RESUMO
Chronic mountain sickness is a maladaptive syndrome that affects individuals living permanently at high altitude and is characterized primarily by excessive erythrocytosis (EE). Recent results concerning the impact of EE in Andean highlanders on clotting and the possible promotion of hypercoagulability, which can lead to thrombosis, were contradictory. We assessed the coagulation profiles of Andeans highlanders with and without excessive erythrocytosis (EE+ and EE-). Blood samples were collected from 30 EE+ and 15 EE- in La Rinconada (Peru, 5100-5300 m a.s.l.), with special attention given to the sampling pre-analytical variables. Rotational thromboelastometry tests were performed at both native and normalized (40%) haematocrit using autologous platelet-poor plasma. Thrombin generation, dosages of clotting factors and inhibitors were measured in plasma samples. Data were compared between groups and with measurements performed at native haematocrit in 10 lowlanders (LL) at sea level. At native haematocrit, in all rotational thromboelastometry assays, EE+ exhibited hypocoagulable profiles (prolonged clotting time and weaker clot strength) compared with EE- and LL (all P < 0.01). At normalized haematocrit, clotting times were normalized in most individuals. Conversely, maximal clot firmness was normalized only in FIBTEM and not in EXTEM/INTEM assays, suggesting abnormal platelet activity. Thrombin generation, levels of plasma clotting factors and inhibitors, and standard coagulation assays were mostly normal in all groups. No highlanders reported a history of venous thromboembolism based on the dedicated survey. Collectively, these results indicate that EE+ do not present a hypercoagulable profile potentially favouring thrombosis.
Assuntos
Altitude , Coagulação Sanguínea , Policitemia , Tromboelastografia , Trombofilia , Humanos , Policitemia/sangue , Coagulação Sanguínea/fisiologia , Adulto , Trombofilia/sangue , Masculino , Tromboelastografia/métodos , Feminino , Hematócrito/métodos , Peru , Pessoa de Meia-Idade , Doença da Altitude/sangue , Doença da Altitude/fisiopatologia , Trombina/metabolismoRESUMO
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
Chronic exposure to altitude has been associated with hypobaric hypoxia in its inhabitants. Two entities have been associated with it, high altitude pulmonary hypertension and chronic mountain sickness. Its physiological and pulmonary circulation characteristics are described, as well as its clinical profile and diagnosis.
La exposición crónica a la altitud se ha asociado a hipoxia hipobárica en quienes la experimentan. Dos entidades se han asociado a la hipoxia hipobárica: la hipertensión pulmonar de la alta altitud y el mal de montaña crónico. Se describen sus características fisiológicas y de la circulación pulmonar, así como su perfil clínico y el diagnóstico.
Assuntos
Doença da Altitude/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Hipóxia/etiologia , Circulação Pulmonar/fisiologia , Altitude , Doença da Altitude/diagnóstico , Doença da Altitude/etiologia , Humanos , Hipertensão Pulmonar/complicações , Hipertrofia Ventricular Direita , Hipóxia/diagnóstico , Hipóxia/fisiopatologia , Fatores de RiscoRESUMO
Exposure to hypoxic environments when ascending at high altitudes may cause life-threatening pulmonary edema (HAPE) due to a rapid accumulation of extracellular fluid flooding in the pulmonary alveoli. In Andeans, high-altitude adaptation occurs at the expense of being more prone to chronic mountain sickness: relative hypoventilation, excess pulmonary hypertension, and secondary polycythemia. Because HAPE prevalence is high in the Andes, we posit the hypothesis that a high hemoglobine mass may increase HAPE risk. In support of it, high intrapulmonary hypertension along with hyperviscosity produced by polycytemia may enhance sear forces and intravascular hemolysis, thus leading to increased acellular hemoglobin and the subsequent damage of the alveolar and endothelial barrier. It is proposed to investigate the relationship between the vaso-endothelial homeostasis and erythropoiesis in the maladaptation to high altitude and HAPE. This research is especially important when reentry HAPE, since rheologic properties of blood changes with rapid ascent to high altitudes.
