Introduction

Left bundle branch block (LBBB) is a common cardiac conduction abnormality characterised by delayed or blocked electrical conduction within the left bundle branch of the heart’s conduction system. This conduction abnormality results in asynchronous ventricular activation, potentially leading to impaired cardiac function and increased risk for heart failure, arrhythmias, and cardiovascular mortality .

Historically, LBBB has often been attributed to acquired conditions such as hypertension, ischemic heart disease, or structural abnormalities . However, recent scientific advances increasingly underscore the importance of genetic factors in the development and progression of LBBB, particularly highlighting familial forms of the disorder . This article explores the genetic and familial components of LBBB, emphasising current knowledge, clinical implications, and future directions for research and patient management.

Understanding the Genetic Basis of LBBB

The human heart relies on intricate electrical pathways to coordinate contraction efficiently. Genetic mutations can disrupt the structure and function of proteins essential for cardiac electrical conduction, such as ion channels, gap junction proteins, and structural proteins of the cardiac conduction system . Recent genome-wide association studies (GWAS) have identified multiple genetic variants associated with cardiac conduction diseases, including LBBB .

Li et al. (2025) demonstrated through GWAS that certain genetic loci predispose individuals to cardiac conduction disturbances. These genetic variants affect genes that encode critical proteins involved in electrical signalling pathways, potentially explaining why certain individuals without traditional cardiovascular risk factors develop LBBB at younger ages .

Ion Channels and Their Role in LBBB

Ion channels, which regulate the flow of ions across cell membranes, play a fundamental role in cardiac electrical activity. Mutations in ion channel genes can lead to disturbances in cardiac conduction, manifesting clinically as various types of heart blocks, including LBBB .

One notable example is the gene encoding the transient receptor potential melastatin member 4 (TRPM4) ion channel. Daumy et al. (2016) found TRPM4 mutations linked explicitly to progressive familial heart block type I, a condition closely related to LBBB. These mutations disrupt ion homeostasis, affecting cardiac electrical stability and increasing susceptibility to conduction block . Identifying such genetic defects helps clarify disease mechanisms and provides potential targets for therapeutic interventions.

Gap Junction Proteins and Genetic Predisposition

Gap junction proteins, particularly connexins, are essential for electrical coupling between cardiac cells. Connexins facilitate coordinated electrical propagation by enabling rapid cell-to-cell communication. Connexin 43, specifically, has emerged as a significant factor influencing LBBB susceptibility .

Ladenvall et al. (2013) identified a clear genetic association between variations at the Connexin 43 locus and the incidence of LBBB, suggesting that genetically determined impairment of electrical coupling significantly contributes to familial LBBB. This finding underscores the pivotal role of cellular electrical coupling and offers insights into potential therapeutic strategies targeting gap junction function .

Familial Clustering and Hereditary Transmission of LBBB

Familial clustering of cardiac conduction disorders strongly supports the concept that genetics significantly influences disease onset. Epidemiological studies confirm clear familial inheritance patterns, suggesting a hereditary basis for certain cases of LBBB and other conduction disorders .

Gourraud et al. (2012) conducted an extensive epidemiological investigation and provided robust evidence of familial aggregation in progressive cardiac conduction defects, highlighting the existence of a strong genetic component. Their study revealed consistent hereditary transmission patterns, reinforcing the importance of genetic predisposition in understanding disease progression .

Additionally, parental electrocardiographic screening studies performed by Baruteau et al. (2012) identified high rates of inheritance in congenital and childhood nonimmune isolated conduction disorders. Such studies emphasise the need for thorough familial assessments in patients with unexplained LBBB, particularly younger individuals who present without traditional cardiovascular risk factors .

Genetic Links with Cardiomyopathies

The association between cardiomyopathies, particularly dilated cardiomyopathy (DCM), and conduction abnormalities like LBBB is increasingly recognised. Many inherited cardiomyopathies involve mutations affecting structural or functional components of cardiac muscle cells, contributing to cardiac remodelling and conduction disturbances .

Recent studies, such as the investigation by Ferro et al. (2024), suggest that genetic backgrounds linked to DCM significantly influence the clinical course and therapeutic response in patients with LBBB. Ferro et al. demonstrated that specific genetic mutations responsible for DCM profoundly affect patient responsiveness to cardiac resynchronisation therapy (CRT), a common therapeutic approach for symptomatic LBBB. Genetic testing thus holds promise for personalised treatment plans and improved patient outcomes .

