Skip to main content

Advertisement

SpringerLink
Log in

Neurohormonal activation and pharmacological inhibition in pulmonary arterial hypertension and related right ventricular failure

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

During the last decade, hyperactivity of the sympathetic nervous and renin-angiotensin-aldosterone systems (SNS and RAAS, respectively) has repeatedly been related to the pathophysiology of pulmonary arterial hypertension (PAH) and PAH-related right ventricular failure (PAH-RVF), raising the question of whether neurohormonal inhibition may be indicated for these conditions. Experimental data indicate that the RAAS may be involved in pulmonary vascular remodeling, which is in fact halted by RAAS antagonism. Favorable actions of β-blockers on the pulmonary vasculature have also been described, even if information about β-adrenergic receptors in PAH is lacking. Furthermore, the available evidence suggests that stimulation of the pressure-overloaded RV by the SNS and RAAS is initially compensatory, but becomes maladaptive over time. Consistently, RV reverse remodeling has been shown in PAH animal models treated with either β-blockers or RAAS inhibitors, although important differences with human PAH may limit the translational value of these findings. Only few observational studies of neurohormonal antagonism in PAH and PAH-RVF have been published. Nonetheless, β-blockers on top of specific therapy appear to be safe and possibly also effective. The combination of mineralocorticoid receptor and endothelin-A receptor antagonists may result in an additive effect because of a positive pharmacodynamic interaction. While neurohormonal inhibitors cannot be recommended at present for treatment of PAH and PAH-RVF, they are worth being further investigated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Galiè N, Humbert M, Vachiery JL, Gibbs S et al (2016) 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 37(1):67–119. doi:10.1093/eurheartj/ehv317

    Article  PubMed  Google Scholar 

  2. Abraham WT, Raynolds MV, Gottschall B, Badesch DB, Wynne KM, Groves BM, Lowes BD, Bristow MR, Perryman MB, Voelkel NF (1995) Importance of angiotensin-converting enzyme in pulmonary hypertension. Cardiology 10(Suppl 1):9–15

    Article  Google Scholar 

  3. Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF (2009) The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest 20(135):794–804. doi:10.1378/chest.08-0492

    Article  Google Scholar 

  4. Florea VG, Cohn JN (2014) The autonomic nervous system and heart failure. Circ Res 114:1815–1826. doi:10.1161/CIRCRESAHA.114.302589

    Article  CAS  PubMed  Google Scholar 

  5. Bristow MR, Minobe W, Rasmussen R, Larrabee P, Skerl L, Klein JW, Anderson FL et al (1992) β-adrenergic neuroeffector abnormalities in the failing human heart are produced by local, rather than systemic mechanisms. J Clin Invest 89(3):803–815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sakamaki F, Satoh T, Nagaya N, Kyotani S, Oya H, Nakanishi N, Kuribayashi S, Ishida Y (2000) Correlation between severity of pulmonary arterial hypertension and 123I-Metaiodobenzylguanidine left ventricular imaging. J Nucl Med 41:1127–1133

    CAS  PubMed  Google Scholar 

  7. Haneda T, Nakajima T, Shirato K et al (1983) Effects of oxygen breathing on pulmonary vascular input impedance in patients with pulmonary hypertension. Chest 83:520–527

    Article  CAS  PubMed  Google Scholar 

  8. Richards AM, Ikram H, Crozier IG et al (1990) Ambulatory pulmonary arterial pressure in primary pulmonary hypertension: variability, relation to systemic arterial pressure, and plasma catecholamines. Br Heart J 63:103–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Velez-Roa S, Ciarka A, Najem B, Vachiery JL, Naeije R, van de Borne P (2004) Increased sympathetic nerve activity in pulmonary artery hypertension. Circulation 10(10):1308–1312. doi:10.1161/01.CIR.0000140724.90898.D3

    Article  Google Scholar 

  10. Sanyal SN, Ono K (2002) Derangement of autonomic nerve control in rat with right ventricular failure. Pathophysiology 8(3):197–203

    Article  PubMed  Google Scholar 

  11. Fauchier L, Babuty D, Melin A, Bonnet P, Cosnay P, Fauchier JP (2004) Heart rate variability in severe right or left heart failure: the role of pulmonary hypertension and resistances. Eur J Heart Fail 6(2):181–185

    Article  PubMed  Google Scholar 

  12. Ciarka A, Doan V, Velez-Roa S, Naeije R, van de Borne P (2010) Prognostic significance of sympathetic nervous system activation in pulmonary arterial hypertension. Am J Respir Crit Care Med 181(11):1269–1275. doi:10.1164/rccm.200912-1856OC