Assuntos
Doença da Altitude , Edema Pulmonar , Altitude , Doença da Altitude/complicações , Hemoglobinas , Humanos , PulmãoRESUMO
Little is known about hemostasis modifications induced by chronic hypoxic exposure in high-altitude residents, especially in those who develop excessive erythrocytosis (EE, i.e. hemoglobin concentration ≥ 21 g·dL-1 in male and ≥ 19 g·dL-1 in female). The aim of this preliminary study was to assess coagulation alterations in highlanders with or without EE using simple hemostatic tests such as bleeding (BT) and clotting (CT) times. Eighty-one male (43 ± 7 years), permanent residents from La Rinconada (Peru), the highest city in the world (5,100-5,300 m), were evaluated. Thirty-six subjects (44 %) presented with EE. EE subjects compared to non-EE subjects had lower BT (3.6 ± 1.2 vs. 7.0 ± 1.9 min, p < 0.001) and CT (11.7 ± 1.7 vs. 15.1 ± 2.3 min, p < 0.001). These results support the notion that highlanders with EE are in a state of hypercoagulability and call for further hemostasis investigations in this population using more detailed hemostatic methods.
Assuntos
Doença da Altitude/sangue , Altitude , Coagulação Sanguínea/fisiologia , Hemostasia/fisiologia , Policitemia/sangue , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , PeruRESUMO
Se describen las respuestas fisiológicas que el ser humano desarrolla en respuesta a la exposición a la altitud geográfica. Se describen no sólo las alteraciones debidas a una mala coordinación de los ajustes fisiológicos desencadenados durante la aclimatación a la altura sino también sus manifestaciones clínicas más relevantes. Se detallan los mecanismos moleculares subyacentes a tales respuestas y cómo su mejor conocimiento puede permitir aplicar la exposición intermitente a hipoxia como una herramienta útil para la resolución o alivio de determinadas alteraciones y patologías.
We depict the physiological responses developed by the human body in response to the exposure to geographic altitude. The main alterations due to a noncoordinated setup of the physiological adjustments triggered during the acclimatization at altitude are also described, as its most relevant clinical manifestations. The molecular mechanisms underlying such responses are detailed, and how a better knowledge of these processes can allow us to apply intermittent exposure to hypoxia programs as a useful tool for the resolution or relief of certain disorders and pathologies.
Assuntos
Humanos , Adaptação Fisiológica , Altitude , Doença da Altitude , Edema Encefálico , Aclimatação , HipóxiaRESUMO
Los adaptados genéticamente a la altura son los tibetanos, sherpas y etíopes; los aymaras y quechuas están aclimatados (Bolivia, Perú y norte de Chile). En Bolivia el mal crónico de montaña afecta 10% de la población masculina. El objetivo fue determinar la función ventricular derecha en residentes sanos y con mal crónico de montaña mediante ecocardiografía transtoráxica. Se utilizaron participantes sanos y con mal crónico de montaña admitidos por el IBBA, desde el año 2012 al 2013. Las variables tomadas son: demográficas, espirometria forzada, gasometría arterial en reposo e hiperoxia, ECG y ECCTT. Los controles (n 40), la edad promedio (44,13±9,69 años), predominio masculino y sobrepeso (IMC 26,27±6,68kg /m2), procedentes de La Paz 3.600 msnm (54%), Potosí 4.000 msnm (22%), El Alto 4.100 msnm (15%) y Oruro 3.800 msnm (9%), el promedio