Left bundle branch area pacing (LBBAP) is a physiological pacing modality that preserves ventricular synchrony. In patients with sinus node dysfunction, who frequently exhibit delayed intrinsic atrioventricular conduction, the optimal postimplant programming strategy remains uncertain. Minimal ventricular pacing algorithms prioritize intrinsic conduction but may permit nonphysiological atrioventricular (AV) prolongation, potentially contributing to left atrial remodeling and atrial tachyarrhythmias. This is a prospective, single-center, randomized, open-label trial with blinded endpoint assessment (PROBE design). A total of 216 patients with sinus node dysfunction and successful LBBAP implantation will be randomized 1:1 to either a fixed optimized AV delay strategy (paced AV 150 ms; sensed AV 120 ms; minimal ventricular pacing algorithms disabled) or a minimal ventricular pacing strategy using device-specific algorithms (paced AV 200 ms; sensed AV 150 ms). The primary endpoint is the change in left atrial volume from baseline to 12 months, evaluated in a noninferiority comparison. Secondary endpoints include device-detected atrial high-rate episodes and atrial fibrillation burden (AF burden). In conclusion, this trial is designed to determine whether active optimization of AV synchrony after LBBAP implantation is noninferior to a conventional minimal ventricular pacing strategy in preventing left atrial remodeling and whether it may reduce atrial arrhythmia burden.
Sinus node dysfunction (SND) is a common indication for permanent pacemaker implantation. Although pacing alleviates bradycardia-related symptoms, long-term programming may influence atrial loading and atrioventricular (AV) coupling, thereby affecting left atrial remodeling and susceptibility to atrial fibrillation and other adverse outcomes. , Left atrial volume (LAV) provides a robust and reproducible integrative marker of chronic diastolic burden, AV dyssynchrony, and elevated filling pressures, and has been consistently associated with incident atrial fibrillation even in patients with preserved left ventricular systolic function. Left bundle branch area pacing (LBBAP) has emerged as a physiologic pacing modality that preserves ventricular activation via the His–Purkinje system and may mitigate the adverse ventricular effects historically attributed to chronic right ventricular pacing ,,,, ; however, in patients with SND who often retain intrinsic AV conduction with prolonged PR intervals, the optimal postimplant programming strategy remains uncertain. Minimal ventricular pacing algorithms are widely used in SND to reduce unnecessary ventricular pacing by extending AV delay and promoting intrinsic conduction, , a rationale largely derived from the right ventricular pacing era. , Yet in patients with prolonged PR intervals, excessive AV delay may impair AV mechanical synchrony, contribute to elevated left atrial pressure, and potentially promote progressive atrial remodeling and atrial tachyarrhythmias. , Conversely, a fixed, physiologically appropriate AV delay may better preserve AV synchrony and atrial–ventricular coupling; in the setting of conduction system pacing, concerns regarding pacing-induced ventricular dyssynchrony are attenuated, suggesting that the traditional “less ventricular pacing is always better” paradigm may not uniformly apply. ,,,, Nevertheless, a fixed AV delay strategy increases ventricular pacing exposure, and whether prioritizing AV synchrony yields net benefit compared with a minimal ventricular pacing approach has not been tested in randomized studies of patients treated with LBBAP, particularly with respect to atrial remodeling and device-detected atrial tachyarrhythmias. ,,,, Therefore, we designed a randomized trial comparing a fixed optimized AV delay strategy with a minimal ventricular pacing strategy in patients with SND undergoing LBBAP implantation, with the primary endpoint being change in LAV from baseline to 12 months and secondary endpoints including device-detected atrial high-rate episodes (AHRE) and atrial fibrillation burden.
Methods
Study design
This study is a prospective, single-center, randomized, open-label, parallel-group clinical trial with blinded assessment of study endpoints (PROBE design). Participants will be randomized in a 1:1 ratio to either a fixed optimized AV delay programming strategy or a minimal ventricular pacing strategy. The overall study design, including patient eligibility, randomization, intervention allocation, and follow-up schedule, is summarized in Figure 1 .
Schematic overview of the study design and follow-up assessments.
Abbreviations: AF = atrial fibrillation; AVB = atrioventricular block; ECG = electrocardiogram; IRSplus = Intrinsic Rhythm Support Plus; LVEF = left ventricular ejection fraction; MVP = Managed Ventricular Pacing; PAV = paced atrioventricular delay; PR = PR interval; SAV = sensed atrioventricular delay; VIP = Ventricular Intrinsic Preference; Δ = change.