    Article  PubMed  Google Scholar 

  13. Ponikowski P, Chua TP, Piepoli M, Ondusova D, Webb-Peploe K, Harrington D, Anker SD, Volterrani M, Colombo R, Mazzuero G et al (1997) Augmented peripheral chemosensitivity as a potential input to baroreflex impairment and autonomic imbalance in chronic heart failure. Circulation 96:2586–2594

    Article  CAS  PubMed  Google Scholar 

  14. Notarius CF, Atchison DJ, Floras JS (2001) Impact of heart failure and exercise capacity on sympathetic response to handgrip exercise. Am J Physiol Heart Circ Physiol 280:H969–H976

    CAS  PubMed  Google Scholar 

  15. Grassi G, Seravalle G, Cattaneo BM, Lanfranchi A, Vailati S, Giannattasio C, Del BA, Sala C, Bolla GB, Pozzi M (1995) Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure. Circulation 92:3206–3211

    Article  CAS  PubMed  Google Scholar 

  16. Wensel R, Opitz CF, Anker SD, Winkler J, Hoffken G, Kleber FX, Sharma R, Hummel M, Hetzer R, Ewert R (2002) Assessment of survival in patients with primary pulmonary hypertension: importance of cardio-pulmonary exercise testing. Circulation 106:319–324

    Article  PubMed  Google Scholar 

  17. De Man FS, Handoko ML, van Ballegoij JJ, Schalij I, Bogaards SJ, Postmus PE, van der Velden J, Westerhof N, Paulus WJ, Vonk-Noordegraaf A (2012) Bisoprolol delays progression towards right heart failure in experimental pulmonary hypertension. Circ Heart Fail 5:97–105. doi:10.1161/CIRCHEARTFAILURE.111.964494

    Article  PubMed  Google Scholar 

  18. Forfia PR, Mathai SC, Fisher MR, Housten-Harris T, Hemnes AR, Champion HC, Girgis RE, Hassoun PM (2008) Hyponatremia predicts right heart failure and poor survival in pulmonary arterial hypertension. Am J Respir Crit Care Med 177:1364–1369. doi:10.1164/rccm.200712-1876OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Orte C, Polak JM, Haworth SG, Yacoub MH, Morrell NW (2000) Expression of pulmonary vascular angiotensin-converting enzyme in primary and secondary plexiform pulmonary hypertension. J Pathol 192:379–384

    Article  CAS  PubMed  Google Scholar 

  20. Rondelet B, Kerbaul F, Van Beneden R, Hubloue I, Huez S, Fesler P, Remmelink M, Brimioulle S, Salmon I, Naeije R (2005) Prevention of pulmonary vascular remodeling and of decreased BMPR-2 expression by losartan therapy in shunt-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 289:H2319–H2324

    Article  CAS  PubMed  Google Scholar 

  21. Rouleau JL, Kapuku G, Pelletier S, Gosselin H, Adam A, Gagnon C, Lambert C, Meloche S (2001) Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit: importance of kinins and influence on angiotensin II type 1 receptor signaling pathway. Circulation 104:939–944

    Article  CAS  PubMed  Google Scholar 

  22. Maron BA, Zhang YY, White K, Chan SY, Handy DE, Mahoney CE, Loscalzo J, Leopold JA (2012) Aldosterone inactivates the endothelin-B receptor via a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and modulate pulmonary arterial hypertension. Circulation 126(8):963–974. doi:10.1161/CIRCULATIONAHA.112.094722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zisman LS, Asano K, Dutcher DL, Ferdensi A, Robertson AD, Jenkin M, Bush EW, Bohlmeyer T, Perryman MB, Bristow MR (1998) Differential regulation of cardiac angiotensin converting enzyme binding sites and AT1 receptor density in the failing human heart. Circulation 98(17):1735–1741

    Article  CAS  PubMed  Google Scholar 

  24. Abraham WT, Raynolds MV, Badesch DB, Wynne KM, Groves BM, Roden RL, Robertson AD, Lowes BD, Zisman LS, Voelkel NF, Bristow MR, Perryman MB (2003) Angiotensin-converting enzyme DD genotype in patients with primary pulmonary hypertension: increased frequency and association with preserved haemodynamics. J Renin Angiotensin Aldosterone Syst 4:27–30

    Article  CAS  PubMed  Google Scholar 

  25. Iusuf D, Henning RH, van Gilst WH, Roks AJ (2008) Angiotensin-(1–7): pharmacological properties and pharmacotherapeutic perspectives. Eur J Pharmacol 585:303–312. doi:10.1016/j.ejphar.2008.02.090

    Article  CAS  PubMed  Google Scholar 

  26. Shenoy V, Ferreira AJ, Qi Y, Fraga-Silva RA, Diez-Freire C, Dooies A, Jun JY, Sriramula S, Mariappan N, Pourang D et al (2010) The angiotensin-converting enzyme 2/angiogenesis-(1–7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 182:1065–1072. doi:10.1164/rccm.200912-1840OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bogaard HJ, Natarajan R, Mizuno S et al (2010) Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats. Am J Respir Crit Care Med 182:652–660. doi:10.1164/rccm.201003-0335OC