de Hematocrito 51,34±2,91%, hemoglobina 17,15±0,89gr/ dl, Espirometria forzada y Gasometría arterial en reposo e hiperoxia normales, la ECCTT muestra hipertensión pulmonar leve (35,85±3,64mmHg), aumento de grosor del VD (0,51±0,08), TAPSE (2,94±3,85mmHg) y el índice de Tei (0,44±0,22) normales. Los casos (n 40), la edad promedio (48,43±8,08 años), predominio masculino y sobrepeso (IMC 29,54±3,41kg / m2), procedente de La Paz 3.600 msnm (56%), Potosí 4.000 msnm (24%), El Alto 4.100 msnm (13%) y Oruro 3.800 msnm (7%), Hematocrito 63,08±6,2%, Hemoglobina 21,01±2,01gr/dl con eritrotrocitosis, espirometría forzada normal, gasometría arterial en reposo con hipoxemia moderada (PaO2 51,73±4,68mmHg), hipocapnia (PaCO2 27,62±2,04mmHg) y gradiente Alveolo-arterial aumentado (7,61±3,15). Gasometría arterial en hiperoxia descarta shunt (PaO2 308,9±52,58mmHg), el ECG muestra 2 de 11 criterios de crecimiento VD, la ECCTT con hipertensión pulmonar moderada (PSAP 45,22±5,69mmHg), aumento de grosor del VD (0,73±0,22), TAPSE (2,08±0,18cm), normal e índice de Tei (0,51±0,10) ligeramente aumentado. Se concluyó que la función ventricular derecha se encuentra conservada, a pesar de tener hipertensión pulmonar leve (controles) y moderada (casos), con aumento del grosor del ventrículo derecho.
Those genetically adapted to the height are the Tibetans, Sherpas, and Ethiopians; the Aymara and Quechuas are acclimatized (Bolivia, Peru, and northern Chile). In Bolivia, chronic mountain sickness affects 10% of the male population. The objective was to determine the right ventricular function in healthy residents with chronic mountain sickness using transthoracic echocardiography. Use the healthy and chronically ill mountain participants admitted by the IBBA, from 2012 to 2013. The variables taken are demographic, forced spirometry, arterial blood gas at rest and hyperoxia, ECG, and ECCTT. Controls (n 40), average age (44.13 ± 9.69 years), male predominance and overweight (BMI 26.27 ± 6.68kg / m2), frequency from La Paz 3,600 masl (54%), Potosí 4,000 masl (22%), El Alto 4,100 masl (15%) and Oruro 3,800 masl (9%), the average Hematocrit 51.34 ± 2.91%, hemoglobin 17.15 ± 0.89gr / dl, Forced spirometry y Resting arterial blood gas and normal hyperoxia, ECCTT shows mild pulmonary hypertension (35.85 ± 3.64 mmHg), increased RV thickness (0.51 ± 0.08), TAPSE (2.94 ± 3.85 mmHg ) and the Tei index (0.44 ± 0.22) normal. The cases (n 40), the average age (48.43 ± 8.08 years), male predominance and overweight (BMI 29.54 ± 3.41kg / m2), derived from La Paz 3,600 masl (56%), Potosí 4,000 masl (24%), El Alto 4,100 masl (13%) and Oruro 3,800 masl (7%), Hematocrit 63.08 ± 6.2%, Hemoglobin 21.01 ± 2.01gr / dl with erythrocytosis, normal forced spirometry , resting arterial blood gas with moderate hypoxemia (PaO2 51.73 ± 4.68mmHg), hypocapnia (PaCO2 27.62 ± 2.04mmHg) and increased Alveolo-arterial gradient (7.61 ± 3.15). Arterial blood gas in hyperoxia rules out shunt (PaO2 308.9 ± 52.58mmHg), ECG shows 2 of 11 RV growth criteria, ECCTT with moderate pulmonary hypertension (PSAP 45.22 ± 5.69mmHg), increased RV thickness (0.73 ± 0.22), TAPSE (2.08 ± 0.18cm), normal and Tei index (0.51 ± 0.10) slightly increased. It was concluded that the right ventricular function is preserved, a weight of having mild pulmonary hypertension (controls) and moderate (cases), with increased thickness of the right ventricle.
