**3.2 Activation pattern**

HBP has potential advantages in comparison to the CRT with the use of coronary sinus (CS) for left ventricular (LV) pacing [11]. LV pacing through CS cannot provide ideal resynchronization because of asynchronicity from the LV epicardial pre-excitation (**Figure 2**) [12]. Predominantly pacing comes from a lateral wall of the LV. The higher degree of asynchronicity can be seen through LV apical pacing and pacing in the areas with myocardial fibrotic scarring.

Both RV pacing and BVP change QRS pattern to a greater or lesser extent. Complete identically of QRS pattern to an intrinsic one differentiates HBP from the rest of pacing techniques [11]. Moreover, it is possible to completely or partly renew the intrinsic ventricular conduction in patients with BBBs by obtaining the normal width and form of the QRS complex [13, 14].

#### **Figure 1.**

*Locations of the permanent lead placement for ventricular pacing along with strategies for cardiac resynchronization therapy. 1 – His bundle pacing; 2 – Left bundle branch pacing; 3 – Left septal pacing; 4 – Right septal pacing; 5 – Epicardial left ventricular pacing; 6 – Endocardial left ventricular pacing. Cardiac resynchronization therapy strategies: 1 – SINGLE SPOT (1, 2, 3, 4); 2 – CRT (4 + 5); 3 – HOT-CRT (1 + 5); 4. LOT-CRT (2, 3 + 5); 5. CSP-RV (2, 3 + 4). SINGLE SPOT = pacing from a single site, CRT = cardiac resynchronization therapy, HOT-CRT = His-optimized cardiac resynchronization therapy, LOT-CRT = left bundle branch-optimized cardiac resynchronization therapy, CSP-RV = conduction system pacing + right ventricular pacing.*

#### **Figure 2.**

*Comparison of epicardial activation maps for intrinsic QRS, selective HBP, non-selective HBP, and BVP in a patient with normal QRS morphology and duration. The color scale on the left indicates the activation times. Activation from the selective HBP is identical to intrinsic activation. Activation from the non-selective HBP is identical to the intrinsic activation for LV, but evidence of pre-excitation can be seen for RV in the basal and mid areas, which indicates the capture RV myocardium alongside the HB. The activation pattern in the case of BVP is different from an intrinsic one. Differences between selective and non-selective HBP will be discussed later in the chapter. AP – Anterior–posterior projection, PA – Posterior–anterior projection, LAD – Left anterior descending artery.*

#### **3.3 Clinical implications**

Clinical interest in the HBP significantly increased in the previous 5 years.

The largest study regarding the clinical of HBP compared to the RV pacing was published in 2018 [7]. Patients requiring pacemaker implantation were included in the study between 2013 and 2016. HBP was performed in consecutive patients at 1 hospital, while other patients received RV pacing at a sister hospital. A total of 765 people underwent pacemaker implantation: RV pacing in 433 patients and HBP in 332 patients. HBP was technically successful in 304 patients (92%). The mean follow-up duration for the entire cohort was 725 + 423 days.

Implant characteristics, heart failure hospitalization (HFH), upgrades to BVP and all-case mortality were tracked. The primary endpoint of death, HFH, or upgrade to BiVP was significantly reduced in the HBP group (83 of 332 patients [25%]) compared to RVP (137 of 433 patients [32%]; hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.534 to 0.944; p = 0.02). The incidence of HFH was significantly reduced in HBP (12.4% vs. 17.6%; HR: 0.63; 95% CI: 0.430 to 0.931; p = 0.02). There was a trend toward reduced mortality in HBP (17.2% vs. 21.4%, respectively; p = 0.06).

From the abovementioned data, it is possible to conclude that HBP can be an alternative to conventional RV pacing in clinical practice while improving patient outcomes, taking into account the technical capabilities of the clinic and accumulated experience. Best candidates for HBP are patients with AV blocks, "narrow" QRS, and impaired LV function [15–17].

