Article

Transvenous Phrenic Nerve Stimulation - A Novel Therapy for Central Sleep Apnea in Heart Failure

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Abstract

Central sleep apnea (CSA) is a prominent co-morbidity in heart failure (HF) resulting from dysregulated neurological responses to abnormal carbon dioxide levels. The presence of CSA in HF has been linked with deleterious physiological changes and is associated with increased mortality, yet treatment options for CSA in HF are currently lacking. This article briefly reviews the mechanisms of CSA in HF as well as the available evidence on present therapies, and describes phrenic nerve stimulation as a potential novel therapeutic approach.

Support: The publication of this article was funded by Respicardia. The views and opinions expressed are those of the authors and not necessarily those of Respicardia.

Keywords

Central sleep apnea, heart failure, sleep disordered breathing, phrenic nerve stimulation,

Disclosure:Sitaramesh Emani, MD, has no conflicts of interest to declare. William T Abraham, MD, FACC, is a consultant to Respicardia.

Received:

Accepted:

DOI:https://doi.org/10.15420/usc.2012.9.1.53

Correspondence Details:Sitaramesh Emani, MD, 473 W. 12th Ave, Suite 200, Columbus, OH. E: sitaramesh.emani@osumc.edu

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Heart failure (HF) is a growing epidemiological challenge in the US and worldwide. In the US, it is estimated that at least 5 million people are affected by it, with more than a half-million new diagnosis being made each year.1 Despite major improvements in the treatment of HF, almost 30 % of patients treated for acute HF require readmission within 30 days.2,3 These sobering statistics underscore the need for continuing developments in the treatment of HF. One strategy for improving outcomes in HF is to better address the treatment of co-existing conditions that are linked with it.4

Sleep disordered breathing (SDB) is now recognized as a significant category of co-morbidities associated with HF. Contained within the realm of SDB are both obstructive sleep apnea (OSA) and central sleep apnea (CSA). Clinically, CSA in HF is associated with a higher degree of mortality than OSA.5–8 The overall prevalence of SDB in HF is estimated between 60 and 75 %, but ranges considerably; specifically, OSA is thought to occur in about 35 % of HF patients and CSA in up to 66 %.9–13 Common to both forms of sleep apnea are periods of abnormal breathing, including changes in frequency and depth of breaths as well as apnea.14 However, the two forms differ in their cause; OSA is primarily a mechanical issue arising from upper airway obstruction, whereas CSA stems from neurological responses to changing partial pressure of carbon dioxide (PaCO2) levels.15,16 Breathing patterns between the two disorders are similar but unique to each process (see Figure 1). Good detailed reviews of OSA and its treatment have been published elsewhere.17 In this article, we will review the impact of CSA on HF and novel therapeutic options in development.

Central Sleep Apnea and Heart Failure

As mentioned, HF causes changes in PaCO2 levels resulting in CSA. The initial imbalance is thought to be hyperventilation, which may occur when filling pressures within the left side of the heart lead to pulmonary congestion.18–20 Hyperventilation in turn leads to hypocapnea; when PaCO2 levels drop below a certain threshold (apnea threshold), central chemoreceptors trigger compensatory apnea.21 As a consequence, relative hypoxemia and recurrent hypercapnea occur.15 The fluctuations in PaCO2 levels around the apnea threshold create a continuous cycle of hyperventilation and apnea periods. Clinically, this cycle manifests as Cheyne-Stokes breathing.22

Cheyne-Stokes breathing can occur at any time and is not limited to periods of sleep. However, the effect of increased left-sided filling pressures on breathing regulation is more pronounced in the recumbent position, which may help explain the higher frequency of breathing disturbances at night.23 Furthermore, HF is associated with a reduced ability of central chemoreceptors to appropriately adjust for changes in PaCO2 levels, leading to greater swings in levels that increasingly cross the apnea threshold.24 These tendencies give rise to the belief that CSA may be under-recognized and underdiagnosed in the HF population.10

