HATCH Score and Left Atrial Size Predict Atrial High-Rate Episodes in Patients With Cardiac Implantable Electronic Devices

Background: Patients with sustained atrial high-rate episodes (AHRE) have a high risk of major adverse cardio/cerebrovascular events (MACCE). However, the prediction model and factors for the occurrence of AHRE are unknown. We aimed to identify independent factors and various risk models for predicting MACCE and AHRE. Methods: We retrospectively enrolled 314 consecutive patients who had cardiac implantable electronic devices (CIEDs). The primary endpoint was MACCE after AHRE ≥3, 6 min, and 6 h. Atrial high-rate episodes was defined as >175 bpm (Medtronic®) lasting ≥30 s. Multivariate Cox and logistic regression analysis with time-dependent covariates were used to determine variables associated with independent risk of MACCE and occurrence of AHRE ≥3 min, respectively. Results: One hundred twenty-five patients (39.8%) developed AHRE ≥3 min, 103 (32.8%) ≥6 min, and 55 (17.5%) ≥6 h. During follow-up (median 32 months), 77 MACCE occurred (incidence 9.20/100 patient years, 95% CI 5.66–18.39). The optimal AHRE cutoff value was 3 min for MACCE, with highest Youden index 1.350 (AUC, 0.716; 95% CI, 0.638–0.793; p < 0.001). Atrial high-rate episodes ≥3 min−6 h were independently associated with MACCE. HATCH score and left atrial diameter were independently associated with AHRE ≥3 min. The optimal cutoff for HATCH score was 3 and for left atrial diameter was 4 cm for AHRE ≥3 min. Conclusion: Patients with CIEDs who develop AHRE ≥3 min have an independently increased risk of MACCE. Comprehensive assessment using HATCH score and echocardiography of patients with CIEDs is warranted.


INTRODUCTION
All cardiac implantable electronic devices (CIEDs), including dual-chamber pacemakers; dual-chamber implantable cardioverter defibrillators; cardiac resynchronization therapy; and resynchronization-defibrillator, if an atrial lead is present, may record atrial tachyarrhythmias. Pacemaker-detected atrial high-rate episodes (AHRE), are predictors for atrial fibrillation (AF)    (1) and major cardiovascular events (MACCE), including myocardial infarction, coronary revascularization, ventricular tachyarrhythmia, cardiovascular or heart failure hospitalization, and cardiovascular death (2)(3)(4)(5)(6)(7). Therefore, the latest guidelines (8) recommend that AHRE be closely monitored and treated. However, the prediction of CIED-detected AHRE for MACCE has not been sufficiently assessed. The cutoff value for AHRE duration that is associated with increased risk of MACCE remains controversial. The European Society of Cardiology guidelines state that non-valvular AF (8) with AHRE >5-6 min and >180 bpm increase the risk for ischemic stroke, but the risk for MACCE is unknown. Atrial high-rate episodes lasting ≥30 s (2) also has been shown associated with increased risk of stroke. These differences in cutoff values suggest that patients with implanted CIEDs should undergo regular assessment for detection of AHRE (8), and those with AHRE should undergo further rhythm assessment (including Abbreviations: AF, atrial fibrillation; AHRE, atrial high-rate episodes; CIEDs, cardiac implantable electronic devices; MACCE, major adverse cardio/cerebrovascular events; TIA, transient ischemic attacks. long-term electrocardiographic monitoring) for MACCE risk factors.
Several risk scoring systems for predicting AF, including CHA 2 DS 2 -VASc score (9), C 2 HEST score (10), and HATCH (11,12) have been evaluated, but only C 2 HEST score has been evaluated for sustained AHRE >24 h (13). Independent predictors for AHRE in patients with dual-chamber pacemakers include sick sinus syndrome (14), increased left atrial diameter (14,15), paced QRS duration (15), prior AF and inflammatory markers (16), and C 2 HEST score (13). However, a metaanalysis of 28 studies with 24,984 patients revealed that patients' baseline characteristics of advanced age, lower resting heart rate, diabetes, hypertension, coronary artery disease, stroke and thromboembolic events, congestive heart failure, increased left atrial diameter, and even CHADS 2 scores were not associated with device-detected AHRE (17). These results suggest that predictors of AHRE are not well-established, and additional study is needed to identify independent predictors.
The present study investigated the optimal cutoff durations of AHRE for MACCE in patients who had CIEDs but no history of AF, and assessed independent predictive factors and validation of risk-prediction scoring systems (CHA 2 DS 2 -VASc score, HASBLED score, C 2 HEST score, and HATCH score) for AHRE in such patients.

