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Role of the Carotid Body Chemoreflex in the Pathophysiology of Heart Failure: A Perspective from Animal Studies

  • Harold D. SchultzEmail author
  • Noah J. Marcus
  • Rodrigo Del Rio
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 860)

Abstract

The treatment and management of chronic heart failure (CHF) remains an important focus for new and more effective clinical strategies. This important goal, however, is dependent upon advancing our understanding of the underlying pathophysiology. In CHF, sympathetic overactivity plays an important role in the development and progression of the cardiac and renal dysfunction and is often associated with breathing dysregulation, which in turn likely mediates or aggravates the autonomic imbalance. In this review we will summarize evidence that in CHF, the elevation in sympathetic activity and breathing instability that ultimately lead to cardiac and renal failure are driven, at least in part, by maladaptive activation of the carotid body (CB) chemoreflex. This maladaptive change derives from a tonic increase in CB afferent activity. We will focus our discussion on an understanding of mechanisms that alter CB afferent activity in CHF and its consequence on reflex control of autonomic, respiratory, renal, and cardiac function in animal models of CHF. We will also discuss the potential translational impact of targeting the CB in the treatment of CHF in humans, with relevance to other cardio-respiratory diseases.

Keywords

Heart failure Carotid body Sympathetic nerve activity Breathing Oxidative stress Nitric oxide Blood flow KLF2 

Notes

Conflicting Interests

The authors have no conflicts of interest to disclose.