Physiological consequences of CSA extend beyond fluctuations in PaCO2 levels. A detailed review, by Khayat et al., of CSA and its pathophysiological pathways can be found in this edition, with major points summarized here. Cardiac preload is directly affected by changes in intrathoracic pressures during both apneic and hyperventilatory phases, leading to increased myocardial strain and increased ventricular afterload, particularly of the right ventricle.25,26 Additionally, hypoxemia from apnea can lead to an increase in inflammatory markers, which are now thought to have deleterious effects in HF.27 But perhaps the most important consequence of SDB in HF is the effect on neurohormonal balance. Recurrent apneic cycles can lead to an increase in systemic sympathetic tone, with worsening apnea leading to higher degrees of sympathetic activation.25,28,29 Growing evidence suggests that SDB creates an internal environment in which circulating neurohormonal levels are elevated during sleep and remain high throughout the day.30,31 Downstream consequences include the upregulation of the renin–angiotensin–aldosterone system.16 Pharmacological neurohormonal blockade is the foundation of HF treatment;1,32 therefore, it is not surprising that CSA’s counteraction against this goal makes it an independent predictor of poor outcomes.1,5,8,33 Given these strong physiological links between CSA and HF, an important need exists for proven therapies.34

Current Treatment Evidence

The treatment of OSA is well established and aimed at improving mechanical airway obstruction causing cyclic apnea through the use of continuous or bi-level positive airway pressure (CPAP or BiPAP) support.15 Several investigations have noted improvements in cardiovascular function, ejection fraction, and autonomic tone as a result of CPAP therapy in OSA.35–39 The role of CPAP in CSA, however, is less certain. It is accepted that patients can present with combined forms of sleep apnea, and therefore CPAP has been used to treat CSA as well as OSA. Several small studies of CSA treatment suggested optimistic results of the use of CPAP on cardiovascular function, similar to those seen in the treatment of OSA.40-42 Unfortunately, the larger Canadian continuous positive airway pressure (CANPAP) trial did not show significant improvements with CPAP therapy in HF-associated CSA with regards to mortality, ejection fraction, and quality of life.43 As a result, CPAP is not considered part of the standard therapy for CSA.44 Additional controversy exists concerning the appropriate therapy for CSA, since the treatment of the underlying HF can result in sleep improvements.45,46

A newer method of ventilation, adaptive servo-ventilation (ASV), has shown early promise in the treatment of CSA. ASV attempts to mechanically mimic a patient’s minute ventilation through breaths of variable rate and tidal volume.47,48 Compared with CPAP, ASV resulted in improved markers of sleep and cardiac function.47,49 These initial small studies have led to the development of the Serve-HF study (Treatment of predominant central sleep apnoea by adaptive servo ventilation in patients with heart failure, ClinicalTrials.gov identifier: NCT00733343), a large, randomized, multicenter trial currently under way aimed at investigating improvements in morbidity and mortality through the use of ASV in patients with HF and CSA. Results are expected in 2014.50 Importantly, ASV attempts to externally correct the consequences of CSA (i.e., air flow hypercapnea) through mechanical ventilation, but does not attempt to correct the underlying loss of neuromuscular stimulation. Treatment focused on eliminating the occurrence of apneic episodes by stimulating natural breathing patterns may provide an even more unique and effective therapy.

Phrenic Nerve Stimulation—A Novel Approach

Historically used to treat patients with diaphragmatic paralysis from cervical spine injuries or central alveolar hypoventilation syndrome, phrenic nerve stimulation has been shown to be a safe, effective, and tolerated treatment modality.51–53 In CSA, stimulation of the phrenic nerve results in a reduction of apnea and the restoration of physiologic respiration.54 It has been hypothesized that implantable phrenic nerve stimulation devices may provide a novel treatment approach that could effectively be used to treat HF-associated CSA.

Traditional phrenic nerve stimulation systems have been surgically implanted, an approach that has inherent technical limitations and surgical complication risks. These risks may be increased in HF patients because of their underlying cardiac dysfunction.55 As an alternative, transvenous approaches to device implantation have been developed. The remedē™ System (Respicardia, Inc., Minnetonka, MN) is a fully implantable, unilateral transvenous phrenic nerve stimulation system that has been developed to treat CSA in HF patients. The system, shown in Figure 2, delivers an electrical stimulus to the phrenic nerve through a stimulation lead in order to prevent apneas. Compliance with therapy, which is a major limitation of CPAP and ASV, is not a concern with an implanted system;48,56 therefore, transvenous phrenic nerve stimulation may provide an avenue of treatment superior to other modalities, such as CPAP and ASV.57–59

