Atrial high‑rate episodes and risk of major adverse cardiovascular events in patients with dual chamber permanent pacemakers: a retrospective study

Patients with atrial high-rate episodes (AHRE) are at higher risk of major adverse cardiovascular events (MACE). The cutoff threshold for AHRE duration for MACE, with/without history of atrial fibrillation (AF) or myocardial infarction (MI), is unknown. A total of 481 consecutive patients with/without history of AF or MI receiving dual-chamber pacemaker implantation were included. The primary outcome was a composite endpoint of MACE after AHRE ≥ 5 min, ≥ 6 h, and ≥ 24 h. AHRE was defined as > 175 bpm (MEDTRONIC) or > 200 bpm (BIOTRONIK) lasting ≥ 5 min. Cox regression analysis with time-dependent covariates was conducted. Patients’ mean age was 75.3 ± 10.7 years and 188 (39.1%) developed AHRE ≥ 5 min, 115 (23.9%) ≥ 6 h, and 83 (17.3%) ≥ 24 h. During follow-up (median 39.9 ± 29.8 months), 92 MACE occurred (IR 5.749%/year, 95% CI 3.88–5.85). AHRE ≥ 5 min (HR 5.252, 95% CI 2.575–10.715, P < 0.001) and ≥ 6 h (HR 2.548, 95% CI 1.284–5.058, P = 0.007) was independently associated with MACE, but not AHRE ≥ 24 h. Patients with history of MI (IR 17.80%/year) had higher MACE incidence than those without (IR 3.77%/year, p = 0.001). Significant differences were found between MACE patients with/without history of AF in AHRE ≥ 5 min but not AHRE ≥ 6 h or ≥ 24 h. Patients with dual-chamber pacemakers who develop AHRE have increased risk of MACE, particularly after history of AF or MI.

. Baseline characteristics of the overall study group. Data are presented as mean ± SD or median, IQR or n (%). AF atrial fibrillation, AHRE atrial high-rate episodes, BMI body mass index, EF ejection fraction, IQR interquartile range, LA left atrium, LVEF left ventricular ejection fraction, RV right ventricle, non-DHP CCBs non-dihydropyridine calcium channel blockers, RAAS renin-angiotensin-aldosterone system, SGLT2 sodium glucose co-transporters 2.    www.nature.com/scientificreports/ or other supraventricular tachy-arrhythmias and visually verified AF in the detected AHRE. Atrial sensitivity was initially programmed to 0.2 mV with bipolar sensing of BIOTRONIK and 0.3 mV with bipolar sensing of MEDTRONIC.
The primary endpoint for this study was the occurrence of MACE as recorded in patients' charts after the date of implantation of pacemakers, including ST elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), unstable angina, heart failure with acute exacerbation 4 , cardiovascular hospitalization (peripheral artery disease or stable angina) and cardiac death. AHRE was defined as atrial rate > 175 bpm (MEDTRONIC) or > 200 bpm (BIOTRONIK) and lasting for at least 5 min of atrial tachyarrhythmia recorded by the devices on any day during the study period. We also divided the different AHRE durations by time, including ≥ 5 min, ≥ 6 h and ≥ 24 h, to evaluate the cutoff threshold for MACE. If the patient had multiple AHREs, the longest AHRE duration was used for analysis. Then, if the patient's longest AHRE duration was 24 h, this patient would be counted in AHRE ≥ 5 min, ≥ 6 h, and ≥ 24 h. Statistical analysis. Among baseline characteristics, categorical variables are presented as percentages.
Continuous variables are presented as means and standard deviations if normally distributed and median, interquartile range (IQR) if not normally distributed. Chi-square test or Fisher's exact test was used for categorical variables, and a 2-sample student's t test for normally distributed continuous variables or Mann-Whitney U test if not normally distributed. The receiver-operating characteristic (ROC) area under the curve (AUC) of AHRE and the associated 95% confidence intervals (CI) were investigated for associations with future MACE. The cutoff values were chosen based on the results of ROC curve analysis and used to evaluate the associated values of AHRE, in minutes, for determining endpoints. Cox regression analysis was used to identify variables associated with AHRE occurrence, reported as hazard ratios with 95% confidence intervals (CI). Indicators of AHRE ≥ 5 min, ≥ 6 h, and ≥ 24 h were determined separately as time-dependent covariates in multivariable Cox proportional hazards regression and survival curves were generated for patients without MACE. If the p value in univariable analysis was < 0.05, the parameter was entered into multivariable analysis, except for devices, which were essential confounders because of different detecting rates in AHRE definitions. Because LVEF was significantly associated with heart failure (Tables 3 and 4), heart failure was selected for inclusion into multivariable analysis. Because mitral E/e' ratio was significantly associated with LA diameter, LA diameter was selected for inclusion into multivariable analysis. Because drug history was significantly associated with history of heart failure and myocardial infarction, it was not entered into multivariable analysis. Only mitral E/e' ratio of echocardiographic parameter was included in multivariable analysis (Table 5). For all comparisons, p < 0.05 was considered statistically significant. All data were analyzed using SPSS statistical package version 23.0 (SPSS Inc. Chicago, IL, USA). Ethics approval and consent to participate. This study was approved by the ethics committee of National Cheng Kung University Hospital and was conducted according to the guidelines of the International Conference on Harmonization for Good Clinical Practice. All patients provided written informed consent before enrollment. Consent for publication. All patients provided signed informed consent before enrollment.

