Abstract
Polycythemia is one of the key factors involved in the chronic mountain sickness syndrome, a condition frequent in Andean natives but whose causes still remain unclear. In theory, polycythemia may be secondary to abnormalities in ventilation, occurring during day or night (e.g. due to sleep abnormalities) stimulating excessive erythropoietin (Epo) production, or else it may result from either autogenous production, or from co-factors like cobalt. To assess the importance of these points, we studied subjects with or without polycythemia, born and living in Cerro de Pasco (Peru, 4330m asl, CP) and evaluated the relationship between Epo and respiratory variables both in CP and sea level. We also assessed the relationship between sleep abnormalities and the circadian rhythm of Epo. Polycythemic subjects showed higher Epo in all conditions, lower SaO2and hypoxic ventilatory response, higher physiological dead space and higher CO2, suggesting ventilatory inefficiency. Epo levels could be highly modified by the level of oxygenation, and were related to similar directional changes in SaO2. Cobalt levels were normal in all subjects and correlated poorly with hematologic variables. The diurnal variations in Epo were grossly abnormal in polycythemic subjects, with complete loss of the circadian rhythm. These abnormalities correlated with the levels of hypoxemia during the night, but not with sleep abnormalities, which were only minor even in polycythemic subjects. The increased Epo production is mainly related to a greater ventilatory inefficiency, and not to altered sensitivity to hypoxia, cobalt or sleep abnormalities. Improving oxygenation can represent a possible therapeutic option for this syndrome.
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References
Abbrecht PH and Littell JK. Plasma erythropoietin in men and mice during acclimatization to different altitudes. J Appl Physiol 32: 54–58, 1972.
Agostoni PG, Bussotti M, Palermo P and Guazzi M. Does lung diffusion impairment affect exercise capacity in patients with heart failure? Heart 88: 453–459, 2002.
Alippi RM, Barcelo’ AC and Bozzini CE. Erythropoietic response to hypoxia in mice with polycythemia induced by hypoxia or transfusion. Exp Hematol 11: 122–128, 1983.
Bernardi L, Spadacini G, Bellwon J, Hajiric R, Roskamm H and Frey AW. Effect of breathing rate on oxygen saturation and exercise performance in chronic heart failure. Lancet 351: 1308–1311. 1998.
Bernardi L, Gabutti A, Porta C and Spicuzza L. Slow breathing reduces chemoreflex response to hypoxia and hypercapnia and increases baroreflex sensitivity. J. Hypertens. 19:2221–2229, 2000.
Bernardi L, Passino C, Wilmerding V, Dallam GM, Parker DL, Robergs RA and Appenzeller O. Breathing patterns and cardiovascular autonomic modulation during hypoxia induced by simulated altitutde. J Hypertens 19: 947–958, 2001.
Bernardi L, Bonflchi M, Gamboa A, Gamboa J, Passino C, Tapia Ramirez R, Malcovati L, Appenzeller O and Roach RC. Slow breathing restores oxygen saturation in Andean altitude natives. High Alt Med Biol 2: 93, 2001.
Bernardi L, Passino C, Gamboa J, Gamboa A, Tapia Ramirez R, Bonflchi M, Malcovati L, Appenzeller O and Roach R. Central depression affects ventilatory parameters in high altitude Andean natives with or without polycitemia. High Alt Med Biol 2: 94, 2001.
Bernardi L, Passino C, Gamboa J, Gamboa A, Bonflchi M, Vargas M, malcovati L and Roach R. Improved oxygenation relieves baroreflex dysfunction in Andean altitude natives with chronic mountain sickness. Eur Heart J 23(suppl): 489, 2002.
Bernardi L, Casiraghi N, Spicuzza L, Gamboa A, Schneider A, Mori A, Arbustini E, LeonVelarde F and Keyl C. Circadian rhythm of erythropoietin in Andean altitude natives with and without excessive erythrocitosis. 13th High Alt Med BioL 2003, in press.
