Cumulative Burden of Metabolic Syndrome and Its Components on the Risk of Atrial Fibrillation: A Nationwide Population-based Study

Abstract

Background: The metabolic syndrome (MetS) and its components are associated with the development of atrial fibrillation (AF). However, the impact of time-burden of MetS on the risk of AF is unknown. We investigated the effect of the cumulative longitudinal burden of MetS on the development of AF. 

Methods: We included 2 885 189 individuals without AF who underwent four annual health examinations during 2009–2013. Metabolic burdens were evaluated in the following three ways: (1) cumulative number of MetS diagnosed at each health examination (0–4 times); (2) cumulative number of each MetS component diagnosed at each health examination (0–4 times per MetS component); and (3) cumulative number of total MetS components diagnosed at each health examination (0 to a maximum of 20). The risk of AF according to the metabolic burden was estimated using Cox proportional-hazards models.

Results: Of all individuals, 62.4%, 14.8%, 8.7%, 6.5%, and 7.6% met the MetS diagnostic criteria 0, 1, 2, 3, and 4 times, respectively. During a mean follow-up of 5.3 years, the risk of AF showed a positive association with the cumulative number of MetS diagnosed over four health examinations: adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of 1, 2, 3, and 4 times compared to 0 times were 1.18 (1.13–1.24), 1.31 (1.25–1.39), 1.46 (1.38–1.55), and 1.72 (1.63–1.82), respectively; P for trend < 0.001. All five components of MetS, when diagnosed repeatedly, were independently associated with an increased risk of AF: adjusted HR (95% CI) from 1.22 (1.15–1.29) for impaired glucose intolerance to 1.96 (1.87–2.07) for elevated blood pressure. As metabolic components were accumulated from 0 to 20 counts, the risk of AF also gradually increased up to 3.1-fold (adjusted HR 3.11, 95% CI 2.52–3.83 in those with 20 cumulative components of MetS), however, recovery from MetS was linked to a decreased risk of AF.

Conclusions: Given the positive correlations between the cumulative metabolic burdens and the risk of incident AF, maximal effort to detect and correct metabolic derangements even before MetS development might be important to prevent AF and related cardiovascular diseases. 

Background

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia associated with an increased risk of stroke, heart failure, myocardial infarction (MI), dementia, and death [1–3]. The prevalence of AF in adults is 2%-4%, and the lifetime AF risk was recently estimated as 1 in 3 individuals of European ancestry at an index age of 55 years [4, 5]. As the incidence of AF is expected to increase, management of AF has been emphasized as integrating stroke prevention, symptom control, risk factors, and lifestyle modification [6, 7].

Metabolic syndrome (MetS) is a cluster of metabolic disorders including glucose intolerance, low level of high-density lipoprotein cholesterol (HDL-C), high level of triglyceride (TG), obesity, and hypertension [8, 9]. MetS, frequently combined with other atherosclerotic risk factors, has become a pandemic that increases the risk of cardiovascular morbidity and mortality [8, 10].

As both AF and MetS lead to significant cardiovascular diseases, imposing an enormous healthcare burden, many studies have attempted to reveal the relationship between MetS and AF development; MetS and its components are known to be associated with AF development [11]. Elevated levels of inflammation, oxidative stress, and mechanical stimuli to the atrium have been proposed as the underlying pathophysiology of AF development in MetS [10, 12, 13]. However, MetS status and its components are variable as they can change over time dynamically. A recent study demonstrated the association between the exposure duration or extent of metabolic disturbances and the increased risk of MI and stroke, which are AF-related complications [14]. Nonetheless, to what extent the time-burden of MetS affects the risk of AF itself has not been evaluated. Therefore, we aimed to investigate the effect of the cumulative longitudinal burden of MetS on AF development through a nationwide population-based cohort analysis.

