Clinical Efficacy and Safety of Left Bundle Branch Area Pacing Using Quantitative Guidance of Multimodal Data in the Treatment of Heart Failure

Cardiac resynchronization therapy is a standard treatment for heart failure patients with complete left bundle branch block, and traditional biventricular pacing is the most widely used approach to achieve resynchronization. However, biventricular pacing is restricted by the variable anatomy of the coronary venous system, with common intraoperative complications and a 30% to 40% rate of non-response. His bundle pacing, as the most physiological pacing modality, is limited by high operation difficulty, gradually increasing pacing thresholds and unstable long-term capture. Left bundle branch area pacing is an emerging physiological pacing technique originating in China, which can correct conduction block and restore ventricular synchrony with stable pacing parameters. Existing studies are mostly single-center observational research with short follow-up periods, lacking high-quality multicenter randomized controlled evidence on long-term hard clinical endpoints. In addition, there is no unified quantitative standard for intraoperative lead positioning, and the procedure relies heavily on operator experience. Based on the previously established multimodal quantitative positioning system, this study conducts a multicenter randomized controlled trial to compare the long-term efficacy and safety of multimodal-guided left bundle branch area pacing and traditional biventricular pacing in heart failure patients.

• Study Design and Overall Framework This study is a multicenter, prospective, randomized controlled clinical trial led by the Second Affiliated Hospital of Nanchang University, with the participation of three other tertiary general hospitals including the People's Hospital of Inner Mongolia Autonomous Region, Hohhot First Hospital and Chifeng Hospital. The study will continuously screen eligible patients from March 2024 to March 2025. The entire study will be conducted in strict compliance with the Declaration of Helsinki, and the protocol will be reviewed and approved by the ethics committees of all participating institutions. All enrolled patients must sign a paper informed consent form before enrollment, and all original clinical data will be transmitted to the Second Affiliated Hospital of Nanchang University for unified statistical analysis. The study adopts a 1:1 parallel group design with a preset crossover rule, to ensure that patients who fail the initially assigned pacing strategy can still receive appropriate treatment without compromising clinical safety.
• Study Population and Eligibility Criteria The study enrolls patients diagnosed with non-ischemic cardiomyopathy complicated by complete left bundle branch block and heart failure. The inclusion criteria are as follows. First, patients aged between 18 and 80 years old. Second, patients with sinus rhythm and complete left bundle branch block meeting the Strauss criteria, defined as QRS duration > 140 ms for male patients and > 130 ms for female patients. Third, patients with non-ischemic cardiomyopathy, left ventricular ejection fraction ≤ 40%, and New York Heart Association functional class II to IV. Fourth, patients who voluntarily sign the written informed consent form. All enrolled patients must have received at least 3 months of guideline-recommended standard anti-heart failure drug therapy before enrollment. The exclusion criteria are as follows. First, patients with ischemic cardiomyopathy confirmed by coronary CT. Second, patients with wide QRS waves of non-left bundle branch block morphology, including right bundle branch block and non-specific intraventricular conduction block. Third, patients with persistent atrial fibrillation. Fourth, patients undergoing pacemaker replacement who do not need reimplantation of ventricular leads. Fifth, patients with special conditions such as pregnancy and advanced malignant tumor.
• Group Assignment and Crossover Rules Eligible patients will be randomly assigned to the left bundle branch area pacing group and the biventricular pacing group at a 1:1 ratio through a central randomization system. A crossover mechanism is set in the study to guarantee clinical safety and treatment effect. For patients assigned to the left bundle branch area pacing group, if no evidence of left bundle branch capture is observed after standard attempts intraoperatively, the procedure will be judged as failed, and the patient will cross over to the biventricular pacing group. For patients assigned to the biventricular pacing group, if left ventricular lead implantation fails due to anatomical reasons such as no accessible target vein, excessively high pacing threshold or intolerable phrenic nerve stimulation, the patient will cross over to the left bundle branch area pacing group. All crossover cases will be recorded in detail and included in the final statistical analysis according to the intention-to-treat principle.
• Intervention Procedures For patients in the left bundle branch area pacing group, the trans-septal approach is adopted for implantation. All procedures are performed by three experienced clinicians with rich pacemaker implantation experience from the research team. A 3830 active fixation lead is delivered through a C315 delivery sheath under 30-degree right anterior oblique fluoroscopy guidance. The lead implantation site is selected under the guidance of the multimodal quantitative system established in previous research. The 12-lead surface electrocardiogram and intracardiac electrogram are synchronously displayed and recorded on the Bard LabSystem Pro electrophysiology recording system during the whole procedure.