Bernardi L, Hilz M, Stemper B, Passino C, Welsch G and Axelrod FB. Respiratory and cerebrovascular responses to hypoxia and hypercapnia in familial dysautonomia. Am J Respir Crit Care Med 167: 141–149, 2003.
Bonflchi M, Bernardi L, Malcovati L, Balduini A, Passino C, Gamboa J, Gamboa A, Vargas M, Appenzeller O, Roach RC and Bernasconi C. Effects of acute normoxia and hypoxia on Erythropoietin production in altitude Andean natives with polycythemia. High Alt Med Biol 2:88, 2001.
Bonflchi M, Malcovati L, Bernardi L, Balduini C, Marseglia C, Gamboa J, Roach RC, Appenzeller O and Bernarsconi C. Proliferative activity of hemopoietic erythroid precursors and erythropoietin levels in subjects with physiologic and pathologic response (chronic mountain sickness) to high altitude stay. Haematologica 86: 301, 2001.
Cohen RA, Miller ME, Garcia JF, Moccia G and Cronkite ER. Regulatory mechanism of erythropoietin production: effects of hypoxemia and hypercarbia. Exp Hematol 9: 513–521, 1981.
Cotes MP and Brozovic B. Diurnal variation of serum immunoreactive erythropoietin in a normal subject Clin Endoccrinol 17: 419–422, 1982.
Coote JH, Stone BM and Tsang G. Sleep of Andean high altitudes natives. Eur J Appl Physiol 64: 178–181, 1992.
Coote JH, Tsang G, Baker A and Stone BM. Respiratory changes and structure of sleep in young high-altitude dwellers in the Andes of Peru. Eur J Appl Physiol 66: 249–253, 1993.
Cruz JC, Diaz C, Marticoreana E and Hilario V. Phlebotomy improves pulmonary gas exchange in chronic mountain polycythemia. Respiration 38: 305–313, 1979.
Curran LS, Zhuang J, Sun SF and Moore LG. Ventilation and hypoxic ventilatory responsiveness in Chinese-Tibetan residents of 3658m. J Appl Physiol 83: 2098–2104, 1997.
Daghman NA, McHale CM, Savage GM, Price S, Winter PC, Maxwell PA and Lappin RJT. Regulation of erythropoietin gene expression depends on two different oxygen-sensing mechanisms. Mol Gen Metab 67: 113–117, 1999.
Eckardt KU, Butellier U, Kurtz A, Schopen M, Roller EA and Bauer C. Rate of erythropoietin formation in humans in reponse to acute hypobaric hypoxia. J Appl Physiol 66: 1785–1788, 1989.
Ehmke H, Just A, Eckardt KU, Persson PB, Bauer C and Kirchheim HR. Modulation of erythropoietin formation by changes in blood volume in conscious dog. J Phys (Lond) 488: 181–191, 1995.
Embury SH, Garcia JF, Mohandas N, Pennathur-Das R and Clark M. Effects of oxygen inhalation on endogenous erythropoietin kinetics, erythropoiesis, and properties of blood cells in sickle-cell anemia. N Eng J Med 311: 291–295, 1984.
Ergueta J, Speilvogel H and Cudkowicz L. Cardiorespiratory studies in chronic mountain sickness (Monee’s syndrome). Respiration 28: 485–517, 1971.
Faura J, Ramos J, Reynafarje C, English E, Finne P and Finch C. Effect of altitude on Erythropoiesis. Blood 33 668–676, 1969.
Fitzpatrick MF, Mackay T, Whythe KF, Allen M, Tarn RC, Dore CJ, Henley M, Cotes MP and Douglas NJ. Nocturnal desaturation and serum erythropoietin: a study in patients with chronic obstructive pulmonary disease and in normal subjects. Clin Sci 84: 319–324, 1993.
Hurtado A. Some clinical aspects of life at high altitudes. Ann Intern Med 53: 247–258, 1960.
