Atrial natriuretic peptide and red cell 2,3-diphosphoglycerate in patients with chronic mountain sickness

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Abstract
Methods We determined plasma atrial natriuretic peptide (ANP), red cell 2,3-diphosphoglycerate (2,3-DPG), hematocrit, hemoglobin, and arterialized ear lobe blood gas values in 13 patients with CMS (9 Hans, 4 Tibetans) and 18 control Han Chinese men of similar age, height, and weight who had been living at 4300 m on the Tibetan plateau of Qinghai Province, China, for approximately 14 years. Results A significantly higher level of ANP was found in the CMS patients compared to the non-CMS patients (113.4 ± 5.5 pg/mL vs 87.6 ± 4.7 pg/mL, P < .01), and the levels of ANP correlated positively with the hemoglobin concentration ( r = 0.8282, P < .01). The 2,3-DPG levels in the CMS patients were significantly increased compared to the non-CMS subjects (5.23 ± 0.16 mmol/L vs 4.40 ± 0.12 mmol/L, P < .01), and the 2,3-DPG concentrations in the CMS patients were negatively correlated with their Pa o 2 values ( r = −0.7898, P < .01). The CMS patients had significantly higher Pa co 2 levels, lower pH values, lower Pa o 2 levels, and greater alveolar-arterial oxygen differences (P ao 2 − Pa o 2 ) compared to the non-CMS subjects. Conclusions These findings suggest that overproduction of ANP and 2,3-DPG at high altitudes may play an important role in the pathophysiology of chronic mountain sickness. Key words chronic mountain sickness hypoxia polycythemia gas exchange pulmonary hypertension Introduction Human beings who live at high altitude usually undergo several types of adaptation that allow them to survive in hypoxic environments. However, a small number of people who are lifelong residents at altitudes above 3000 m develop various clinical symptoms and signs of chronic mountain sickness (CMS), including headache, dyspnea, sleepiness, cyanosis of lips and face, and physical and mental fatigue. Chronic mountain sickness was first described in 1928 by Carlos Monge 1 and is a multifactorial and multisystemic syndrome. The most striking features of this syndrome are severe hypoxemia, excessive polycythemia, and pulmonary hypertension. An epidemiological study 2 of CMS in Qinghai Province, China, estimated that the incidence of CMS was 10.1% at 3714 m and reported that the Tibetan natives had a substantially lower incidence of CMS than did the immigrant Hans. Studies in Peru by Leon-Velarde et al 3 showed that the incidence of CMS in females, particularly in their premenopausal years, is far less than that in males, and that the hemoglobin concentration increases with age. It is known that hypoxia is an etiologic key to the development of CMS, but the pathogenesis of CMS is not fully understood. In the present study, we measured the plasma atrial natriuretic peptide (ANP) and red cell 2,3-diphosphoglycerate (2,3-DPG) levels in 13 patients with CMS and 18 subjects without CMS (non-CMS). We discuss the possible role of these 2 substances in the development of CMS at high altitude. Materials and Methods Subjects This study was performed using 13 male patients with CMS (9 Han Chinese and 4 Tibetans) and 18 healthy male control subjects (Han Chinese, non-CMS) at an altitude of 4300 m (barometric pressure 440 mm Hg) in the Madu area of Qinghai Province. The Han subjects were born at or near sea level and had migrated to Madu 14.5 ± 2.3 years earlier (in the non-CMS group) or 14.4 ± 1.8 years earlier (in the CMS group). The 4 Tibetans with CMS were born at an altitude of 2260 m in Qinghai and had lived at 4300 m for the preceding 20 years. The occupations of the subjects were clerical workers, schoolteachers, and road workers. The majority of the subjects in both groups smoked cigarettes, and the average pack-year was 10.5 ± 0.9 in the non-CMS group and 27.2 ± 2.6 in the CMS group. The general characteristics of the subjects are given in Table 1 . All subjects gave informed consent to participate in the study, and the study protocol was approved by the Institutional Committee for Human Research of the High Altitude Medical Science Institute, Qinghai. Diagnosis The diagnosis of CMS was made according to the classification and criteria of CMS reported by the Chinese Society for High Altitude Medicine, 4 which include the following items: hemoglobin level > 20 g/dL, hematocrit > 65%, headache, dizziness, cyanosis of lips and face, tinnitus, physical weakness, mental fatigue, sleep disturbance, anorexia, and breathlessness. The patients had no clear evidence of underlying heart disease or chronic obstructive lung disease based on physical examination, electrocardiograms, pulmonary function tests, and chest radiography. Pulmonary Function Test Spirometry was performed in triplicate using a flow-based spirometer with a microcomputer (CHA-1600, Fukuda, Tokyo, Japan), and the highest values were used for the analysis. Vital capacity, percentage of forced expiratory volume in 1 second (FEV 1% ), mean forced expiratory flow during half of the forced vital capacity (FEF 25%–75% ), and maximal voluntary ventilation values were recorded and analyzed. The instrument was calibrated with a 1-L syringe at room temperature and by the daytime barometric pressure. Blood Gas Analysis Arterialized blood was obtained from the subject's ear after resting for 20 minutes in a chair. The method for the measurement of blood gases has been described previously. 5 Briefly, a hot water bag (at 45°C) was placed on the ear to establish arterialization of regional blood, and the ear-prick blood was withdrawn with a 125-μL heparinized capillary tube. The pH, Pa o 2 , and Pa co 2 levels were then analyzed immediately using a blood gas analyzer (BME-33; Radiometer, Copenhagen, Denmark). The alveolar-arterial oxygen difference (P ao 2 − Pa o 2 ) was calculated using a simplified form of the alveolar air equation (P a = P io 2 − Pa co 2 /R); the respiratory exchange ratio (R) was assumed to be 0.80. Blood Measurements Four milliliters of blood was taken...