References

  1. Adrian ED, Bronk DW, Phillips G (1932) Discharges in mammalian sympathetic nerves. J Physiol 74(2):115–133PubMedPubMedCentralGoogle Scholar
  2. Anavekar NS, Solomon SD (2005) Angiotensin II receptor blockade and ventricular remodelling. J Renin Angiotensin Aldosterone Syst 6(1):43–48. doi: 10.3317/jraas.2005.006 PubMedGoogle Scholar
  3. Bock JS, Gottlieb SS (2010) Cardiorenal syndrome: new perspectives. Circulation 121(23):2592–2600. doi: 10.1161/CIRCULATIONAHA.109.886473 PubMedGoogle Scholar
  4. Brack T, Randerath W, Bloch KE (2012) Cheyne-Stokes respiration in patients with heart failure: prevalence, causes, consequences and treatments. Respiration 83(2):165–176. doi: 10.1159/000331457 PubMedGoogle Scholar
  5. Branson RD, Johannigman JA (2013) Pre-hospital oxygen therapy. Respir Care 58(1):86–97. doi: 10.4187/respcare.02251 PubMedGoogle Scholar
  6. Chua TP, Ponikowski P, Webb-Peploe K, Harrington D, Anker SD, Piepoli M, Coats AJ (1997) Clinical characteristics of chronic heart failure patients with an augmented peripheral chemoreflex. Eur Heart J 18(3):480–486PubMedGoogle Scholar
  7. Clayton SC, Haack KK, Zucker IH (2011) Renal denervation modulates angiotensin receptor expression in the renal cortex of rabbits with chronic heart failure. Am J Physiol Renal Physiol 300(1):F31–F39. doi: 10.1152/ajprenal.00088.2010 PubMedPubMedCentralGoogle Scholar
  8. Cohn JN, Ferrari R, Sharpe N (2000) Cardiac remodeling–concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol 35(3):569–582PubMedGoogle Scholar
  9. Colombo PC, Ganda A, Lin J, Onat D, Harxhi A, Iyasere JE, Uriel N, Cotter G (2012) Inflammatory activation: cardiac, renal, and cardio-renal interactions in patients with the cardiorenal syndrome. Heart Fail Rev 17(2):177–190. doi: 10.1007/s10741-011-9261-3 PubMedGoogle Scholar
  10. Dekker RJ, van Thienen JV, Rohlena J, de Jager SC, Elderkamp YW, Seppen J, de Vries CJ, Biessen EA, van Berkel TJ, Pannekoek H, Horrevoets AJ (2005) Endothelial KLF2 links local arterial shear stress levels to the expression of vascular tone-regulating genes. Am J Pathol 167(2):609–618. doi: 10.1016/S0002-9440(10)63002-7 PubMedPubMedCentralGoogle Scholar
  11. Del Rio R, Marcus NJ, Schultz HD (2013a) Carotid chemoreceptor ablation improves survival in heart failure: rescuing autonomic control of cardiorespiratory function. J Am Coll Cardiol 62(25):2422–2430. doi: 10.1016/j.jacc.2013.07.079 PubMedGoogle Scholar
  12. Del Rio R, Marcus NJ, Schultz HD (2013b) Inhibition of hydrogen sulfide restores normal breathing stability and improves autonomic control during experimental heart failure. J Appl Physiol (1985) 114(9):1141–1150. doi: 10.1152/japplphysiol.01503.2012 Google Scholar
  13. Deo SH, Fisher JP, Vianna LC, Kim A, Chockalingam A, Zimmerman MC, Zucker IH, Fadel PJ (2012) Statin therapy lowers muscle sympathetic nerve activity and oxidative stress in patients with heart failure. Am J Physiol Heart Circ Physiol 303(3):H377–H385. doi: 10.1152/ajpheart.00289.2012 PubMedPubMedCentralGoogle Scholar
  14. Ding Y, Li YL, Schultz HD (2008) Downregulation of carbon monoxide as well as nitric oxide contributes to peripheral chemoreflex hypersensitivity in heart failure rabbits. J Appl Physiol (1985) 105(1):14–23. doi: 10.1152/japplphysiol.01345.2007 Google Scholar
  15. Ding Y, Li YL, Zimmerman MC, Davisson RL, Schultz HD (2009) Role of CuZn superoxide dismutase on carotid body function in heart failure rabbits. Cardiovasc Res 81(4):678–685. doi: 10.1093/cvr/cvn350 PubMedPubMedCentralGoogle Scholar
  16. Ding Y, Li YL, Zimmerman MC, Schultz HD (2010) Elevated mitochondrial superoxide contributes to enhanced chemoreflex in heart failure rabbits. Am J Physiol Regul Integr Comp Physiol 298(2):R303–R311. doi: 10.1152/ajpregu.00629.2009 PubMedPubMedCentralGoogle Scholar
