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Characteristics of Primary Bradyarrhythmia in Hypertrophic Cardiomyopathy: A 10-Year, Single-Center Analysis

Background: Secondary bradyarrhythmias in hypertrophic cardiomyopathy (HCM) have been extensively reported. The prevalence and characteristics of primary bradyarrhythmias in HCM have yet to be investigated. Methods: We retrospectively enrolled 101 consecutive patients with HCM who were referred to the arrhythmia center from May 2010 to October 2020. The clinical features of patients with bradyarrhythmias were analyzed. Results: Twenty-nine (28.7%) patients had primary bradyarrhythmias, and six (5.9%) patients had secondary third-degree atrioventricular block (AVB). Of the 29 patients, 17 (58.6%) had sinus node dysfunction (SND), 14 (48.3%) had AVB, and two (6.9%) had both SND and AVB. The median age was 62 years old, and 69% were male. Six (20.7%) patients had left ventricular obstructive outflow tract obstruction, 15 (51.7%) had a history of syncope, and one (3.4%) had a family history of HCM. Most patients (86.2%) had New York Heart Association functional class I or II, and the median left ventricular ejection fraction was 63%. A total of 22 patients received pacemaker implantation, including 17 (77.3%) dual-chamber pacing, four (18.2%) single-chamber ventricular pacing, and one (4.5%) cardiac resynchronization therapy. Conclusions: Primary bradyarrhythmias need to be evaluated in HCM patients with arrhythmia-related symptoms. Patients with HCM might need pacemaker implantation for primary bradyarrhythmias.


Introduction
Patients with hypertrophic cardiomyopathy (HCM) often experience different kinds of arrhythmias, including both tachyarrhythmias and bradyarrhythmias [1,2]. Atrial fibrillation is the most common, and ventricular fibrillation is the most fatal arrhythmia in HCM, and they have been extensively investigated [1][2][3][4]. Symptomatic bradycardia caused by sinus node dysfunction (SND) and atrioventricular block (AVB) is relatively uncommon in HCM [2]. Most studies on bradycardia focused on secondary third-degree AVB after either ventricular septal myectomy (the Morrow procedure) or percutaneous septal alcohol or radiofrequency ablation [5]. Few studies have evaluated the primary bradyarrhythmias in HCM. This study aimed to comprehensively investigate the characteristics of primary bradyarrhythmias in patients with HCM. The prevalence and characteristics of primary bradyarrhythmias in hypertrophic cardiomyopathy (HCM) have yet to be investigated. The results show that 29 (28.7%) of the enrolled patients with HCM had primary bradyarrhythmias. We suggest that primary bradyarrhythmias be evaluated in HCM patients with arrhythmia-related symptoms.

Study Population
Between May 2010 and October 2020, 101 consecutive patients with HCM who had arrhythmia-related symptoms were admitted to the Arrhythmia Center, Fuwai Hospital, 2 of 8 Beijing, for electrophysiological evaluation. The symptoms included palpitations, syncope, or presyncope. The final inclusion criteria included: (1) diagnosed with HCM; (2) primary SND or AVB. The exclusion criteria included: (1) secondary AVB due to ventricular septal myectomy or percutaneous septal alcohol ablation; (2) secondary SND or AVB due to drugs, intrinsic diseases other than cardiomyopathy, or extrinsic causes listed in the current HCM guidelines [6]. Whether the bradyarrhythmia was primary or secondary was adjudicated by three independent reviewers, two electrophysiologists from the Arrhythmia Center, and one expert from the Cardiomyopathy Center. This was conducted through a detailed chart review. This study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board and ethics committee on 6 December 2021 (Approval No. 2021-1574). Informed consent was obtained from all participants.

Diagnosis of HCM
HCM was defined by a wall thickness ≥15 mm in one or more left ventricular myocardial segments measured by echocardiography and/or cardiovascular magnetic resonance imaging (MRI), which was not explained solely by loading conditions [1,2]. In patients with intensive physical training, hypertension, or valve diseases, the diagnosis was made by at least two experts from the Cardiomyopathy Center based on additional information, including family history, noncardiac symptoms and signs, ECG abnormalities, laboratory tests, and multimodality cardiac imaging, especially cardiac MRI. In this study, all patients were evaluated by echocardiography, and nearly half of them were also assessed by cardiac MRI. Left ventricular outflow tract obstruction was defined as an instantaneous peak Doppler left ventricular outflow tract pressure gradient of ≥30 mmHg [1,2]. A gradient ≥50 mmHg was considered hemodynamically significant [1,2].

