Development Of Chronic Mountain Sickness Research Articles

Reversal of Pulmonary Hypertension in a Patient with Chronic Mountain Sickness after Relocation to Low Altitude

Long-term high altitude residence can be complicated by development of Chronic Mountain Sickness (CMS) characterised by excessive erythrocytosis and neurological symptoms. In some patients, CMS may be associated with various degrees of Pulmonary Hypertension (PH). There have been no reports on changes in the pulmonary circulation and Right Ventricular (RV) structure following translocation to low altitude of patients with CMS. Here the authors report a case of 56 years old female patient, resident of Sary Mogol (3,000 m, Kyrgyzstan), diagnosed of CMS on clinical and laboratory examination. Transthoracic echocardiography revealed slightly dilated Right ventricle and significantly enlarged Pulmonary Artery diameter was found. The patient undergone complete resolution of symptoms and alleviation of PH within three years of residence at low altitude. Thus, relocation to low altitude cures CMS and reverses PH.

Association between serum concentrations of hypoxia inducible factor responsive proteins and excessive erythrocytosis in high altitude Peru.

Painschab, Matthew S., Gary E. Malpartida, Victor G. Davila-Roman, Robert H. Gilman, Todd M. Kolb, Fabiola Leon-Velarde, J. Jaime Miranda, and William Checkley. Association between serum concentrations of hypoxia inducible factor responsive proteins and excessive erythrocytosis in high altitude Peru. High Alt Med Biol 16:26-33, 2015.-Long-term residence at high altitude is associated with the development of chronic mountain sickness (CMS), which is characterized by excessive erythrocytosis (EE). EE occurs under chronic hypoxia, and a strongly selected mutation in hypoxia-inducible factor 2α (HIF2A) has been found in native Tibetans that correlates with having a normal hemoglobin at high altitude. We sought to evaluate differences in plasma levels of four HIF-responsive proteins in 20 participants with EE (hemoglobin >21 g/dL in men and >19 in women) and in 20 healthy, age- and sex-matched participants without EE living at high altitude in Puno, Peru. We performed ELISA to measure plasma levels of the four HIF-responsive proteins: vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGF-R1), endothelin-1, and erythropoietin. As a secondary aim, we evaluated the association between HIF-responsive proteins and echocardiography-estimated pulmonary artery systolic pressure (PASP) in a subset of 26 participants. sVEGF-R1 was higher in participants with vs. without EE (mean 107 pg/mL vs. 90 pg/mL; p=0.007). Although plasma concentrations of endothelin-1, VEGF, and erythropoietin were higher in participants with vs. without EE, they did not achieve statistical significance (all p>0.25). Both sVEGF-R1 (p=0.04) and erythropoietin (p=0.04) were positively associated with PASP after adjustment for age, sex, and BMI. HIF-responsive proteins may play a pathophysiological role in altitude-related, chronic diseases but our results did not show consistent changes in all measured HIF-responsive proteins. Larger studies are needed to evaluate for additional genetic and environmental risk factors.

Sleep disturbances in long-term immigrants with chronic mountain sickness: A comparison with healthy immigrants at high altitude

The aim of this study was to examine sleep disturbances in patients with chronic mountain sickness (CMS). The sleep of 14 patients with CMS and 11 healthy controls with or without sleep disorders (control N: without sleep disorders; control D: with sleep disorders) was studied by polysomnography. Hypopnea was the sleep disorder most commonly suffered by CMS patients and control D subjects. No major differences were observed in sleep structure between CMS and control groups, with the exception of shorter rapid eye movement latency in controls and increased deep non-rapid eye movement in the control N group. Periodic breathing was observed in only two study participants, one each in the CMS and control D groups. The level of saturated oxygen was significantly lower in the CMS group during sleep than the control groups (P<0.05). CMS scores were positively correlated with the apnea–hypopnea index, and negatively correlated with saturated oxygen levels. These results demonstrate that sleep disorders and nocturnal hypoxia are important in the development of CMS.

Does chronic mountain sickness (CMS) have perinatal origins?

Chronic mountain sickness (CMS) occurs in approximately 10% of male high-altitude residents. It is characterized by hypoventilation and hypoxemia but its underlying cause remains unknown. We hypothesized that CMS' origins reside in exaggerated perinatal hypoxia that serves, in turn, to impair the development of pulmonary structure and/or respiratory control. As a preliminary test, we asked if birth weights were low and other signs of perinatal hypoxia were present in 12 young men with excessive erythrocytosis (EE, Hb>or=18.3g/dL), a condition thought to be a preclinical phase of CMS. Their birth weights were uniformly low (2571+/-243g) and all but one demonstrated perinatal hypoxia as manifested either by being small for their gestational age (SGA, 8%), preterm (67%), born to a preeclamptic (PE) mother (50%), or diagnosed with neonatal hypoxia (83%). Impaired growth in utero has been shown to raise susceptibility to adult disease; these are the first data to demonstrate a possible influence of reduced fetal growth and/or exaggerated perinatal hypoxia on increasing the susceptibility to CMS. Future studies, with more detailed testing in larger samples of control as well as EE subjects, with longitudinal follow-up, are required to determine the role of perinatal hypoxia in the development of CMS.