  17. Ding Y, Li YL, Schultz HD (2011) Role of blood flow in carotid body chemoreflex function in heart failure. J Physiol 589(Pt 1):245–258. doi: 10.1113/jphysiol.2010.200584 PubMedPubMedCentralGoogle Scholar
  18. Downing J, Balady GJ (2011) The role of exercise training in heart failure. J Am Coll Cardiol 58(6):561–569. doi: 10.1016/j.jacc.2011.04.020 PubMedGoogle Scholar
  19. Edgley AJ, Krum H, Kelly DJ (2012) Targeting fibrosis for the treatment of heart failure: a role for transforming growth factor-beta. Cardiovasc Ther 30(1):e30–e40. doi: 10.1111/j.1755-5922.2010.00228.x PubMedGoogle Scholar
  20. Esler M (2010) The 2009 Carl Ludwig Lecture: Pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management. J Appl Physiol (1985) 108(2):227–237. doi: 10.1152/japplphysiol.00832.2009 Google Scholar
  21. Eyzaguirre C, Lewin J (1961) The effect of sympathetic stimulation on carotid nerve activity. J Physiol 159:251–267PubMedPubMedCentralGoogle Scholar
  22. Florea VG, Cohn JN (2014) The autonomic nervous system and heart failure. Circ Res 114(11):1815–1826. doi: 10.1161/CIRCRESAHA.114.302589 PubMedGoogle Scholar
  23. Fontana M, Emdin M, Giannoni A, Iudice G, Baruah R, Passino C (2011) Effect of acetazolamide on chemosensitivity, Cheyne-Stokes respiration, and response to effort in patients with heart failure. Am J Cardiol 107(11):1675–1680. doi: 10.1016/j.amjcard.2011.01.060 PubMedGoogle Scholar
  24. Fu Y, Xiao H, Zhang Y (2012) Beta-adrenoceptor signaling pathways mediate cardiac pathological remodeling. Front Biosci (Elite Ed) 4:1625–1637Google Scholar
  25. Fung ML, Tipoe GL, Leung PS (2014) Mechanisms of maladaptive responses of peripheral chemoreceptors to intermittent hypoxia in sleep-disordered breathing. Sheng Li Xue Bao 66(1):23–29PubMedGoogle Scholar
  26. Giannoni A, Emdin M, Poletti R, Bramanti F, Prontera C, Piepoli M, Passino C (2008) Clinical significance of chemosensitivity in chronic heart failure: influence on neurohormonal derangement, Cheyne-Stokes respiration and arrhythmias. Clin Sci (Lond) 114(7):489–497. doi: 10.1042/CS20070292 Google Scholar
  27. Haack KK, Marcus NJ, Del Rio R, Zucker IH, Schultz HD (2014) Simvastatin treatment attenuates increased respiratory variability and apnea/hypopnea index in rats with chronic heart failure. Hypertension 63(5):1041–1049. doi: 10.1161/HYPERTENSIONAHA.113.02535 PubMedPubMedCentralGoogle Scholar
  28. Haselton JR, Guyenet PG (1989) Central respiratory modulation of medullary sympathoexcitatory neurons in rat. Am J Physiol 256(3 Pt 2):R739–R750PubMedGoogle Scholar
  29. Iturriaga R (2013) Intermittent hypoxia: endothelin-1 and hypoxic carotid body chemosensory potentiation. Exp Physiol 98(11):1550–1551. doi: 10.1113/expphysiol.2013.075820 PubMedGoogle Scholar
  30. Iturriaga R, Moya EA, Rio RD (2014) Inflammation and oxidative stress during intermittent hypoxia: the impact on chemoreception. Exp Physiol. doi: 10.1113/expphysiol.2014.079525 PubMedGoogle Scholar
  31. Johnson FL (2014) Pathophysiology and etiology of heart failure. Cardiol Clin 32(1):9–19. doi: 10.1016/j.ccl.2013.09.015, viiPubMedGoogle Scholar
  32. Jonsson S, Agic MB, Narfstrom F, Melville JM, Hultstrom M (2014) Renal neurohormonal regulation in heart failure decompensation. Am J Physiol Regul Integr Comp Physiol 307(5):R493–R497. doi: 10.1152/ajpregu.00178.2014 PubMedGoogle Scholar
  33. Karim F, Poucher SM, Summerill RA (1987) The effects of stimulating carotid chemoreceptors on renal haemodynamics and function in dogs. J Physiol 392:451–462PubMedPubMedCentralGoogle Scholar
  34. Kishi T (2012) Heart failure as an autonomic nervous system dysfunction. J Cardiol 59(2):117–122. doi: 10.1016/j.jjcc.2011.12.006 PubMedGoogle Scholar