Keyl C, Schneider A, Gamboa A, Spicuzza L, Casiraghi N, Mori A, Ramirez RT, LeonVelarde F and Bernardi L. Autonomic cardiovascular function in high-altitude Andean natives with chronic mountain sickness. J Appl Physiol 94: 213–219, 2003.
Kryger M, Glas R, Jackson D, McCullough RE, Scoggin C, Grover RF and Weil JV. Impaired oxygenation during sleep in polycythemia of high altitude: improvement with respiratrory stimulation. Sleep 1: 3–17, 1978.
Kryger M and Weil J. Chronic mountain polycythemia: a disorder of the regulation of breathing during sleep? Chest 73:303–304, 1978.
Jefferson JA, Esudero E, Hurtado ME, Pando J, Tapia R, Swenson ER, Prchal J, Schreier GF, Schoene RB, Hurtado A and Johnson RJ. Excessive erythroeitosis, chronic mountain sickness, and serum cobalt levels. Lancet 359: 407–408, 2002.
Jelkmann W. Erythropoietin: structure, control of production and function. Phys Rev72: 449–489, 1992.
Leon-Velarde F, Monge CC, Vidal A, Carcagno, M, Criscuolo M and Bozzini CE. Serum immunoreactive erythropoietin in high altitude natives with and without excessive erythrocytosis. Exp Hematol 19: 257–260, 1991.
Leon-Velarde F, Arregui A, Vargas M, Huicho L and Acosta R. Chronic mountain sickness and chronic lower respiratory disorders. Chest 106: 151–155, 1994.
Malcovati L, Bonfichi M, Bernardi L, Balduini A, Marseglia C, Gamboa J, Passino C, Vargas M, Roach RC and Bernasconi C. Serum Cobalt is not involved in the pathologic arythrocitosis related to high altitude (CMS). Blood 2001 (suppl), Abstract 3630
Manier G, Guenard H, Castaing Y, Varene N and Vargas E. Pulmonary gas exchange in Andean natives with excessive polycythemia-effect of hemodilution. J Appl Physiol 65: 2107–2117, 1988.
Milledge JS and Cotes PM. Serum erythropoietin in humans at high altitude and its relation to plasma renin. J Appl Physiol 59: 360–364, 1985.
Miller ME, Garcia JE, Cohen RA, Cronkite EP, Moccia G and Acevedo J. Diurnal levels of immunoreactive Erythropoietin in normal subjects and subjects with chronic lung disease. Br J Haematol 49: 189–200, 1981.
Monge CC, Leon-Velarde F and Arregui A. Chronic mountain sickness in Andeans. In: Hornbein T and Schoene RB High Altitude, New York: Decker, 2001, p. 815–838.
Moore LG. Comparative human ventilatory adaptation to high altitude. Resp Physiol 121: 257–276, 2000.
Normand H, Vargas E, Bordachar J, Benoit O and Raynaud J. Sleep apneas in high altitude residents (3800m). Int J Sports Med 13: 40–42, 1992.
Ponikowski P, Chua TP, Piepoli M, Ondusova D, Webb-Peploe K, Harrington D, Anker SD, Volterrani M, Colombo R, Mazzuero G, Giordano A and Coats AJS. Augmented peripheral chemosensitivity as a potential input to baroreflex impairmnt and autonomic imbalance in chronic heart failure. Circulation 96: 2586–2594, 1997.
Reeves JT and Weil JV. Chronic mountain sickness. A view from the crow’s nest. Adv Exp Med Biol 502:419–437, 2001.
Roach R, Passino C, Bernardi L, Gamboa J, Gamboa A and Appenzeller O. Cerebrovascular reactivity to C02 at high altitude and sea level in Andean natives. Clin Aut Res 11: 183, 2001.
Sanchez C, Merino C and Figallo M. Simultaneous measurement of plasma volume and cell mass in polycythemia of higeh altitude. J Appl Physiol 28: 775–778, 1970.