The implantation of the remede System is technically similar to that of cardiac resynchronization therapy (CRT) devices. Venous access is obtained via either the right or left axillary or subclavian vein, through which the stimulation lead is passed until it reaches an appropriate location to provide unilateral phrenic nerve stimulation. Custom stimulation leads have been designed to deliver electrical stimulation through the vessel wall.60 Cannulation into the left pericardiophrenic vein is feasible from both the left and right axillary and/or subclavian regions, making it one of the two target sites for unilateral phrenic nerve stimulation.60 The other target site is the right phrenic nerve, which lies in an anterolateral orientation to the right brachiocephalic vein. The right pericardiophrenic vein, which is anatomically situated next to its respective phrenic nerve, is generally too small to allow the passage of a lead.61 A sensing lead is placed in the azygous vein.62 Both the sensing and stimulation leads are connected to a generator device, which is programmable so as to provide adequate phrenic nerve stimulation. The generator device is then implanted sub-pectorally on the chosen side.

It is anticipated that physicians proficient in implantation techniques of CRT devices would readily gain familiarity with the implantation of phrenic nerve stimulation systems. Contraindications to implantation include phrenic nerve paralysis, severe underlying lung conditions, primary pulmonary hypertension, and anatomical limitations that would prevent the accurate placement of the leads or generator.

Early studies evaluating the use of transvenous phrenic nerve stimulation to treat CSA in HF patients have yielded promising results. In one acute study, 16 patients underwent nocturnal polysomnography to assess the severity of CSA on consecutive nights following the implantation of a transvenous phrenic nerve stimulating lead. One night, phrenic nerve stimulation took place via the implanted lead, while on another night there was no stimulation. Comparison between the treatment night and the control night demonstrated a mean reduction of 88 % in CSA episodes as well as an improvement in related parameters—including a 48 % decrease in the apnea-hypopnea index (AHI)—during the treatment night.59 A significant decrease of 49 % in arousals was also noted. Such reductions carry particular clinical implications, given the link between arousals and norepinephrine levels.63 Furthermore, long-standing CSA can lead to PaCO2 chemoreceptor desensitization and dysfunction and thus to a worsening of the negative cycle in HF. Treatment with phrenic nerve stimulation aims to break the cycle of CSA in HF (see Figure 3) and allow for PaCO2 chemoreceptor re-equilibration. In patients using other implantable devices for the treatment of HF (notably a CRT device, with or without an implantable cardioverter defibrillator), the implantation of a phrenic nerve stimulation device did not affect the functioning of these other devices.64

A chronic study is now under way to evaluate the remede System (Safety and efficacy evaluation of Respicardia therapy for central sleep apnea, ClinicalTrials.gov identifier: NCT01124370), with results expected in 2012. Pending the results of this trial, ongoing research will be required to confirm benefits and clinical improvements in patients.

Conclusion

CSA is an underdiagnosed condition co-existent with HF and linked with an associated worsened prognosis. Evolving understanding of the underlying pathophysiology of CSA has strengthened the link between HF and CSA, and provided insights into the negative effects of CSA on cardiovascular function. Despite the large prevalence of CSA, treatment options are currently limited and clinically relevant outcomes have not yet been definitively demonstrated. New treatment modalities, including ASV and transvenous phrenic nerve stimulation, are being investigated. Transvenous phrenic nerve stimulation in particular, with its physiological mechanism and improved patient compliance, holds promise as a novel approach. Results of ongoing studies will be available soon to help clinicians provide adequate treatment to patients. 