Assuntos
Humanos , Adulto , Pessoa de Meia-Idade , Adaptação Fisiológica/genética , Função Ventricular Direita/fisiologia , Doença da Altitude , Valores de Referência , Espirometria/métodos , Gasometria , Bolívia , Ecocardiografia , Estudos Transversais , Estudos Prospectivos , Povos IndígenasRESUMO
KEY POINTS: Highlanders develop unique adaptative mechanisms to chronic hypoxic exposure, including substantial haemoglobin and haematocrit increases. However, a significant proportion of populations living permanently at high altitude develop maladaptive features known as chronic mountain sickness (CMS). This study aimed to assess the effects of permanent life at high altitude on clinical and haemorheological parameters (blood viscosity and red blood cell aggregation) and to compare clinical and haemorheological parameters of dwellers from the highest city in the world according to CMS severity. Blood viscosity increased with altitude, together with haemoglobin concentration and haematocrit. At 5100 m, highlanders with moderate-to-severe CMS had higher blood viscosity mainly at high shear rate and even at corrected haematocrit (40%), with a lower red blood cell aggregation. Blood viscosity may contribute to CMS symptomatology but the increased blood viscosity in CMS patients cannot solely be explained by the rise in haematocrit. ABSTRACT: Chronic mountain sickness (CMS) is a condition characterised by excessive erythrocytosis (EE). While EE is thought to increase blood viscosity and subsequently to trigger CMS symptoms, the exact relationship between blood viscosity and CMS symptoms remains incompletely understood. We assessed the effect of living at high altitude on haemoglobin, haematocrit and haemorheological parameters (blood viscosity and red blood cell aggregation), and investigated their relationship with CMS in highlanders living in the highest city in the world (La Rinconada, Peru, 5100 m). Ninety-three men participated in this study: 10 Caucasian lowlanders, 13 Andean highlanders living at 3800 m and 70 Andean highlanders living at 5100 m (35 asymptomatic, CMS score ≤5; 15 with mild CMS, CMS score between 6 and 10; 20 with moderate-to-severe CMS, CMS score >10). Blood viscosity was measured at native and corrected haematocrit (40%). Haemoglobin concentration and haematocrit increased with the altitude of residency. Blood viscosity also increased with altitude (at 45 s-1 : 6.7 ± 0.9 mPa s at sea level, 14.0 ± 2.0 mPa s at 3800 m and 27.1 ± 8.8 mPa s at 5100 m; P < 0.001). At 5100 m, blood viscosity at corrected haematocrit was higher in highlanders with moderate-to-severe CMS (at 45 s-1 : 18.9 ± 10.7 mPa s) than in highlanders without CMS (10.2 ± 5.9 mPa s) or with mild CMS (12.1 ± 6.1 mPa s) (P < 0.05). In conclusion, blood viscosity may contribute to CMS symptomatology but the increased blood viscosity in CMS patients cannot solely be explained by the rise in haematocrit.
Assuntos
Doença da Altitude , Viscosidade Sanguínea , Adaptação Fisiológica , Altitude , Doença Crônica , Humanos , Masculino , PeruRESUMO
Excessive erythrocytosis (EE) is the main sign of chronic mountain sickness (CMS), a maladaptive clinical syndrome prevalent in Andean and other high-altitude populations worldwide. The pathophysiological mechanism of EE is still controversial, as physiological variability of systemic respiratory, cardiovascular, and hormonal responses to chronic hypoxemia complicates the identification of underlying causes. Induced pluripotent stem cells derived from CMS highlanders showed increased expression of genes relevant to the regulation of erythropoiesis, angiogenesis, cardiovascular, and steroid-hormone function that appear to explain the exaggerated erythropoietic response. However, the cellular response to hypoxia in native CMS cells is yet unknown. This study had three related aims: to determine the hypoxic proliferation of native erythroid progenitor burst-forming unit-erythroid (BFU-E) cells derived from CMS and non-CMS peripheral blood mononuclear cells; to examine their sentrin-specific protease 1 (SENP1), GATA-binding factor 1 (GATA1), erythropoietin (EPO), and EPO receptor (EPOR) expression; and to investigate the functional upstream role of SENP1 in native progenitor differentiation into erythroid precursors. Native CMS BFU-E colonies showed increased proliferation under hypoxic conditions compared with non-CMS cells, together with an upregulated expression of SENP1, GATA1, EPOR; and no difference in EPO expression. Knock-down of the SENP1 gene abolished the augmented proliferative response. Thus, we demonstrate that native CMS progenitor cells produce a larger proportion of erythroid precursors under hypoxia and that SENP1 is essential for proliferation. Our findings suggest a significant intrinsic component for developing EE in CMS highlanders at the cellular and gene expression level that could be further enhanced by systemic factors such as alterations in respiratory control, or differential hormonal patterns.
