RESUMO
Physical exercise may improve hematological conditions in high altitude dwellers suffering from Chronic Mountain Sickness (CMS), in reducing hemoglobin concentration. Therefore, the present study aimed to characterize the effects of 1-month exercise training session in a model of rats exposed to chronic hypoxia. Four groups of male rats were studied: normoxic sedentary (NS, n = 8), normoxic training (NT, n = 8), hypoxic sedentary (HS, n = 8), and hypoxic training group (HT, n = 8). Hypoxic groups were exposed to hypobaric hypoxia for one month (PB =433 Torr). Training intensity was progressively increased from a running speed of 10.4 to 17.8 m/min. Chronic hypoxia led to an increase in hematocrit (HCT) associated with a decrease in plasma volume despite an increase in water intake. Training led to a reduction in HCT (p < 0.01), with a non-significant increase in plasma volume and weight gain. Hypoxia and training had inhibitory effects on haptoglobin (NS group: 379 ± 92; HT: 239 ± 34 µg/ml, p < 0.01). Chronic hypoxia and exercise training increased SpO2 measured after acute hypoxic exposure. Training blunted the decrease in VË O2 peak, time of exhaustion, and maximum speed associated with chronic exposure to hypoxia. Chronic hypoxia led to a right ventricular hypertrophy, which was not corrected by 1-month exercise training. Altogether, by decreasing hematocrit, reducing body weight, and limiting performance decrease, training in hypoxia may have a beneficial effect on excessive erythropoiesis in chronic hypoxia. Therefore, regular exercise training might be beneficial to avoid worsening of CMS symptoms in high altitude dwellers and to improve their quality of life.
Assuntos
Doença da Altitude/fisiopatologia , Hipóxia/fisiopatologia , Condicionamento Físico Animal/métodos , Doença da Altitude/sangue , Doença da Altitude/terapia , Animais , Peso Corporal , Hematócrito , Hipóxia/sangue , Hipóxia/terapia , Masculino , Consumo de Oxigênio , Volume Plasmático , Ratos , Ratos Sprague-Dawley , Remodelação VentricularRESUMO
Millions of people worldwide live at high altitude, being chronically exposed to hypobaric hypoxia. Hypertension is a major cardiovascular risk factor but data on its prevalence and determinants in highlanders are limited, and systematic studies with ambulatory blood pressure monitoring are not available. Aim of this study was to assess the prevalence of clinic and ambulatory hypertension and the associated factors in a sample of Andean highlanders. Hypertension prevalence and phenotypes were assessed with office and ambulatory blood pressure measurement in a sample of adults living in Cerro de Pasco, Peru (altitude 4340 m). Basic clinical data, blood oxygen saturation, hematocrit, and Qinghai Chronic Mountain Sickness score were obtained. Participants were classified according to the presence of excessive erythrocytosis and chronic mountain sickness diagnosis. Data of 289 participants (143 women, 146 men, mean age 38.3 years) were analyzed. Office hypertension was present in 20 (7%) participants, while ambulatory hypertension was found in 58 (20%) participants. Masked hypertension was common (15%), and white coat hypertension was rare (2%). Among participants with ambulatory hypertension, the most prevalent phenotypes included isolated nocturnal hypertension, isolated diastolic hypertension, and systodiastolic hypertension. Ambulatory hypertension was associated with male gender, age, overweight/obesity, 24-hour heart rate, and excessive erythrocytosis. Prevalence of hypertension among Andean highlanders may be significantly underestimated when based on conventional blood pressure measurements, due to the high prevalence of masked hypertension. In highlanders, ambulatory hypertension may be independently associated with excessive erythrocytosis.