References

  1. Hunt SA, Abraham WT, Chin MH, et al., 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation, J Am Coll Cardiol, 2009;53(15):e1–e90.
    Crossref | PubMed
  2. Bueno H, Ross JS, Wang Y, et al., Trends in length of stay and short-term outcomes among Medicare patients hospitalized for heart failure, 1993-2006, JAMA, 2010;303(21):2141–7.
    Crossref | PubMed
  3. Jencks SF, Williams MV, Coleman EA, Rehospitalizations among patients in the Medicare fee-for-service program, N Engl J Med, 2009;360(14):1418–28.
    Crossref | PubMed
  4. Naughton MT, The link between obstructive sleep apnea and heart failure: underappreciated opportunity for treatment, Curr Heart Fail Rep, 2006;3(4):183–88.
    Crossref | PubMed
  5. Hanly PJ, Zuberi-Khokhar NS, Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure, Am J Respir Crit Care Med, 1996;153(1):272–6.
    Crossref | PubMed
  6. Andreas S, Hagenah G, Moller C, et al., Cheyne-Stokes respiration and prognosis in congestive heart failure, Am J Cardiol, 1996;78(11):1260–4.
    Crossref | PubMed
  7. Wilcox I, McNamara SG, Wessendorf T, et al., Prognosis and sleep disordered breathing in heart failure, Thorax, 1998;53(Suppl. 3):S33-36.
    Crossref | PubMed
  8. Lanfranchi PA, Braghiroli A, Bosimini E, et al., Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure, Circulation, 1999;99(11):1435–40.
    Crossref | PubMed
  9. Khayat RN, Jarjoura D, Patt B, et al., In-hospital testing for sleep-disordered breathing in hospitalized patients with decompensated heart failure: report of prevalence and patient characteristics, J Card Fail, 2009;15(9):739–46.
    Crossref | PubMed
  10. Ferrier K, Campbell A, Yee B, et al., Sleep-disordered breathing occurs frequently in stable outpatients with congestive heart failure, Chest, 2005;128(4):2116–22.
    Crossref | PubMed
  11. Schulz R, Blau A, Börgel J, et al., Sleep apnoea in heart failure, Eur Respir J, 2007;29(6):1201–5.
    Crossref | PubMed
  12. Mared L, Cline C, Erhardt L, et al., Cheyne-Stokes respiration in patients hospitalised for heart failure, Respir Res, 2004;5:14.
    Crossref | PubMed
  13. Oldenburg O, Lamp B, Faber L, et al., Sleep-disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients, Eur J Heart Fail, 2007;9(3):251–7.
    Crossref | PubMed
  14. Brenner S, Angermann C, Jany B, et al., Sleep-disordered breathing and heart failure a dangerous liaison, Trends Cardiovasc Med, 2008;18(7):240–7.
    Crossref | PubMed
  15. Abraham W, Khayat R, Pederzoli A, Central sleep apnea in heart failure, US Cardiology, 2009;6(2):72–8.
  16. Yumino D, Bradley TD, Central sleep apnea and Cheyne- Stokes respiration, Proc Am Thorac Soc, 2008;5(2):226–36.
    Crossref | PubMed
  17. Park JG, Ramar K, Olson EJ, Updates on definition, consequences, and management of obstructive sleep apnea, Mayo Clin Proc, 2011;86(6):549–54; quiz 554–5.
    Crossref | PubMed
  18. Szollosi I, Thompson BR, Krum H, et al., Impaired pulmonary diffusing capacity and hypoxia in heart failure correlates with central sleep apnea severity, Chest, 2008;134(1):67–72.
    Crossref | PubMed
  19. Bradley TD, Floras JS, Sleep apnea and heart failure: Part II: central sleep apnea, Circulation, 2003;107(13):1822–6.
    Crossref | PubMed
  20. Chenuel BJ, Smith CA, Skatrud JB, et al., Increased propensity for apnea in response to acute elevations in left atrial pressure during sleep in the dog, J Appl Physiol, 2006;101(1):76–83.
    Crossref | PubMed
  21. Dempsey JA, Crossing the apnoeic threshold: causes and consequences, Exp Physiol, 2005;90(1):13–24.
    Crossref | PubMed
  22. Cheyne J, A case of apoplexy in which the fleshy part of the heart was converted into fat, Dublin Hospital Reports, 1818;2:216–23. [K15]
  23. Sahlin C, Svanborg E, Stenlund H, Franklin KA, Cheyne-Stokes respiration and supine dependency, Eur Respir J, 2005;25(5):829–33.
    Crossref | PubMed
  24. Xie A, Skatrud JB, Khayat R, et al., Cerebrovascular response to carbon dioxide in patients with congestive heart failure, Am J Respir Crit Care Med, 2005;172(3):371–8.