The Qinghai-Tibetan plateau: how high do Tibetans live?

A lower incidence of chronic mountain sickness (CMS) has apparently been observed in Tibetans in comparison to Andeans of South America. In the past, the hypothesis of "geographic differences" has been constructed to explain these population differences. In order to assess the importance of this hypothesis in the development of CMS, this article will first review the geographic factors of the Qinghai-Tibetan plateau where Tibetans live. The plateau is bounded by the Himalayas in the southwest and the Kunlun and Aljin mountains in the northeast. It towers over southwestern China at an average elevation of 4000 m above sea level and is known as "the roof of the world." Covering more than 2.5 million km(2), the Qinghai-Tibetan plateau is the highest and largest plateau in the world. The plateau has a highland continental climate and a very complex topography with great variations. Second, at what altitude do Tibetans live? In 1990 it was estimated that 4,594,188 Tibetans live on the plateau, with 53% living at an altitude over 3500 m. Fairly large numbers (about 600,000) live at an altitude exceeding 4500 m in the Chantong-Qingnan area. People of Tibetan ethnic descent are lifelong high-altitude residents and cannot easily move to higher or lower elevations. Over 90% of the population are engaged in farming and herding. The upper altitude limit of crops is around 4500 m, while the nomads reside above 4800 m and 5500 m. Recently, mining activities in the plateau have sustained a part of the population that lives permanently at altitudes between 3700 and 6000 m. Therefore, the Tibetans living in the Qinghai-Tibetan plateau live at an altitude as high as the Andeans in South America. Thus the apparently low incidence of CMS in Tibetans cannot be ascribed to "geographic differences." We propose that the genetic adaptation to hypoxia that has occurred in Tibetans is of importance in CMS.

Role of the spleen in the exaggerated polycythemic response to hypoxia in chronic mountain sickness in rats.

In a rat model of chronic mountain sickness, the excessive polycythemic response to hypoxic exposure is associated with profound splenic erythropoiesis. We studied the uptake and distribution of radioactive iron and red blood cell (RBC) morphology in intact and splenectomized rats over a 30-day hypoxic exposure. Retention of (59)Fe in the plasma was correlated with (59)Fe uptake by both spleen and marrow and the appearance of (59)Fe-labeled RBCs in the blood. (59)Fe uptake in both the spleen and the marrow paralleled the production of nucleated RBCs. Splenic (59)Fe uptake was approximately 10% of the total marrow uptake under normoxic conditions but increased to 60% of the total marrow uptake during hypoxic exposure. Peak splenic (59)Fe uptake and splenomegaly occurred at the most intense phase of erythropoiesis and coincided with the rapid appearance of (59)Fe-labeled RBCs in the blood. The bone marrow remains the most important erythropoietic organ under both resting and stimulated states, but inordinate splenic erythropoiesis in this rat strain accounts in large measure for the excessive polycythemia during the development of chronic mountain sickness in chronic hypoxia.

The role of menopause in the development of chronic mountain sickness.

The objective of this study was to investigate the role of menopause in the appearance of the physiopathological sequence that leads to chronic mountain sickness (CMS) in a high-altitude female population. The females studied are 30-54 yr old (n = 152) and have permanent residence in Cerro de Pasco (Pasco, Peru; 4,300 m). The sample was divided into postmenopausal and premenopausal groups for comparison. Blood oxygen saturation (SaO2), excessive erythrocytosis [EE, measured by the level of hematocrit (Het)], peak expiratory flow rates (PEFR), and a score that represents the main signs and symptoms of CMS (CMSscore) were measured. Postmenopausal women had higher Het (50.2 +/- 4.04 vs. 47.4 +/- 4.13%, P < 0.001), lower SaO2 (81.9 +/- 4.12 vs. 84.7 +/- 3.14%, P < 0.001) and PEFR values (489 +/- 101 vs. 534 +/- 90 l/min, P < 0.02), and slightly higher CMSscore (19.1 +/- 3.37 vs. 17.9 +/- 3.48, P < 0.06) than premenopausal women. The prevalence of women with EE (EE = Hct > 56%) was found to be 8.8%. Forty-five percent of the postmenopausal subjects presented a high CMSscore (> 21), whereas only 22% of the premenopausal subjects presented this high value (P < 0.02). We can therefore conclude that menopause may represent a contributing factor for the development of CMS.