Assuntos
Doença da Altitude/epidemiologia , Altitude , Células Precursoras Eritroides/metabolismo , Oxigênio/metabolismo , Oxigênio/farmacologia , Doença Crônica , Eritropoetina/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Predisposição Genética para Doença , Homeostase , Humanos , Hipóxia , Ferro/metabolismo , Leucócitos Mononucleares , TranscriptomaRESUMO
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
Excessive erythrocytosis [EE; hemoglobin concentration (Hb) ≥ 21 g/dL in adult men] is a maladaptive high-altitude pathology associated with increased cardiovascular risk and reduced reactive hyperemia flow-mediated dilation (FMD); however, whether a similar impairment occurs in response to more commonly encountered sustained increases in shear stress [sustained stimulus (SS)-FMD] over a range of overlapping stimuli is unknown. We characterized SS-FMD in response to handgrip exercise in Andeans with and without EE in Cerro de Pasco, Peru (4,330 m). Andean highlanders with EE (n = 17, Hb = 23.2 ± 1.2 g/dL) and without EE (n = 23, Hb = 18.7 ± 1.9 g/dL) performed 3 min of rhythmic handgrip exercise at 20, 35, and 50% of maximum voluntary contraction (MVC). Duplex ultrasound was used to continuously record blood velocity and diameter in the brachial artery, and blood viscosity was measured to accurately calculate shear stress. Although baseline shear stress did not differ, Andeans with EE had 22% lower shear stress than Andeans without at 50% MVC (P = 0.004). At 35 and 50% MVC, SS-FMD was 2.1 ± 2.0 and 2.8 ± 2.7% in Andeans with EE compared with 4.1 ± 3.4 and 7.5 ± 4.5% in those without (P = 0.048 and P < 0.001). The stimulus-response slope (∆shear stress vs. ∆diameter) was lower in Andeans with EE compared with Andeans without (P = 0.028). This slope was inversely related to Hb in Andeans with EE (r2 = 0.396, P = 0.007). A reduced SS-FMD in response to small muscle mass exercise in Andeans with EE indicates a generalized reduction in endothelial sensitivity to shear stress, which may contribute to increased cardiovascular risk in this population.NEW & NOTEWORTHY High-altitude excessive erythrocytosis (EE; hemoglobin concentration ≥ 21 g/dL) is a maladaptation to chronic hypoxia exposure and is associated with increased cardiovascular risk. We examined flow-mediated dilation (FMD) in response to sustained elevations in shear stress achieved using progressive handgrip exercise [sustained stimulus (SS)-FMD] in Andean highlanders with and without EE at 4,330 m. Andeans with EE demonstrated lower SS-FMD compared with those without. Heightened hemoglobin concentration was related to lower SS-FMD in Andeans with EE.
