Relationship Between Diabetes Mellitus and Atrial Fibrillation Prevalence in the Polish Population. A Report From the Non- Invasive Monitoring for Early Detection of Atrial Fibrillation (NOMED- AF) Prospective Cross-Sectional Observational Study

Jakub Janusz Gumprecht (  kubagumprecht@gmail.com ) Medical University of Silesia: Slaski Uniwersytet Medyczny w Katowicach https://orcid.org/0000-0002-0575-9150 Gregory Y.H Lip University of Liverpool Adam Sokal Medical University of Silesia: Slaski Uniwersytet Medyczny w Katowicach Beata Średniawa Medical University of Silesia: Slaski Uniwersytet Medyczny w Katowicach Katarzyna Mitręga Medical University of Silesia: Slaski Uniwersytet Medyczny w Katowicach Jakub Stokwiszewski National Institute of Hygiene and Epidemiology Łukasz Wierucki Medical University of Gdansk: Gdanski Uniwersytet Medyczny Aleksandra Rajca Medical University of Gdansk: Gdanski Uniwersytet Medyczny Marcin Rutkowski Medical University of Gdansk: Gdanski Uniwersytet Medyczny Tomasz Zdrojewski Medical University of Gdansk: Gdanski Uniwersytet Medyczny Tomasz Grodzicki Jagiellonian University Medical College Faculty of Medicine: Uniwersytet Jagiellonski Collegium Medicum Wydzial Lekarski Jarosław Kaźmierczak Pomeranian Medical University in Szczecin: Pomorski Uniwersytet Medyczny w Szczecinie Grzegorz Opolski Medical University of Warsaw: Warszawski Uniwersytet Medyczny Zbigniew Kalarus Medical University of Silesia: Slaski Uniwersytet Medyczny w Katowicach

In this ancillary analysis to NOMED-AF, we aimed to evaluate the relationships between DM and AF prevalence using a mobile long-term continuous ECG telemonitoring vest in a representative Polish and European population ≥ 65 years, for detection of AF, symptomatic or silent.

Methods
The study was conducted as a sub-analysis of Non-invasive Monitoring for Early Detection of Atrial Fibrillation (NOMED-AF) study, a cross-sectional observational study aiming to evaluate the AF prevalence and its associated comorbidities in the Polish population. The detailed study protocol has been previously described. [12] The study used a long-term wearable non-invasive ECG monitoring system linked with an online platform for data analysis and storage, designed and developed by Comarch Healthcare (Kraków, Poland).
The enrolment period was between March 15th, 2017 and March 10th, 2018. The trial schedule comprises population sampling, during which the representative Polish population ≥ 65 was strati ed by province and place of residence. After the regions from each stratum (villages, towns, cities) were randomly selected by the proportional probability, the study participants from the previously chosen areas were also selected at random manner, based on the personal identity number. A similar number of men and women in each 5-year age group were designated. DM type 2 diagnosis was established in line with the American Diabetes Association [23] and European Association for the Study of Diabetes [24] Guidelines if the haemoglobin A1c (HbA1c) measured by HPLC was ≥ 6.5% or if the patient was aware of diabetes and a glucose-lowering treatment was applied. Physical activity threshold was de ned as exercise at least > 30 minutes ≥ 3 times a week.
The studied cohort was divided into two study groups based on DM presence: DM (+) group -participants with concomitant DM; and DM (-) group -subjects without DM. AF prevalence was also analysed in correlation to age and gender. The detailed baseline characteristics were described for both -NOMED and Polish population, while all other analyses were weighted and reported for the Polish population.
Signed, informed consent was obtained from each eligible participant of the trial in accordance with protocol regulations approved by the local review boards governing research involving human subjects and local bioethical committee (26/2015), and the Declaration of Helsinki. The trial was registered on clinicaltrials.gov (NCT03243474).

Statistical analysis
Continuous variables were presented as mean and standard deviation (SD). Categorical variables were depicted as counts and percentages, analysed by chi-squared test. National estimation, i.e., the frequency of comorbidities prevalence, average values for age, BMI etc., were analysed on weighted data. The estimations were calculated so that the sample proportions were strati ed by sex, age and city class were the same as in the Polish population. 95% Con dence intervals were determined, including the complex sampling scheme and were used to express the signi cance of differences between speci c categories. Fisher's exact test was performed to compare differences between individual age categories. A logistic regression analysis was conducted to obtain the risk changes relative to age and sex. A multiple logistic regression analysis was conducted to obtain independent risk factors of AF and SAF in DM + and DMpopulations. The independent variable was 5-year age groups and gender. A two-sided p-value < 0.05 was considered to be statistically signi cant.
Prolonged screening for AF was associated with more newly established AF diagnoses in participants with concomitant DM compared to those without DM (5% vs 4.5% respectively, p < 0.001). Also, DM + patients had a greater prevalence of persistent or sustained AF than those in the DM-group (12.2%; 95% CI 10.3-14.3 vs 6.9%; 95% CI 5.9-8.1 respectively, p < 0.001). The arrhythmia classi cation is described in Table 2.

