Heart failure with reduced ejection fraction (HFrEF) represents a major, pandemic medical and societal challenge, characterized by high morbidity, mortality, and healthcare costs. Left bundle branch block (LBBB) occurs in approximately 30% of these patients and acts both as a marker and a causal contributor to the reduction in left ventricular ejection fraction (“pump function”), as demonstrated multicentrically by our research group. LBBB induces mechanical dyssynchrony between the interventricular septum and the lateral free wall, resulting in inefficient and diminished cardiac pump performance. Our group has introduced and validated a staging system for LBBB in which the degree of dyssynchrony and pump dysfunction increases progressively from stage 0 to stage 4.

This LBBB classification forms the central framework of the proposed research, which consists of the following unique aims:

1. Natural history of LBBB.
   The UZ Ghent database of our research group contains a unique cohort of more than 500 patients with LBBB since 2017. As only scarce data exist regarding the natural course of LBBB—information that is essential to understanding its pathophysiology—we will analyze clinical, biochemical, and echocardiographic follow-up data to determine how and why patients transition through the stages of the LBBB classification. These insights are fundamental to understanding the mechanisms underlying progression within the LBBB classification.

2. Genetic determinants of LBBB with or without HFrEF.
   Between 20% and 50% of all HFrEF patients carry a (hereditary) pathogenic genetic variant, yet this has been only minimally studied in the LBBB population, with or without concomitant HFrEF. In collaboration with Maastricht University (Prof. S. Heymans), we are currently investigating the prevalence, characteristics, and distribution of pathogenic variants across the LBBB stages. These data will provide unique insights and may have important practical implications for genetic testing, risk stratification, and clinical decision-making in LBBB patients with HFrEF, particularly concerning the indication for implantable cardioverter-defibrillators (ICDs) or pacemakers with or without resynchronization therapy. Ultimately, this research aims to improve risk stratification and management of patients with HFrEF and LBBB.

3. Polygenic risk and progression within the LBBB classification.
   The reasons why some patients progress from early to late LBBB stages while others remain stable are largely unknown. Using prospective data (see Aim 1), we will seek to identify potential risk factors, including polygenic contributors. In collaboration with Maastricht University and the Department of Medical Genetics at UZ Ghent, we will examine whether a significant polygenic risk profile predisposes certain LBBB patients to deteriorate to more advanced stages. This work may yield important insights into LBBB pathophysiology through polygenic risk stratification.

4. Response to guideline-directed medical therapy and implications for device implantation.
   A subset of LBBB patients with severely impaired left ventricular function (ejection fraction < 35%) meet international guideline criteria for implantation of a pacemaker or ICD with cardiac resynchronization therapy (CRT). However, it remains unclear to what extent, and in which patients, left ventricular function may still improve under contemporary heart-failure therapy, particularly since the introduction of SGLT2 inhibitors. Such medical therapy might theoretically improve cardiac function sufficiently to obviate the need for device implantation. Current guidelines recommend waiting at least 3 to 6 months to assess the effect of medical therapy before implanting a CRT device, yet this recommendation is based on outdated expert opinion, and the proportion of patients who ultimately no longer require CRT remains unknown. We therefore aim to determine which LBBB stages respond best to medical therapy, addressing important practical questions (e.g., optimal treatment duration before deciding on CRT; whether early prediction of treatment response is possible). This research, the MIRABBEL study, is an ongoing multicenter, prospective, observational study in Flanders (9 centers), initiated in 2025.

5. Physiologic conduction-system pacing (CSP) versus conventional biventricular pacing.
   Our center holds a national and international leading position in physiologic pacing using conduction-system pacing (CSP), which offers several advantages over conventional right ventricular pacing. CSP involves pacing close to the natural conduction fibers of the left bundle (i.e., on the left side of the interventricular septum), theoretically resulting in near-normal ventricular activation. CSP also appears promising in LBBB patients and may even outperform the classical and still widely applied biventricular (BiV) CRT technique. In this part of the project (in collaboration with KU Leuven and other participating centers in the randomized LeCartes trial), we will investigate the effects of CSP across the different stages of the LBBB classification. We will assess whether CSP yields similar improvements in pump function as BiV pacing within each LBBB stage and whether the characteristic septal contraction patterns associated with each stage can be effectively corrected by CSP compared with classical BiV CRT. This research is novel and unique in that it examines the mechanistic basis of therapeutic success or failure of both BiV pacing and CSP, with important implications for clinical practice in cardiology.