Santolaya RB, Lahiri S, Alfaro RT and Schoene RB. Respiratory adaptation in the highest inhabitants and highest Sherpa mountainneers. Res Physiol 77: 253–262, 1989.
Schmidt W, Spielvogel H, Eckardt KU, Quintela A and Penaloza R. Effects of chronic hypoxia and exercise on plasma erythropoietin in high altitude residents. J Appl Physiol 74: 1874–1878, 1993.
Severinghaus JW, Bainton CR and Carcelen A. Respiratory insensitivity to hypoxia in chronically hypoxic man. Resp Physiol 1: 308–334, 1966.
Soerensen SC and Severinghaus JW. Irreversible respiratory insensitivity to acute hypoxia in man born at high altitude. J Appl Physiol 25: 217–220, 1968.
Somers VK, Mark AL and Abboud FM. Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans. J Clin Invest 87: 19531975, 1991.
Spicuzza L, Gabutti A, Porta C, Montano N and Bernardi L. Yoga practice decreases chemoreflex response to hypoxia and hypercapnia. Lancet 356: 1495–1496, 2000.
Spicuzza L, Casiraghi N, Gamboa A, Keyls C, Schneider A, Mori A, Leon-Velarde F, DiMaria GU and Bernardi L. Sleep-disordered breathing and erythropoietin levels in Andean high-altitude natives with excessive erythrocitosis. High Alt Med Biol, 2003, in press.
Spivak JL. Erythropoietin use and abuse. In: Roach R. C. , Wagner P. D. and Hackett PH. Hypoxia From genes to the bedside. Adv Exp Med Biol vol 502, New York: Kluwer Academic/Plenum, 2001, p. 207–224.
Sun SF, Huang SY, Zhang JG, Droma TS, Banden G, McCullogh RE, McCullogh RG, Cymerman A, Reeves JT and Moore LG. Decreased ventilation and hypoxic ventilatory reponsiveness are not reversed by naloxone in Lhasa residents with chronic mountain sickness. Am Rev Resp Dis 142: 1294–1300, 1990.
Sun S, Oliver-Pickett C, Ping Y, Micco AJ, Droma T, Zamudio S, Zhuang J, Huang SY, McCullough RG, Cymerman A and Moore LG. Breathing and brain blood flow during sleep in patients with chronic mountain sickness. J Appl Physiol 81: 611–618, 1996.
Walle AJ, Wong GY, Clemons GK, Garcia JF and Niedermayer W. Erythropoietinhematocrit feedback circuit in the anemia of end-stage renal disease. Kidney Int 31: 1205–1209, 1987.
Weil JV and Zwillich CW. Assessment of ventilatory response to hypoxia. Methods and interpretation. Chest 70: 124–128, 1976.
Wide L, Bengtsson G and Birgegaard G. Circadian rhythm of erythropoietin in human serum. Br J Haematol 72: 85–90, 1989.
Winslow RM, Chapman KW, Gibson CC, Samaja M, Monge CC, Goldwasser E, Sherpa M, Blume DF and Santolaya R. Different hematologic responses to hypoxia in Sherpas and Quechua Indians J Appl Physiol 66: 1561–1569, 1989.
Zhuang J, Droma T, Sun S, Janes C, McCullogh RE, McCullogh RG, Cymerman A, Huang SY, Reeves JT and Moore LG. Hypoxic ventilatory responsiveness in Tibetan compared with Han residents of 3658m. J Appl Physiol 74: 303–311, 1993.
Zhuang J, Droma T, Sutton JR, Groves B, McCullogh RE, McCullogh RG, Sun S and Moore LG. Resp Physiol 103: 75–82, 1996.
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Bernardi, L. et al. (2003). Ventilation, Autonomic Function, Sleep and Erythropoietin. In: Roach, R.C., Wagner, P.D., Hackett, P.H. (eds) Hypoxia. Advances in Experimental Medicine and Biology, vol 543. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8997-0_12
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DOI: https://doi.org/10.1007/978-1-4419-8997-0_12
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