Villafuerte, Francisco C., and Noemí Corante. Chronic mountain sickness: clinical aspects, etiology, management, and treatment. High Alt Med Biol. 17:61–69, 2016.—Millions of people worldwide live at a high altitude, and a significant number are at risk of developing Chronic Mountain Sickness (CMS), a progressive incapacitating syndrome caused by lifelong exposure to hypoxia. CMS is characterized by severe symptomatic excessive erythrocytosis (EE; Hb ≥19 g/dL for women and Hb ≥21 g/dL for men) and accentuated hypoxemia, which are frequently associated with pulmonary hypertension. In advanced cases, the condition may evolve to cor pulmonale and congestive heart failure. Current knowledge indicates a genetic predisposition to develop CMS. However, there are important risk factors and comorbidities that may trigger and aggravate the condition. Thus, appropriate medical information on CMS is necessary to provide adequate diagnosis and healthcare to high-altitude inhabitants. After reviewing basic clinical aspects of CMS, including its definition, diagnosis, and common clinical findings, we discuss aspects of its etiology, and address its epidemiology, risk factors, and treatment.

Corante, Noemí, Cecilia Anza-Ramírez, Rómulo Figueroa-Mujíca, José Luis Macarlupú, Gustavo Vizcardo-Galindo, Grzegorz Bilo, Gianfranco Parati, Jorge L. Gamboa, Fabiola León-Velarde, and Francisco C. Villafuerte. Excessive erythrocytosis and cardiovascular risk in Andean highlanders. High Alt Med Biol. 19:221–231, 2018.—Cardiovascular diseases are the main cause of death worldwide. Life under high-altitude (HA) hypoxic conditions is believed to provide highlanders with a natural protection against cardiovascular and metabolic diseases compared with sea-level inhabitants. However, some HA dwellers become intolerant to chronic hypoxia and develop a progressive incapacitating syndrome known as chronic mountain sickness (CMS), characterized by excessive erythrocytosis (EE; Hb ≥21 g/dL in men, Hb ≥19 g/dL in women). Evidence from HA studies suggests that, in addition to CMS typical signs and symptoms, these highlanders may also suffer from metabolic and cardiovascular disorders. Thus, we hypothesize that this syndrome is also associated to the loss of the cardiometabolic protection observed in healthy highlanders (HH), and therefore to a higher cardiovascular risk (CVR). The aim of the present work was to evaluate the association between EE and CVR calculated using the Framingham General CVR Score and between EE and CVR factors in male highlanders. This cross-sectional study included 342 males from Cerro de Pasco, Peru at 4340 m (HH = 209, CMS = 133). Associations were assessed by multiple logistic regressions adjusted for potential confounders (BMI, pulse oxygen saturation and age). The adjusted models show that the odds of high CVR (>20%) in highlanders with EE was 3.63 times the odds in HH (CI 95%:1.22–10.78; p = 0.020), and that EE is associated to hypertension, elevated fasting serum glucose, insulin resistance, and elevated fasting serum triglycerides. Our results suggest that individuals who suffer from EE are at increased risk of developing cardiovascular events compared with their healthy counterparts.

Excessive erythrocytosis (EE) is the hallmark of chronic mountain sickness (CMS), a prevalent syndrome in high-altitude Andean populations. Although hypoxemia represents its underlying stimulus, why some individuals develop EE despite having altitude-normal blood erythropoietin (Epo) concentration is still unclear. A soluble form of the Epo receptor (sEpoR) has been identified in human blood and competes directly for Epo with its membrane counterpart (mEpoR). Thus, reduced levels of circulating sEpoR could lead to higher Epo availability and ultimately to EE. We characterized the relationship between Epo and sEpoR, with hematocrit and hemoglobin concentration in healthy highlanders and CMS patients at 4,340 m in Cerro de Pasco, Peru. Our results show that EE patients show decreased plasma sEpoR levels and can be subdivided into two subgroups of normal and high plasma Epo concentration for the altitude of residence, with hemoglobin concentration rising exponentially with an increasing Epo-to-sEpoR ratio (Epo/sEpoR). Also, we showed that the latter varies as an inverse exponential function of arterial pulse O2 saturation. Our findings suggests that EE is strongly associated with higher Epo/sEpoR values, leading to elevated plasma Epo availability to bind mEpoR, and thereby a stronger stimulus for augmented erythropoiesis. Differences in the altitude normal and high Epo CMS patients with a progressively higher Epo/sEpoR supports the hypothesis of the existence of two genetically different subgroups suffering from EE and possibly different degrees of adaptation to chronic high-altitude hypoxia.