  35. Lam SY, Liu Y, Ng KM, Lau CF, Liong EC, Tipoe GL, Fung ML (2012) Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways. Histochem Cell Biol 137(3):303–317. doi: 10.1007/s00418-011-0900-5 PubMedPubMedCentralGoogle Scholar
  36. Leung PS, Fung ML, Tam MS (2003) Renin-angiotensin system in the carotid body. Int J Biochem Cell Biol 35(6):847–854PubMedGoogle Scholar
  37. Li YL, Schultz HD (2006) Enhanced sensitivity of Kv channels to hypoxia in the rabbit carotid body in heart failure: role of angiotensin II. J Physiol 575(Pt 1):215–227. doi: 10.1113/jphysiol.2006.110700 PubMedPubMedCentralGoogle Scholar
  38. Li YL, Li YF, Liu D, Cornish KG, Patel KP, Zucker IH, Channon KM, Schultz HD (2005) Gene transfer of neuronal nitric oxide synthase to carotid body reverses enhanced chemoreceptor function in heart failure rabbits. Circ Res 97(3):260–267. doi: 10.1161/01.RES.0000175722.21555.55 PubMedGoogle Scholar
  39. Li YL, Xia XH, Zheng H, Gao L, Li YF, Liu D, Patel KP, Wang W, Schultz HD (2006) Angiotensin II enhances carotid body chemoreflex control of sympathetic outflow in chronic heart failure rabbits. Cardiovasc Res 71(1):129–138. doi: 10.1016/j.cardiores.2006.03.017 PubMedGoogle Scholar
  40. Li YL, Gao L, Zucker IH, Schultz HD (2007) NADPH oxidase-derived superoxide anion mediates angiotensin II-enhanced carotid body chemoreceptor sensitivity in heart failure rabbits. Cardiovasc Res 75(3):546–554. doi: 10.1016/j.cardiores.2007.04.006 PubMedPubMedCentralGoogle Scholar
  41. Li YL, Ding Y, Agnew C, Schultz HD (2008) Exercise training improves peripheral chemoreflex function in heart failure rabbits. J Appl Physiol (1985) 105(3):782–790. doi: 10.1152/japplphysiol.90533.2008 Google Scholar
  42. Lombardi F, Mortara A (1998) Heart rate variability and cardiac failure. Heart 80(3):213–214PubMedPubMedCentralGoogle Scholar
  43. Lu Y, Whiteis CA, Sluka KA, Chapleau MW, Abboud FM (2013) Responses of glomus cells to hypoxia and acidosis are uncoupled, reciprocal and linked to ASIC3 expression: selectivity of chemosensory transduction. J Physiol 591(Pt 4):919–932. doi: 10.1113/jphysiol.2012.247189 PubMedPubMedCentralGoogle Scholar
  44. Lymperopoulos A, Rengo G, Koch WJ (2013) Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res 113(6):739–753. doi: 10.1161/CIRCRESAHA.113.300308 PubMedGoogle Scholar
  45. Mak S, Azevedo ER, Liu PP, Newton GE (2001) Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure. Chest 120(2):467–473PubMedGoogle Scholar
  46. Marcus NJ, Schultz HD (2001) Role of carotid body chemoreflex function in the development of Cheyne-Stokes respiration during progression of congestive heart failure. FASEB J 25:841.847Google Scholar
  47. Marcus NJ, Del Rio R, Schultz EP, Xia XH, Schultz HD (2014a) Carotid body denervation improves autonomic and cardiac function and attenuates disordered breathing in congestive heart failure. J Physiol 592(Pt 2):391–408. doi: 10.1113/jphysiol.2013.266221 PubMedPubMedCentralGoogle Scholar
  48. Marcus NJ, Del Rio R, Schultz HD (2014b) Carotid body denervation reduces renal sympathetic nerve activity and fibrosis, and increases renal blood flow in congestive heart failure. FASEB J 28:875.814Google Scholar
  49. Marcus NJ, Del Rio R, Schultz HD (2014c) Central role of carotid body chemoreceptors in disordered breathing and cardiorenal dysfunction in chronic heart failure. Front Physiol 5:438. doi: 10.3389/fphys.2014.00438 PubMedPubMedCentralGoogle Scholar
  50. McCloskey DI (1975) Mechanisms of autonomic control of carotid chemoreceptor activity. Respir Physiol 25(1):53–61PubMedGoogle Scholar
