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) remains a major cause of morbidity, mortality, and healthcare utilization worldwide. Cardiac resynchronization therapy (CRT) is an established treatment for selected patients with symptomatic heart failure, reduced left ventricular ejection fraction, and evidence of electrical dyssynchrony, particularly in the presence of a wide QRS complex. Numerous randomized clinical trials have demonstrated that conventional biventricular CRT improves symptoms, exercise capacity, quality of life, left ventricular function, and survival while reducing heart failure hospitalizations.

Despite these well-established benefits, approximately 30% of patients receiving conventional biventricular CRT fail to achieve a clinically meaningful response. Several mechanisms may contribute to CRT non-response, including suboptimal lead positioning, myocardial scar burden, unfavorable coronary venous anatomy, and the inability of conventional biventricular pacing to fully restore physiological ventricular activation.

Recent advances in cardiac pacing have led to the development of conduction system pacing (CSP), including His bundle pacing and left bundle branch area pacing (LBBAP). These pacing techniques directly recruit the intrinsic cardiac conduction system and may provide a more physiological ventricular activation pattern than conventional right ventricular or biventricular pacing. Growing evidence suggests that CSP-based CRT strategies may improve electrical synchrony, facilitate reverse ventricular remodeling, and potentially improve long-term clinical outcomes.

Among these approaches, LBBAP combined with CRT devices and LBBAP-optimized CRT strategies have emerged as promising alternatives to conventional biventricular CRT. However, long-term real-world data evaluating their effectiveness and safety remain limited. Additional evidence is required to better define the role of physiologic CRT in contemporary heart failure management.

Study Rationale

The RESYNC-PACE study was designed to evaluate whether physiologic cardiac resynchronization strategies based on conduction system pacing are associated with improved clinical outcomes compared with conventional biventricular CRT in patients with HFrEF and significant electrical dyssynchrony.

The study aims to assess the effectiveness of physiologic CRT approaches implemented during routine clinical practice and compare their outcomes with a historical cohort of patients who underwent conventional biventricular CRT implantation at the same institution.

By utilizing advanced imaging, electrocardiographic, echocardiographic, device-derived, and clinical outcome data, the study seeks to identify factors associated with successful CRT response and improved long-term outcomes.

Study Objectives

Primary Objective

To compare the composite endpoint of all-cause mortality and heart failure hospitalization between patients undergoing physiologic CRT and patients treated with conventional biventricular CRT.

Secondary Objectives

To evaluate differences between treatment groups regarding:

• Left ventricular reverse remodeling.
• Changes in left ventricular ejection fraction.
• Changes in left ventricular dimensions.
• Electrical resynchronization as assessed by QRS duration and pacing parameters.
• Device-related performance and safety.
• Clinical status during follow-up.
• Identification of predictors of favorable CRT response.

Exploratory Objectives

The study will further investigate the relationship between:

• Cardiac magnetic resonance imaging findings and CRT response.
• Myocardial scar burden and long-term outcomes.
• Septal scar distribution and physiologic pacing effectiveness.
• Conduction system capture characteristics and clinical outcomes.
• Electrocardiographic markers of electrical synchrony and reverse remodeling.

Study Design

RESYNC-PACE is a single-center observational cohort study conducted at the University of Pécs Clinical Centre Heart Institute.

The study includes both prospective and retrospective components.

Prospective Cohort

Patients undergoing implantation of physiologic CRT systems using left bundle branch area pacing-based strategies will be enrolled prospectively during routine clinical care.

Historical Control Cohort

A retrospective cohort of patients who previously underwent conventional biventricular CRT implantation according to contemporary guideline recommendations will serve as the comparison group.

The study is non-randomized and reflects real-world clinical practice. Device selection and implantation strategy are determined by the treating physicians based on clinical considerations and current professional guidelines.

Study Population

The study population consists of adult patients with symptomatic heart failure and reduced left ventricular ejection fraction who meet established indications for CRT.

Key eligibility criteria include:

• Age 18 years or older.
• Symptomatic heart failure.
• Reduced left ventricular ejection fraction.
• Significant QRS prolongation and electrical dyssynchrony.
• Guideline-directed medical therapy.
• Eligibility for CRT implantation according to contemporary clinical practice.

