Tissue attached to retrieved left bundle pacing leads: histopathological evaluation of tissue composition in relation to difficult lead advancement

Introduction

Conduction system pacing (CSP), particularly left bundle branch area pacing (LBBAP), has become a preferred approach for bradycardia due to its high success rate and stable electrical performance. Nevertheless, ∼10% of procedures remain unsuccessful, and the underlying reasons are not fully understood. Previous reports have speculated that septal fibrosis, inadequate sheath support, and structural alterations may contribute to these difficulties.^1–4 However, the actual tissue characteristics encountered during failed attempts remain unclear, and the direct relationship between lead advancement failure and septal fibrosis has yet to be established.

Method

This prospective, single-centre study (July 2021–February 2022) enrolled patients with indications for CSP, excluding those requiring defibrillator-based cardiac resynchronization therapy. Procedures used the Medtronic 3830 lead and C315HIS catheter, following prior standard anatomical techniques⁵ with modifications. Successful LBBAP was defined by deep intra-septal lead placement with characteristic QRS morphology or V6RWPT < 80 ms, consistent with EHRA 2023 criteria.⁶ Failed advancement was defined as inability to reach the left ventricular sub-endocardium. Retrieved tissue from unsuccessful screwing attempts was fixed, stained with haematoxylin and eosin (H&E) and Masson’s trichrome, and analysed by ImageJ software (NIH) for collagen and myofibril proportions. Statistical analysis used t-test or Fisher’s exact test, with P < 0.05 considered significant.

Result

A total of 25 tissue specimens were collected from 14 patients (mean age 73.5 years; 50% female) undergoing LBBAP. Most had preserved systolic function (mean LVEF 56.9 ± 8.6%), with an average septal thickness of 8.8 ± 2.0 mm and left atrial volume index of 37.7 ± 15.3 mL/m². Comorbidities and medication use are summarized in Figure 1A. Among the 25 tissue specimens, 20 from failed lead advancement attempts (failure group) and 5 from non-failure cases (non-failure group), including accidental lead extraction (N = 1), spontaneous dislodgement (N = 1), septal perforation (N = 1), and unsatisfactory pacing morphology (N = 2).

Figure 1.

Comparison of Masson’s trichrome staining and scatter plot analysis of tissue composition between non-failure and failure group. (A) Patient characteristics. Continuous variables are presented as mean ± standard deviation. Categorical variables are presented as n (%). LVEF, left ventricular ejection fraction; IVS, interventricular septum; LVEDD, left ventricular end-diastolic dimension; LAVI, left atrial volume index; RA, right atrium. (B) Masson’s trichrome staining of the two group. (C) The failure group revealed significantly higher collagen content compared with the non-failure group (28.1 ± 11.3% vs. 13.9 ± 10.7%, P = 0.0183) and lower myofibril content (18.6 ± 18.2% vs. 41.5 ± 27.4%, P = 0.0321). (D) Comparison of collagen content in subgroup patients with organized myocardial specimens between the two group. Within the subgroup of patients with organized myocardial specimens, the failure group exhibited significantly greater interstitial and replacement fibrosis compared with the non-failure group (29.2 ± 13.0% vs. 7.2 ± 4.2%, P = 0.0240). (E) The x-axis represents myofibril content, and the y-axis represents collagen content. Specimens from the failure group clustered in low myofibril/high collagen regions, whereas non-failure specimens showed a broader distribution with higher myofibril and lower collagen in some cases. (F) In patients with multiple lead advancement attempts, specimens showed heterogeneous composition, ranging from collagen-rich to myofibril-rich.

