Atrial high-rate episodes predict major adverse cardio/cerebrovascular events in patients with cardiac implantable electrical devices

Patients with atrial high-rate episodes (AHRE) have a high risk of neurologic events, although the causal role and optimal cutoff threshold of AHRE for major adverse cardio/cerebrovascular events (MACCE) are unknown. This study aimed to identify independent factors for AHRE and subsequent atrial fibrillation (AF) after documented AHRE. We enrolled 470 consecutive patients undergoing cardiac implantable electrical device (CIED) implantations. The primary endpoint was subsequent MACCE after AHRE ≥ 6 min, 6 h, and 24 h. AHRE was defined as > 175 beats per minute (bpm) (Medtronic®) or > 200 bpm (Biotronik®) lasting ≥ 30 s. Multivariate Cox regression analysis with time-dependent covariates was used to determine variables associated with independent risk of MACCE. The patients’ median age was 76 year, and 126 patients (26.8%) developed AHRE ≥ 6 min, 63 (13.4%) ≥ 6 h, and 39 (8.3%) ≥ 24 h. During follow-up (median: 29 months), 142 MACCE occurred in 123 patients. Optimal AHRE cutoff value was 6 min, with highest Youden index for MACCE. AHRE ≥ 6 min ~ 24 h was independently associated with MACCE and predicted subsequent AF. Male gender, lower body mass index, or BMI, and left atrial diameter were independently associated with AHRE ≥ 6 min ~ 24 h. Patients with CIEDs who develop AHRE ≥ 6 min have an independently increased risk of MACCE. Comprehensive assessment of patients with CIEDs is warranted.

Ethical considerations. The protocol for this cohort study was reviewed and 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 (B-ER-108-278). All patients provided signed informed consent at the time of their implantation procedures for data to be recorded for later publication. 4 . Patients' medical histories and data of co-morbidities and echocardiographic parameters were collected from chart records for retrospective evaluation. Diabetes mellitus was defined by the presence of symptoms and casual plasma glucose concentrations ≥ 200 mg/dL, fasting plasma glucose concentrations ≥ 126 mg/dL, 2-h plasma glucose concentrations ≥ 200 mg/dL from a 75-g oral glucose tolerance test, or when the patient was taking medication for diabetes mellitus. Hypertension was defined as inoffice systolic blood pressure values ≥ 140 mmHg and/or diastolic blood pressure values ≥ 90 mmHg, or when the patient was taking antihypertensive medication. Dyslipidemia was defined as: low-density lipoprotein ≥ 140 mg/ dL, high-density lipoprotein < 40 mg/dL, triglycerides ≥ 150 mg/dL, or when the patient was taking medication for dyslipidemia. Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/ min/1.73 m 2 for at least 3 months.

