Conduction System Pacing—Five Questions Facing the Field

“Revolutions usually begin as replacements for older certainties, and not as pristine discoveries in uncharted terrain.” ~Stephen Jay Gould

Permanent pacing for bradyarrhythmia was first developed over a half century ago, when Furman and Schwedel’s first report of a transvenous intracardiac pacemaker in 1959 showed a right ventricular (RV) lead position similar in course and shape to most conventional modern devices.¹ Biventricular (BiV) pacing in the mid-1990s was the first notable shift from this paradigm, which sought to address electromechanical dyssynchrony in patients with left bundle branch block (LBBB) and heart failure (HF) with the use of a left ventricular (LV) lead.

Techniques to position the RV lead, however, remained relatively unchanged. It has only been in recent years that conduction system pacing (CSP) has brought about a revolution in how the RV lead itself is placed. In contrast to the large, multicenter, industry-led trials which established BiV pacing, research into CSP has been more organic and grass-roots—driven by numerous, often single-center, investigator-initiated cohort studies. While these efforts have spurred the growth of CSP on an international scale, there are key questions which must be definitively answered for the field to move forward and for CSP to become first-line therapy.

Question 1: How can we accurately predict the risk for pacing-induced cardiomyopathy (PIC)?

A major impetus for enthusiasm in CSP has been reducing the risk of PIC and PIC-associated HF. PIC, defined as LV dysfunction induced by ventricular pacing, has been noted since the early days of ventricular pacing, with variable incidence ranging between 6%-60% of patients based on the criteria applied.^2,3 Indeed, RV apical pacing has been associated with reduced myocardial perfusion,^4,5 increased myocardial work,⁶ increased myofibrillar disarray,⁷ intracellular lipid deposition, and apoptosis at the cellular level.⁸ The mystery, of course, is that not all patients receiving traditional RV pacemakers develop PIC. Predictors for PIC include >20% RV pacing (RVP), wider paced QRS duration (with some work suggesting QRS duration ≥140 ms associated with risk), male gender, and history of myocardial infarction or preexisting nonischemic cardiomyopathy.^9-11 With that noted, the sensitivity and specificity of these features remains limited. At the present time, we may reasonably infer that CSP is unlikely to provide early benefit for patients who are undergoing pacemaker placement for exclusive sinus node dysfunction (SND) with narrow underlying QRS. The justification to pursue CSP even in SND is the risk of progression to atrioventricular (AV) nodal disease. The tradeoff here is whether the risks of CSP are truly comparable to RVP.

Coincident with echocardiographic diagnosis of PIC has been the clinical diagnosis of HF after pacemaker placement, which may be associated with the risk of HF hospitalization. In large registry studies, the incidence of HF after pacemaker implantation has been as high as 10.6% (vs 6.7% in age and sex-matched controls), and associated with increased risk of all-cause mortality.¹² The relative risk also manifests early, in the first 6 months after implant.¹³ However, for patients who do not experience clinical decline, traditional pacing appears to be both sufficient and robust. As the safety profile of traditional RVP for bradyarrhythmia indications is well-defined, it may not be necessary to pursue CSP in all-comers. Being able to accurately predict the risk of PIC or HF after RVP would be a dramatic step forward for the field, as it would identify patients with the most potential benefit from CSP.

Question 2: Can we accurately assess conduction system capture and conduction block from the surface electrocardiogram (ECG)?

The criteria for assessing conduction system capture for patients undergoing His bundle pacing (HBP) have now been established.¹⁴ Particularly among patients with narrow QRS at baseline, the template for assessing conduction system capture is the patient’s intrinsic QRS. In patients undergoing HBP for CSP, the goal is to reproduce this QRS as closely as possible across all 12 leads of the standard surface ECG. Selective capture is present when an identical QRS or near-identical is inscribed with an isoelectric segment present between the stimulation artifact and the QRS onset in all 12 leads (Figure 1). Nonselective capture is present when there is a “pseudo-delta” or slurred upstroke beginning at the stimulation artifact in at least one lead (Figure 2). Critical in patients undergoing HBP is that output-dependent morphology (ODM) changes should be present, which allow implanters to distinguish between nonselective HBP and RV septal capture.^15,16 There may be a small cohort of patients in whom ODM changes are not present with HBP, and use of pacing maneuvers may be helpful to help distinguish morphologic differences in this setting.^17,18

The situation is more complex for left bundle branch pacing (LBBP), in which nonselective pacing is associated with a narrower paced QRS than selective LBBAP.¹⁹ Unlike HBP, the criteria for assessing conduction system capture for LBBP have not yet been standardized, and discriminating nonselective LBBP from left ventricular septal myocardium-only capture remains challenging (see Question 4 below).