To evaluate tissue composition in relation to lead advancement difficulty, Masson’s trichrome staining was performed (Figure 1B). Compared with the non-failure group, the failure group showed significantly lower myofibril content (18.58 ± 18.2% vs 41.52 ± 27.4%, P = 0.0321) and significantly higher collagen content (28.13 ± 11.3 vs 13.91 ± 10.7%, P = 0.0183, Figure 1C). These findings suggest that, in many cases, the lead helix did not penetrate deeply into the myocardium but rather engaged primarily at the endocardium–myocardium junction, which is inherently collagen-rich. We further examined whether myocardial fibrosis affected lead deployment. Within the subgroup of patients with organized myocardial specimens, the failure group showed more pronounced interstitial and replacement fibrosis than the non-failure group (29.20 ± 13.0 vs. 7.21 ± 4.2%, P = 0.0240), supporting the possibility that septal fibrosis contributes to failed lead advancement (Figure 1D). Furthermore, failure group clustered with low myofibril and high collagen content (Figure 1E), indicating that excessive fibrosis and reduced muscle density may impede lead advancement, whereas non-failure group were more widely distributed. In addition, 14 tissue samples obtained from three patients who underwent more than two attempts were analysed separately (Figure 1F). Repeated attempts in the same patient produced tissues with variable composition, reflecting septal heterogeneity that influences procedural outcomes.

Discussion

In this study, failed lead advancement was associated with higher collagen content, lower myofibril density, and septal heterogeneity, suggesting that fibrosis and structural variability hinder deep lead penetration during LBBAP. Previous studies have speculated that septal fibrosis can hinder lead penetration during CSP.^1–3 Our analysis supports this view, showing that failure specimens contained significantly more collagen and less myofibrillar tissue compared with non-failure samples. Importantly, some tissues appeared to originate from the endocardial surface or endocardium–myocardium junction, both normally rich in collagen.⁷ This observation suggests that not all collagen represents pathological fibrosis; the physiological endocardial barrier itself may limit penetration. Nevertheless, in organized myocardial samples, the failure group exhibited more pronounced interstitial and replacement fibrosis, reinforcing the contribution of pathological remodelling to procedural difficulty.

The multicentre European MELOS study⁸ reported that failure to achieve deep penetration into the interventricular septum occurred in 41.8% of cases, unsatisfactory paced QRS in 27.8%, and high capture threshold or unstable lead in 0.8%, with chamber enlargement and septal fibrosis as key contributing factors. These large-scale findings resonate with our histological observations, underscoring that septal fibrosis and endocardial barriers are clinically relevant obstacles to effective lead advancement. While tissue composition provides one explanation for failure, procedural factors must also be considered. Inadequate sheath support, sub-optimal sheath–septum orientation, or kinking of the delivery system can also prevent effective lead advancement, even in the absence of significant fibrosis. Thus, unsuccessful implantation is likely multifactorial, arising from the interplay between tissue characteristics, patient anatomy, and technical factors. Repeated attempts within the same patient yielded tissues with varying collagen and myofibril content, reflecting septal heterogeneity and localized structural differences. Clinically, this suggests that failure at one screwing site does not necessarily predict failure at another, as different trajectories may engage different substrates. In addition, Lead-derived tissue sampling is supported by Yang Ye et al.⁹ showing lumenless pacing leads can safely and effectively obtain myocardial specimens, validating our collection method.

Our study highlights several implications for practice. First, recognition of the endocardial barrier and septal fibrosis as potential obstacles may encourage operators to adjust sheath position or screwing trajectory early, rather than persisting with repeated attempts in the same location. Second, pre-procedural imaging or adjunctive tools to evaluate septal thickness and fibrosis¹⁰ may help identify patients at higher procedural risk. Finally, refinements in lead and sheath design could help overcome both tissue resistance and delivery-system limitations, potentially improving success rates.

Limitation

Limitations include the small, single-centre sample size, potential sampling bias from crushed or limited tissue fragments, and lack of long-term outcome correlation. Larger multicentre studies integrating imaging and histopathology are needed to validate these findings.

Conclusion

Failure of lead advancement during LBBAP is associated with increased collagen content, reduced myofibril density, and tissue disorganization. In addition to tissue factors, technical and anatomical challenges may also underlie implantation failure. Recognition of tissue composition as a contributing factor may help explain procedural difficulties and guide strategies to improve LBBAP success.

Data availability

The data underlying this article cannot be shared publicly due to patient privacy and institutional policy. The data will be shared on reasonable request to the corresponding author.