The quantitative guidance system includes two core parts: imaging distance indicators and electrocardiographic indicators. For imaging indicators, a quantitative coordinate system is established with the contraction line as the reference axis under fluoroscopy. The longitudinal distance and lateral distance from the lead tip to the reference axis are measured, and corrected values are calculated to eliminate the influence of individual differences in heart size. The conversion between measured distance and real anatomical distance is calibrated by the known true diameter of the pacing lead, and all imaging distance measurements are performed on LibreCAD software with three repeated measurements to take the average value. For electrocardiographic indicators, positioning pacing is performed at 2.0V/0.5ms output, and parameters including local left ventricular activation time, local paced QRS duration and their ratio are measured, along with the waveform amplitude and direction of lead II and III. The optimal implantation site must meet the comprehensive quantitative criteria: corrected longitudinal distance ≥ 26.9 mm, local paced QRS duration ≤ 141 ms, local left ventricular activation time ≤ 92 ms, local left ventricular activation time / QRS duration ratio ≤ 63.9%, and negative QRS waveform in lead II/III during positioning pacing.

After confirming the target site, the lead is screwed clockwise into the deep septum until left bundle branch capture is achieved. During the screwing process, unipolar sensing, pacing electrocardiogram and pacing impedance are tested continuously, with simultaneous monitoring of surface electrocardiogram, intracardiac electrogram and fluoroscopic images. Left bundle branch capture is defined by the following criteria. First, the paced QRS waveform in lead V1 presents typical or atypical right bundle branch block morphology. Second, left ventricular activation time ≤ 90 ms under low voltage pacing. Third, at least one of the following evidences is met: sudden shortening of left ventricular activation time by more than 10 ms during lead screwing with no further change with deeper screwing; QRS morphology changes from non-selective to selective pacing with stable left ventricular activation time when reducing pacing voltage; left ventricular activation time prolongs by more than 10 ms when pacing mode changes from non-selective left bundle branch pacing to left ventricular septal pacing. If left bundle branch capture cannot be achieved after attempts at 5 sites, the procedure will be converted to biventricular pacing. After surgery, the pacemaker is programmed to DDD mode, and the atrioventricular interval is optimized to achieve the narrowest paced QRS width.

For patients in the biventricular pacing group, retrograde coronary venography is routinely performed during surgery to display the main coronary sinus trunk and all branch vessels. The lateral vein or posterolateral vein is usually selected as the target vein for coronary sinus lead implantation. The defibrillation lead is placed in the right ventricular outflow tract septum or right ventricular apex. If there is no suitable target vessel, or the lead cannot be implanted successfully, or the pacing threshold is too high, or phrenic nerve stimulation occurs, the patient will cross over to the left bundle branch area pacing group. After surgery, the pacemaker is programmed to DDD mode, and the atrioventricular interval and interventricular interval are optimized to ensure a biventricular pacing ratio higher than 92%. For patients with quadripolar left ventricular leads, the optimal pacing vector is selected according to pacing threshold and paced QRS width. All patients receive atrioventricular and interventricular interval optimization before discharge to achieve the best atrioventricular synchrony and maximum aortic flow velocity.

• Outcome Measures The primary endpoint of the study is the composite endpoint of all-cause death and/or heart failure rehospitalization. Heart failure rehospitalization is defined as worsening of heart failure symptoms and signs in outpatient, emergency or inpatient settings, requiring oral or intravenous diuretics to relieve clinical symptoms.

The secondary endpoints include the following items. First, all-cause death. Second, heart failure rehospitalization. Third, malignant ventricular arrhythmia. The definition of malignant ventricular arrhythmia is consistent with the previously published VANIS study, meeting any of the following criteria: three or more episodes of ventricular tachycardia all terminated by anti-bradycardia pacing, with at least one episode accompanied by clinical symptoms; one or more appropriate implantable cardioverter defibrillator shocks; three or more episodes of ventricular tachycardia within 24 hours; sustained ventricular tachycardia with frequency not reaching the implantable cardioverter defibrillator treatment standard. Fourth, the occurrence of procedure-related complications, including lead perforation, lead dislodgement, excessively high pacing threshold, phrenic nerve stimulation, hemothorax, pneumothorax, pocket hematoma, pocket infection and pericardial effusion. During follow-up, if a patient experiences any of the above clinical endpoints or is lost to follow-up, the follow-up for that patient will be terminated. The electrocardiogram morphological diagnosis criteria in this study refer to the 2009 AHA/ACC/HRS standard for electrocardiogram standardization and interpretation.

In addition to clinical endpoints, the study also collects multiple evaluation indicators during follow-up, including 12-lead electrocardiogram parameters, echocardiographic parameters such as left ventricular ejection fraction, left ventricular end-diastolic diameter, left ventricular end-diastolic volume and left ventricular end-systolic volume, N-terminal pro-B-type natriuretic peptide level, 6-minute walk distance, New York Heart Association functional class, and pacing parameters including pacing threshold, impedance and sensing at intraoperative, 3-month, 6-month and 12-month time points. Baseline clinical data including age, gender, comorbidities, medication use and baseline electrocardiogram characteristics are also collected completely.

