Introduction
Following optimal medical therapy, cardiac resynchronization therapy (CRT) is indicated in patients with persistent symptomatic heart failure (HF), severely reduced ejection fraction (EF) (EF ≤35%), and widened QRS. Clinical trials have demonstrated significant improvements in 6-minute walk, functional class, and quality of life, along with corresponding reductions in HF hospitalization and death in patients with both ischemic and non-ischemic cardiomyopathy.^1-4 CRT is associated with reductions in left ventricular (LV) size and improvements in LVEF.⁴ The 2013 American College of Cardiology Foundation and American Heart Association guidelines⁵ recommend CRT implantation in patients with symptomatic HF (New York Heart Association [NYHA] Class II to IVa) and reduced EF (≤35%) with the following:

1. Sinus rhythm, left bundle branch block (LBBB) and a QRS duration ≥150 ms (Class 1 indication)
2. LBBB with intermediate QRS duration (120-149 ms) or non-LBBB with QRS duration ≥150 ms (Class IIa indication)
3. Anticipated ventricular pacing >40% or atrial fibrillation with anticipated near 100% pacing (Class IIa indication)

These guidelines for CRT implantation are consistent across national and international cardiovascular guideline bodies, including the Canadian Cardiovascular Society and European Society of Cardiology.^6,7

However, CRT lead implantation can be challenging due to unfavorable coronary sinus anatomy, leading to poor capture, lead instability, or insufficient cardiac resynchronization (QRS shortening). Despite advances in LV resynchronization and lead delivery systems, approximately one-third of patients receiving CRT may be non-responders.⁸ Thus, His-bundle (HB) pacing has recently garnered significant interest as a rescue strategy for patients undergoing CRT implantation when coronary sinus lead implantation is unsuccessful or in cases of non-response to CRT.⁹ HB pacing lead implantation can achieve either selective or non-selective HB capture, with the former resulting in a paced QRS interval equal to the His-QRS interval and often a narrow QRS morphology.¹⁰ In contrast, non-selective capture results from capture of both the HB and surrounding ventricular myocardium, typically resulting in a wider paced QRS.¹⁰ Thresholds can be measured for both selective and non-selective capture; the threshold for selective capture is typically lower than non-selective capture, allowing for selective HB pacing.

Currently, only one pacing lead (SelectSecure 3830 [Medtronic, Inc.; Minneapolis, MN]) and two sheaths (C315HIS and C304-HIS SelectSite [Medtronic, Inc.; Minneapolis, MN]) are designed specifically for HB pacing, giving the operator limited options when performing HB pacing lead implantation.¹⁰ Despite these limitations, HB pacing has garnered significant interest over the last 3 years, leading to the first randomized trial comparing HB pacing and biventricular CRT.^11,12

His-SYNC Trial
The His-SYNC (His Bundle Pacing Versus Coronary Sinus Pacing for Cardiac Resynchronization Therapy) trial was presented at the Heart Rhythm Society's 40th Annual Scientific Sessions and simultaneously published in the Journal of the American College of Cardiology.¹² The His-SYNC trial was an investigator-initiated, multi-center, randomized controlled trial comparing HB pacing with conventional biventricular lead placement in patients undergoing CRT implantation.¹² Patients were eligible on the basis of conventional CRT guideline indications and were randomized with 1:1 allocation to His-CRT or biventricular CRT through coronary sinus lead implantation. The primary outcome measures of the His-SYNC trial included 1) reduction in QRS duration on electrocardiogram, 2) absolute improvement in LVEF and echocardiographic response (EF improvement >5%) at 6 months, and 3) cardiovascular hospitalization or death at 12 months.¹²

A total of 41 patients was enrolled in the His-SYNC trial (age 64±13 years, 38% female, EF = 28%). Patients had QRS prolongation including LBBB (88%), right bundle branch block (5%), or paced QRS (7%). Periprocedural events included 1 transient ischemic attack (HB pacing), 2 micro-dislodgements of atrial leads (1 per group), and 1 hematoma requiring evacuation (HB pacing).¹² Patients were followed for an average of 12.2 months, with 1 patient withdrawing after randomization to biventricular CRT and 1 patient lost to follow-up in the biventricular CRT group. By intention-to-treat analysis, there was no significant difference in QRS duration between the HB pacing and biventricular CRT groups (p = 0.42).¹² At 6 months, LV function improved in both groups, with no significant differences between HB pacing and biventricular CRT (p = 0.33).¹² At 12 months, there was no difference in cardiovascular hospitalization or death between groups. Patients with HB pacing had higher pacing thresholds compared with biventricular CRT, but pacing thresholds remained stable at 12 months.

Proof of Principle
The His-SYNC trial demonstrated the feasibility and safety of HB pacing as an alternative to CRT. Prior studies of HB pacing have been small cohort or crossover studies between HB pacing and CRT. Although there were no significant differences in the primary outcomes between groups in the His-SYNC trial, HB pacing resulted in a significant narrowing in paced QRS duration from baseline (p = 0.002) and corresponding improvements in LV function at 6 months (p < 0.001).¹² Furthermore, HB pacing proved to be safe and reliable, with no episodes of His lead dislodgement during the 12-month follow-up. Notably, in the His-SYNC trial, HB pacing lead placement was performed by expert operators, and routine implantation of HB pacing in HF is likely still premature. Longer follow-up to evaluate the stability of the His lead, battery and device longevity, and clinical outcomes will provide greater insight into the long-term feasibility of HB pacing.