Assuntos
Doença da Altitude/fisiopatologia , Altitude , Monitorização Ambulatorial da Pressão Arterial/métodos , Hipertensão/fisiopatologia , Visita a Consultório Médico , Adulto , Doença da Altitude/diagnóstico , Estudos Transversais , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipóxia/diagnóstico , Hipóxia/fisiopatologia , Masculino , Hipertensão Mascarada/diagnóstico , Hipertensão Mascarada/fisiopatologia , Pessoa de Meia-Idade , Peru/epidemiologia , PrevalênciaRESUMO
Chronic mountain sickness (CMS) is a pathological condition resulting from chronic exposure to high-altitude hypoxia. While its prevalence is high in native Andeans (>10%), little is known about the genetic architecture of this disease. Here, we performed the largest genome-wide association study (GWAS) of CMS (166 CMS patients and 146 controls living at 4,380 m in Peru) to detect genetic variants associated with CMS. We highlighted four new candidate loci, including the first CMS-associated variant reaching GWAS statistical significance (rs7304081; P = 4.58 × 10-9). By looking at differentially expressed genes between CMS patients and controls around these four loci, we suggested AEBP2, CAST, and MCTP2 as candidate CMS causal genes. None of the candidate loci were under strong natural selection, consistent with the observation that CMS affects fitness mainly after the reproductive years. Overall, our results reveal new insights on the genetic architecture of CMS and do not provide evidence that CMS-associated variants are linked to a strong ongoing adaptation to high altitude.
RESUMO
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.
Assuntos
Altitude , Pressão Sanguínea , Doenças Cardiovasculares/epidemiologia , Policitemia/epidemiologia , Adolescente , Adulto , Idoso , Glicemia/metabolismo , Doenças Cardiovasculares/fisiopatologia , Estudos Transversais , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Peru/epidemiologia , Policitemia/fisiopatologia , Fatores de Risco , Triglicerídeos/sangue , Adulto JovemAssuntos
Altitude , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/fisiologia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Teste de Caminhada/métodos , Adulto , Benzimidazóis/administração & dosagem , Benzoatos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hipertensão/diagnóstico , Masculino , Pessoa de Meia-Idade , Nifedipino/administração & dosagem , Telmisartan , Resultado do TratamentoRESUMO
Excessive erythrocytosis (EE) is the main sign of Chronic Mountain Sickness (CMS), a highly prevalent syndrome in Andean highlanders. Low pulse O2 saturation (SpO2) during sleep and serum androgens have been suggested to contribute to EE in CMS patients. However, whether these factors have a significant impact on the erythropoietin (Epo) system leading to EE is still unclear. We have recently shown that morning soluble Epo receptor (sEpoR), an endogenous Epo antagonist, is decreased in CMS patients suggesting increased Epo availability (increased Epo/sEpoR). The present study aimed to characterize the nocturnal concentration profile of sEpoR and Epo and their relationship with SpO2, Hct, and serum testosterone in healthy highlanders (HH) and CMS patients. Epo and sEpoR concentrations were evaluated every 4 h (6 PM to 6 AM) and nighttime SpO2 was continuously monitored (10 PM to 6 AM) in 39 male participants (CMS, n = 23; HH, n = 16) aged 21-65 yr from Cerro de Pasco, Peru (4,340 m). CMS patients showed higher serum Epo concentrations throughout the night and lower sEpoR from 10 PM to 6 AM. Consequently, Epo/sEpoR was significantly higher in the CMS group at every time point. Mean sleep-time SpO2 was lower in CMS patients compared with HH, while the percentage of sleep time spent with SpO2 < 80% was higher. Multiple-regression analysis showed mean sleep-time SpO2 and Epo/sEpoR as significant predictors of hematocrit corrected for potential confounders (age, body mass index, and testosterone). Testosterone levels were associated neither with Hct nor with erythropoietic factors. In conclusion, our results show sustained erythropoietic stimulus driven by the Epo system in CMS patients, further enhanced by a continuous exposure to accentuated nocturnal hypoxemia.
Assuntos
Doença da Altitude/sangue , Doença da Altitude/metabolismo , Receptores da Eritropoetina/sangue , Receptores da Eritropoetina/metabolismo , Sono/fisiologia , Adulto , Idoso , Altitude , Doença da Altitude/fisiopatologia , Androgênios/sangue , Doença Crônica , Hematócrito/métodos , Humanos , Hipóxia/sangue , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Oxigênio/metabolismo , Peru , Policitemia/metabolismo , Policitemia/fisiopatologia , Testosterona/sangue , Adulto JovemRESUMO
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.