    Crossref | PubMed
  25. Naughton MT, Rahman MA, Hara K, et al., Effect of continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure, Circulation, 1995;91(6):1725–31.
    Crossref | PubMed
  26. Tilkian AG, Guilleminault C, Schroeder JS, et al., Hemodynamics in sleep-induced apnea. Studies during wakefulness and sleep, Ann Intern Med, 1976;85(6):714–9.
    Crossref | PubMed
  27. Selmi C, Montano N, Furlan R, et al., Inflammation and oxidative stress in obstructive sleep apnea syndrome, Exp Biol Med (Maywood), 2007;232(11):1409–13.
    Crossref | PubMed
  28. Lopez-Jimenez F, Sert Kuniyoshi FH, Gami A, Somers VK, Obstructive sleep apnea: implications for cardiac and vascular disease, Chest, 2008;133(3):793–804.
    Crossref | PubMed
  29. Morgan BJ, Denahan T, Ebert TJ, Neurocirculatory consequences of negative intrathoracic pressure vs. asphyxia during voluntary apnea, J Appl Physiol, 1993;74(6):2969–75.
    PubMed
  30. Somers VK, Dyken ME, Clary MP, Abboud FM, Sympathetic neural mechanisms in obstructive sleep apnea, J Clin Invest, 1995;96(4):1897–904.
    Crossref | PubMed
  31. Cutler MJ, Swift NM, Keller DM, et al., Hypoxia-mediated prolonged elevation of sympathetic nerve activity after periods of intermittent hypoxic apnea, J Appl Physiol, 2004;96(2):754–61.
    Crossref | PubMed
  32. Cohn JN, Levine TB, Olivari MT, et al., Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure, N Engl J Med, 1984;311(13):819–23.
    Crossref | PubMed
  33. Javaheri S, Shukla R, Zeigler H, Wexler L, Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure, J Am Coll Cardiol, 2007;49(20):2028–34.
    Crossref | PubMed
  34. Schocken DD, Benjamin EJ, Fonarow GC, et al., Prevention of heart failure: a scientific statement from the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group, Circulation, 2008;117(19):2544–65.
    Crossref | PubMed
  35. Maser RE, Lenhard MJ, Rizzo AA, Vasile AA, Continuous positive airway pressure therapy improves cardiovascular autonomic function for persons with sleep-disordered breathing, Chest, 2008;133(1):86–91.
    Crossref | PubMed
  36. Tkacova R, Liu PP, Naughton MT, Bradley TD, Effect of continuous positive airway pressure on mitral regurgitant fraction and atrial natriuretic peptide in patients with heart failure, J Am Coll Cardiol, 1997;30(3):739–45.
    Crossref | PubMed
  37. Tkacova R, Rankin F, Fitzgerald FS, et al., Effects of continuous positive airway pressure on obstructive sleep apnea and left ventricular afterload in patients with heart failure, Circulation, 1998;98(21):2269–75.
    Crossref | PubMed
  38. Khayat RN, Abraham WT, Patt B, et al., Cardiac effects of continuous and bilevel positive airway pressure for patients with heart failure and obstructive sleep apnea: a pilot study, Chest, 2008;134(6):1162–8.
    Crossref | PubMed
  39. Yoshinaga K, Burwash IG, Leech JA, et al., The effects of continuous positive airway pressure on myocardial energetics in patients with heart failure and obstructive sleep apnea, J Am Coll Cardiol, 2007;49(4):450–8.
    Crossref | PubMed
  40. Naughton MT, Benard DC, Rutherford R, Bradley TD, Effect of continuous positive airway pressure on central sleep apnea and nocturnal PCO2 in heart failure, Am J Respir Crit Care Med, 1994;150(6 Pt 1):1598–604.
    Crossref | PubMed
  41. Naughton MT, Liu PP, Bernard DC, et al., Treatment of congestive heart failure and Cheyne-Stokes respiration during sleep by continuous positive airway pressure, Am J Respir Crit Care Med, 1995;151(1):92–7.
    Crossref | PubMed
  42. Sin DD, Logan AG, Fitzgerald FS, et al., Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration, Circulation, 2000;102(1):61–6.
    Crossref | PubMed
  43. Bradley TD, Logan AG, Kimoff RJ, et al., CANPAP Investigators, Continuous positive airway pressure for central sleep apnea and heart failure, N Engl J Med, 2005;353(19):2025–33.
    Crossref | PubMed
  44. Somers VK, White DP, Amin R, et al., Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing, J Am Coll Cardiol, 2008;52(8):686–717.
    Crossref | PubMed