Genetic Overlap with Other Cardiac Conduction Disorders and Arrhythmias

Interestingly, genetic mutations implicated in LBBB often overlap with mutations responsible for other cardiac conduction disorders and arrhythmias, including atrial fibrillation (AF) and progressive conduction system diseases .

Martin and Lambiase (2018) noted considerable genetic overlap between inherited conduction diseases and AF, suggesting shared pathogenic mechanisms affecting cardiac electrical stability. Similarly, Asatryan and Medeiros-Domingo (2019) described genetic mutations underlying progressive conduction system disease that frequently coexist with various arrhythmic disorders, further emphasising the interrelatedness of these conditions .

Clinical Implications: Diagnostic Approaches and Genetic Counselling

Recognising genetic factors in LBBB significantly impacts clinical practice, influencing diagnosis, prognosis, and management strategies. A comprehensive family history should be routinely included in patient evaluations, especially for younger adults presenting with LBBB, as hereditary factors may be underlying contributors .

Silvetti et al. (2023) emphasised the critical role of electrocardiography (ECG) combined with genetic screening for diagnosing cardiomyopathies and conduction abnormalities. Early genetic testing could identify at-risk individuals, facilitate early diagnosis, and enable preventive or therapeutic interventions tailored to individual genetic profiles .

Clinicians should also consider genetic counselling for families affected by familial forms of LBBB to inform family members about their risk and potential management strategies.

Future Research Directions and Potential Therapies

Ongoing genetic research continues to unravel the complexity underlying familial LBBB, promising future advances in personalised medicine. Investigating additional candidate genes, refining risk stratification, and enhancing genetic diagnostic methods are critical steps forward. Future studies should also aim to elucidate the mechanisms linking genetic variants to disease manifestations, further clarifying pathogenesis and potential therapeutic targets.

Advancements in genetic therapies, such as targeted gene editing or pharmacological modulation of ion channels and gap junction proteins, could eventually provide precise treatments addressing the underlying genetic defects in familial LBBB.

Conclusion

Understanding the genetic and familial basis of LBBB represents an essential step forward in cardiology. Increasing evidence indicates that genetic factors significantly contribute to disease susceptibility, progression, and therapeutic response, especially in familial cases. Clinicians should maintain high awareness of genetic influences when evaluating patients, particularly younger individuals, with unexplained LBBB.

Integrating genetic screening and counselling into clinical practice will enhance diagnosis accuracy, improve risk stratification, and personalise therapeutic interventions, ultimately improving clinical outcomes for affected individuals and families.

References

Tan NY, Witt CM, Oh JK, Cha YM. Circ Arrhythm Electrophysiol. 2020 Apr;13(4):e008239. Available from: https://doi.org/10.1161/circep.119.008239

Pérez‐Riera AR, et al. Ann Noninvasive Electrocardiol. 2019 Jun;24(2):e12572. Available from: https://doi.org/10.1111/anec.12572

Li B, et al. Hum Genomics. 2025 Feb;19(1). Available from: https://doi.org/10.1186/s40246-025-00732-x

Daumy X, et al. Int J Cardiol. 2016 Mar;207:349–58. Available from: https://doi.org/10.1016/j.ijcard.2016.01.052

PaperQA. OpenTargets Disease-Associations: Left bundle branch block. 2025.

Ladenvall P, et al. Eur Heart J. 2013 Aug;34(suppl 1):P4960. Available from: https://doi.org/10.1093/eurheartj/eht310.p4960

Gourraud JB, et al. Heart. 2012 Jun;98(17):1305–10. Available from: https://doi.org/10.1136/heartjnl-2012-301872

Baruteau AE, et al. Circulation. 2012 Sep;126(12):1469–77. Available from: https://doi.org/10.1161/circulationaha.111.069161

Ferro MD, et al. JACC Clin Electrophysiol. 2024 Jul;10(7):1455–64. Available from: https://doi.org/10.1016/j.jacep.2024.03.019

Martin CA, Lambiase P. Cardiovasc Genet Genomics. 2018;481–522. Available from: https://doi.org/10.1007/978-3-319-66114-8_15

Asatryan B, Medeiros-Domingo A. Europace. 2019 Aug;21(8):1145–58. Available from: https://doi.org/10.1093/europace/euz109

Balla C, et al. J Am Heart Assoc. 2025 May;14(9). Available from: https://doi.org/10.1161/jaha.124.040274

Silvetti E, et al. Front Cardiovasc Med. 2023 Jun;10:1178163. Available from: https://doi.org/10.3389/fcvm.2023.1178163