Results
Between January 1, 2014 and August 31, 2019, a total of 498 patients receiving dual chamber permanent pacemaker at our hospital were initially recruited. Seventeen patients were excluded due to loss of follow-up, inadequate or missing data and not providing informed consent. Therefore, the data of 481 patients were finally included as the analytic sample for this retrospective study. The mean follow-up period was 39.9 ± 29.8 months after the implantation of dual chamber permanent pacemakers.

Univariable and multivariable Cox regression analysis of associations between duration of AHRE and MACE in all patients.
Univariable analysis revealed that the CHA2DS2-VASc score and HAS-BLED score for stroke risk; diabetes mellitus, hyperlipidemia, history of MI, heart failure, and chronic kidney disease; LV ejection fraction, mitral E/e ratio; LA diameter; RV systolic function, and AHRE duration ≥ 5 min, ≥ 6 h and ≥ 24 h; were significantly associated with MACE occurrence in all patients (

Univariable and multivariable Cox regression analysis of associations between AHRE duration and MACE in patients with or without history of AF.
In the subgroup of patients with or without history of atrial fibrillation, multivariate Cox regression analysis showed that AHREs ≥ 5 min were significantly associated with MACEs in patients without history of AF (HR 4.266, 95% CI 1.856-9.805, p = 0.001) as same as heart failure reduced ejection fraction (HR 5.729, 95% CI 1.917-17.301, P = 0.002) ( Table 4). For patients with history of AF, only AHREs ≥ 5 min (HR 18.383, 95% CI 2.006-168.428, p = 0.010) has significant difference ( Table 5). Both patients demonstrated that AHREs ≥ 6 h and AHREs ≥ 24 h had no significant difference with MACEs.

Univariable and multivariable Cox regression analysis of associations between duration of AHRE and MACEs in patients with or without history of MI. Multivariate Cox regression analy-
sis showed that AHRE ≥ 5 min (HR 4.086, 95% CI 1.638-10.192, p = 0.003), AHRE ≥ 6 h (HR 2.756, 95% CI 1.166-6.517, p = 0.021) and AHRE ≥ 24 h (HR 3.348, 95% CI 1.359-8.243, p = 0.009) were all significantly associated with MACE in patients without history of MI (Table 6), but only AHRE ≥ 5 min (HR 10.370, 95% CI 2.860-37.595, p < 0.001) were significantly associated with MACE in patients with history of MI (Table 7). Other risk factor such as heart failure reduced ejection was also independently associated with MACE in patients with all three AHRE durations without history of MI.

Freedom from MACE.
We divided the duration of AHREs into five groups. No AHRE, AHRE < 5 min, AHRE ≥ 5minutes and < 6 h, AHRE ≥ 6 h and < 24 h, and AHRE ≥ 24 h for all patients and with history of AF, history of MI or not. Cox regression survival analysis of all patients showed that only AHRE ≥ 5 min and < 6 h were significantly different compared with patients with no AHRE (Fig. 2). No significant differences were found between patients with no AHRE and any specific duration of AHRE in patients with history of AF. For patients without history of AF, only those with AHRE ≥ 6 h and < 24 h showed significant differences between AHRE duration and MACE occurrence. For patients without history of MI, only AHRE > 24 h had significant differences between AHRE duration and MACE occurrence. In patients with history of MI, AHRE ≥ 5 min and < 6 h, AHRE ≥ 6 h and < 24 h had significant differences between AHRE duration and occurrence of MACE.

