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

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.