Patients with contraindications to study procedures, inability to provide informed consent, severe competing illnesses limiting life expectancy, or contraindications to cardiac magnetic resonance imaging may be excluded from the prospective cohort.

Study Procedures

All procedures performed within the study correspond to routine clinical care and standard diagnostic evaluation of patients undergoing CRT implantation.

Baseline Assessment

Participants may undergo:

• Medical history assessment.
• Physical examination.
• Electrocardiography.
• Transthoracic echocardiography.
• Laboratory evaluation.
• Device interrogation where applicable.
• Cardiac magnetic resonance imaging.

Cardiac Magnetic Resonance Imaging

Cardiac magnetic resonance imaging is performed before implantation whenever clinically feasible and appropriate. MRI data are used to assess myocardial scar burden, scar localization, ventricular volumes, and structural substrate characteristics.

Implantation Procedure

Patients in the prospective cohort undergo implantation of physiologic CRT systems utilizing conduction system pacing techniques according to institutional practice and operator expertise.

Implanted devices may include CRT-defibrillator systems and associated conduction system pacing leads and delivery tools routinely used in clinical practice.

Follow-Up

Patients are followed according to standard clinical protocols.

Follow-up visits include assessment of:

• Clinical status.
• Heart failure symptoms.
• Device function.
• Electrocardiographic parameters.
• Echocardiographic parameters.
• Adverse events.

Follow-up evaluations are typically performed at discharge, approximately six weeks after implantation, and subsequently at one and two years after implantation.

Outcome Measures

Primary Outcome

The primary outcome is a composite endpoint consisting of:

• All-cause mortality.
• Heart failure hospitalization.

Secondary Outcomes

Secondary outcomes include:

• Changes in left ventricular ejection fraction.
• Changes in ventricular dimensions.
• Changes in QRS duration.
• Echocardiographic measures of reverse remodeling.
• Device-related outcomes.
• Procedural success.
• Adverse events.

Safety Evaluation

Because all implanted devices used in the study are commercially available, CE-marked medical devices used according to their approved intended purpose, no experimental device-related procedures are performed.

Safety analyses include monitoring of:

• Procedure-related complications.
• Device-related adverse events.
• Lead-related complications.
• Hospitalizations.
• Serious adverse events.

All adverse events are recorded according to institutional and regulatory requirements.

Data Collection and Management

The study collects demographic, clinical, imaging, procedural, laboratory, device-related, and outcome data.

Data are stored in a secure research database using pseudonymized identifiers. Personal identifying information is protected according to applicable data protection regulations, including the General Data Protection Regulation (GDPR).

Only authorized study personnel have access to study data.

Statistical Considerations

Clinical outcomes will be analyzed using standard statistical methods appropriate for observational cohort studies.

Time-to-event analyses will be performed for the primary composite endpoint. Additional analyses will evaluate predictors of favorable CRT response, reverse remodeling, and long-term clinical outcomes.

Comparisons between physiologic CRT and conventional CRT groups will be performed using multivariable statistical adjustment techniques to minimize the impact of baseline differences between treatment groups.

Expected Significance

The RESYNC-PACE study is expected to provide important real-world evidence regarding the effectiveness and safety of physiologic CRT strategies based on conduction system pacing.

The results may help identify patient populations most likely to benefit from physiologic pacing approaches and improve individualized treatment selection in patients with heart failure requiring cardiac resynchronization therapy.

By integrating clinical outcomes, advanced imaging findings, electrocardiographic characteristics, and device-derived data, the study aims to contribute to the growing body of evidence supporting next-generation CRT strategies and to improve long-term outcomes for 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.	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.	Baseline to 24 months
Change in paced QRS Duration	Reduction in QRS duration following cardiac resynchronization therapy compared with baseline electrocardiographic measurements.	Baseline to 24 months
Heart Failure Functional Status	Change in New York Heart Association (NYHA) functional class from baseline to follow-up.	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 6, 2026
• Last Update Submitted That Met QC Criteria: June 28, 2026
• Last Verified: June 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