  51. Miyakawa AA, de Lourdes JM, Krieger JE (2004) Identification of two novel shear stress responsive elements in rat angiotensin I converting enzyme promoter. Physiol Genomics 17(2):107–113. doi: 10.1152/physiolgenomics.00169.2003 PubMedGoogle Scholar
  52. Niewinski P (2014) Pathophysiology and potential clinical applications for testing of peripheral chemosensitivity in heart failure. Curr Heart Fail Rep 11(2):126–133. doi: 10.1007/s11897-014-0188-6 PubMedGoogle Scholar
  53. Niewinski P, Janczak D, Rucinski A, Jazwiec P, Sobotka PA, Engelman ZJ, Fudim M, Tubek S, Jankowska EA, Banasiak W, Hart EC, Paton JF, Ponikowski P (2013) Carotid body removal for treatment of chronic systolic heart failure. Int J Cardiol 168(3):2506–2509. doi: 10.1016/j.ijcard.2013.03.011 PubMedGoogle Scholar
  54. Niewinski P, Janczak D, Rucinski A, Tubek S, Engelman ZJ, Jazwiec P, Banasiak W, Sobotka PA, Hart EC, Paton JF, Ponikowski P (2014) Dissociation between blood pressure and heart rate response to hypoxia after bilateral carotid body removal in men with systolic heart failure. Exp Physiol 99(3):552–561. doi: 10.1113/expphysiol.2013.075580 PubMedGoogle Scholar
  55. Peng YJ, Nanduri J, Raghuraman G, Wang N, Kumar GK, Prabhakar NR (2013) Role of oxidative stress-induced endothelin-converting enzyme activity in the alteration of carotid body function by chronic intermittent hypoxia. Exp Physiol 98(11):1620–1630. doi: 10.1113/expphysiol.2013.073700 PubMedGoogle Scholar
  56. Ponikowski P, Banasiak W (2001) Chemosensitivity in chronic heart failure. Heart Fail Monit 1(4):126–131PubMedGoogle Scholar
  57. Ponikowski P, Chua TP, Piepoli M, Ondusova D, Webb-Peploe K, Harrington D, Anker SD, Volterrani M, Colombo R, Mazzuero G, Giordano A, Coats AJ (1997) Augmented peripheral chemosensitivity as a potential input to baroreflex impairment and autonomic imbalance in chronic heart failure. Circulation 96(8):2586–2594PubMedGoogle Scholar
  58. Ponikowski P, Anker SD, Chua TP, Francis D, Banasiak W, Poole-Wilson PA, Coats AJ, Piepoli M (1999) Oscillatory breathing patterns during wakefulness in patients with chronic heart failure: clinical implications and role of augmented peripheral chemosensitivity. Circulation 100(24):2418–2424PubMedGoogle Scholar
  59. Ponikowski P, Chua TP, Anker SD, Francis DP, Doehner W, Banasiak W, Poole-Wilson PA, Piepoli MF, Coats AJ (2001) Peripheral chemoreceptor hypersensitivity: an ominous sign in patients with chronic heart failure. Circulation 104(5):544–549PubMedGoogle Scholar
  60. Prabhakar NR (1994) Neurotransmitters in the carotid body. Adv Exp Med Biol 360:57–69PubMedGoogle Scholar
  61. Prabhakar NR (2012) Carbon monoxide (CO) and hydrogen sulfide (H(2)S) in hypoxic sensing by the carotid body. Respir Physiol Neurobiol 184(2):165–169. doi: 10.1016/j.resp.2012.05.022 PubMedPubMedCentralGoogle Scholar
  62. Querido JS, Kennedy PM, Sheel AW (2010) Hyperoxia attenuates muscle sympathetic nerve activity following isocapnic hypoxia in humans. J Appl Physiol (1985) 108(4):906–912. doi: 10.1152/japplphysiol.01228.2009 Google Scholar
  63. Roy A, Guatimosim S, Prado VF, Gros R, Prado MA (2014) Cholinergic activity as a new target in diseases of the heart. Mol Med. doi: 10.2119/molmed.2014.00125 PubMedCentralGoogle Scholar
  64. Schultz HD, Marcus NJ (2012) Heart failure and carotid body chemoreception. Adv Exp Med Biol 758:387–395. doi: 10.1007/978-94-007-4584-1_52 PubMedGoogle Scholar
  65. Schultz HD, Li YL, Ding Y (2007) Arterial chemoreceptors and sympathetic nerve activity: implications for hypertension and heart failure. Hypertension 50(1):6–13. doi: 10.1161/HYPERTENSIONAHA.106.076083 PubMedGoogle Scholar
  66. Schultz HD, Del Rio R, Ding Y, Marcus NJ (2012) Role of neurotransmitter gases in the control of the carotid body in heart failure. Respir Physiol Neurobiol 184(2):197–203. doi: 10.1016/j.resp.2012.07.010 PubMedPubMedCentralGoogle Scholar
