| Aims: Subclinical atrial fibrillation(SCAF)is often asymptomatic nonetheless harmful.It accounts for at least 1 in 3 patients with AF and current evidence suggests that the presence of device-detected SCAF among patients with no history of AF increases the risk of thromboembolism,heart failure,and cardiovascular mortality.Though cardiac implantable electronic devices(CIED),including permanent pacemakers(PM),implantable cardioverter defibrillators(ICD),and cardiac resynchronization therapy(CRT)improved management of multiple types of arrhythmias,it is important to explore early indicators of SCAF in these patients.In patients with cardiac implantable electronic devices(CIED),we evaluated the combined performance of homocysteine(Hcy)and uric acid(UA)biomarkers to discriminate high-risk patients for SCAF.Methods: A total of 3291 patients who had an indication for the implantation of a CIED were evaluated of SCAF in Dalian,China between January 2013 and December 2019 were screened after satisfying the requirements of a minimum age of 18 years and complete clinical data.To monitor SCAF,implanted CIEDs without algorithms for the detection of atrial tachycardia/atrial fibrillation(AT/AF)episodes were excluded(n=279).Patients with rheumatic heart disease were excluded because they were expected to have a higher risk of AF(n=47).Also,patients with a prior diagnosis of AF, atrial flutter(AFL),and atrial tachycardia(AT)evidenced by ECG or Holter monitoring were excluded(n=981).Additionally,we excluded 19 patients who presented with early SCAF incidence during the first month of CIED-implantation.Finally,a total of 1224 patients were included in the present study.Clinical data was obtained from patients selected according to the absence(no SCAF)or presence of atrial high-rate episodes(AHRE)> 6 minutes.Blood samples were obtained,and Hcy and UA biomarkers were tested in all patients to distinguish their prognostic performance for SCAF.Results: A total of 1224 patients were included in the present study.The median age was 69 years and the proportion of females(50.6%)and males(49.4%)was similar.The cohort was followed up for a total of 2,810 person-years and the median follow-up time was 642 days(range,180–2684 days).Over the follow-up period,225 individuals(18.4%)developed detected SCAF.Hcy and UA biomarkers were significantly different in SCAF vs.no SCAF(all P<0.001).For both males and females,a positive association was significantly found between Hcy and UA levels(both P<0.01).We explored the association between quantitative measures of plasma Hcy and UA levels and SCAF using restricted cubic spline analysis in order to stratify participants into low and high-risk groups based on the new reference values of Hcy and UA.The cut-point for UA was 420 μmol/L in men,and 320 μmol/L in women,respectively.Whereas the cut-off points for Hcy 14 μmol/L in men and 12 μmol/L in women,respectively.On multivariable Cox regression analysis with potential confounders,elevated Hcy and UA biomarkers were significantly associated with an increased risk of SCAF.A rise in 1 SD of Hcy(5.7μmol/L)was associated with an increased risk of SCAF in men and women regardless of their UA levels.Similarly,1-SD increase of UA(91 μmol/L)was associated with an increased risk of SCAF among the patients with high levels of Hcy in men(HR: 1.81,95%CI: 1.43-2.30)and women(HR: 2.11,95%CI: 1.69-2.62).We performed ROC analysis to determine the diagnostic utility of the biomarkers(Hcy and UA)and traditional AF risk factors recommended by the 2020 ESC Guidelines(ESC model)to identify patients with SCAF.The AUC was 0.607(95%CI:0.579–0.634)for the ESC model.The combination of ESC model,Hcy and UA reached the highest AUC(0.717,95%CI: 0.691–0.742)followed by the models of risk factors and Hcy(0.691,95%CI: 0.664–0.717)and risk factors and UA(0.688,95%CI: 0.662–0.714).Moreover,the ESC model combined with Hcy and UA biomarkers yielded an increase of 25.7% in NRI and 11.3% in IDI(P<0.001).Conclusion: Four main conclusions can be drawn from this study.First,higher serum levels of Hcy or UA were associated with SCAF in patients with CIEDs,independent of traditional risk factors,and other baseline prognostic factors.Second,a positive association was found between Hcy serum levels and UA serum levels.Third,a significant interaction effect of homocysteine and uric acid for increasing the incidence of SCAF.Patients with both higher levels of the two biomarkers had the highest risk of developing SCAF.Last,the addition of Hcy and UA to the AF risk factors recommended by the 2020 ESC Guidelines significantly improved risk discrimination for SCAF. |
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