Study population and representativeness
Patients will be recruited from the Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University.
Inclusion criteria
Participants must meet all of the following criteria:
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1.
Diagnosis of SND requiring permanent pacing and successful LBBAP implantation.
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2.
Confirmed LBBAP capture with paced QRS duration <130 ms.
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Device programmed in DDD mode.
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4.
Age between 18 and 80 years.
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5.
Ability to provide written informed consent.
Exclusion criteria
Participants meeting any of the following will be excluded:
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1.
Third-degree or high-grade AV block, or first-degree AV block with PR interval ≥300 ms.
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2.
Indication for cardiac resynchronization therapy (CRT).
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3.
Persistent atrial fibrillation.
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4.
Left ventricular ejection fraction <50%.
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5.
Severe coronary artery disease, significant valvular heart disease, or congenital heart disease.
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6.
Life expectancy <12 months.
LBBAP is defined as pacing capture of the subendocardial area on the left side of the interventricular septum, with or without concomitant conduction system capture, encompassing left bundle branch pacing (LBBP), left fascicular pacing (LFP), and left ventricular septal pacing (LVSP), in accordance with contemporary consensus statements on conduction system pacing implantation. Patients with an indication for cardiac resynchronization therapy (CRT) will be excluded. CRT indications are defined according to current ESC guidelines on cardiac pacing and resynchronization therapy, including Class I and Class IIa recommendations for symptomatic heart failure patients with reduced left ventricular ejection fraction and prolonged QRS duration despite optimal medical therapy. To reduce confounding from nonpacing-related atrial remodeling, patients with significant structural heart disease will be excluded. Severe coronary artery disease will be defined as obstructive epicardial coronary stenosis ≥70% in at least 1 major coronary artery, based on prior angiographic documentation or clinically confirmed diagnosis. Moderate-to-severe or severe native valvular heart disease will be defined according to contemporary echocardiographic criteria using an integrative multiparametric assessment (including quantitative measures such as effective regurgitant orifice area and regurgitant volume), in line with European Association of Cardiovascular Imaging recommendations. Patients with moderate or severe adult congenital heart disease (ACHD), as defined by the ESC Guidelines for the Management of Adult Congenital Heart Disease, will be excluded. This includes cyanotic congenital heart disease, Fontan circulation, univentricular physiology, Eisenmenger syndrome or pulmonary vascular disease related to congenital shunts, and other complex structural abnormalities. Patients with isolated, small, or completely repaired simple lesions without residual hemodynamic significance may be eligible.
Randomization
Eligible participants will be randomized in a 1:1 ratio to either the fixed optimized AV delay group or the minimal ventricular pacing group using a computer-generated randomization schedule. Balanced allocation will be maintained using block randomization with randomly permuted block sizes of 4 and 6. Allocation will be concealed until the time of device programming. Allocation concealment will be ensured using sequentially numbered, opaque, sealed envelopes prepared by an independent staff member not involved in patient enrollment or outcome assessment. The envelope will be opened only after completion of baseline assessments and immediately prior to implementation of the assigned programming strategy. Allocation concealment will be ensured by an independent study coordinator who will retain the randomization list and disclose group assignment only after completion of baseline assessments and immediately prior to device programming. Investigators responsible for enrollment and endpoint assessment will not have access to the allocation sequence.
Interventions and programming standardization
Fixed optimized AV delay strategy
Minimal ventricular pacing algorithms (e.g., MVP, VIP, IRSplus) will be disabled.
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Paced AV delay: 150 ms.
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Sensed AV delay: 120 ms.
This strategy is intended to optimize atrioventricular mechanical synchrony and ensure effective atrial contribution to ventricular filling.
Minimal ventricular pacing strategy
A device-specific minimal ventricular pacing algorithm (e.g., MVP, VIP, IRSplus) will be enabled.
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Paced AV delay: 200 ms.
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Sensed AV delay: 150 ms.