Among patients with wide QRS, assessing conduction capture relies on evaluating for inferred changes with QRS correction, and no simple criteria can parse level of block based on assessment of surface ECG alone. This is because the bundle branch block pattern on surface ECG is due to heterogeneous underlying pathophysiology.^20,21 This includes both patients with complete conduction block (CCB) at the level of the left-sided His fibers or proximal LBB (which may be correctable with CSP), and patients with intact Purkinje activation who exhibit wide QRS due to distal disease or myopathic delay (and cannot be corrected with CSP). Some patients may demonstrate both CCB along with concomitant myocardial delay. For these patients, newer approaches such as hybrid CSP and BiV pacing (ie, HBP or LBB area pacing combined with an LV lead) may hold promise.^22-25 Determining underlying pathophysiology noninvasively would help plan procedural approach and reduce rates for crossover for CSP.

Question 3: Are all forms of CSP comparable? Or put differently—does it matter if one captures the conduction system proximally or distally?

Just over 2 decades ago, Deshmukh and colleagues were the first report on CSP with permanent HBP to treat patients with systolic HF and permanent atrial fibrillation.²⁶ HBP has now been shown to be associated with improved measures of mechanical synchrony,²⁷ improved or preserved LV ejection fraction,²⁸ and reduced HF hospitalization relative to RVP.²⁹ Indeed, HBP was the mainstay approach for CSP until 2017, when Huang and colleagues reported on the novel technique of pacing more distally along the left conduction system (LCS) by embedding a lead deep within the interventricular septum.³⁰ Initially termed LBBP, this technique appears to offer similar benefits as HBP with a simpler implant procedure and more stable thresholds over time. The goal of LBBP is to engage the conduction system just distal to the target of the HBP, by capturing either the proximal left bundle or early ramifications of the left posterior fascicle (LPF), left anterior fascicle (LAF), or septal fascicle. This may be quickly assessed by evaluating the paced QRS axis, which is superiorly directed with LPF pacing, inferiorly directed with LAF, and upright in II and downward in III (ie, “para-Hisian”) among more proximal sites.³¹

During LBBP, a right bundle branch block (RBBB) pattern is inscribed on the surface 12-lead during unipolar pacing, which reflects a degree of right-to-left interventricular dyssynchrony. Indeed, when utilizing ultra-high frequency ECG, nonselective LBBP was associated with greater interventricular dyssynchrony than HBP, although with similar lateral LV wall depolarization.³² The clinical significance of this interventricular dyssynchrony is unknown, although it appears modest given that both LV ejection fraction and functional class improves in HF after successful LBBP. Furthermore, in a manner analogous to LV-only pacing, LBBP may be fused with intrinsic right bundle branch conduction by adjusting device AV intervals; this abrogates the r’ in V1 during LBBP and may reduce overall QRS duration to within the normal range.³³ Other means to narrow QRS include anodal capture of the RV septum (or right conduction system) with the ring electrode, which may be utilized even in patients with native RBBB. Whether patients who may achieve QRS narrowing with fusion during LBBP fare differently than those with right bundaloid pattern remains to be seen.

Question 4: Can we reliably distinguish left ventricular septal pacing (LVSP) from LBBAP?

Contemporaneous with the surge of interest in LBBP have been approaches focused on LVSP as an alternative to RVP (and perhaps also to traditional CSP). Reported in 2016 by Mafi-Rad and colleagues,³⁴ the goal of LVSP is to bypass slow conduction through the interventricular septum and capture the LV endocardial surface.³⁵ Anatomically, this is a similar area that is targeted during LV endocardial pacing. This surface approximates the physiologic breakout of conduction system and may engage fast-acting fibers at the endocardial layer of the LV.^36,37 Importantly, LBB or Purkinje potentials are not noted with LVSP, although a right bundaloid QRS in V1 is common, particularly when the lead tip is at the basal LV endocardium.

Selective LBBP may be distinguished from LVSP since an isoelectric segment will be present in all 12 leads (Figures 3-4). Similar to HBP, nonselective LBBP will also have a right bundaloid configuration in V1 with a pseudo-delta apparent in multiple leads (Figure 5). In the case of nonselective LBBP, then, adjacent LV septal capture is present along with LCS capture. LCS capture may be assessed at implant through observation of an LBB or Purkinje potential at the lead tip during implant, although the presence of a potential does not necessarily mean it will be captured. The interval between the potential to the QRS onset should then also be similar to the width of the isoelectric segment in selective LBBP.