Assuntos
Doença da Altitude/sangue , Eritropoetina/sangue , Hemoglobinas/metabolismo , Policitemia/sangue , Adulto , Estudos de Casos e Controles , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peru , Análise de RegressãoRESUMO
A study of chronic mountain sickness (CMS) with a candidate gene--vascular endothelial growth factor A (VEGFA)--was carried out in a Peruvian population living at high altitude in Cerro de Pasco (4380 m). The study was performed by genotyping of 11 tag SNPs encompassing 2.2 kb of region of VEGFA gene in patients with a diagnosis of CMS (n = 131; 49.1 ± 12.7 years old) and unrelated healthy controls (n = 84; 47.2 ± 13.4 years old). The VEGFA tag SNP rs3025033 was found associated with CMS (p < 0.05), individuals with AG genotype have 2.5 more risk of CMS compared to those with GG genotype (p < 0.02; OR, 2.54; 95% CI: 1.10-5.88). Pairwise Fst and Nei's distance indicate genetic differentiation between Cerro de Pasco population and HapMap3 population (Fst > 0.36, p < 0.01), suggesting selection is operating on the VEGF gene. Our results suggest that VEGFA is associated with CMS in long-term residents at high altitude in the Peruvian Andes.
Assuntos
Doença da Altitude/genética , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Altitude , Estudos de Casos e Controles , Doença Crônica , Feminino , Marcadores Genéticos , Genótipo , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , PeruRESUMO
RATIONALE: Monge's disease is characterized by an excessive erythrocytosis, frequently associated with pulmonary hypertension, in high-altitude dwellers. It has a considerable impact on public health in high-altitude regions. A preliminary study demonstrated the efficiency of acetazolamide (Acz) (250 mg/d for 3 wk) in reducing serum erythropoietin and hematocrit. OBJECTIVES: Evaluate the efficacy and tolerance of a 6-month treatment with 250 mg Acz that could be chronically implemented and its effects on pulmonary artery pressure and cardiac function. METHODS: A two-phase study was performed in patients (hematocrit > or = 63%) from Cerro de Pasco, Peru (4,300 m). First phase: a double-blind, placebo-controlled study in 55 patients who received a single dose of either 250 mg Acz (n = 40) or placebo (n = 15) by daily oral administration for 12 weeks. Second phase (open label): after a 4-week washout period, all patients received 250 mg Acz for 12 weeks. Hematocrit, blood gases, clinical outcome, and pulmonary artery circulation were evaluated. MEASUREMENTS AND MAIN RESULTS: First phase: Acz decreased by 44% the number of polycythemic subjects (P = 0.02), decreased hematocrit from 69 to 64% (P < 0.001), and increased arterial O(2) pressure from 42 to 45 mm Hg (P < 0.001). No severe adverse effect or hypokalemia was recorded. The second phase reproduced the effects observed during the first phase, without cumulative effects on hematocrit. A 4-week washout restored basal hematocrit. Only patients who received Acz for 6 months showed a clear reduction in pulmonary vascular resistance. CONCLUSIONS: Acz reduces erythrocytosis and improves pulmonary circulation in Monge's disease without adverse effects. Its implementation as a chronic treatment for this disease appears efficient and safe.