Methods

We defined a population-based cohort from the National Health Information Database (NHID) incorporating all data from the National Health Insurance Service, which covers the entire population of the Republic of Korea (hereafter, Korea). All insured adults aged 40 years and older are recommended to undergo biannual general health screening without cost [15]. Not only the regular health examination records, including laboratory results, anthropometric measurements, and detailed lifestyle questionnaires, but also sociodemographic data, income-based insurance contributions, prescription records, inpatient and outpatient usage, and date of death of all insured Koreans are available in the NHID [15, 16]. The Institutional Review Board at the Seoul National University Hospital (E-2009-091-1157) authorized this study.

We selected 3 981 515 adults aged ≥ 20 years who underwent four serial health examinations between January 1, 2009, and December 31, 2013, from the NHID. Individuals with a prior history of AF and missing values of health examination data or covariates were excluded (Additional file 1: Fig. S1.). Finally, 2 885 189 adults were included in the analysis.

Results

The baseline characteristics of 2 885 189 participants grouped according to the number of MetS diagnosed over four health examinations are summarized in Table 1. The mean participant age was 44.5 ± 10.9 years, and 2 058 645 (71.4%) were men. Individuals were divided into five groups: 1 800 268 (62.4%), 428 143 (14.8%), 250 073 (8.7%), 188 847 (6.5%), and 217 858 (7.6%) who met the diagnostic criteria of MetS 0, 1, 2, 3, and 4 times, respectively. Diabetes, hypertension, and dyslipidemia were present in 7.1%, 20.7%, and 17.3% of the total population, respectively. The prevalence of comorbidities was higher as individuals fulfilled more MetS criteria.

Discussion

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 [24]. 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 [23]. 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 [27], as well as insulin resistance, and is known to increase blood glucose levels [28]. 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 [38], 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 [39]. 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 [40].

Conclusions

In this large Asian population-based cohort, the cumulative burden of MetS diagnostic criteria over time and its components has a positive correlation with the risk of incident AF. Given the close association between the cumulative number of total MetS components and the risk of AF, maximal effort to detect and correct metabolic derangements even before the development of MetS might be important to prevent AF and related cardiovascular diseases.

Abbreviations

AF: Atrial fibrillation; MI: myocardial infarction; MetS: Metabolic syndrome; HDL-C: high-density lipoprotein cholesterol; TG: high level of triglyceride; NHID: National Health Information Database; WC: waist circumference; HR: hazard ratio; CI: 95% confidence interval.

Declarations

Authors’ contributions

HJA had primary responsibility for writing of the article. KDH and JHJ carried out data analyses. HJA, KDH, SRL, SK conceived the idea and initiated the analysis plan for the current study. EKC, SO supervised the current study. EKC, GYHL reviewed and commented on draft. All authors coordinated the study and provided comments on drafts of the manuscript, and have revised and approved the manuscript. EKC is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

This work was supported by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, Republic of Korea, the Ministry of Food and Drug Safety) (Project Number: HI20C1662), and by the Korea National Research Foundation funded by the Ministry of Education, Science and Technology (grant 2020R1F1A106740).

Competing interests

HJA, KDH, SRL, JHJ, SK, SO: None to disclose.

EKC: Research grants from Bayer, BMS/Pfizer, Biosense Webster, Chong Kun Dang, Daiichi-Sankyo, Samjinpharm, Sanofi-Aventis, Seers Technology, Skylabs, and Yuhan.

GYHL: Consultant for Bayer/Janssen, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon and Daiichi-Sankyo. Speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are received personally.

The external funders and sponsors of the study had no role in study design and conduct of the study; in the collection, analysis, and interpretation of the data; in the preparation, review, or approval of the manuscript; or in the decision to submit the manuscript for publication.

Availability of data and materials

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The Institutional Review Board at the Seoul National University Hospital (E-2009-091-1157) authorized this study. Informed consent was waived since anonymous and deidentified information was used for analysis.

Consent for publication

Not applicable

Acknowledgements

None

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