The physiological ventricular rhythm resetting is a registry-based, prospective, randomized, parallel, single-center trial. The primary aim is to determine whether the irregular ventricular rhythm is an important reversible factor for patients with AF and HF and whether physiological ventricular resetting reduces the composite clinical endpoints, including the rate of all-cause mortality and rehospitalization for HF. The second aims are to determine whether physiological ventricular resetting improves cardiac function, ventricular remodeling, and the quality of life. The study was approved by Ethics Review Boards in China. No. of the ethic committee: 2021-SRFA-417. Clinical Trials Registration number: ChiCTR2100047640.
The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents.
Study Population And Follow Up
Inclusion and exclusion criteria in Table I. The study concerned with patients enrolled in the first affiliated hospital of Nanjing Medical University from July 2021 to June 2023. 110 eligible patients are expected to be included in the trial with a 1:1 allocation to receive treatment with either physiological ventricular resetting group or medical rate control group (Figure I) with 1 year follow-up. A computer-generated list of random treatment allocations will be used to randomize enrolled subjects. If a subject is randomized to the physiological ventricular resetting group, the procedure should implement within 30 days.
All subjects should undergo a detailed evaluation before the randomization, including baseline echocardiography (TTE), 24h-Holter electrographic monitoring, pro-B-type natriuretic peptide (pro-BNP), NYHA class, 6-minute walk test (6MWT), and the six-item specific symptom scale score (SSS). All subjects will be followed up at 1week, 1, 3, 6, and 12 months after discharge. If a subject experienced increased edema, decreased urine, or chest tightness during follow-up, pro-BNP and TTE tests should be evaluated as early as possible. Adverse events will be recorded and handled promptly.
Procedure
All patients will receive standard treatment for AF and HF. β-blocker is the first choice for rate control (digoxin can be used when β-blocker is contraindications or not effective), aiming to make heart rate below 110 beats per minute. Any changes in the medication regimen should be written and documented.
The patients of the physiological ventricular resetting group will undergo extra AVNA and LBBP. Before the procedure, patients need to sign the consent form.
LBBP: The procedure is performed under local anesthesia. The 7-Fr guiding catheter (Model C315-S10; Medtronic Inc) and the pacing electrodes (models 3830, Medtronic Inc)were advanced into the right ventricular transvenous by left subclavian or axillary vein puncture. Move the catheter towards the apex of the heart by 1.5-2.0cm after mapping His bundle potential. Then the pacing lead was perpendicularly screwed through the interventricular septum (IVS) to the LV septal sub-endocardium of the LBB region. The paced QRS morphology and duration, pacing impedance were assessed and recorded frequently via unipolar pacing. Intra-catheter angiography was performed at the left anterior oblique position of 40° to assess the position of the electrodes and the presence of perforation. The pacing QRS and the peak time of the left ventricle were measured after high-voltage and low-voltage single-pole pacing. A pacing threshold below [email protected] is acceptable. During the procedure, if the left interventricular septal surface is penetrated during the screwing of the electrode, the electrode should be withdrawn, replaced, and re-implanted. All pacemakers use the VVI model and determine if defibrillation function is required according to the guidelines. The lower rate of pacemaker sets according to the mean heart rate of 24h-Holter, to ensure the heart rate is at the same level before and after the procedure. The lower rate of the pacemaker will be set according to the doctor's request and the patient's condition after the trial.
AVNA: We will perform AVN ablation after successful LBBP at the same procedure time. AVNA was performed using the quadripolar 7-Fr 4-mm tip ablation catheter. An 8.0F venous sheath is inserted through the right femoral vein. The key point is to record his potential after sent the ablation catheter into the right atrium. The methods for AVNA are described as follows: (i) The compact AV node was ablated from the atrial side marked by HIS potential. (ii) The ablation catheter was positioned at least 10mm away from the LBBP electrode tip. (iii) The ablation power was set at 30-50W and temperature at 43℃ for a duration of 60-120s. The criteria of successful ablations are as follows: 1) persistent complete atrioventricular block; 2) the left bundle capture threshold and QRS morphology remain unchanged after ablation.
Clinical Endpoints
The primary endpoints are all-cause mortality and rehospitalization for HF. All-cause mortality is defined as the percentage of deaths for any cause. Rehospitalization for HF is defined as requiring hospitalization due to worsening symptoms of HF or AF.
The secondary endpoints are the changes in cardiac structure and function. Left atrial diameter (LAD), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), and left ventricular ejection fraction (LVEF) will be analyzed by TTE. Pro-BNP will also be examined to evaluate cardiac function. The functional status of general health-related quality of life will be measured by changes in the classification of NYHA, the distance of 6MWT, and the scores of the SSS scale (Table II).
Safety
Safety endpoints will be collected at visit or telephone interviews at 1, 3, 6, and 12 months post the procedure. Both the intraoperative and long-term adverse events will be well documented. Adverse events define as pneumothorax, hemopneumothorax, hematoma, pericardial effusion, an episode of acute HF, deteriorating quality of life, rehospitalization for HF and sudden death. Among them, a prolonged hospitalization, disability, impair work capacity or endanger life or death are defined as severe adverse events. The trials will be suspended if more than one subject experience severe adverse events or over half of the subjects experience adverse events. Request the evaluation of relevant experts before deciding whether to continue the trial.
Statistics Methods
The study will be considered a success if the primary endpoint is met. The expected rate of success is estimated to be an increased LVEF of 7.4% (SD=11.7), based on the data from historical trials [6, 11]. Given a one-side test significance level of 2.5%, a total of 88 randomized subjects will provide 90% power to demonstrate superiority after adjusting for attrition. Consider the rate of loss to follow up maybe 20%, 110 subjects will be required.
Continuous variables will be expressed as mean ± standard deviation and categorical variables will be expressed as percentages. Paired comparisons were made using a Student’s t-test for continuous variables. The Chi-squared or Fisher’s test will be used for categorical data. Cox Proportional Risk regression model will be used to assess the risk ratio (HR) for different treatment regimens. P-value ≤ 0.05 was considered significant. Data management and analysis will be applied with SPSS v20.0 (IBM Corp).