Cover Story

Neuromodulation in Atrial Fibrillation and Heart Failure

Krishan K. Kataria, MD,1 Sana Grover, MBBS,2 and Abraham G. Kocheril, MD, FACC, FACP, FHRS1
1Christie Clinic, Presence Covenant Medical Center, University of Illinois College of Medicine at Urbana-Champaign; 2Pt. B.D. Sharma Post Graduate Institute of Medical Sciences, India

Krishan K. Kataria, MD,1 Sana Grover, MBBS,2 and Abraham G. Kocheril, MD, FACC, FACP, FHRS1
1Christie Clinic, Presence Covenant Medical Center, University of Illinois College of Medicine at Urbana-Champaign; 2Pt. B.D. Sharma Post Graduate Institute of Medical Sciences, India

Introduction

Among the spectrum of cardiovascular conditions, atrial fibrillation (AF) and heart failure are the most common. By 2050, it is estimated that AF will affect about 10 million patients in the United States.1 In 2013, the estimated prevalence of patients with heart failure was about 5.8 million,2,3 which continues to increase with an incidence rate of >550,000 new cases per year. 

Despite the current advances in pharmacologic and device-based management, AF and heart failure are associated with high morbidity and mortality attributed to sudden cardiac death, increased risk of ischemic stroke, and an increased rate of hospitalizations related to left ventricular dysfunction.4-7

Faced with these challenges, recent research has focused on redefining the role of the autonomic nervous system in the pathophysiology of AF and heart failure. In this review, we will summarize the important aspects of the autonomic nervous system in these conditions, and highlight the current clinical literature focused on restoring the neurohormonal balance. 

The Heart and the Autonomic Nervous System

Cardiac autonomic innervation is complex, and comprises of intrinsic and extrinsic components.8,9 Both sympathetic and parasympathetic innervations exert its effects via ganglionic plexi (GP), which are a part of the intrinsic cardiac autonomic nervous system. These ganglionic plexi are located on the posterior surface of the atria and superior aspect of the ventricles. 

Effects of parasympathetic innervation are mediated via acetylcholine mainly through the vagus nerve. The adrenergic system exerts its effects through epinephrine and norepinephrine (NE). Among other ganglions, the stellate ganglion is an important contributor in cardiac sympathetic innervation. GP release norepinephrine locally, and the adrenal medulla acts as an external source of epinephrine. Both epinephrine and NE have varied effects on the myocardium and peripheral vessels.

Carotid and cardiopulmonary baroreceptors, via autonomic nervous system inhibition, play an important role in maintaining vascular tone and heart rate.10 

Autonomic Nervous System in AF

Ectopic focal activity and reentry are central to initiation and maintenance of AF.11 Atrial sympathetic nerve densities are significantly greater in AF patients compared to patients in sinus rhythm, suggesting abnormal autonomic innervation as a likely contributor to AF.12,13 This observation is clinically supported by the decreased risk of AF recurrence with the addition of autonomic denervation compared with pulmonary vein (PV) isolation alone.14

Increased neural activity from the anterior right GP during rapid atrial pacing suggests that hyperactivity of GP may play a role in the pathogenesis of AF. Hyperactivity of GP has also been linked to complex fractionated atrial electrograms (CFAEs), which are thought by some to localize the most specific substrate of AF.15-18 

The vagus nerve is primarily parasympathetic, but a sympathetic component has also been found in the nerve fibers.19 This finding supports the fact that vagus nerve stimulation can be used to induce or maintain sustained AF in animal models.20 Seemingly contrary to this observation, low-level vagus nerve stimulation (LLVNS) suppresses AF inducibility and duration of AF episodes.21-23

Autonomic Nervous System in Heart Failure

Heart failure is known to be associated with neurohormonal hyperactivity. Myocardial systolic dysfunction provokes a compensatory mechanism that leads to activation of the cardiac autonomic nervous system (producing excessive amounts of epinephrine and norepinephrine), as well as activation of the renin-angiotensin-aldosterone system (RAAS).24 The neurohormonal hyperactivity has an adverse effect on the failing heart. Cholinergic stimulation in heart failure has been shown to decrease heart rate and negate some effects of norepinephrine. It also leads to reverse remodeling and has a positive impact on cardiac function.25 

Clinical Implications of Neuromodulation in AF

After the observation that AF is initiated by rapid focal firing arising from the myocardial sleeve of the pulmonary veins, circumferential PV ablation has become the preferred treatment for drug-refractory AF.26 However, recently published data on the long-term efficacy of these procedures has been less than optimal.27,28 In an effort to improve outcomes, various other approaches have been employed, as discussed below.