Assuntos
Aclimatação , Doença da Altitude/fisiopatologia , Altitude , Artéria Braquial/fisiopatologia , Policitemia/fisiopatologia , Vasodilatação , Adulto , Doença da Altitude/sangue , Doença da Altitude/diagnóstico por imagem , Biomarcadores/sangue , Velocidade do Fluxo Sanguíneo , Viscosidade Sanguínea , Artéria Braquial/diagnóstico por imagem , Estudos de Casos e Controles , Força da Mão , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Contração Muscular , Peru , Policitemia/sangue , Policitemia/diagnóstico , Fluxo Sanguíneo Regional , Estresse Mecânico , Fatores de Tempo , Ultrassonografia Doppler DuplaRESUMO
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 JovemRESUMO
Human high-altitude (HA) adaptation or mal-adaptation is explored to understand the physiology, pathophysiology, and molecular mechanisms that underlie long-term exposure to hypoxia. Here, we report the results of an analysis of the largest whole-genome-sequencing of Chronic Mountain Sickness (CMS) and nonCMS individuals, identified candidate genes and functionally validated these candidates in a genetic model system (Drosophila). We used PreCIOSS algorithm that uses Haplotype Allele Frequency score to separate haplotypes carrying the favored allele from the noncarriers and accordingly, prioritize genes associated with the CMS or nonCMS phenotype. Haplotypes in eleven candidate regions, with SNPs mostly in nonexonic regions, were significantly different between CMS and nonCMS subjects. Closer examination of individual genes in these regions revealed the involvement of previously identified candidates (e.g., SENP1) and also unreported ones SGK3, COPS5, PRDM1, and IFT122 in CMS. Remarkably, in addition to genes like SENP1, SGK3, and COPS5 which are HIF-dependent, our study reveals for the first time HIF-independent gene PRDM1, indicating an involvement of wider, nonHIF pathways in HA adaptation. Finally, we observed that down-regulating orthologs of these genes in Drosophila significantly enhanced their hypoxia tolerance. Taken together, the PreCIOSS algorithm, applied on a large number of genomes, identifies the involvement of both new and previously reported genes in selection sweeps, highlighting the involvement of multiple hypoxia response systems. Since the overwhelming majority of SNPs are in nonexonic (and possibly regulatory) regions, we speculate that adaptation to HA necessitates greater genetic flexibility allowing for transcript variability in response to graded levels of hypoxia.
Assuntos
Aclimatação/genética , Doença da Altitude/genética , Adaptação Fisiológica/genética , Adulto , Alelos , Altitude , Doença da Altitude/metabolismo , Doença da Altitude/fisiopatologia , Animais , Doença Crônica , Drosophila/genética , Evolução Molecular , Frequência do Gene/genética , Haplótipos/genética , Humanos , Hipóxia/genética , Hipóxia/fisiopatologia , Masculino , Peru , Polimorfismo de Nucleotídeo Único/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Sequenciamento Completo do Genoma/métodosRESUMO
High altitudes (>8,000 ft or 2,500 m) provide an experiment of nature for measuring adaptation and the physiological processes involved. Studies conducted over the past ~25 years in Andeans, Tibetans, and, less often, Ethiopians show varied but distinct O2 transport traits from those of acclimatized newcomers, providing indirect evidence for genetic adaptation to high altitude. Short-term (acclimatization, developmental) and long-term (genetic) responses to high altitude exhibit a temporal gradient such that, although all influence O2 content, the latter also improve O2 delivery and metabolism. Much has been learned concerning the underlying physiological processes, but additional studies are needed on the regulation of blood flow and O2 utilization. Direct evidence of genetic adaptation comes from single-nucleotide polymorphism (SNP)-based genome scans and whole genome sequencing studies that have identified gene regions acted upon by natural selection. Efforts have begun to understand the connections between the two with Andean studies on the genetic factors raising uterine blood flow, fetal growth, and susceptibility to Chronic Mountain Sickness and Tibetan studies on genes serving to lower hemoglobin and pulmonary arterial pressure. Critical for future studies will be the selection of phenotypes with demonstrable effects on reproductive success, the calculation of actual fitness costs, and greater inclusion of women among the subjects being studied. The well-characterized nature of the O2 transport system, the presence of multiple long-resident populations, and relevance for understanding hypoxic disorders in all persons underscore the importance of understanding how evolutionary adaptation to high altitude has occurred.NEW & NOTEWORTHY Variation in O2 transport characteristics among Andean, Tibetan, and, when available, Ethiopian high-altitude residents supports the existence of genetic adaptations that improve the distribution of blood flow to vital organs and the efficiency of O2 utilization. Genome scans and whole genome sequencing studies implicate a broad range of gene regions. Future studies are needed using phenotypes of clear relevance for reproductive success for determining the mechanisms by which naturally selected genes are acting.