In the minimal ventricular pacing group, paced and sensed AV delays were programmed at 200 ms and 150 ms, respectively. These nominal settings are consistent with prior randomized studies evaluating ventricular pacing minimization strategies, in which extended AV delays were adopted to promote intrinsic atrioventricular conduction while maintaining conduction safety. ,
In the fixed optimized AV delay group, paced and sensed AV delays were set at 150 ms and 120 ms, respectively. These values were informed by prior studies of atrioventricular delay optimization in cardiac resynchronization therapy, in which physiologically appropriate sensed AV intervals frequently clustered around 120 ms and were associated with favorable hemodynamic profiles. ,
Standardized echocardiographic protocol
Transthoracic echocardiography will be performed at baseline (prior to randomization) and at the 12-month follow-up visit using a standardized acquisition protocol. All echocardiographic examinations will be conducted with commercially available ultrasound systems in accordance with institutional standards and current guideline recommendations. Digital images will be stored for offline analysis.
LAV will be measured using the biplane method of disks (modified Simpson’s method) from apical 4-chamber and 2-chamber views at left ventricular end-systole, corresponding to maximal left atrial size. Measurements will be performed in accordance with established echocardiographic guidelines for chamber quantification. All measurements will be electrocardiographically gated and averaged over 3 consecutive cardiac cycles.
Echocardiographic analyses will be performed by experienced readers blinded to treatment allocation and clinical data. To ensure measurement consistency and reproducibility, all studies will be analyzed according to a predefined analysis protocol, and a randomly selected subset of examinations will be reanalyzed to assess intra-observer and inter-observer variability.
Concomitant device parameters and nonstudy interventions
Device-related parameters other than the protocol-mandated atrioventricular delay programming, including pacing capture thresholds, lead impedance, sensing amplitudes, output amplitude, and pulse duration, will be programmed and adjusted according to standard clinical practice. These parameters are influenced by individual patient characteristics and lead position and are not protocol-mandated.
Output amplitude and pulse duration may be adjusted at the discretion of the treating physician to ensure reliable capture with an appropriate safety margin. No systematic differences in these parameters are intended between the 2 study groups, and they will not be considered study interventions. Adjustments during follow-up will be permitted when clinically indicated to maintain device performance and patient safety.
Patient follow-up
After randomization and implementation of the assigned programming strategy on Day 0, all patients will be followed for 12 months according to a standardized follow-up schedule identical in both study groups.
Baseline evaluations and follow-up assessments are summarized in Table 1 . The 12-month visit will serve as the primary analysis time point and will include transthoracic echocardiography for LAV measurement and device interrogation for assessment of AHRE and AF burden.
Table 1
Schedule of assessments
| Investigation/Procedure | Baseline (prior to randomization) | 12-mo follow-up | Unscheduled visit 1 | Unscheduled visit 2 | Unscheduled visit 3 |
|---|---|---|---|---|---|
| Written informed consent | X | ||||
| Inclusion/Exclusion criteria | X | ||||
| Medical history | X | ||||
| Clinical symptom assessment | X | X | X | X | X |
| 12-lead ECG (intrinsic/paced) | X | X | X | X | X |
| Echocardiography (LAV measurement) | X | X | |||
| Device interrogation (AHRE/AF) | X | X | X | X | X |
| Device programming | X | X | X | X |
Baseline evaluations are performed prior to randomization and include written informed consent, confirmation of eligibility criteria, medical history, clinical symptom assessment, 12-lead electrocardiography (intrinsic and paced rhythm), transthoracic echocardiography for left atrial volume (LAV) measurement, device interrogation, and implementation of the assigned programming strategy. The 12-month follow-up visit serves as the primary analysis time point and includes clinical symptom assessment, 12-lead ECG, repeat echocardiographic LAV measurement, and device interrogation for atrial high-rate episodes (AHRE) and atrial fibrillation (AF) burden. Unscheduled visits may occur as clinically indicated for symptom evaluation, ECG, device interrogation, or device reprogramming to ensure patient safety and appropriate device function. These visits are not protocol-mandated. “X” indicates that the specified assessment is performed at the corresponding time point.
Unscheduled visits are permitted as clinically indicated for device interrogation or reprogramming to ensure patient safety or symptom control and do not represent protocol-driven interventions.
Outcome measures
Outcome measures are prespecified and include 1 primary efficacy endpoint and secondary rhythm-related endpoints.
Primary endpoint
The primary efficacy endpoint is the change in LAV (ΔLAV, ml) from baseline to 12 months. LAV will be measured using the biplane method of disks (modified Simpson’s method) in apical 4- and 2-chamber views, at left ventricular end-systole, in accordance with current echocardiographic guidelines.
The primary analysis is designed as a noninferiority comparison, to test whether the fixed optimized atrioventricular delay programming strategy is noninferior to the minimal ventricular pacing strategy with respect to LAV at 12 months.
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