Ganglionic Plexus Ablation

In the initial small randomized and cohort studies by Pokushalov et al, increased success in eliminating AF was demonstrated with a combination of GP and PV ablation. Recent large trials carried out by Katritsis and Pokushalov et al have shown promising results with higher success rates for the combined procedure.29-33 

When tested alone, GP ablation for persistent AF failed to demonstrate significant benefit.34 This suggests that the autonomic nervous system may play an important role earlier in the course of AF pathophysiology.

CFAE Ablation

In 2004, Nademanee et al suggested that CFAEs were the most specific substrate for AF.18 Earlier studies that incorporated CFAE ablation along with circumferential PV isolation (CPVI) noted improved success rates compared to CPVI alone, but the latest data has failed to demonstrate significant benefit by incorporating this approach.35,36

LLVNS

In pre-clinical studies, LLVNS has been effectively shown to significantly increase the effective refractory period (ERP) in the atria as well as the PV myocardium, which suppressed AF inducibility and decreased the duration of AF episodes.37 Marked inhibition of GP activity has been noted with LLVNS. 

Stavrakis et al recently tested this hypothesis in a first-in-human trial.38 This study demonstrated that low-level tragus stimulation decreased rapid atrial pacing AF duration, increased AF cycle length, increased the atrial ERP, and suppressed inflammatory cytokines.

Clinical Implications of Neuromodulation in Heart Failure

Pharmacological Therapies

Both beta-blockers and angiotensin-converting-enzyme (ACE) inhibitors decrease all-cause mortality and are the cornerstone for pharmacological management of heart failure. 

Beta-blockers improve left ventricular function and reduce mortality when used long term in patients with heart failure.39 Chronic use of beta-blockers promotes reverse remodeling of the left ventricle, reduces the risk of hospitalization, improves survival, reduces the risk of sudden cardiac death, and helps in restoring reflex control of the heart and circulation. This effect is mediated via direct antagonism of catecholaminergic effects, suppression of the RAAS system, and enhancement of coronary blood flow. 

A hallmark of heart failure is hyperactivity of the RAAS.39 ACE inhibitors reduce the plasma angiotensin II and aldosterone, and thus, have a positive impact on hemodynamics. ACE inhibitors decrease the sympathetic outflow by increasing the NE uptake from autonomic nervous system neurons and decreasing NE release. 

Baroreflex Stimulation in Heart Failure

Baroreflex activation leads to decreased sympathetic outflow and increased parasympathetic activity by its effects on the central nervous system.40 

The effects of baroreceptor stimulation were studied by Gronda et al in a single-center open-label trial.41 This study demonstrated that baroreflex activation therapy (BAT) is safe and provided chronic improvement in clinical variables.

In a recent randomized trial by Abraham et al, effects of BAT with medical therapy vs medical therapy alone were studied in patients with NYHA class III heart failure. Patients who received BAT showed significant improvement in their functional status, quality of life, exercise capacity, and N-terminal pro–brain natriuretic peptide.42 This trial also suggested that BAT might reduce the burden of heart failure hospitalizations in patients already receiving guideline-directed medical therapy. 

Spinal Cord Stimulation 

Spinal cord stimulation (SCS) in a canine model of heart failure has been shown to improve LVEF and reduce arrhythmogenecity.43 A prospective, randomized, double-blind trial to test the feasibility of SCS implantation in patients with symptomatic heart failure on optimal medical therapy concluded that the SCS system was safe and did not interfere with ICD function.44

The DEFEAT-HF trial by Zipes et al failed to demonstrate the efficacy of SCS in improving clinical outcomes when implanted in NYHA class III heart failure patients. 

Vagal Nerve Stimulation

In 2008, Schwartz et al reported the first-in-human experience of long-term vagal stimulation in patients with advanced heart failure.45 Following the success of this study, other trials have evaluated the effects of vagal nerve stimulation in heart failure patients. 

ANTHEM-HF trial46: Patients with systolic and NYHA class II/III heart failure were randomized to receive a right or left vagal nerve stimulation device. Vagal nerve stimulation was up-titrated over a period of 10 weeks, and cyclic VNS was continued thereafter. The investigators noted that left- or right-side VNS was well tolerated and not associated with significant side effects. Significant improvement in the cardiac function and clinical outcomes was noted at the end of the trial.

ENCORE study: An extension of the ANTHEM-HF trial showed that autonomic regulation therapy via vagus nerve stimulation improves LVEF, NYHA class, and quality of life in patients with advanced heart failure. Patients were followed for a total of 12 months in this perspective, open-label study. 

NECTAR-HF trial47: In this sham-controlled trial, patients were randomized in a 2:1 ratio to receive vagal nerve stimulation or serve as control with vagal nerve stimulation off. The primary endpoint was the change in LV end systolic diameter at 6 months. Patients who received the therapy with vagal nerve stimulation did not show any significant changes when compared to the control group. Among the secondary endpoints, quality of life measures showed significant improvement. 