    Article  CAS  PubMed  Google Scholar 

  28. Mochizuki M, Yano M, Oda T, Tateishi H, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M (2007) Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca21 leak via stabilization of ryanodine receptor in heart failure. J Am Coll Cardiol 49:1722–1732

    Article  CAS  PubMed  Google Scholar 

  29. Kurum T, Tatli E, Yuksel M (2007) Effects of carvedilol on plasma levels of pro-inflammatory cytokines in patients with ischemic and nonischemic dilated cardiomyopathy. Tex Heart Inst J 34:52–59

    PubMed  PubMed Central  Google Scholar 

  30. Voelkel NF, McMurtry IF, Reeves JT (1980) Chronic propranolol treatment blunts right ventricular hypertrophy in rats at high altitude. J Appl Physiol 48:473–478

    CAS  PubMed  Google Scholar 

  31. Tual L, Morel OE, Favret F, Fouillit M, Guernier C, Buvry A, Germain L, Dhonneur G, Bernaudin JF, Richalet JP (2006) Carvedilol inhibits right ventricular hypertrophy induced by chronic hypobaric hypoxia. Pflugers Arch 452:371–379

    Article  CAS  PubMed  Google Scholar 

  32. Ishikawa M, Sato N, Asai K, Takano T, Mizuno K (2009) Effects of a pure alpha/beta-adrenergic receptor blocker on monocrotaline-induced pulmonary arterial hypertension with right ventricular hypertrophy in rats. Circ J 73:2337–2341

    Article  CAS  PubMed  Google Scholar 

  33. Fujio H, Nakamura K, Matsubara H, Kusano KF, Miyaji K, Nagase S, Ikeda T, Ogawa A, Ohta-Ogo K, Miura D et al (2006) Carvedilol inhibits proliferation of cultured pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension. J Cardiovasc Pharmacol 47:250–255

    Article  CAS  PubMed  Google Scholar 

  34. Perros F, Ranchoux B, Izikki M, Bentebbal S, Happé C, Antigny F, Jourdon P, Dorfmüller P, Lecerf F, Fadel E, Simonneau G, Humbert M, Bogaard HJ, Eddahibi S (2015) Nebivolol for improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function in pulmonary hypertension. J Am Coll Cardiol 65(7):668–680. doi:10.1016/j.jacc.2014.11.050

    Article  CAS  PubMed  Google Scholar 

  35. Lowes BD, Minobe W, Abraham WT, Rizeq MN, Bohlmeyer TJ, Quaife RA, Roden RL, Dutcher DL, Robertson AD, Voelkel NF, Badesch DB, Groves BM, Gilbert EM, Bristow MR (1997) Changes in gene expression in the intact human heart: downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium. J Clin Invest 100:2315–2324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gomez-Arroyo J, Mizuno S, Szczepanek K, Van Tassell B, Natarajan R, dos Remedios CG, Drake JI, Farkas L, Kraskauskas D, Wijesinghe DS, Chalfant CE, Bigbee J, Abbate A, Lesnefsky EJ, Bogaard HJ, Voelkel NF (2013) Metabolic gene remodeling and mitochondrial dysfunction in failing right ventricular hypertrophy due to pulmonary arterial hypertension. Circ Heart Fail 6(1):136–144. doi:10.1161/CIRCHEARTFAILURE.111.966127

    Article  CAS  PubMed  Google Scholar 

  37. Wang L, Li W, Yang Y, Wu W, Cai Q, Ma X, Xiong C, He J, Fang W (2015) Quantitative assessment of right ventricular glucose metabolism in idiopathic pulmonary arterial hypertension patients: a longitudinal study. Eur Heart J Cardiovasc Imaging. doi:10.1093/ehjci/jev297

    Google Scholar 

  38. Drake JI, Gomez-Arroyo J, Dumur CI, Kraskauskas D, Natarajan R, Bogaard HJ, Fawcett P, Voelkel NF (2013) Chronic carvedilol treatment partially reverses the right ventricular failure transcriptional profile in experimental pulmonary hypertension. Physiol Genomics 45:449–461. doi:10.1152/physiolgenomics.00166.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lowes BD, Gilbert EM, Abraham WT, Minobe WA, Larrabee P, Ferguson D, Wolfel EE, Lindenfeld J, Tsvetkova T, Robertson AD, Quaife RA, Bristow MR (2002) Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. N Engl J Med 346:1357–1365