Role of sex hormones in development of chronic mountain sickness in rats.

After chronic exposure to hypoxia, Hilltop Sprague-Dawley rats developed excessive polycythemia and severe pulmonary hypertension and right ventricular (RV) hypertrophy, signs consistent with human chronic mountain sickness; however, there were gender differences in the magnitude of the polycythemia and susceptibility to the fatal consequence of chronic mountain sickness. Orchiectomy and ovariectomy were performed to evaluate the role of sex hormones in the gender differences in these hypoxic responses. After 40 days of exposure to simulated high altitude (5,500 m; barometric pressure of 370 Torr and inspired Po2 of 73 Torr), both sham-gonadectomized male and female rats developed polycythemia and had increased RV peak systolic pressure and RV hypertrophy. The hematocrit was slightly but significantly higher in males than in females. Orchiectomy did not affect these hypoxic responses, although total ventricular weight was less in the castrated high-altitude rats. At high altitude, the mortality rates were 67% in the sham-operated male rats and 50% in the castrated animals. In contrast, ovariectomy aggravated the high-altitude-associated polycythemia and increased RV peak systolic pressure and RV weight compared with the sham-operated high-altitude female rats. Both sham-operated control and ovariectomized females suffered negligible mortality at high altitude. The present study demonstrated that 1) the male sex hormones play no role in the development of the excessive polycythemia, pulmonary hypertension, and RV hypertrophy during chronic hypoxic exposure or in the associated high mortality and 2) the female sex hormones suppressed both the polycythemic and cardiopulmonary responses in vivo during chronic hypoxic exposure.

Chronic Mountain Sickness and Chronic Lower Respiratory Tract Disorders

To determine whether chronic lower respiratory tract disorders contributed to the development of chronic mountain sickness (CMS), we compared hemoglobin (Hb), oxygen saturation (SaO2), peak expiratory flow rate (PEFR), and CMS scores (CMSsco) in 97 normal men at high altitude with those of men at high altitude with acute (ARD; n = 12), chronic upper (CURD; n = 33), and chronic lower (CLRD; n = 34) respiratory diseases. The clinical diagnosis of the different types of respiratory disorders was based on the results of a questionnaire and physical examination performed during an epidemiologic study. The CLRD group had higher CMSsco and Hb concentrations, and lower SaO2 and PEFR values when compared with the other groups. The frequency of low PEFR and SaO2 and high Hb and CMSsco was substantially higher in men with CLRD when compared with normal subjects. The results support the hypothesis that there is an association between signs and symptoms of CMS, as measured by the CMSsco, and CLRD. The chronic hypoxemia, product of chronic lung diseases, would cause excessive erythrocytosis and increase the signs and symptoms of CMS. Studies of Hb, PEFR, pulse oximetry, and CMSsco are recommended for early detection of high-altitude natives at risk of developing CMS.

The role of pulmonary vascular responses to chronic hypoxia in the development of chronic mountain sickness in rats

A strain of Sprague-Dawley rat obtained from Hilltop Labs, Scottsdale, PA (H rats), develops more severe pulmonary hypertension, right ventricular hypertrophy, and polycythemia than a strain obtained from Madison, WI (M rats), following exposure to simulated high altitude. We sought to determine whether differences in pulmonary vascular responses to chronic hypoxia could explain the differing high altitude susceptibilities of the two strains. Vasoconstrictor responses to hypoxia and angiotensin II were tested in blood perfused lungs isolated from rats of both groups exposed to simulated high altitude (4 to 5 weeks, 0.5 atm), or from sea level controls. Pressure-flow curves, serving as an index of ‘passive’ vascular resistance, were also determined in the isolated lungs. Vasoconstrictor responses to hypoxia were blunted in high altitude rats of both the H and M strains compared to sea level controls, and the H sea level rats had blunted vasoconstrictor responses to hypoxia compared to the M sea level rats. Vasoconstrictor responses to angiotensin II were similar among the groups and were unaffected by chronic high altitude exposure. Pressure-flow curves were greater in both high altitude groups than in the sea level groups, and those of the H high altitude rats were slightly greater than those of the M high altitude rats. Thus, differences in vasoconstrictor responses to hypoxia do not explain the greater pulmonary hypertension of H high altitude rats. However, greater ‘passive’ vascular resistance, probably due to more extensive structural remodeling of pulmonary vessels, does appear to contribute to the greater pulmonary hypertension of the H rats.