Data collection and definitions
The primary endpoint for this study was the occurrence of MACCE after the date of CIED implantation, including ST elevation MI, non-ST elevation MI, unstable angina, systemic thromboembolism, sustained ventricular tachycardia/fibrillation, cerebrovascular events, including stroke or TIA diagnosed by experienced neurologists, or death (cardiac and non-cardiac).
AHRE were extracted from the devices via telemetry at each office visit (3 ~ 6 months). AHRE electrograms were reviewed by at least one experienced electrophysiologist, who carefully considered the possibility that AHRE included lead noise or artifacts, far-field R-waves, paroxysmal supraventricular tachycardia, and visually confirmed AF in the detected AHRE. Atrial sensitivity was programmed to 0.3 mV with bipolar sensing of Medtronic devices and 0.2 mV with bipolar sensing of Biotronik devices. AHRE was defined as heart rate > 175 bpm (Medtronic) or > 200 bpm (Biotronik) and at least 30 s of atrial tachyarrhythmia recorded by the devices on any day during the study period. In order to evaluate the cutoff threshold for primary endpoints, AHRE was categorized by duration: ≥ 6 min ≥ 6 h and ≥ 24 h. If patients had multiple AHREs, the longest AHRE duration was used for analysis. If a patient's longest AHRE duration was 8 min, the result was counted as AHRE ≥ 6 min and ≥ 6 h. Statistical analysis. Categorical variables are presented as percentages, continuous variables as means, and standard deviations for normally distributed values or medians, and interquartile interval (IQI) for non-normally distributed values. The normal distribution for continuous variables was assessed using the Kolmogorov-Smirnov method. Pearson's chi-square test or Fisher's exact test was used to determine differences in baseline characteristics for categorical variables, and a two-sample student's t-test or Mann-Whitney U-test was used to analyze continuous variables. Multivariate Cox regression analysis was used to identify variables associated with MACCE occurrence, reported as hazard ratios (HR) with 95% confidence intervals (CI). If the p-value in univariable analysis was < 0.05, the parameter was entered into multivariable analysis. Indicators of AHRE ≥ 6 min, 6 h, and 24 h were determined separately as time-dependent covariates in multivariate Cox proportional hazards regression. Because CHA 2 DS 2 -VASc scores overlapped many factors in univariate analysis, it was used as an www.nature.com/scientificreports/ independent factor in multivariate Cox regression analysis in model B (Table 3). Multivariate logistic regression analysis was used to identify variables associated with subsequent AF and AHRE occurrence, because we could not confirm the time to subsequent AF and AHRE, reported as hazard ratios (HR) with 95% confidence intervals (CI). If the p-value in univariable analysis was < 0.05, the parameter was entered into multivariable logistic analysis. The receiver-operating characteristic (ROC) area under the curve (AUC) of AHRE, and the associated 95% confidence intervals (CI) were evaluated for association with future MACCE and new-onset AF after CIED implantation. The optimal cutoff values with the highest Youden index were chosen based on the results of ROC curve analysis and used to evaluate the associated values of AHRE, in minutes, for determining endpoints. 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).

Independent factors associated with different AHRE durations.
Univariate analysis revealed that male gender, ventricular pacing percentage, hypertension, hyperlipidemia, chronic kidney disease, and left atrial diameter were significantly different between AHRE ≥ 6 min to 24 h (data not shown). Multivariate logistic regression analysis revealed that only left atrial diameter was consistently and independently associated with the occurrences of AHRE ≥ 6 min to 24 h (Table 5).