METHODS
Consecutive patients aged 18 years or older who had CIEDs implanted (Medtronic R dual chamber pacemaker, dual chamber implantable cardioverter defibrillator, cardiac resynchronization therapy-pacing, or cardiac resynchronization therapy-defibrillator) in the Cardiology Department of National Cheng Kung University Hospital from January 2015 to April 2021 were included. Every time of interrogation data of CIEDs of each enrolled patients were saved in a chart-record system in our hospital.

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 guidelines of the  International Conference on Harmonization for Good Clinical Practice (B-ER-108-278). All included patients provided signed informed consent at the time of their implantation procedures for data to be recorded for later publication.

Data Collection and Definitions
Patients' medical history and data of co-morbidities and echocardiographic criteria were collected from chart records for retrospective evaluation. Diabetes mellitus was defined by the presence of symptoms and casual plasma glucose concentration ≥200 mg/dl, fasting plasma glucose concentration ≥126 mg/dl, 2-h plasma glucose concentration ≥200 mg/dl from a 75-g oral glucose tolerance test, or taking medication for diabetes mellitus. Atrial high-rate episodes were extracted from the devices via telemetry at each office visit (3-6 months). Atrial high-rate episodes electrograms were reviewed by at least one experienced electrophysiologist, who excluded lead noise or artifacts, far-field R-waves, paroxysmal supraventricular tachycardia, and visually confirmed AF that had been recorded as AHRE. Atrial sensitivity was programmed to 0.3 mV with bipolar sensing of Medtronic devices. Atrial high-rate episodes was defined as heart rate >175       Components of primary endpoints, including MACCE, time to primary endpoints, incidence rates, and distribution of MACCE, are reported in Table 2. The total number of MACCE was 77 (incidence rate 9.20/100 patient-years, 95% CI 5.66-18.39). The endpoints were acute coronary syndrome, systemic thromboembolism events, and all-cause mortality. We also compared the incidence rates between the patients with or without AHRE in Table 2. The patients with AHRE had higher incidence rates of MACCE than those without AHRE.