#### **4. His bundle pacing in different patient groups**

#### **4.1 Patients with indications for CRT**

HBP is more frequently used nowadays as an alternative to conventional RV pacing in patients with intraventricular conduction disturbances and indications for CRT. The idea of overcoming distal His-Purkinje system injury with the help of HBP and thus renew normal ventricular conduction seems very appealing [10]. Several groups of patients with intraventricular blocks that were previously treated as distal His-Purkinje injury can successfully restore conduction despite BBB [4, 13, 18–21].

An exact mechanism of QRS complex normalization in these cases is not fully understood. A hypothesis of functional longitudinal dissociation in HB that is the most widespread nowadays for explaining HBP efficiency in BBB was initially proposed by Kaufman R. and Rothberger C in the already distant 1919 [22]. The core of the hypothesis is that there are fibers inside the HB that conduct pacing impulses to the left and right bundle branches, being predominantly isolated from each other. Because of that, damage of these fibers in one of the HBs results in HB branch blocks [23]. It means that His-Purkinje system fibers may be blocked proximally, not distally inside the interventricular septum (IVS), and this block can be corrected with direct HBP.

Basing on the HB anatomy, the current amplitude for pacing specialized HB branch fibers (partially isolated by connective tissue) may be relatively high and involve neighboring myocardial areas [24, 25]. It is necessary to discuss the mechanisms of the non-selective HBP [26, 27]. In non-selective HBP, besides the activation of the HB fibers with block overcoming, additional areas of the adjacent myocardium (mostly septal part of the RV, rarely basal parts of the LV) may be activated.

The main aim of the research conducted by Huang W. et al. was to assess the efficacy of HBP to correct LBB block (LBBB) and long-term clinical outcomes with HBP in patients with heart failure (HF) [13]. Permanent HBP leads were implanted in HB under the guidance of ECG criteria for LBBB correction and pacing threshold <3.5 V / 0.5 ms or 3.0 V / 1 ms. Left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), pacing parameters, and NYHA class was assessed during a follow-up. HBP was performed in 74 patients (mean age 69.6 ± 9.2 years and 43 men). LBBB correction was reached in 72 patients (97.3%). 56 patients (75.7%) had adequate pacing thresholds during HB lead implantation. Lead implantation wasn't performed in 18 patients because of a lack of LBBB correction (n = 2) or high pacing threshold for LBBB correction (n = 16). An average follow-up was 37 (range 15.0–48.7) months. Follow-up exceeded 3 years in 30 patients with HBP. Patients had an increase in LVEF from baseline32.4 ± 8.9% to 55.9 ± 10.7% (p < 0.001), LVESV decreased from a baseline of 137.9 ± 64.1 mL to 52.4 ± 32.6 mL (p < 0.001) and NYHA Class improvement from baseline 2.73 ± 0.58 to 1.03 ± 0.18 (p < 0.001). The pacing threshold required for LBBB correction remained the same: 2.13 ± 1.19 V / 0.5 ms during a procedure and 2.29 ± 0.92 V / 0.5 ms at a 3-year follow-up (p > 0.05). The conclusions are as follows: HBP with LBBB resolution can be seen in 76% of patients and accompanied by a significant improvement of LV contraction properties. On the other hand, almost a quarter of patients cannot overcome LBBB while performing HBP; the question remains opened which technique should be considered next after HBP failure.

Close results were obtained by Ajijola O. et al. [28]. Selective HBP was successful in 16 patients (76%) out of 21 patients with LBBB. It lead to a significant decrease in the QRS complex duration from 180 ± 23 ms to 129 ± 13 ms (p < .0001) and LVEF improvement from 27% ± 10–41% ± 13% (p < .001) during a 12-month follow-up.

Sharma et al. performed HBP in candidates for CRT, to whom it was technically impossible to achieve LV epicardial pacing, or to the ones who were non-responders to a conventional CRT. HBP was technically successful in 95 patients out of 106 (90%). The mean follow-up period was 14 months. It was marked a significant decrease of QRS duration from 157 ± 33 ms to 117 ± 18 ms (p = .0001), an increase in LVEF from 30 ± 10% to 43 ± 13% (p = .0001), and NYHA Class improvement from 2.8 ± 0.5 to 1.8 ± 0.6 (p = .0001).

HBP nowadays is considered as an alternative to a conventional BVP in patients with LBBB and broad QRS complexes in addition to chronic ventricular pacing with heart failure and ventricular asynchrony [18, 19, 29–32].