As an LBB potential is only variably encountered during LBBP (between 27%-80% in early work),¹⁶ approaches to ascertaining LCS capture have relied upon ECG assessment of lateral wall activation.³⁸ Indeed, the term left bundle branch area pacing (LBBAP) has now increasingly been utilized to describe patients in whom nonselective LBBP was felt to be present based on ECG criteria, but selective LBBP could not be established. In these patients, the most commonly used criteria have examined the time from the stimulation artifact to the peak of R-wave in the lateral precordial leads (ie, V5 or V6), also called the left ventricular activation time (LVAT). Abrupt shortening of LVAT by ≥10 ms during increasing output at the time of implant and the use of a cutoff of LVAT of ≤75 ms (for non-LBBB) and LVAT of ≤85 ms (for LBBB) have been proposed.³⁹ An important caveat here is that these LVAT references are based on a small series of patients, and there may be considerable overlap between LBBAP and LVSP over a range of LVAT measurements.^19,32 The abrupt shortening of the LVAT at the time of implant during lead delivery (which occurs while traversing from the RV septum to the LV) may be the more critical criterion.

More recently, the difference between the V6-V1 interpeak interval during pacing has been proposed as a novel means to rapidly distinguish between LBBAP and LVSP.⁴⁰ In patients with LBBAP, the V6-V1 interval (measured as the difference between peak of the R-wave in V6 to the time to the R’ in V1) is longer than 33 ms in patients where LCS capture is present. A note here is that there are other factors which may impact the timing and amplitude of the R-wave in V6, including cardiac rotation, degree of eccentric hypertrophy, or underlying fibrosis or scar. As such, it is unlikely that absolute cutoffs will demonstrate adequate sensitivity (although perhaps reasonable specificity) among patients with underlying cardiomyopathy.

From a more sanguine perspective, the salient question may simply be if the distinction between LVSP and CSP is meaningful. In a small hemodynamic study, LVSP was compared to HBP among patients referred for cardiac resynchronization therapy, and was found to demonstrate similar changes in QRS area, standard deviation of activation times, and LV pressure as CSP.⁴¹ Whether these acute observations translate into similar clinical outcomes in longer-term studies of at-risk patient populations, including those with HF, remains to be seen.

Question 5: What are the concerns associated with CSP, and should we drive to adopt CSP with currently available leads?

In addition to fundamental concerns having to do with ascertaining presence of conduction system capture already noted, other criticisms of CSP have included the relatively long learning curve related to implant, particularly with respect to HBP.^42-44 Longer-term data regarding pacing thresholds are now available for HBP and may well highlight the Achilles’ heel of the technology, with both higher outputs required at implant along with late and unpredictable rises in follow-up leading to premature battery depletion and need for system revision. On the other hand, LBBP appears to demonstrate lower thresholds, but a more concerning complication profile than HBP, including risk for tricuspid leaflet entrapment, intraseptal hematoma, septal myocardial infarction of the septal artery, septal artery fistula, and delayed LV septal perforation and dislodgement.^45-48 There are also a dearth of data regarding longer-term extraction risks associated with LBBP.

While there have been advances in the availability of sheaths to deliver leads to the septal surface of the heart, the leads utilized were not designed for the purpose of CSP. Commercially available leads are designed with helix lengths between 1.6-2 mm, with the majority 1.8 mm in length.⁴⁹ This relatively short helix has been a limitation for both QRS correction and acceptable thresholds when attempting HBP. With respect to LBBP, the helix creates a “tunnel” from the number of rotations required to reach the LV endocardial surface. Given this, the tissue within the helix itself may be pulverized and insufficient to fix the lead tip, leading to acute macrodislodgements and predisposing to microdislodgements over time. In contrast to the nascent period of BiV pacing, when CS leads were being developed simultaneously with dedicated BiV systems, CSP has repurposed available leads and cans, and with it has come potential technological ceilings to implant success.

While there has been a ground swell of enthusiasm for CSP, new leads may still take years to materialize. Should we drive to adopt CSP with the current leads? The answer may simply be that it is our only pragmatic option.

Conclusion

After years of relative certainties of options and approaches, the field of pacing is going through a period of renaissance and renewal. Much of the interest in CSP stems from fundamentals in electrophysiology, with the goal of understanding how to deliver leads to targets within the human conduction system. HBP may be the most physiological of CSP strategies, but is associated with nontrivial implant difficulty and rising thresholds over time. More recently, LBBP has emerged as a viable alternative, although there is need to elucidate capture criteria to distinguish LBBAP vs LVSP. With that noted, both may offer benefits over traditional RV pacing, and perhaps also to suboptimal BiV pacing. Large, randomized, comparative clinical trials that can test these hypotheses and that are powered to detect differences in meaningful clinical end points, including hospitalization and survival, are now being designed. It is with this in mind that one cannot help but feel optimistic for CSP; the revolution has started, plans are underway, and questions will soon be answered. 

Gaurav A. Upadhyay, MD, FACC, FHRS

Center for Arrhythmia Care, Heart and Vascular Institute, The University of Chicago Medicine

Disclosures: Dr Upadhyay has been a speaker or consultant for Abbott, BioTel, Biotronik, Boston Scientific, Medtronic, and Zoll Medical.

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