Discussion
The main finding of this study is that AHRE lasting ≥ 6 min, ≥ 6 h or ≥ 24 h were significantly and independently associated with MACCE in a Taiwanese population with CIEDs and no history of AF. The optimal cutoff value of AHRE for subsequent MACCE and AF was 6 min. Increased LA diameter was independently associated with www.nature.com/scientificreports/ www.nature.com/scientificreports/ AHRE duration ≥ 6 min ~ 24 h. These results suggest that early detection of AHRE ≥ 6 min and measurement of LA diameter in patients with CIEDs will allow for early, aggressive therapy to prevent MACCE. This study was conducted because the optimal cutoff for AHRE duration to predict subsequent MACCE in patients with CIEDs had not been well studied previously and predictive factors were not well established. Sometimes, an exceptionally short duration of atrial tachyarrhythmias may be misclassified as AHRE, due to artifacts and false detection of far-field R-waves by the atrial lead. Current ESC guidelines 11 recommend that AF can only be diagnosed by 12-lead electrocardiography or by more than 30 s in an ECG strip. The updated ESC guidelines 11 also recommend that if AHRE ≥ 6 min with high CHA 2 DS 2 -VASc score or AHRE ≥ 24 h occurs, more aggressive monitoring of clinical AF is highly warranted. Although most previous studies have focused on systemic embolic events or neurological events occurring after AHRE, more recent studies have found that MACE, including ventricular tachyarrhythmias 6,8 , heart failure 6 , MI 6 , and cardiovascular death 6 , was also strongly associated with AHRE. Also, the use of different settings for AHRE detection is an important limitation when comparing results between these studies. Vergara et al. 8 used 200 beats/min as the threshold rate, and Pastori et al. 6 used 175 beats/min and lasting ≥ 5 min. In the present study, AHRE was defined as heart rate > 175 bpm (Medtronic) or > 200 bpm (Biotronik), and at least 30 s of atrial tachyarrhythmia recorded by the CIEDs on any day during the study period. All study results showed that AHRE was a significant risk factor for future MACE, even with different settings for AHRE detection. Only the present study has demonstrated that AHRE is an independent risk factor for MACCE, and the optimal cutoff value for predicting MACCE is 6 min.
Several pathophysiological mechanisms of MACCE in AHRE have been described, including: (1) AHRE is a precursor of AF, leading to direct coronary or systemic thromboembolism from the left atrium or left atrial appendage; (2) AHRE is associated with multiple atherosclerotic risks and associated inflammatory process, yielding a pro-thrombotic state; and (3) AHRE results in a supply-demand mismatch between the coronary system and heart function 20 .However, while AHRE may not be the only consideration in patients with neurologic events, AHRE duration remains an important area of research for MACCE. Future larger-scale studies are needed to explore AHRE duration cutoffs, with the goal of establishing a standard cutoff for further evaluation of MACCE in patients with AHRE.
The threshold of AHRE for subsequent clinical AF is an important issue in primary care for patients with CIEDs. A recent Japanese study showed that AHRE lasting ≥ 30 s (the shortest AHRE duration reported to date) is a risk factor for ischemic stroke 12 . However, a 5-min cut-off value excludes most misclassified episodes of oversensing or artifacts, and appropriately detects clinical AF 21 . Our study is the first to report that AHRE ≥ 6 min is an independent risk factor for subsequent AF in a Taiwanese population with CIEDs without a history of AF. The percentages of AF occurrence increased as the AHRE duration increased from ≥ 6 min [19.0% (24/126)] to ≥ 24 h [35.9% (14/39)] (data not shown). Early identification of patients with AHRE ≥ 6 min is critical in the clinical detection of AF, and supports a management strategy including early stroke prevention measures.
Awareness of risk factors that contribute to the occurrence of AHRE ≥ 6 min ~ 24 h is clinically relevant to early prevention in CIEDs patients. Previous studies [17][18][19] identified several predictors for AHRE, and the common predictive factor in these studies was increased LA diameter 17,18 . A Korean study 17 demonstrated that LA > 41 mm was significantly associated with occurrence of AHRE ≥ 6 min, and an Indian study reported increased LA diameter contributed to prolonged AHRE 18 . In the present study, increased LA diameter was consistently and significantly associated with AHRE ≥ 6 min to 24 h, comparable to results of the two studies mentioned before 17,18 . Results suggest that, before implantation of CIEDs, evaluation of patients' echocardiographic parameters must include measurement of LA size, which may lead to early prediction of AHRE ≥ 6 min-a strong predictor for subsequent AF and MACCE.
Limitations. This study has several limitations. First, this was a single-center, retrospective, observational study with a relatively small number of patients with CIEDs in a hospital setting, and all patients were Taiwanese. As a result, causality cannot be inferred between AHRE and MACCE, and the presence of confounding factors cannot be denied. Also, the results may not be generalizable to other populations. Second, AHRE may have been under-or overestimated due to the default settings in devices designed by different companies, including only Medtronic and Biotronik, used in the present study. Prospective multicenter studies with larger samples are required to confirm the results of this study. Third, this study did not investigate the nature of heart rhythms at the time of the onset of MACCE. Multivariate analysis (model A in Table 3) showed none of the traditional risk factors (DM, HTN, hyperlipidemia, prior MI) were found to be significantly associated with increased MACCE, which left us to wonder whether there was an interaction between these risk factors and AHRE. Finally, in this retrospective analysis of patient data, we could not confirm that patients started anticoagulants due to AHRE detection by the device, although these patients were not excluded because no significant differences were found between anticoagulants use and presence (8, 6.5%) or absence (34, 9.8%) of MACCE (p = 0.271), as shown in Table 1.

Conclusions
MACCE are not uncommon in Taiwanese patients after CIEDs implantation. Episodes of AHRE lasting ≥ 5 min to ≥ 24 h were independent risk factors for MACCE in this population during mid-term follow-up. When AHRE ≥ 5 ~ 6 min is detected in patients with CIEDs, long-term monitoring is advisable, to detect clinical AF as well as to perform comprehensive assessment of MACCE risk using CHA 2 DS 2 -VASc score and echocardiographic study (especially LA size). Our results suggest that early detection of AHRE ≥ 6 min and measurement of LA diameter in patients with CIEDs allows early recognition of the risk of future AF and MACCE. More investigations during early and aggressive antithrombotic therapy in patients with AHRE ≥ 6 min to prevent MACCE are warranted.

Consent to participate. All patients provided signed informed consent at the time of CIEDs implantation
for their data to be recorded for later publication.