four health examinations, each may carry a different risk of AF depending on the change in metabolic burden. Those with a decreased number of MetS components over time showed a lower risk of AF than participants with an increase or maintenance in the number of MetS components at the last health examination compared to the first examination. Given that recovery from MetS is known to be significantly associated with a decreased risk of major adverse cardiovascular events , our results are consistent with previous findings by focusing on the most common cardiac rhythm disorder, AF. Therefore, it would be important to manage MetS component(s) to mitigate the risk of AF, and this management should be considered as part of the overall management strategy for preventing AF . Indeed, lifestyle modification (including addressing many risk factors within the MetS components) is part of the atrial fibrillation better care (ABC) pathway for holistic AF care, which is advocated in the new 2020 ESC guidelines .
Our study has several limitations. First, a considerable proportion of the study population already had diabetes mellitus and hypertension, which are evident and strong risk factors for AF. Instead, we show the risk gradient of AF by investigating the cumulative burden of metabolic derangements in a large general population at a relatively young age. Second, more than two-thirds of the study participants were men because employees are more likely to undergo regular health examinations provided at work places; hence, selection bias of sex might be introduced. However, subgroup analysis did not show any significant interaction with sex. Third, the degree and the relationship of AF risk with metabolic burden may differ in western populations because our study was conducted in an Asian population. Fourth, we incorporated many covariates including lifestyle behaviors, but unavailable confounding and unmeasured factors such as the presence of other inflammatory diseases or the measure of left atrial size could not be fully adjusted. Fifth, the metabolic status may change during the follow-up period and mitigate the risk. Lastly, the causality and underlying mechanistic link between MetS and AF were not answered. Nevertheless, we expanded our previous understanding of the association between MetS and AF by showing the biological gradient of metabolic derangements and AF risk in this large population-based study with serial health examination data.