The goal of this observational study is to evaluate the long-term clinical outcomes of physiologic cardiac resynchronization therapy (CRT) using conduction system pacing strategies compared with conventional biventricular CRT in patients with heart failure with reduced ejection fraction (HFrEF) and electrical dyssynchrony.

The main questions it aims to answer are:

• Does physiologic CRT (including left bundle branch area pacing [LBBAP] and LBBAP-optimized CRT) reduce the combined risk of all-cause mortality and heart failure hospitalization compared with conventional biventricular CRT?
• Does physiologic CRT improve cardiac function and reverse ventricular remodeling more effectively than conventional CRT?

Participants receiving physiologic CRT as part of routine clinical care will undergo standard follow-up evaluations, including electrocardiography, echocardiography, laboratory testing, and device interrogation. Clinical outcomes will be collected prospectively for 24 months and compared with a historical cohort of patients treated with conventional biventricular CRT.

The study will assess clinical outcomes, echocardiographic response, electrical resynchronization parameters, and device-related safety in a real-world heart failure population.

Background

Heart failure with reduced ejection fraction (HFrEF) is associated with substantial morbidity, mortality, and healthcare utilization despite continuous advances in guideline-directed medical therapy. Cardiac resynchronization therapy (CRT) has become an established treatment for patients with symptomatic HFrEF and electrical dyssynchrony. Conventional biventricular pacing improves ventricular synchrony and clinical outcomes; however, approximately one-third of treated patients do not achieve a satisfactory response.

Conduction system pacing (CSP), particularly left bundle branch area pacing (LBBAP), has emerged as a physiological pacing strategy capable of directly engaging the native His-Purkinje conduction system. Compared with conventional biventricular pacing, CSP may produce more physiological ventricular activation, narrower paced QRS complexes, improved electrical synchrony, and greater reverse ventricular remodeling. Nevertheless, evidence regarding its long-term effectiveness in routine clinical practice remains limited, particularly in heterogeneous populations with different conduction abnormalities.

Study Rationale

The RESYNC-PACE study was designed to evaluate the effectiveness of individualized physiologic cardiac resynchronization strategies in a real-world population of patients with HFrEF requiring CRT.

The study investigates two complementary physiologic CRT approaches according to the underlying conduction disturbance. In patients with typical left bundle branch block (LBBB), left ventricular lead implantation is guided by the qLV ratio to achieve optimal electrical resynchronization through individualized coronary sinus lead positioning. In patients with intraventricular conduction delay (IVCD), a conduction system pacing strategy is applied using left bundle branch area pacing. When conduction system pacing alone results in incomplete electrical correction, defined by a paced QRS duration greater than 130 ms, an additional coronary sinus left ventricular lead is implanted to establish Left Bundle Branch Area Pacing Optimized Cardiac Resynchronization Therapy (LOT-CRT).

This individualized treatment algorithm reflects contemporary physiological concepts of ventricular resynchronization rather than a single implantation strategy and represents the principal scientific concept investigated in the study.

Scientific Objectives

The study aims to determine whether physiologic CRT strategies provide superior long-term clinical outcomes compared with conventional biventricular CRT when implemented in routine clinical practice.

In addition to evaluating clinical outcomes, the study investigates the relationship between electrical resynchronization, ventricular reverse remodeling, myocardial scar characteristics assessed by cardiac magnetic resonance imaging, and long-term prognosis. Particular emphasis is placed on identifying imaging-, electrocardiographic-, and device-derived predictors of CRT response that may facilitate patient selection and optimization of resynchronization therapy.

Study Methodology

RESYNC-PACE is a single-center, ambispective observational cohort study performed at the University of Pécs Clinical Centre Heart Institute. Consecutive patients undergoing physiologic CRT constitute the prospective cohort, while a historical cohort of patients treated with conventional biventricular CRT serves as the comparator.

All therapeutic procedures are performed as part of routine clinical care using commercially available CE-marked cardiac implantable electronic devices according to their approved indications and current international guideline recommendations. The study does not introduce experimental devices or procedures beyond standard clinical practice but prospectively evaluates the clinical performance of an individualized physiological CRT algorithm.

The comprehensive study database integrates demographic, clinical, electrocardiographic, echocardiographic, cardiac magnetic resonance imaging, procedural, device-derived, and long-term follow-up data. This integrated approach enables detailed evaluation of the mechanisms underlying CRT response and supports the development of patient-specific resynchronization strategies.

Expected Clinical Significance

The RESYNC-PACE study is expected to generate real-world evidence regarding the effectiveness of conduction system pacing-guided CRT strategies and individualized resynchronization algorithms. The findings may improve patient selection, optimize implantation strategies for different conduction disorders, and contribute to the growing evidence supporting physiologic cardiac resynchronization therapy in patients with heart failure.

Inclusion Criteria:

• Age ≥18 years.
• Symptomatic heart failure despite guideline-directed medical therapy.
• Left ventricular ejection fraction (LVEF) ≤40%.
• Indication for cardiac resynchronization therapy according to contemporary ESC guideline recommendations.
• QRS duration ≥150 ms with either:

Left bundle branch block (LBBB), or Intraventricular conduction delay (IVCD).

• Planned implantation of a CRT system
• Ability to provide written informed consent
• Expected survival greater than 24 months.

Exclusion Criteria:

• Age <18 years and Age 100 < years
• Pregnancy or breastfeeding.
• Inability or unwillingness to provide informed consent.
• Life expectancy <12 months due to non-cardiac comorbidities.
• Active systemic infection or infection involving a cardiac implantable electronic device.
• Reversible causes of heart failure expected to improve without CRT.
• Participation in another interventional clinical trial that may affect study outcomes.
• Inability to comply with follow-up requirements.
• Missing essential baseline or follow-up data (retrospective cohort).
• Any condition that, in the opinion of the investigators, would make participation inappropriate or interfere with study assessments.

The study population consists of adult patients with heart failure with reduced ejection fraction (HFrEF) who are treated at the University of Pécs Clinical Centre Heart Institute and meet contemporary guideline indications for cardiac resynchronization therapy (CRT). Eligible participants have symptomatic heart failure despite guideline-directed medical therapy, left ventricular systolic dysfunction, and evidence of electrical dyssynchrony manifested by left bundle branch block (LBBB) or intraventricular conduction delay (IVCD). The prospective cohort includes patients undergoing conduction system pacing-based CRT as part of routine clinical care, while the historical control cohort includes patients previously treated with conventional biventricular CRT at the same institution. The study population represents a real-world heart failure population routinely referred for CRT implantation in tertiary cardiovascular care.

ndividual participant data will be shared only in a de-identified form and in accordance with applicable data protection regulations, institutional policies, and informed consent provisions. Data sharing may be limited where participant privacy, ethical considerations, or legal requirements prevent full disclosure of individual-level data.