Andean highlanders are challenged by chronic hypoxia and many exhibit elevated hematocrit (Hct) and blunted ventilation compared to other high-altitude populations. While many Andeans develop Chronic Mountain Sickness (CMS) and excessive erythrocytosis, Hct varies markedly within Andean men and women and may be driven by individual differences in ventilatory control and/or sleep events which exacerbate hypoxemia. To test this hypothesis, we quantified relationships between resting ventilation and ventilatory chemoreflexes, sleep desaturation, breathing disturbance, and Hct in Andean men and women. Ventilatory measures were made in 109 individuals (n = 63 men; n = 46 women), and sleep measures in 45 of these participants (n = 22 men; n = 23 women). In both men and women, high Hct was associated with low daytime SpO 2 (p < 0.001 and p < 0.002, respectively) and decreased sleep SpO 2 (mean, nadir, and time <80%; all p < 0.02). In men, high Hct was also associated with increased end-tidal P CO2 (p < 0.009). While ventilatory responses to hypoxia and hypercapnia did not predict Hct, decreased hypoxic ventilatory responses were associated with lower daytime SpO 2 in men (p < 0.01) and women (p < 0.009) and with lower nadir sleep SpO 2 in women (p < 0.02). Decreased ventilatory responses to CO 2 were associated with more time below 80% SpO 2 during sleep in men (p < 0.05). The obstructive apnea index and apnea-hypopnea index also predicted Hct and CMS scores in men after accounting for age, BMI, and SpO 2 during sleep. Finally, heart rate response to hypoxia was lower in men with higher Hct (p < 0.0001). These data support the idea that hypoventilation and decreased ventilatory sensitivity to hypoxia are associated with decreased day time and nighttime SpO 2 levels that may exacerbate the stimulus for erythropoiesis in Andean men and women. However, interventional and longitudinal studies are required to establish the causal relationships between these associations.

Rationale Excessive erythrocytosis (EE; Hb≥21g/dL in men and ≥19g/dL in women) is the main sign of Chronic Mountain Sickness (CMS), a maladaptive clinical syndrome prevalent in Andean and other high‐altitude populations. Although the pathophysiological mechanism for EE is still controversial, chronic hypoxemia is accepted as its underlying stimulus. Although EE is common to all CMS subjects, most studies have shown similar mean values for serum erythropoietin compared to healthy highlanders (HH). We have previously shown that plasma concentration of the soluble Epo receptor (sEpoR), an endogenous Epo antagonist, is decreased in highlanders with CMS, which would lead to higher Epo circulating availability and contribute to EE. However, it is also possible that erythroid progenitor cells of CMS subjects are more sensitive to Epo, and have a stronger proliferative response than HH cells exposed to similar circulating Epo concentration. Thus, the aim of the present study was to determine the hypoxic proliferative response of erythroid progenitor cells (BFU‐E) of CMS and HH to equal rhEpo concentration. Methods SamplesThirty‐six highlanders (CMS, n=17; HH, n=19) from Cerro de Pasco, Peru, at 4340m, were recruited for the study. A small blood sample was obtained for hematocrit determination and CMS score was assessed. A 10ml blood sample was taken in heparin‐coated BD Vacutainer tubes for peripheral blood mononuclear cells (PBMCs) isolation. Two additional 6ml blood samples were also obtained in clot‐activator‐coated tubes for Epo and iron profile determination. Serum was separated by centrifugation and stored in liquid N2 until analysis. CulturePBMCs were isolated using Histopaque 1077 (Sigma) and were cultured in Methocult H‐4534 medium (Stemcell Technologies) at a final density of 2.5×105cells/ml in the presence of 3U/ml of rhEpo (Stemcell Technologies) for 14 days. Cultures were maintained at 37°C in a Biospherix X3 hood set for cellular hypoxia (1%O2, 5% CO2). BFU‐E identification and countColony identification and count were performed at days 7 and 10 using an inverted microscope (LS 560, Lumascope) inside the hypoxic hood at a magnification of 20X. On day 14 cultures were removed from the hood and analyzed using an AxioZoom Stereomicroscope (Carl Zeiss Microscopy) at a magnification of 10X. Data analysisStudent's t‐test for equal and unequal variances was applied as parametric test of comparison and Wilcoxon as nonparametric to evaluate differences between CMS and HH. Results As expected, Hct and CMS score were significantly higher in the CMS group (Table 1). Mean serum Epo concentration was higher in CMS subjects (12.79±2.8 vs 26.8±8.1pg/ml, p<0.05) due to two participants showing very high Epo values (high‐Epo CMS highlanders, as previously described). Percentage of change in BFU‐E number from day 7 to day 14 was larger in the CMS group (87.84±27.2 vs 258.6±69.12%, Figure 1B), and CMS BFU‐E colonies occupied a larger total area compared to HH (4.31±0.5 vs 6.4±0.5mm2, Figure 1A). Conclusion Our findings show th...