Discussion
In this prospective cross-sectional observational study, our principal ndings are as follows: (i) we found a higher AF prevalence when diabetes was present; (ii) subjects with DM are more likely to have silent, asymptomatic AF; and (iii) DM patients were more commonly associated with persistent and permanent AF, and (iv) independent risk factors for AF incidence may vary in patients with concomitant DM comparing to the general population.
To the best of our knowledge, this is the rst prospective study on AF prevalence in patients with DM, which, based on a comprehensive epidemiological methodology, was conducted on a randomly selected cohort. Unlike prior surveys based mainly on registries or cohort studies, the current study was based on prolonged non-invasive continuous ECG monitoring with a mean monitoring time span of almost 22 days. The data were transmitted remotely to the cardiovascular centres and analysed by quali ed medical professionals, resulting in a more accurate investigation. Hence, our novel nding is that 1 out of 4 Polish subjects aged ≥ 65 years with concomitant diabetes has AF.
Also, diabetic patients are at a substantially higher risk of AF comparing to non-DM subjects.
AF prevalence has been reported in around 1-4% of the general European population. [25] The intimate association between AF and DM has been previously reported. The Framingham Heart Study demonstrated a 40% increase in the AF incidence among patients with concomitant DM.
[26] A study of nearly 846 thousand patients from Veterans Health Administration Hospitals revealed a signi cantly higher AF prevalence in DM patients vs the control group without this metabolic disorder (14.9% vs 10.3%, p < 0.001). [15] Similar results were also obtained by Huxley et al. in a case-control study on a cohort of over 100 thousand subjects. [17] Finally, a systematic review based on 32 studies and over 10 million participants found a 28% higher risk of developing AF among patients with diabetes. [27] Many of these studies have been based on 'one off' ECG recordings, and few studies have used prolonged ECG monitoring.
Furthermore, 9% of the Polish population with coexisting DM was diagnosed with asymptomatic AF. Even short runs of SAF may increase the risk of stroke and should not be ignored.
[28] [29] Indeed, the vast majority of diabetes patients aged ≥ 65 would bene t from oral anticoagulation, and Chao et al. reported that the age threshold for initiating oral anticoagulation was 50 years in an AF patient with diabetes as a single risk factor [30]. Hence, long-term monitoring plays a pivotal role in stroke prevention, which is often the rst arrhythmia symptom, and the whole population age ≥ 50 with concomitant DM should be actively screened for AF, even opportunistically when they attend clinic check-ups.
Nonetheless, the associations between DM and AF have been subject to debate and controversy. [31] Although the precise pathophysiological and clinical mechanisms are still not completely understood, there seems to be a multifactorial and bidirectional in uence, including atrial structural and electrical remodelling as well as autonomic regulation. [32] The Danish population-based registry studies have either pointed out that the DM occurrence did not elevate the risk of AF incidence or that the association between AF and DM was only evident among the obese. [33] [34] Furthermore, the impact of sex on incident AF also seems to be unclear. [19] [35] In our study among DM patients, there was no signi cant in uence of sex on AF prevalence.
The current study con rms prior observations referring to a higher number of comorbidities in the AF population with diabetes versus those without. Although there are multiple reports investigating AF risk factors in the general population, analyses evaluating independent AF risk factors in diabetic patients are lacking. Hence, we conducted a multivariate analysis, which indicated that the risk factors for the arrhythmia incidence might differ in subjects with concomitant DM compared to the general population. In contrast to the entire population, in individuals burdened by DM, comorbidities such as hypertension, PAD, obesity, or thromboembolism seem to play a pivotal role in AF development. The results are compliant with the Swedish National Diabetes Register report, which emphasised the independent association of elevated blood pressure, increased BMI, and heart failure in AF development.
[36] These outcomes underline that DM should not be treated as a separate disease entity but need to be considered a complex syndrome including hypertension, dyslipidaemia or thromboembolic complications. Therefore, relevant efforts should be undertaken in the holistic management of AF patients with DM.

Strengths and Limitations
As far as we are aware, this is the rst observational and epidemiological study evaluating the AF prevalence in patients with concomitant DM using a nationwide, representative population sample. Furthermore, all visits and procedures conducted during the study were taken at the subject's home; hence, even disabled and critically ill individuals were eligible to take part. Our study is also one of the few surveys using long term ECG monitoring and the rst-ever, which enrolled randomly selected participants from the general population. These facts contribute signi cantly to objectivity and reduce possible bias. Furthermore, we analysed independent AF risk factors in the diabetic population, which is novel and seems to be relevant in the holistic management of diabetic subjects in everyday clinical practice.
However, the study also has some limitations. Although the participants' selection was at random manner, the response rate was modest, which could possibly in uence a selection bias. Nonetheless, due to the fact that presumably healthier subjects are more likely not to respond, the response rates in the study probably might be underestimated than overestimate AF prevalence. Finally, the current study is based on a nationwide representative sample from the Polish population. Therefore, the results re ect this particular population and can be directly applied only to Polish inhabitants, mainly Caucasians, who were ethnically homogenous, with universal access to healthcare.
Conclusions AF affects 1 out of 4 subjects with concomitant DM. The higher prevalence of AF and SAF among DM subjects compared to those without DM highlights the necessity of active AF screening and evaluation of speci c AF risk factors amongst the diabetic population.

Declarations
Ethics approval: Signed, informed consent was obtained from each eligible participant of the trial in accordance with protocol regulations approved by the local review boards governing research involving human subjects and local bioethical committee (26/2015), and the Declaration of Helsinki. The trial was registered on clinicaltrials.gov (NCT03243474).

Consent for publication:
Not applicable Availability of data and materials: Figure 1 Prevalence of AF in the Polish population with (DM+) and without (DM-) concomitant diabetes mellitus in correlation to age. * -p<0.001 between DM+ and DM-study groups. Figure 2