VANGUARD study48: This is an ongoing trial to demonstrate the safety of vagal nerve stimulation for the treatment of congestive heart failure with reduced ejection fraction. The study will be completed by December 2015, and will also measure the efficacy of vagal stimulation in secondary endpoints.

INOVATE-HF trial49: This is a large trial that aims to study the long-term safety and efficacy of vagus nerve stimulation in patients with heart failure. The primary outcome measures will be all-cause mortality or unplanned heart failure hospitalization. This study is expected to complete in December 2016.

Conclusion

Neuromodulation is an exciting and novel concept in the management of heart disease. Although still in its infancy, some studies have provided a glimpse of what the future may hold in the management of these common conditions. Further research is certainly warranted, and large ongoing trials such as VANGUARD and INOVATE-HF will provide further insight in the role of autonomic modulation in atrial fibrillation and heart failure. 

Disclosure: The authors have no conflicts of interest to report regarding the content herein. 

References

  1. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114:119-125.
  2. Braunwald E. Shattuck lecture—cardiovascular medicine at the turn of the millennium: triumphs, concerns and opportunities. N Engl J Med. 1997;337:1360-1369.
  3. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112:e154-235.
  4. Miyasaka Y, Barnes ME, Bailey KR, et al. Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study. J Am Coll Cardiol. 2007;49:986-992.
  5. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012;366:120-129.
  6. Cowie MR, Wood DA, Coats AJ, et al. Survival of patients with a new diagnosis of heart failure: a population-based study. Heart. 2000;83(5):505-510.
  7. Chugh SS, Reinier K, Teodorescu C. Epidemiology of sudden cardiac death: clinical and research implications. Prog Cardiovasc Dis. 2008;51(3):213-228.
  8. Janes RD, Brandys C, Hopkins DA, et al. Anatomy of human extrinsic cardiac nerves and ganglia. Am J Cardiol. 1986;57:299-309.
  9. Armour JA, Murphy DA, Yuan BX, et al. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec. 1997;247:289-298.
  10. Malliani A, Pagani M, Pizzinelli P, et al. Cardiovascular reflexes mediated by sympathetic afferent fibers. J Auton Nerv Syst. 1983;7(3-4):295-301.
  11. Nattel S. New ideas about atrial fibrillation 50 years on. Nature. 2002;415:219-226.
  12. Volders PG. Novel insights into the role of the sympathetic nervous system in cardiac arrhythmogenesis. Heart Rhythm. 2010;7(12):1900-1906.
  13. Nguyen BL, Fishbein MC, Chen LS, et al. Histopathological substrate for chronic atrial fibrillation in humans. Heart Rhythm. 2009;6(4):454-460.
  14. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endocardial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. Heart Rhythm. 2007;4(9):1177-1182.
  15. Lemola K, Chartier D, Yeh YH, et al. Pulmonary vein region ablation in experimental vagal atrial fibrillation: role of pulmonary veins versus autonomic ganglia. Circulation. 2008;117:470-477.
  16. Nishida K, Maguy A, Sakabe M, et al. The role of pulmonary veins vs. autonomic ganglia in different experimental substrates of canine atrial fibrillation. Cardiovasc Res. 2011;89:835-833.
  17. Lin J, Scherlag BJ, Zhou J, et al. Autonomic mechanism to explain complex fractionated atrial electrograms (CFAE). J Cardiovasc Electrophysiol. 2007;18(11):1197-1205.
  18. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol. 2004;43:2044-2053.
  19. Onkka P, Maskoun W, Rhee KS, et al. Sympathetic nerve fibers and ganglia in canine vagus nerves: localization and quantitation. Heart Rhythm. 2013;10;4:585-591.
  20. Goldberger AL, Pavelec RS. Vagally-mediated atrial fibrillation in dogs: conversion with bretylium tosylate. Int J Cardiol. 1986;13(1):47-55.
  21. Sheng X, Schelag BJ, Yu L, et al. Prevention and reversal of atrial fibrillation inducibility and autonomic remodeling by low-level vagosympathetic nerve stimulation. J Am Coll Cardiol. 2011;57:563-571.
  22. Sha Y, Scherlag BJ, Yu L, et al. Low-level right vagal stimulation: anticholinergic and antiadrenergic effects. J Cardiovasc Electrophysiol. 2011;22(10):1147-1153.
  23. Li S, Scherlag BJ, Yu L, et al. Low-level vagosympathetic stimulation: a paradox and potential new modality for the treatment of focal atrial fibrillation. Circ Arrhythm Electrophysiol. 2009;2:645-651.