Assuntos
Acetazolamida/uso terapêutico , Doença da Altitude/tratamento farmacológico , Inibidores da Anidrase Carbônica/uso terapêutico , Policitemia/tratamento farmacológico , Acetazolamida/efeitos adversos , Acetazolamida/farmacologia , Doença da Altitude/complicações , Doença da Altitude/diagnóstico por imagem , Análise de Variância , Inibidores da Anidrase Carbônica/efeitos adversos , Inibidores da Anidrase Carbônica/farmacologia , Débito Cardíaco/efeitos dos fármacos , Doença Crônica , Método Duplo-Cego , Ecocardiografia , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Peru , Estudos Prospectivos , Insuficiência da Valva Tricúspide/etiologiaRESUMO
We used transgenic mice constitutively over-expressing erythropoietin ("tg6" mice) and wild-type (wt) mice to investigate whether the high hematocrit (hct), consequence of Epo over-expression affected: (1) the normoxic ventilation (V (E)) and the acute hypoxic ventilatory response (HVR) and decline (HVD), (2) the increase in ventilation observed after chronic exposure to hypobaric hypoxia (430mmHg for 21 days), (3) the respiratory "blunting", and (4) the erythrocythemic response induced by chronic hypoxia exposure. V (E) was found to be similar in tg6 and wt mice in normoxia (FIO2=0.21). Post-acclimation V (E) was significantly elevated in every time point in wt mice at FIO2=0.10 when compared to pre-acclimation values. In contrast, tg6 mice exhibited a non-significant increase in V (E) throughout acute hypoxia exposure. Changes in V (E) are associated with adjustments in tidal volume (V(T)). HVR and HVD were independent of EE in tg6 and wt mice before chornic hypoxia exposure. HVR was significantly greater in wt than in tg6 mice after chronic hypoxia. After acclimation, HVD decreased in tg6 mice. Chronic hypoxia exposure caused hct to increase significantly in wt mice, while only a marginal increase occurred in the tg6 group. Although pre-existent EE does not appear to have an effect on HVR, the observation of alterations on V(T) suggests that it may contribute to time-dependent changes in ventilation and in the acute HVR during exposure to chronic hypoxia. In addition, our results suggest that EE may lead to an early "blunting" of the ventilatory response.
Assuntos
Aclimatação/fisiologia , Eritropoetina/metabolismo , Hipóxia/metabolismo , Policitemia/metabolismo , Ventilação Pulmonar/fisiologia , Aclimatação/genética , Animais , Eritropoetina/genética , Feminino , Hematócrito , Hemoglobinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Consumo de Oxigênio/fisiologia , Policitemia/genética , Volume de Ventilação Pulmonar/fisiologiaRESUMO
PURPOSE: Both training and chronic hypoxia act on the autonomic nervous system. Because trained Andean high-altitude natives could perform a high-altitude marathon (4220 m above sea level) in 02:27:23 h, we hypothesized that living in chronic hypoxia does not limit the training-induced benefits on the autonomic modulation of the heart. METHODS: Trained (N=13) and sedentary (N=11) Andean high-altitude natives performed an active orthostatic test. Eight of the trained subjects repeated the test 6-8 and 20-24 h after the end of a high-altitude marathon. Resting heart rate (HR) and the autonomic modulation of the heart were assessed by time domain and spectral analysis of HR variability (HRV): sympathetic (RR low frequency (LF)) and parasympathetic (RR high frequency (HF)) modulations, and sympathovagal balance (RR-LF:HF ratio). RESULTS: Trained subjects exhibited a higher total power of HRV and a lower resting HR (+30%, P<0.005) than sedentary subjects secondary to a higher and dominant parasympathetic modulation on sympathetic activity (RR-HF, RR-LF:HF ratio). At 6-8 h after the marathon, total power of HRV decreased (-69%), whereas resting HR increased from basal level (+22%), mainly because of a rise in sympathetic modulation (RR-LF, RR-LF:HF ratio). From 8 to 24 h of recovery, sympathetic modulation fell (RR-LF, RR-LF:HF ratio) and all HRV parameters were restored. Responses to the active standing position did not change between each recording session. CONCLUSION: Living in chronic hypoxia does not limit the training-induced benefits on the autonomic control of the cardiovascular system in Andean high-altitude natives. The sympathetic predominance on the heart observed 6-8 h after the high-altitude marathon disappeared after 1 d of recovery. Therefore, living at high altitude does not impair the autonomic response to training.