Discussion
The present 'real world' cohort study of the associations between different cutoff durations of AHRE and the incidence rates of MACE in patients with dual chamber permanent pacemakers with or without history of AF or MI revealed that (1) 4 and heart failure 10 , which depends upon the AHRE burden and duration in individual patients. However, in the present study, no linear relationship was found between duration of AHRE and development of MACE. Although AHRE ≥ 5 min and ≥ 6 h were independently associated with MACE, AHRE ≥ 24 h was not. However, in a study with a similar objective, Pastori et al. 4 found that patients implanted with CIEDs who develop AHRE had a significantly elevated risk of MACE, and that the incidence rate of MACE occurring after AHRE onset was higher in patients with AHRE ≥ 24 h. Although this may correspond with our suggestion that patients with the longest duration of AHRE may be at greater risk of MACE, we did not show this definitively, most likely due to our smaller sample and different definition of MACE.
Results of Pastori et al. 4 agreed with our results showing that AHRE ≥ 5 min, diabetes and heart failure were independent predictors of MACE. In the present study, we also found that hypertension, hyperlipidemia, history of AF, chronic kidney disease, and increased LA diameter were all significantly associated with the occurrence of AHRE. We also found that patients with MEDTRONIC devices have more frequent occurrence of AHRE than those with BIOTRONIK devices (p < 0.05), which may be due to different default settings for detecting AHRE.
In patients with implantable devices and with no history of AF, device-detected AHRE can predict long-term mortality outcomes 11 , and are known to be associated with increased risk of clinical AF, stroke, and thromboembolic events 12 . In the present study, we found that in patients with history of MI, only those with AHRE ≥ 5 min were independently associated with MACE, and for those without history of MI, AHRE ≥ 5 min, ≥ 6 h and ≥ 24 h were all independently associated with MACE. These results suggest that the cutoff value of AHRE may be lower in patients with history of MI than in patients without history of MI, even though the ROC-AUC analysis showed that the optimal cut-off was 5 min.
Three proposed mechanisms of MACE in patients with AF included: (1) both atherosclerosis and inflammatory process yield a pro-thrombotic state; (2) direct coronary thromboembolism from left atrial appendage; and (3) tachycardia episodes resulting in a supply-demand mismatch 13 . However, while AHRE, viewing as subclinical AF, is also recognized as an important clinical entity, therefore it may not always be considered in patients with stroke or transient ischemic attack. As such, AHRE duration remains an important target of research. Future larger prospective studies are needed to explore which duration of AHRE may be the standard cutoff for further evaluation of MACE in patients with AHREs.
Most previous AHRE studies excluded patients with AF history 4,10,14 . We tried evaluating patients with and without AF history in order to identify possible differences. The results showed that only AHRE ≥ 5 min was independently associated with development of MACE, suggesting that in patients with documented history of AF, AHRE may have no important role in the occurrence of MACE.
The other issue we noted was about using anticoagulants in patients with AHRE, even though such a large review of data is not warranted. When we come across a patient with AHRE ≥ 5-min and CHA2DS2-VASc scores > 2 in our daily practice, we follow the current recommendation of 2016 ESC guideline 15 . At the third Joint Consensus Conference of the German Atrial Fibrillation Network (AFNET) and the European Heart Rhythm Association on AF, an algorithm was proposed for management of patients with AHRE 16 . Current updated guidelines recommend that in patients with AHRE ≥ 24 h, clinicians should view them with regard to AF and initiate treatment with a DOAC based on CHA2DS2-VASc scores in order to prevent stroke 16 . Evidence of MACE prevention in AHRE patients is lacking. Results of one study showed that DOAC therapy reduced MI compared with VKA therapy in AF patients 17 . However, other study data showed that the presence of AF was independently associated with a heightened risk of MI despite a lower baseline burden and progression rate of    www.nature.com/scientificreports/ supporting an association between risk and new onset AHRE. Two large ongoing trials (NOAH-AFNET 6 and ARTESiA) 21,22 will address unmet needs regarding the effectiveness of edoxaban and apixaban for stroke and systemic embolism in patients with AHRE. Further studies are needed to focus on this issue and determine definitively whether patients with new-onset AHRE are at greater risk of MACE, including AF. Previous studies 23,24 have shown that AHREs were associated with thromboembolic events in Asian patients. Moreover, two proposed models postulated that atrial cardiomyopathy might play a key role between AHRE and the risk of future ischemic stroke 25,26 . Systemic vascular risk factors accompanied aging can lead to abnormal atrial substrates subsequently resulting in atrial cardiomyopathy, which interacts with hypercoagulability and may be related to atrial dilatation, atrial inflammation/fibrosis, endothelial dysfunction, and/or mechanical dysfunction.
Limitations. The present study has several limitations. First, this is a single-center, retrospective, and observational study in a hospital-based setting with a relatively small number of included patients, and all patients were Taiwanese. As a result, causality cannot be inferred between AHRE and MACE and results may have been affected by confounding factors. Also, results cannot likely be generalized to other populations. Second, AHRE may have been underestimated due to different default settings for AHRE in devices designed by different companies. The device was viewed as a confounder in the multivariable analysis and was not an independent factor for MACE. Prospective multicenter studies with larger samples are required to confirm results of the present study.

Conclusion
Patients with dual chamber pacemakers who develop AHRE have significantly increased risk of MACE, particularly those with history of AF or history of MI. However, although this patient population is at increased risk of MACE, the impact on MACE by different cutoff points for AHRE duration in different subpopulations such as those with history of AF or MI must be considered when evaluating risk. Patients with or without history of AF history may have the same cutoff for predicting MACE, but those with MI history may have a lower cutoff point than those without MI.