However, HBP not always leads to a significant decrease of a ventricular complex. An aim to improve HBP results with the help of additional lead implantation through the coronary sinus to pace LV was set in His-optimized CRT (HOT-CRT) trial to reach a maximum possible resynchronization. This trial demonstrated a possibility of HBP optimization via this additional lead to LV through coronary sinus [33].

HOT-CRT was applied in 27 patients (mean age 72 ± 15 years): 17 with LBBB, 5 with intraventricular blocks, 5 with chronic RV pacing. HOT-CRT protocol was successfully run in 25 patients out of 27. The initial QRS width of 183 ± 27 ms was significantly reduced to 162 ± 17 ms for BVP and 151 ± 24 ms for HBP (p < .0001). With HOT-CRT protocol (His pacing lead implantation + LV pacing through coronary sinus), QRS length decreased even more to 120 ± 16 ms (p < .0001). Mean follow-up was 14 ± 10 months. LVEF increased from 24 ± 7% to 38 ± 10% (p < .0001), and NYHA Class was improved from 3.3 to 2.04. Clinical responders were 21 out of 25 patients (84%), and echocardiographic responders were 23 out of 25 patients (92%).

HOT-CRT trial demonstrated a possibility of electrical resynchronization improvement in patients with indications for CRT and suboptimal HBP by adding LV stimulation site through the coronary sinus.

The most common location for LBBB – is a left part of the HB. HBP eliminates LBBB on this level in 94% of cases. In the case of a more distal location of LBBB, correction is possible in 62% of cases. When the His-Purkinje system is intact on the level of IVS, LBBB correction with HBP does not take place.

In the clinical practice, preferable locations of the LBBB for HBP are left-sided proximal HB fibers blocks with a possibility of activation of the latent distal His-Purkinje system.

#### **4.2 Patients with RBBB**

Positive hemodynamical and clinical effects of BVP are limited in patients with right bundle branch block (RBBB). Permanent HBP is proposed as an option for resynchronization therapy in 39 patients with RBBB and low LVEF who had indications for CRT [21]. HBP was an initial strategy for them or a "rescue" strategy in a case of unsuccessful implantation of the epicardial lead for LV pacing.

Selective HBP was successful in 37 patients out of 39 (95%); however, a markable reduction in QRS duration was reached in 78% of cases. HB pacing thresholds for RBBB correction were 1.4 ± 0.7 V / 1 ms. Mean follow-up was 15 ± 23 months. A significant reduction in QRS length from 158 ± 24 ms to 127 ± 17 ms was achieved. LVEF improved from 31 ± 10% to 39 ± 13% (p = .004), and NYHA Class was decreased from 2.8 ± 0.6 to 2 ± 0.7 (p = .0001). The notable increase in pacing threshold was in 3 cases.

This research concluded that permanent HBS was associated with shortening QRS duration in patients with RBBB and decreased LVEF.

#### **5. His bundle pacing limitations**

#### **5.1 Implantation site**

The main boundary for the wide adoption of HBP is a relatively small area for pacing lead implantation into the cardiac conduction system with an appropriate pacing threshold. As a result, physicians experience lengthening of the procedure time and an increase in fluoroscopy exposure compared to conventional RV pacing. These problems tend to decrease with an accumulation of physician's experience. Nevertheless, even experienced physicians in high-volume centers perform HBP by 27% longer than RV pacing (70 mins and 55 mins) while increasing fluoroscopy time by 39% (10.3 mins and 7.4 mins) [34, 35].

Further improvements in implantation tools will help overcome technical limitations, but even in this case, procedure and fluoroscopy time will remain lengthier than for RV pacing [7].

## **5.2 Pacing thresholds**

Another disadvantage of HBP – higher pacing thresholds and lesser energy efficiency that leads to the earlier cardiac pacemaker battery discharge. An increase in pacing threshold was observed in post-operational period for HBP compared to RV pacing: 1.30 V + 0.85 V for HBP and 0.59 V + 0.42 V for RV pacing. It resulted in a necessity for early pacemaker replacement in 3 out of 75 patients from the HBP group [7].