Diagnosis of SND and AVB
Bradyarrhythmias included in this study were SND and AVB. Bundle branch block was not included in this study. SND included sinus bradycardia and sinus node arrest. ABV included first-degree, second-degree, and third-degree AVB. At least two electrophysiologists made the diagnosis based on ECG and Holter monitoring.

Follow-Up
Patients were followed up by outpatient visits or telephone calls at 3 months, 6 months, 12 months, and every year thereafter. All-cause deaths and cardiac death events were recorded. The final census date for this study was 15 December 2021.

Statistical Analysis
Continuous variables are expressed as mean ± standard deviation (SD) or median (interquartile range (IQR)) as appropriate. Categorical parameters are shown as ratios or percentages. The Student's t-test or Mann-Whitney U test was conducted between two independent samples as appropriate for continuous data. The chi-square test was used for categorical data. A p-value of <0.05 was considered statistically significant. Data analyses were performed using R version 4.0.2. Figure 1 displays the spectrum of all arrhythmias. Of all 101 patients, 97 had arrhythmias, 35 had bradyarrhythmias, and 29 had primary bradyarrhythmias. Of the six patients with secondary third-degree AVB, five were due to the Morrow procedure, and one was due to percutaneous septal radiofrequency ablation. Of the 29 patients with primary bradyarrhythmias, 15 (51.7%) only had SND, 12 (41.4%) only had AVB, and two (6.9%) had both. due to percutaneous septal radiofrequency ablation. Of the 29 patients with primary bradyarrhythmias, 15 (51.7%) only had SND, 12 (41.4%) only had AVB, and two (6.9%) had both.

The Spectrum of Arrhythmias
Of the 17 patients with SND, 12 had sinus bradycardia, six had sinus arrest, and one had both sinus bradycardia and sinus arrest. Of the 14 patients with AVB, five had firstdegree AVB, seven had second-degree AVB, and five had third-degree AVB.  Of the 17 patients with SND, 12 had sinus bradycardia, six had sinus arrest, and one had both sinus bradycardia and sinus arrest. Of the 14 patients with AVB, five had first-degree AVB, seven had second-degree AVB, and five had third-degree AVB.

Baseline Characteristics of Patients with Bradyarrhythmias
The demographic and clinical features of all patients with primary bradyarrhythmias are shown in Table 1. In the overall cohort, 20 (69%) patients were male, and the median (IQR) age at admission was 62 (32.5) years old. Fifteen (51.7%) patients had a history of syncope, and one (3.4%) had a family history of HCM. Hypertension was the most frequent (48.3%) comorbid disease. Cardiac MRI was performed in 12 patients, and late gadolinium enhancement was detected in 10 of these patients.  The echocardiography parameters are displayed in Table 2. The multisegment (48.3%) and interventricular septum (37.9%) comprised the majority of hypertrophic types. Six (20.7%) patients had left ventricular obstructive outflow tract obstruction. The mean maximum left ventricular wall thickness was 20 ± 4.3 mm. Most patients had a normal systolic function with a median (IQR) left ventricular ejection fraction of 63% (10.0). Comparisons of all the baseline characteristics between the two groups are shown in Table 3. More patients with SND had left ventricular obstructive outflow tract obstruction than those with AVB (p = 0.013). Other clinical features were comparable between the two groups.  The baseline characteristics were also compared between male and female patients ( Table 4). Male patients had greater levels of weight, height, and body surface area than female patients, as expected. More male patients had coronary artery disease than female patients (p = 0.042). Male patients seemed to have greater maximum left ventricular wall thickness than female patients with a borderline significant trend (p = 0.067). Other clinical features were comparable between the two groups. Values are expressed as n (%), ratio, mean ± SD, or median (interquartile range). Comparisons between the two groups: student t-test or Mann-Whiney U test for continuous data, and chi-square test for categorical data.

Treatment and Outcomes
A total of 22 patients received pacemaker implantation, including 17 (77.3%) dualchamber pacing, four (18.2%) single-chamber ventricular pacing, and one (4.5%) cardiac resynchronization therapy. The reasons for pacemaker implantation were AVB in 12 patients, SND in 10 patients, and none for improving HCM-related symptoms. At discharge, 20 (69.3%) patients received beta-blockers, and three (10.3%) patients received nondihydropyridine calcium channel blockers to improve HCM-related symptoms (Table 1). There were no death events during follow-up.

Discussion
HCM is one of the leading causes of sudden cardiac death in youths and athletes. Arrhythmias may cause palpitations, syncope, or presyncope in patients with HCM. Syncope could be caused by ventricular tachycardia, supraventricular tachycardia, or bradyarrhythmias, including SND and AVB. Although ventricular fibrillation is the most commonly recorded fatal arrhythmic event, asystole and AVB have been reported [2]. Primary brad-