• Follow-up Schedule and Assessments All patients will receive regular outpatient or telephone follow-up every 3 months after surgery, with a minimum follow-up period of 1 year. At each follow-up visit, the research team will complete a series of standardized assessments. First, clinical evaluation including symptom assessment, New York Heart Association functional classification, and medication adherence review. Second, 12-lead electrocardiogram examination to evaluate paced QRS duration and morphology. Third, pacemaker device interrogation to record pacing threshold, impedance, sensing performance, pacing percentage and arrhythmia events recorded by the device. Fourth, echocardiographic examination at 3 months, 6 months and 12 months after surgery to evaluate cardiac structure and systolic function. Fifth, 6-minute walk test and N-terminal pro-B-type natriuretic peptide detection at specified follow-up time points. Sixth, systematic recording of all clinical endpoint events and adverse events, with detailed documentation of occurrence time, severity, treatment measures and final outcome. All follow-up data are recorded in a unified case report form to ensure data standardization and consistency across all participating centers.
• Sample Size Calculation The sample size is calculated based on the primary composite endpoint of all-cause death and heart failure rehospitalization. According to the previous small-sample clinical study of the research team and the results of related published studies, the incidence of the primary endpoint is 24% in the left bundle branch area pacing group and 52% in the biventricular pacing group. PASS software is used for sample size calculation. Under the conditions of 80% statistical power and two-sided α = 0.05, a total of 88 subjects are required, with 44 cases in each group, to detect the statistical difference between the two groups. Considering a loss to follow-up rate of no more than 15%, the final sample size is determined to be 100 cases, with 50 cases in each group.
• Data Management and Quality Control A unified case report form is used for data collection across all centers. To ensure data accuracy, two data administrators independently perform double data entry and conduct consistency verification of the data files. For questions in the case report form, the data administrator will issue a data query form through clinical research associates, and the researchers will answer and correct the data in a timely manner. The query and correction process is repeated until all data queries are completely resolved.

Data verification includes manual verification and computerized program verification. For data problems such as missing values, abnormal values and logical errors found during verification, the data administrator will promptly issue queries to the researchers for resolution. After data entry and query cleaning are completed, the sponsor, principal investigator, data manager and statistician will jointly conduct a final review of the data, define the analysis datasets including the full analysis set, per-protocol set and safety set, and confirm the handling rules of missing values and outliers. After confirming that the data are correct, the database will be locked with the joint approval of relevant personnel, and the locked data will be exported for subsequent statistical analysis.

Before the start of the study, all participating centers receive unified training on the study protocol, operation specifications and data recording standards. Regular on-site monitoring is conducted during the study period to ensure that all centers implement the protocol in a standardized manner and that the research data are authentic, complete and reliable.

• Statistical Analysis Plan For baseline demographic and clinical characteristics, normally distributed measurement data are expressed as mean and standard deviation, and the difference between the two groups is compared by independent sample t-test. Measurement data that do not follow normal distribution are expressed as median and interquartile range, and the difference between the two groups is compared by independent sample Wilcoxon rank sum test. Categorical data are expressed as frequency and proportion, and the difference between the two groups is compared by chi-square test; if the conditions for chi-square test are not met, Fisher's exact test is used instead.

To maximize the retention of randomization information, the primary endpoint analysis follows the intention-to-treat principle, and per-protocol analysis is used as the sensitivity analysis result. Secondary endpoints also adopt intention-to-treat analysis. Finally, multivariate Cox proportional hazards regression analysis is performed with the primary and secondary endpoints as dependent variables, to explore independent influencing factors of long-term clinical outcomes. The study sets P < 0.05 as the threshold for statistically significant difference.

• Expected Value and Feasibility Support This study is expected to provide high-level evidence-based medical evidence for the clinical application of left bundle branch area pacing, establish a set of quantitative and operable implantation standards, and promote the standardized popularization of physiological pacing technology. The Second Affiliated Hospital of Nanchang University has a strong cardiovascular department with complete medical equipment and rich experience in multicenter clinical trials. The principal investigator and the research team have long been engaged in arrhythmia and cardiac electrophysiology research, and have completed multiple relevant clinical studies, laying a solid methodological foundation for the smooth implementation of this study.

Inclusion criteria

• Age 18-80 years;
• Sinus rhythm, complete left bundle branch block (LBBB) fulfilling the Strauss criteria (QRS duration >140 ms in men or >130 ms in women);
• Non-ischemic cardiomyopathy, left ventricular ejection fraction (LVEF) ≤40%, and New York Heart Association (NYHA) functional class II-IV;
• Signed informed consent.
• All enrolled patients received guideline-recommended pharmacological therapy for heart failure for at least 3 months.

Exclusion criteria

• Coronary CT-confirmed ischemic cardiomyopathy;
• wide QRS complex with non-LBBB morphology, including right bundle branch block and nonspecific intraventricular conduction block;
• persistent atrial fibrillation;
• pacemaker replacement without reimplantation of ventricular leads;
• patients with special conditions, such as pregnancy, gestation, and advanced malignancy.
• All patients underwent detailed recording of electrophysiological pacing parameters intraoperatively and postoperatively, and monitoring for surgical complications.