  45. Mansfield D, Kaye DM, Brunner La Rocca H, et al., Raised sympathetic nerve activity in heart failure and central sleep apnea is due to heart failure severity, Circulation, 2003;107(10):1396–400.
    Crossref | PubMed
  46. Roebuck T, Solin P, Kaye DM, et al., Increased long-term mortality in heart failure due to sleep apnoea is not yet proven, Eur Respir J, 2004;23(5):735–40.
    Crossref | PubMed
  47. Teschler H, Döhring J, Wang YM, Berthon-Jones M, Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure, Am J Respir Crit Care Med, 2001;164(4):614–9.
    Crossref | PubMed
  48. Philippe C, Stoïca-Herman M, Drouot X, et al., Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six month period, Heart, 2006;92(3):337–42.
    Crossref | PubMed
  49. Oldenburg O, Schmidt A, Lamp B, et al., Adaptive servoventilation improves cardiac function in patients with chronic heart failure and Cheyne-Stokes respiration, Eur J Heart Fail, 2008;10(6):581–6.
    Crossref | PubMed
  50. Teschler H, Cowie MR, d’Ortho MP, et al., Rationale and design of the SERVE HF study: treatment of sleep-disordered breathing with predominant central sleep apnea by adaptive servo ventilation in patients with heart failure, Am J Respir Crit Care Med, 2010;181:A5580. [K16]
    Crossref
  51. Glenn WW, Holcomb WG, Gee JB, Rath R, Central hypoventilation; long-term ventilatory assistance by radiofrequency electrophrenic respiration, Ann Surg, 1970;172(4):755–73.
    Crossref | PubMed
  52. Glenn WW, Phelps ML, Diaphragm pacing by electrical stimulation of the phrenic nerve, Neurosurgery, 1985;17(6):974–84.
    Crossref | PubMed
  53. DiMarco AF, Phrenic nerve stimulation in patients with spinal cord injury, Respir Physiol Neurobiol, 2009;169(2):200–9.
    Crossref | PubMed
  54. Abraham W, Zhang SJ, Michalkiewicz D, et al., Results of chronic phrenic nerve stimulation using the Respicardia system are comparable to acute results in the improvement of central sleep apnea: first in man experience, Circulation, 2010;122(21 Suppl.):18661.
  55. Glenn WW, Brouillette RT, Dentz B, et al., Fundamental considerations in pacing of the diaphragm for chronic ventilatory insufficiency: a multi-center study, Pacing Clin Electrophysiol, 1988;11(11 Pt 2):2121–7.
    Crossref | PubMed
  56. Engleman HM, Martin SE, Douglas NJ, Compliance with CPAP therapy in patients with the sleep apnoea/hypopnoea syndrome, Thorax, 1994;49(3):263–6.
    Crossref | PubMed
  57. Javaheri S, Effects of continuous positive airway pressure on sleep apnea and ventricular irritability in patients with heart failure, Circulation, 2000;101(4):392–7.
    Crossref | PubMed
  58. Arzt M, Floras JS, Logan AG, et al., CANPAP Investigators, Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP), Circulation, 2007;115(25):3173–80.
    Crossref | PubMed
  59. Ponikowski P, Javaheri S, Michalkiewicz D, et al., Transvenous phrenic nerve stimulation for the treatment of central sleep apnoea in heart failure, Eur Heart J, 2011; August 19 [Epub ahead of print]. [K17]
  60. Augostini R, A novel approach to the treatment of central sleep apnea in heart failure, Herzschrittmacher und Elektrophysiologie, 2011 [In press]. [K18]
  61. Bramante CT, Westlund R, Weinhaus A, Suitability of the pericardiophrenic veins for phrenic nerve stimulation: an anatomic study, Neuromodulation, 2011;14(4):337–41; discussion 341–2.
    Crossref | PubMed
  62. James KB, Panteleon A, Augostini R, et al., Transvenous ventilation monitoring using transthoracic impedance and a novel lead placement, Heart Rhythm: the Official Journal of the Heart Rhythm Society, 2010;8(5):S261–S84.
  63. Somers VK, Dyken ME, Mark AL, Abboud FM, Sympatheticnerve activity during sleep in normal subjects, N Engl J Med, 1993;328(5):303–7.
    Crossref | PubMed
  64. Augostini R, Jagielski D, Michalkiewicz D, et al., Feasibility of transvenous left phrenic nerve stimulation for periodic breathing in heart failure patients, Heart Rhythm: the Official Journal of the Heart Rhythm Society, 2010;8(5):S455–S93.
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