  24. Mann DL, Bristow MR. Mechanism and models in heart failure: the biomechanical model and beyond. Circulation. 2005;111:2837-2849.
  25. Mudd JO, Kass DA. Tackling heart failure in the twenty-first century. Nature. 2008;451:919-928.
  26. Haïssaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659-666.
  27. Ouyang F, Tilz R, Chun J. Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up. Circulation. 2010;122:2368-2377.
  28. Weerasooriya R, Khairy Paul, Litalien J. Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up? J Am Coll Cardiol. 2011;57:160-166.
  29. Pokushalov E, Turov A, Shugayev P. Catheter ablation of left atrial ganglionated plexi for atrial fibrillation. Asian Cardiovasc Thorac Ann. 2008;16(3):194-201.
  30. Pokushalov E, Romanov A, Artyomenko S. Left atrial ablation at the anatomic areas of ganglionated plexi for paroxysmal atrial fibrillation. Pacing Clin Electrophysiol. 2010;33(10):1231-1238.
  31. Pokushalov E, Romanov A, Shugayev P. Selective ganglionated plexi ablation for paroxysmal atrial fibrillation. Heart Rhythm. 2009;6(9):1257-1264.
  32. Katritsis DG, Pkoshalov E, Romanov A. Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation. J Am Coll Cardiol. 2013;62:2318-2325.
  33. Pokushalov E, Romanov A. Ganglionated plexi ablation for longstanding persistent atrial fibrillation. Europace. 2010;12(3):342-346.
  34. Pokushalov E, Romanov A, Katritsis DG. Ganglionated plexus ablation vs linear ablation in patients undergoing pulmonary vein isolation for persistent/long-standing persistent atrial fibrillation: a randomized comparison. Heart Rhythm. 2013;10(9):1280-1286.
  35. Providencia R, Lambiase PD, Srinivasan N. Is there still a role for CFAE ablation in addition to pulmonary vein isolation in patients with paroxysmal and persistent atrial fibrillation? A meta-analysis of 1415 patients. Circ Arrhythm Electrophysiol. 2015;8(5):1017-1029.
  36. Wong KC, Paisey JR, Sopher M. No Benefit Of Complex Fractionated Atrial Electrogram (CFAE) Ablation in Addition to Circumferential Pulmonary Vein Ablation and Linear Ablation: BOCA study. Circ Arrythm Electrophysiol. 2015 Aug 17. [Epub ahead of print]
  37. Yu L, Scherlag BJ, Shuyan L. Low-level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia. J Cardiovasc Electrophysiol. 2011;22:455-463.
  38. Stavrakis S, Humphrey MB, Scherlag BJ. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol. 2015;65(9):867-875.
  39. Lymperopoulos A, Rengo G, Koch W. Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res. 2013;113:739-753.
  40. Davos CH, Davies LC, Piepoli M. The effect of baroreceptor activity on cardiovascular regulation. Hellenic J Cardiol. 2002;43:145-155.
  41. Gronda E, Servalle G, Brambilla G. Chronic baroreflex activation effects on sympathetic nerve traffic, baroreflex function, and cardiac haemodynamics in heart failure: a proof-of-concept study. Eur J Heart Fail. 2014;16(9):977-983.
  42. Abraham WT, Zile MR, Weaver FA. Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction. JACC Heart Fail. 2015;3:487-496.
  43. Lopshire JC, Zhou X, Dusa C. Spinal cord stimulation improves ventricular function and reduces ventricular arrhythmias in a canine postinfacrtion heart failure model. Circulation. 2009;120(4):286-294.
  44. Torre-Amione G, Alo K, Estep JD. Spinal cord stimulation is safe and feasible in patients with advanced heart failure: early clinical experience. Eur J Heart Fail. 2014;16:788-795.
  45. Schwartz PJ, De Ferrari GM, Sanzo A. Long-term vagal stimulation in patients with advanced heart failure: first experience in man. Eur J Heart Fail. 2008;10(9):884-891.
  46. Zannad F, De Ferrari GM. Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the neural cardiac therapy for heart failure (NECTAR-HF) randomized controlled trial. Eur Heart J. 2015;36(7):425-433.
  47. Premchand RK, Sharma K, Mittal S. Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial. J Card Fail. 2014;20(11):808-816.
  48. VAgal Nerve Stimulation: safeGUARDing Heart Failure Patients (VANGUARD) trial. Clinicaltrials.gov. Published July 16, 2015. Available online at https://clinicaltrials.gov/ct2/show/NCT02113033. Accessed October 14, 2015. 
  49. INcrease Of VAgal TonE in CHF (INOVATE-HF) trial. Clinicaltrials.gov. Published April 10, 2015. Available online at https://clinicaltrials.gov/ct2/show/NCT01303718?term=inovate-hf&rank=1. Accessed October 14, 2015.