Cardiac resynchronization therapy (CRT) obtained by biventricular cardiac pacing (BiVP) is a cornerstone of the therapeutic approach for patients with left bundle branch block (LBBB) and heart failure (HF) due to systolic dysfunction.^1,2 CRT results in ventricular remodeling, improvement in functional class and quality of life and, more importantly, decreased mortality and HF hospitalizations. Despite all its benefits, CRT device implantation is often a challenging procedure, and a substantial number of patients do not respond to the therapy. Recently, conduction system pacing (CSP) has emerged as a viable alternative to BiVP. His bundle pacing (HBP) and left bundle branch pacing (LBBP) have proven to be feasible and safe in selected patients. However, few data are available in the literature supporting its use as an alternative to CRT.

HBP is referred in the American guidelines as a plausible option in the context of an atrioventricular block (AV) and a permanent pacing indication with a left ventricular ejection fraction (LVEF) between 36% and 50%.¹ More recently, the European guidelines supported HBP in patients with failed coronary sinus lead implant or in those with AV and LVEF >40% who are anticipated to have >20% ventricular pacing.² However, HBP is not currently indicated for classical CRT indications in patients with LVEF <35%. Despite the high hopes placed on HBP, it has some drawbacks such as high implant thresholds, increased thresholds during follow-up, low R-wave amplitude that complicates pacing management, and block distal to the His. LBBP was introduced in 2017³ to overcome some of these limitations, however, current guidelines do not refer to it due to the limited evidence available.

The LEVEL-AT trial⁴ (LEft VEntricuLar Activation Time Shortening with Physiological Pacing vs Biventricular Resynchronization Therapy) is the first randomized study comparing BiVP with CSP, including LBBP. The inclusion criteria were symptomatic patients with HF on optimal medical treatment with LVEF ≤35% and wide QRS (LBBB ≥130 ms or QRS ≥150 ms in non-LBB) or a CRT indication due to AV block and cardiac dysfunction. The LEVEL-AT trial was a controlled, non-inferiority trial, and 70 patients were randomized to BiVP or CSP and followed up for 6 months. Crossover was allowed when the primary allocation procedure failed. In the CSP arm, HBP and LBBP were allowed; 4 (4/35) of the patients allocated to CSP received HBP, and the remaining received LBBP. Crossover took place in 8 patients (23%) in the CSP arm and in 2 patients (5.7%) in the BiVP arm.

The primary endpoint of the LEVEL-AT trial was the change in LV activation time (LVAT) measured using electrocardiographic imaging (ECGI). Both arms showed a similar decrease in the LVAT (-28 ± 26ms with CSP vs. -21 ± 20ms with BiVP; p<0.001 for non-inferiority). Secondary endpoints were LV reverse remodeling, the combined endpoint of HF hospitalization or death at 6-month follow-up, New York Heart Association (NYHA) class improvement, and QRS shortening. Both groups presented a similar change in LV end-systolic volume (LVESV) (-37 ± 59 ml CSP vs. -30 ± 41 ml BiVP; p=0.04 for non-inferiority) and similar rates of mortality or HF hospitalizations (2.9% vs. 11.4%, respectively; p=0.002 for non-inferiority) (Figure 1). In addition, the trial showed non-inferiority in the NYHA class improvement and QRS shortening.

Figure 1

In summary, the LEVEL-AT trial showed that similar degrees of cardiac resynchronization, ventricular reverse remodeling, and clinical outcomes were attained by CSP as compared to BiVP. Larger and sufficiently powered randomized clinical trials are needed to evaluate the potential superiority of CSP over BiVP.

Whether CSP could result in better resynchronization of the ventricles remains unknown. ECGI obtained from the LEVEL-AT trial showed that despite similar LVATs, the sequence of LV activation is different between CSP and BiVP. Arnold et al.⁵ found that HBP resulted in a greater reduction in LVAT than BiVP. However, this observation was made in a small cohort of patients (n=23) with temporary HBP (lead was not actively fixed).

