REstoration of SYNChronous Cardiac Function Due to Physiologic cArdiac Pacing Modalities With Clinical Endpoints (RESYNC-PACE)

REstoration of SYNChronous Cardiac Function Due to Physiologic cArdiac Pacing Modalities With Clinical Endpoints RESYNC-PACE

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Left Bundle Branch Area Pacing; Left Bundle Branch Block; Intraventricular Conduction Delay; Resynchronization Therapy; Heart Failure - NYHA II - IV
• Intervention / Treatment: Device: Physiologic cardiac resynchronization using conduction system pacing and selective LV lead optimization.

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Peter Ezer MD PhD, assistant professor; Phone Number: +36305468840; Email: ezerpeti@gmail.com

Study Locations

• Hungary
  • Baranya
    • Pécs, Baranya, Hungary, 7621
      • Heart Institute , University of Pécs

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Left bundle branch block patients; LBBB Cohort (qLV-guided Cardiac Resynchronization Therapy) Patients in this cohort have symptomatic heart failure with reduced left ventricular ejection fraction and complete left bundle branch block (LBBB) according to contemporary guideline criteria. Cardiac resynchronization therapy is performed using a personalized implantation strategy guided by the qLV ratio, defined as the interval between QRS onset and local left ventricular activation divided by the intrinsic QRS duration. The left ventricular lead is positioned at the site with the longest achievable electrical delay to maximize resynchronization benefit. Patients receive either conventional biventricular CRT or LOT- CRT according to clinical decision-making and anatomical feasibility. The cohort is followed longitudinally to evaluate the relationship between qLV-guided lead placement, electrical resynchronization, reverse ventricular remodeling, heart failure hospitalization, and all-cause mortality.	Device: Physiologic cardiac resynchronization using conduction system pacing and selective LV lead optimization.; Conduction System Pacing-Guided Cardiac Resynchronization Therapy is an individualized resynchronization strategy used in patients with heart failure, reduced left ventricular ejection fraction, and electrical dyssynchrony. The intervention is based on direct recruitment of the native cardiac conduction system through left bundle branch area pacing (LBBAP). During implantation, electrical resynchronization is assessed using electrocardiographic and device-derived parameters. In patients with intraventricular conduction delay or incomplete electrical correction, additional left ventricular pacing may be provided using a coronary sinus lead, resulting in Left Bundle Branch Area Pacing Optimized Cardiac Resynchronization Therapy (LOT-CRT). The intervention aims to achieve more physiological ventricular activation than conventional biventricular pacing, improve electrical synchrony, promote reverse ventricular remodeling, and reduce heart failure-related adverse events.; Other Names: Cardiac resynchronization therapy using left bundle branch area pacing with or without LV lead optimization.; Cardiac resynchronization guided by conduction system pacing to improve ventricular synchrony.
Intraventricular conduction delay patients; IVCD Cohort (Conduction System Pacing-Guided Resynchronization Strategy) Patients in this cohort have symptomatic heart failure with reduced left ventricular ejection fraction and intraventricular conduction delay (IVCD) without typical left bundle branch block morphology. The resynchronization strategy is guided by the degree of electrical correction achieved with conduction system pacing. During implantation, left bundle branch area pacing (LBBAP) is attempted and paced QRS duration is assessed. If conduction system pacing alone results in a paced QRS duration greater than 130 ms, a Left Bundle Branch Area Pacing Optimized Cardiac Resynchronization Therapy (LOT-CRT) system is implanted by adding a left ventricular lead to further improve ventricular synchrony. The cohort is followed longitudinally to evaluate the association between electrical resynchronization, reverse ventricular remodeling, heart failure hospitalization, and all-cause mortality.	Device: Physiologic cardiac resynchronization using conduction system pacing and selective LV lead optimization.; Conduction System Pacing-Guided Cardiac Resynchronization Therapy is an individualized resynchronization strategy used in patients with heart failure, reduced left ventricular ejection fraction, and electrical dyssynchrony. The intervention is based on direct recruitment of the native cardiac conduction system through left bundle branch area pacing (LBBAP). During implantation, electrical resynchronization is assessed using electrocardiographic and device-derived parameters. In patients with intraventricular conduction delay or incomplete electrical correction, additional left ventricular pacing may be provided using a coronary sinus lead, resulting in Left Bundle Branch Area Pacing Optimized Cardiac Resynchronization Therapy (LOT-CRT). The intervention aims to achieve more physiological ventricular activation than conventional biventricular pacing, improve electrical synchrony, promote reverse ventricular remodeling, and reduce heart failure-related adverse events.; Other Names: Cardiac resynchronization therapy using left bundle branch area pacing with or without LV lead optimization.; Cardiac resynchronization guided by conduction system pacing to improve ventricular synchrony.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of All-Cause Mortality and Heart Failure Hospitalization	Time to first occurrence of the composite endpoint of all-cause mortality or hospitalization due to worsening heart failure during the 24-month follow-up period.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Left Ventricular Ejection Fraction (LVEF)	Change in left ventricular ejection fraction measured by transthoracic echocardiography between baseline and 24-month follow-up. Ejection fraction is measured in percentage (%). Improvement in ejection fraction is detected as increase in percentage-value.	Baseline to 24 months
Change in Left Ventricular End-Systolic Volume ( LV ESV)	Change in left ventricular end-systolic volumen measured by echocardiography between baseline and 24-month follow-up. Left ventricular end-systolic volume in measured in mililiters ( ml) , decrease in LV ESV is a sign of clinical response on therapy.	Baseline to 24 months
Change in paced QRS Duration	Reduction in QRS duration following cardiac resynchronization therapy compared with baseline electrocardiographic measurements. Paced QRS duration is measured in miliseconds (ms). Decrease in paced QRS duration compared to preoperative QRS duration is marked as a good signal in cardiac resynchronization therapy.	Baseline to 24 months
New York Heart Association Heart Failure Functional Status	Change in New York Heart Association (NYHA) functional class from baseline to follow-up. Stage I-IV. NYHA improvement is detected as decrease in NYHA stage grade.	Baseline to 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Device-Related and Procedure-Related Complications	Incidence of device-related and procedure-related adverse events, including lead dislodgement, infection, pneumothorax, pocket hematoma, and system revision.	24 months