DISCUSSION
The main finding of this study is that AHRE lasting ≥3, ≥6 min, or ≥6 h is significantly and independently associated with MACCE in a Taiwanese population having CIEDs and no history of AF. The optimal cutoff value of AHRE for subsequent MACCE was 3 min. Increased left atrial diameter and HATCH score were independently associated with AHRE duration ≥3 min. These results suggest that early detection of AHRE ≥3 min and measurement of left diameter and calculation of the HATCH score in patients with CIEDs is warranted to prompt early, aggressive therapy to prevent MACCE.
This study was conducted because the optimal cutoff for AHRE duration to predict MACCE in patients with CIEDs had not been well-studied, and predictive factors were not established. Sometimes, a relative short-duration of atrial tachyarrhythmias, such as <30 s, may be misclassified as AHRE due to artifacts and false detection of far-field R-waves by the atrial lead. European Society of Cardiology guidelines (8) recommend that AF can only be diagnosed by 12-lead electrocardiography or more than 30 s in an electrocardiographic strip. The updated guidelines (8) also recommend that if AHRE ≥6 min with high CHA 2 DS 2 -VASc score or AHRE ≥24 h occur, more aggressive monitoring of clinical AF is warranted.
Although most studies have focused on systemic embolic or neurological events occurring after AHRE, more recent studies have found that MACCE, including ventricular tachyarrhythmias (6,7), heart failure (6), myocardial infarction (6), and cardiovascular death (6), also were associated with AHRE ≥5 min, and the association was even stronger for AHRE ≥24 h. Also, the use of different settings for AHRE detection is an important factor that can affect results between these studies. Pastori et al. (6) used 175 beats/min, and Vergara et al. (7) used 200 beats/min as threshold rate. We used 175 beats/min (Medtronic), and at least 30 s of atrial tachyarrhythmia recorded by the CIEDs on any day during the study period. Atrial high-rate episodes ≥3, ≥6 min, and ≥6 h were all significant risk factors for future MACCE. Only the present study has demonstrated that AHRE is an independent risk factor for MACCE, and the optimal cutoff value for predicting MACCE is 3 min.
Several pathophysiological mechanisms of AHRE in MACCE have been proposed (18): (1) AHRE as a precursor of AF, leading to coronary or systemic thromboembolism from the left atrium or left atrial appendage, resulting in acute coronary syndrome or neurologic events; (2) AHRE associated with multiple atherosclerotic risks and associated inflammatory process, yielding a pro-thrombotic state; and (3) AHRE resulting in a supply-demand mismatch between the coronary system and heart function. Hence, the relationship of AHRE duration and MACCE is an Awareness of risk factors that contribute to the occurrence of AHRE ≥3 min is important for early prevention in patients with CIEDs. Previous studies (13)(14)(15)(16)(17) identified several predictors for AHRE; a consistent predictive factor was increased left atrial diameter (14,15). The Korean study (14) demonstrated that left atrial diameter >41 mm was associated with AHRE ≥6 min, and the Indian study (15) reported that increased left atrial diameter contributed to prolonged AHRE. In the present study, increased left atrial diameter was consistently and significantly associated with AHRE ≥3 min, a finding compatible with results of the two studies above. Our results suggest that evaluation of patients' echocardiographic features before implantation of CIEDs should include measurement of left atrial size, which may provide early prediction of AHRE ≥3 min-a strong predictor for MACCE.
Risk scoring systems, such as CHA 2 DS 2 -VASc score (9), C 2 HEST score (10), and HATCH score (11,12), have been evaluated for predicting AF, but only the C 2 HEST score was evaluated for sustained AHRE >24 h (13). We found that the HATCH score independently predicted sustained AHRE ≥3 min (HR 1.546, p < 0.001), but the CHA 2 DS 2 -VASc score and the C 2 HEST score did not. We found also that the percentage of AHRE ≥3 min increased with increasing HATCH score. Recently, Li et al. (19), in China, modified the mC 2 HEST score (adding age ≥65 years as one point), which increased the predictive accuracy and discriminative capability for incident AF.
We also evaluated the performance of the mC 2 HEST score but found it not as suitable as the HATCH score (data not shown).

LIMITATIONS
Our study has 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. Thus, 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. Thus, prospective multicenter studies with larger samples are required to confirm the results of this study. Second, this study did not investigate the nature of heart rhythms at the time of onset of MACCE. Third, in this retrospective analysis of patient data, we could not confirm that patients started anticoagulants due to CIED-detected AHRE, although these patients were not excluded because no significant differences were found between anticoagulants use and the presence (5, 6.5%) or absence (25, 10.5%) of MACCE (p = 0.293), as shown in Table 1.

CONCLUSIONS
Major cardiovascular events are not uncommon in patients after implantation of CIEDs. Episodes of AHRE lasting ≥3 min to ≥6 h are independent risk factors for MACCE in this population during mid-term follow-up. When AHRE ≥3 min is detected in patients with CIEDs, long-term monitoring to detect clinical AF and comprehensive assessment of MACCE risk with HATCH score and echocardiography (to determine left atrial size) for risk stratification are indicated. Early detection of AHRE ≥3 min and measurement of left atrial diameter and calculation of HATCH score in patients with CIEDs may be warranted to prompt early, aggressive therapy and prevent MACCE.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by Institutional Review Board of National Cheng Kung University Hospital (B-ER-108-278).

AUTHOR CONTRIBUTIONS
J-YC: conception and design, data analysis and interpretation, statistical analysis, drafting and finalizing the article, and critical revision of the article for important intellectual content. T-WC and W-DL: data acquisition. All authors contributed to the article and approved the submitted version.