The benefits of CSP with HBP in HF patients is supported by two randomized studies: His-Sync⁶ (n=41) and His-Alternative⁷ (n=50). His-Sync did not find significant differences in LVEF improvement in HBP over BiVP (median 9.1% vs. 5.2%, p=0.33). His-Alternative (which included only HBP) and the LEVEL-AT trial (HBP and LBBP) found that CSP resulted in a similar degree of ventricular reverse remodeling as BiVP (no significant differences regarding LVEF and LVESV in the His-Alternative and a non-inferior decrease in LVESV in the LEVEL-AT trial); however, trials with a primary echocardiographic endpoint are warranted (Table 1).

Table 1

	His-Sync (2019)6	His Alternative (2021)7	LEVEL-AT (2022)
n	41	50	70
Type of pacing	HBP	HBP	HBP and LBP allowed. 4/35 patients received HBP
Crossovers from CSP to BiVP	48%	28%	23%
Primary endpoint	Change in QRS duration; improvement in LVEF at 6 months; and cardiovascular hospitalization or death at 12 months	Success rate of implanting a pacing lead in the His-bundle with capture of the left bundle and maintenance of this effect for 6 months	Decrease in LVAT with CSP that was non-inferior to BiVP
Results	- Significant reduction in QRS duration was observed with HBP but not with BiVP - HBP was not superior to BiVP regarding LVEF improvement - No differences observed in cardiovascular hospitalization or death at 12 months between groups	Successful His-lead implantation with capture of the left bundle sustained through 6 months of follow-up was achieved in 18/25 patients (72%) assigned to HBP	Both groups showed a similar decrease (non-inferior) in LVAT measured with ECGI

The three randomized studies were flawed by a considerable number of crossovers: 48% (His-Sync)⁶, 28% (His-Alternative)⁷ and 23% (LEVEL-AT trial). Recent data from the Multicentre European Left Bundle Branch Area Pacing Outcomes (MELOS) study (n=2533 patients)⁸ reported a failure rate of implantation in patients with HF of 17.8%.

In conclusion, the LEVEL-AT trial has proven that CSP is an acceptable alternative to BiVP in patients undergoing CRT. Whether LBBP will be a faster, safer, and more effective approach to CRT remains to be studied.

References

1. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019;74:e51-e156.
2. Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021;42:3427–520.
3. Huang W, Su L, Wu S, et al. A novel pacing strategy with low and stable output: pacing the left bundle branch immediately beyond the conduction block. Can J Cardiol 2017;33:1736.e1-1736.e3.
4. Pujol-Lopez M, Jiménez-Arjona R, Garre P, et al. Conduction system pacing vs. biventricular pacing in heart failure and wide QRS patients: LEVEL-AT trial. J Am Coll Cardiol EP 2022;Oct 26:[Epub ahead of print].
5. Arnold AD, Shun-Shin MJ, Keene D, et al. His resynchronization versus biventricular pacing in patients with heart failure and left bundle branch block. J Am Coll Cardiol 2018;72:3112-22.
6. Upadhyay GA, Vijayaraman P, Nayak HM, et al. His corrective pacing or biventricular pacing for cardiac resynchronization in heart failure. J Am Coll Cardiol 2019;74:157-59.
7. Vinther M, Risum N, Svendsen JH, Møgelvang R, Philbert BT. A randomized trial of His pacing versus biventricular pacing in symptomatic HF patients with left bundle branch block (His-Alternative). JACC Clin Electrophysiol 2021;7:1422-32.
8. Jastrzębski M, Kiełbasa G, Cano O, et al. Left bundle branch area pacing outcomes: the multicentre European MELOS study. Eur Heart J 2022;43:4161-73.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Implantable Devices, EP Basic Science, Acute Heart Failure, Echocardiography/Ultrasound

Keywords: Bundle of His, Bundle-Branch Block, Cardiac Resynchronization Therapy, Stroke Volume, Quality of Life, Ventricular Function, Left, Atrioventricular Block, Follow-Up Studies, Coronary Sinus, Heart Failure, Hospitalization, Ventricular Remodeling, Echocardiography

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