Collaborators and Investigators

• Sponsor: University of Pecs
• Collaborators: Medical University of Pecs

Publications and helpful links

General Publications

• Jastrzebski M, Moskal P, Huybrechts W, Curila K, Sreekumar P, Rademakers LM, Ponnusamy SS, Herweg B, Sharma PS, Bednarek A, Rajzer M, Vijayaraman P. Left bundle branch-optimized cardiac resynchronization therapy (LOT-CRT): Results from an international LBBAP collaborative study group. Heart Rhythm. 2022 Jan;19(1):13-21. doi: 10.1016/j.hrthm.2021.07.057. Epub 2021 Jul 30.
• Guo J, Luo W, Zhao S, Cui H, Wang X, Li X. Conduction system pacing compared with biventricular pacing for cardiac resynchronization therapy: a systematic review and meta-analysis. Front Cardiovasc Med. 2026 Jun 5;13:1776637. doi: 10.3389/fcvm.2026.1776637. eCollection 2026.
• Leventopoulos G, Nastouli KM, Bozika M, Papastavrou E, Apostolos A, Koros R, Perperis A, Koniari I, Vlassopoulou N, Chronopoulos P, Travlos CK, Moulias A, Davlouros P. Understanding LOT-CRT: Current Insights, Limitations, and Our Center's Experience. J Clin Med. 2025 Apr 27;14(9):3025. doi: 10.3390/jcm14093025.
• Ezer P, Szucs K, Lukacs R, Bisztray T, Vilmanyi G, Szokodi I, Komocsi A, Konyi A. The Suboptimal QLV Ratio May Indicate the Need for a Left Bundle Branch Area Pacing-Optimized Cardiac Resynchronization Therapy Upgrade. J Clin Med. 2024 Sep 26;13(19):5742. doi: 10.3390/jcm13195742.

Study record dates

Study Major Dates

• Study Start (Estimated): June 29, 2026
• Primary Completion (Estimated): June 29, 2030
• Study Completion (Estimated): June 29, 2031

Study Registration Dates

• First Submitted: June 28, 2026
• First Submitted That Met QC Criteria: June 28, 2026
• First Posted (Actual): July 6, 2026

Study Record Updates

• Last Update Posted (Actual): July 10, 2026
• Last Update Submitted That Met QC Criteria: July 8, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Physiologic Pacing; Conduction System Pacing; carrdiac resynchornization therapy; Electrical Resynchronization; Physiologic CRT
• Additional Relevant MeSH Terms: Cardiac Conduction System Disease; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Heart Block; Pathological Conditions, Signs and Symptoms; Bundle-Branch Block
• Other Study ID Numbers: FF107 RESYNC-PACE ver1.0; Biotronik Research Grant FF107 (Other Grant/Funding Number: BIOTRONIK SE & Co. KG Woermannkehre 1 12359 Berlin)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No