    Article  CAS  PubMed  Google Scholar 

  40. Okada M, Kikuzuki R, Harada T, Hori Y, Yamawaki H, Hara Y (2008) Captopril attenuates matrix metalloproteinase-2 and -9 in monocrotaline-induced right ventricular hypertrophy in rats. J Pharmacol Sci 108(4):487–494

    Article  CAS  PubMed  Google Scholar 

  41. Okada M, Harada T, Kikuzuki R, Yamawaki H, Hara Y (2009) Effects of telmisartan on right ventricular remodeling induced by monocrotaline in rats. J Pharmacol Sci 111:193–200

    Article  CAS  PubMed  Google Scholar 

  42. Provencher S, Herve P, Jais X, Lebrec D, Humbert M, Simonneau G, Sitbon O (2006) Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. Gastroenterology 130(1):120–126

    Article  CAS  PubMed  Google Scholar 

  43. Thenappan T, Roy SS, Duval S, Glassner-Kolmin C, Gomberg-Maitland M (2014) β-blocker therapy is not associated with adverse outcomes in patients with pulmonary arterial hypertension: a propensity score analysis. Circ Heart Fail 7(6):903–910

    Article  CAS  PubMed  Google Scholar 

  44. Bandyopadhyay D, Bajaj N, Zein J, Minai OA, Dweik RA (2015) Outcomes of β-blocker use in pulmonary arterial hypertension: a propensity matched analysis. Eur Respir J 46(3):750–760

    Article  CAS  PubMed  Google Scholar 

  45. So PP, Davies RA, Chandy G, Stewart D, Beanlands RS, Haddad H, Pugliese C, Mielniczuk LM (2012) Usefulness of beta-blocker therapy and outcomes in patients with pulmonary arterial hypertension. Am J Cardiol 109(10):1504–1509

    Article  CAS  PubMed  Google Scholar 

  46. Moretti C, Grosso Marra W, D’Ascenzo F, Omedè P, Cannillo M, Libertucci D, Fusaro E, Meynet I, Giordana F, Salera D, Annone U, Chen SL, Marra S, Gaita F (2015) Beta blocker for patients with pulmonary arterial hypertension: a single center experience. Int J Cardiol 184(1):528–532

    Article  PubMed  Google Scholar 

  47. Grinnan D, Bogaard HJ, Grizzard J, Van Tassell B, Abbate A, DeWilde C, Priday A, Voelkel NF (2014) Treatment of group I pulmonary arterial hypertension with carvedilol is safe. Am J Respir Crit Care Med 189(12):1562–1564

    Article  PubMed  Google Scholar 

  48. Maron BA, Waxman AB, Opotowsky AR, Gillies H, Blair C, Aghamohammadzadeh R, Loscalzo J, Leopold JA (2013) Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension (from the [ARIES] study 1 and 2 trials). Am J Cardiol 112(5):720–725. doi:10.1016/j.amjcard.2013.04.051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rich S, Martinez J, Lam W, Rosen KM (1982) Captopril as treatment for patients with pulmonary hypertension. Problem of variability in assessing chronic drug treatment. Br Heart J 48(3):272–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Leier CV, Bambach D, Nelson S, Hermiller JB, Huss P, Magorien RD, Unverferth DV (1983) Captopril in primary pulmonary hypertension. Circulation 67(1):155–161

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

    Authors and Affiliations

    1. Cardiovascular Disease Unit, IRCCS AOU San Martino-IST Hospital and Department of Internal Medicine, University of Genova, 16132, Genoa, Italy

      Pietro Ameri, Edoardo Bertero, Giovanni Meliota, Martino Cheli, Marco Canepa, Claudio Brunelli & Manrico Balbi

    2. Department of Pediatric Cardiology and Cardiac Surgery, Giannina Gaslini Institute, 16148, Genoa, Italy

      Martino Cheli

    3. Department of Internal Medicine, University of Genova, Room 117, Viale Benedetto XV, 6, 16132, Genoa, Italy

      Pietro Ameri

    Authors
    1. Pietro Ameri
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Edoardo Bertero
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Giovanni Meliota
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Martino Cheli
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Marco Canepa
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Claudio Brunelli
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Manrico Balbi
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Pietro Ameri.

    Ethics declarations

    Conflict of interest

    P. Ameri, E. Bertero, G. Meliota, M. Cheli, M. Canepa, C. Brunelli, and M. Balbi declare that they have no conflict of interest.

    Additional information

    Pietro Ameri and Edoardo Bertero have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Ameri, P., Bertero, E., Meliota, G. et al. Neurohormonal activation and pharmacological inhibition in pulmonary arterial hypertension and related right ventricular failure. Heart Fail Rev 21, 539–547 (2016). https://doi.org/10.1007/s10741-016-9566-3

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10741-016-9566-3

    Keywords

    Search

    Navigation