High Crossover
Crossover was mandated as part of HB pacing and CRT implantation based on strict criteria, including inability to correct QRS duration to <130 ms or 20% narrowing (mandating HB pacing crossover to CRT) and unfavorable coronary sinus anatomy, tortuosity, or targets (mandating CRT crossover to HB pacing). As a result, crossover occurred in more than one-third of patients: 48% from HB pacing to CRT and 26% from CRT to HB pacing.¹² Out of 10 patients, 8 crossed over from HB pacing to CRT due to failure to achieve QRS narrowing <130 ms, and all 5 crossovers from CRT to HB pacing occurred due to coronary sinus anatomy and/or vascular occlusion.

The high crossover rate observed in the His-SYNC trial partially reflects the broad enrollment criteria; although most patients had LBBB at baseline (88%), a substantial portion had right bundle branch block (5%) or a paced QRS (7%).¹² Physiologically, CRT in patients with LBBB is expected to yield the greatest improvements in LV function and clinical outcomes, and non-LBBB is one of the strongest predictors of non-response to CRT.⁸ HB pacing is unlikely to have significant effect on QRS narrowing in patients with non-specific interventricular conduction disease; one-half of patients crossing over from HB pacing to CRT had a non-LBBB at baseline.

On the other hand, there also exists significant anatomic variability in coronary sinus anatomy, and failure to position the LV lead remains a major cause of non-response to CRT.^2,3 It is likely that the high crossover rate in both directions limited the ability to demonstrate treatment efficacy of HB pacing. In a per-protocol analysis, HB pacing achieved significant QRS narrowing compared with biventricular CRT (p < 0.001), with a trend toward a higher rate of echocardiographic response with HB pacing (p = 0.078).¹³ These results suggest that HB pacing is, at the very least, a reasonable bailout strategy for biventricular CRT, particularly when His capture and QRS narrowing can be achieved.

Potential for HB Pacing
With His-SYNC trial, there is a growing foundation of evidence for HB pacing. In a small study of 29 patients receiving CRT, patients were implanted with both an HB pacing and coronary sinus lead and randomized to HB pacing or biventricular CRT, with crossover after 6 months.¹⁴ Both HB pacing and CRT had comparable improvements in LV function (EF) and symptoms, including NYHA class, quality of life, and 6-minute walk. HB pacing appeared to result in greater QRS narrowing compared with biventricular CRT, with almost all patients (28 out of 29) having LBBB at baseline. In another recent study, HB pacing was attempted as a rescue strategy in 106 patients undergoing CRT with a failed or non-response CRT or as an alternative to biventricular CRT (in patients with atrioventricular block or high pacing burden).⁹ HB pacing lead implantation was successful in 90%, with resultant QRS narrowing and improvements in EF and NYHA symptom class. In a meta-analysis of 11 studies including 494 patients receiving HB pacing for HF, HB pacing was successful in 82.4% and resulted in QRS narrowing and improvements in LV function and clinical outcomes.¹⁵

Conclusion
Although HB pacing was not superior to CRT in the His-SYNC trial, this trial firmly established HB pacing as a reasonable alternative for patients undergoing CRT where coronary sinus anatomy is unfavorable or inaccessible. The potential role of HB pacing in non-responders to CRT remains unclear. A growing market of His-specific pacing leads, sheaths, and delivery systems may increase future accessibility of HB pacing and form the basis of another clinical trial.

References

1. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845-53.
2. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539-49.
3. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140-50.
4. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329-38.
5. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147-239.
6. Ezekowitz JA, O'Meara E, McDonald MA, et al. 2017 Comprehensive Update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure. Can J Cardiol 2017;33:1342-433.
7. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129-200.
8. Prinzen FW, Vernooy K, Auricchio A. Cardiac resynchronization therapy: state-of-the-art of current applications, guidelines, ongoing trials, and areas of controversy. Circulation 2013;128:2407-18.
9. Sharma PS, Dandamudi G, Herweg B, et al. Permanent His-bundle pacing as an alternative to biventricular pacing for cardiac resynchronization therapy: A multicenter experience. Heart Rhythm 2018;15:413-20.
10. Vijayaraman P, Chung MK, Dandamudi G, et al. His Bundle Pacing. J Am Coll Cardiol 2018;72:927-47.
11. Beer D, Dandamudi G, Mandrola JM, Friedman PA, Vijayaraman P. His-bundle pacing: impact of social media. Europace 2019;Jun 23:[Epub ahead of print].
12. 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;74:157-9.
13. Upadhyay GA, Vijayaraman P, Nayak HM, et al. On-treatment comparison between corrective His bundle pacing and biventricular pacing for cardiac resynchronization: A secondary analysis of His-SYNC. Heart Rhythm 2019;May 13:[Epub ahead of print].
14. Lustgarten DL, Crespo EM, Arkhipova-Jenkins I, et al. His-bundle pacing versus biventricular pacing in cardiac resynchronization therapy patients: A crossover design comparison. Heart Rhythm 2015;12:1548-57.
15. Qian Z, Zou F, Wang Y, et al. Permanent His bundle pacing in heart failure patients: A systematic review and meta-analysis. Pacing Clin Electrophysiol 2019;42:139-45.

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

Keywords: Arrhythmias, Cardiac, Cardiac Resynchronization Therapy, Bundle-Branch Block, Coronary Sinus, Atrial Fibrillation, Bundle of His, American Heart Association, Stroke Volume, Quality of Life, Heart Failure, Heart Ventricles, Heart Ventricles, Ventricular Dysfunction, Left, Hospitalization, Myocardium, Cardiomyopathies, Atrioventricular Block, Ischemic Attack, Transient, Cross-Over Studies, Research Personnel, Follow-Up Studies, Intention to Treat Analysis, Electrocardiography, Echocardiography, Treatment Outcome, Heart Atria, Hematoma

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