  67. Schultz HD, Marcus NJ, Del Rio R (2013) Role of the carotid body in the pathophysiology of heart failure. Curr Hypertens Rep 15(4):356–362. doi: 10.1007/s11906-013-0368-x PubMedPubMedCentralGoogle Scholar
  68. Simms AE, Paton JF, Pickering AE, Allen AM (2009) Amplified respiratory-sympathetic coupling in the spontaneously hypertensive rat: does it contribute to hypertension? J Physiol 587(Pt 3):597–610. doi: 10.1113/jphysiol.2008.165902 PubMedPubMedCentralGoogle Scholar
  69. Sinski M, Lewandowski J, Przybylski J, Zalewski P, Symonides B, Abramczyk P, Gaciong Z (2014) Deactivation of carotid body chemoreceptors by hyperoxia decreases blood pressure in hypertensive patients. Hypertens Res 37(9):858–862. doi: 10.1038/hr.2014.91 PubMedGoogle Scholar
  70. Stickland MK, Morgan BJ, Dempsey JA (2008) Carotid chemoreceptor modulation of sympathetic vasoconstrictor outflow during exercise in healthy humans. J Physiol 586(6):1743–1754. doi: 10.1113/jphysiol.2007.147421 PubMedPubMedCentralGoogle Scholar
  71. Sun SY, Wang W, Zucker IH, Schultz HD (1999a) Enhanced activity of carotid body chemoreceptors in rabbits with heart failure: role of nitric oxide. J Appl Physiol (1985) 86(4):1273–1282Google Scholar
  72. Sun SY, Wang W, Zucker IH, Schultz HD (1999b) Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure. J Appl Physiol (1985) 86(4):1264–1272Google Scholar
  73. Toney GM, Pedrino GR, Fink GD, Osborn JW (2010) Does enhanced respiratory-sympathetic coupling contribute to peripheral neural mechanisms of angiotensin II-salt hypertension? Exp Physiol 95(5):587–594. doi: 10.1113/expphysiol.2009.047399 PubMedPubMedCentralGoogle Scholar
  74. Wang T, Lang GD, Moreno-Vinasco L, Huang Y, Goonewardena SN, Peng YJ, Svensson EC, Natarajan V, Lang RM, Linares JD, Breysse PN, Geyh AS, Samet JM, Lussier YA, Dudley S, Prabhakar NR, Garcia JG (2012) Particulate matter induces cardiac arrhythmias via dysregulation of carotid body sensitivity and cardiac sodium channels. Am J Respir Cell Mol Biol 46(4):524–531. doi: 10.1165/rcmb.2011-0213OC PubMedGoogle Scholar
  75. White HD, Norris RM, Brown MA, Brandt PW, Whitlock RM, Wild CJ (1987) Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 76(1):44–51PubMedGoogle Scholar
  76. Xing DT, May CN, Booth LC, Ramchandra R (2014) Tonic arterial chemoreceptor activity contributes to cardiac sympathetic activation in mild ovine heart failure. Exp Physiol 99(8):1031–1041. doi: 10.1113/expphysiol.2014.079491 PubMedGoogle Scholar
  77. Yang RF, Yin JX, Li YL, Zimmerman MC, Schultz HD (2011) Angiotensin-(1-7) increases neuronal potassium current via a nitric oxide-dependent mechanism. Am J Physiol Cell Physiol 300(1):C58–C64. doi: 10.1152/ajpcell.00369.2010 PubMedPubMedCentralGoogle Scholar
  78. Yokoyama T, Nakamuta N, Kusakabe T, Yamamoto Y (2015) Sympathetic regulation of vascular tone via noradrenaline and serotonin in the rat carotid body as revealed by intracellular calcium imaging. Brain Res 1596:126–135. doi: 10.1016/j.brainres.2014.11.037 PubMedGoogle Scholar
  79. Zoccal DB, Machado BH (2011) Coupling between respiratory and sympathetic activities as a novel mechanism underpinning neurogenic hypertension. Curr Hypertens Rep 13(3):229–236. doi: 10.1007/s11906-011-0198-7 PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Harold D. Schultz
    • 1
    Email author
  • Noah J. Marcus
    • 1
  • Rodrigo Del Rio
    • 1
    • 2
  1. 1.Department of Cellular and Integrative PhysiologyUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Laboratory of Cardiorespiratory ControlUniversidad Autónoma de ChileSantiagoChile

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