Assuntos
Aclimatação/genética , Altitude , Oxigênio/fisiologia , Pressão Arterial/genética , Etiópia , Hemoglobinas/genética , Humanos , Hipóxia/fisiopatologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Seleção Genética , América do Sul , TibetRESUMO
Patients suffering from chronic mountain sickness (CMS) have excessive erythrocytosis. Low -level cobalt toxicity as a likely contributor has been demonstrated in some subjects. We performed a randomized, placebo controlled clinical trial in Cerro de Pasco, Peru (4380m), where 84 participants with a hematocrit (HCT) ≥65% and CMS score>6, were assigned to four treatment groups of placebo, acetazolamide (ACZ, which stimulates respiration), N-acetylcysteine (NAC, an antioxidant that chelates cobalt) and combination of ACZ and NAC for 6 weeks. The primary outcome was change in hematocrit and secondary outcomes were changes in PaO2, PaCO2, CMS score, and serum and urine cobalt concentrations. The mean (±SD) hematocrit, CMS score and serum cobalt concentrations were 69±4%, 9.8±2.4 and 0.24±0.15µg/l, respectively for the 66 participants. The ACZ arm had a relative reduction in HCT of 6.6% vs. 2.7% (p=0.048) and the CMS score fell by 34.9% vs. 14.8% (p=0.014) compared to placebo, while the reduction in PaCO2 was 10.5% vs. an increase of 0.6% (p=0.003), with a relative increase in PaO2 of 13.6% vs. 3.0%. NAC reduced CMS score compared to placebo (relative reduction of 34.0% vs. 14.8%, p=0.017), while changes in other parameters failed to reach statistical significance. The combination of ACZ and NAC was no better than ACZ alone. No changes in serum and urine cobalt concentrations were seen within any treatment arms. ACZ reduced polycythemia and CMS score, while NAC improved CMS score without significantly lowering hematocrit. Only a small proportion of subjects had cobalt toxicity, which may relate to the closing of contaminated water sources and several other environmental protection measures.
Assuntos
Acetazolamida/uso terapêutico , Acetilcisteína/uso terapêutico , Doença da Altitude/tratamento farmacológico , Inibidores da Anidrase Carbônica/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Adulto , Doença da Altitude/sangue , Doença da Altitude/urina , Análise de Variância , Gasometria , Distribuição de Qui-Quadrado , Doença Crônica , Cobalto/sangue , Cobalto/urina , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hematócrito/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Peru , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Alarcón-Yaquetto, Dulce E., Lidia Caballero, and Gustavo F. Gonzales. Association between plasma N-acylethanolamides and high hemoglobin concentration in Southern Peruvian highlanders. High Alt Med Biol 18:322-329, 2017.-High-altitude (HA) hypoxia is a stressful condition endured by organisms through different mechanisms. Failing to adapt to chronic HA exposure leads to a disease called chronic mountain sickness (CMS) characterized by excessive erythrocytosis (hemoglobin [Hb] ≥19 g/dL for women and ≥21 g/dL for men). Genes encoding for peroxisome proliferator-activated receptor (PPAR) subunits α and γ have been proposed as candidate genes for HA adaptation. N-acylethanolamides (NAEs) are endogenous fatty acid substances that bind to PPAR-α and -γ. NAEs are also able to modulate the endocannabinoid system, a signaling pathway activated in physiological stressful conditions. In the frame of a metabolomic study, we measured plasma levels of four NAEs: palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoyl ethanolamide (SEA), and linoleoyl ethanolamide (LEA) in natives from Puno (3830 m), a city located in the Peruvian Southern Andes, and Lima (150 m). All NAEs were significantly higher in the HA population (p < 0.001, q < 0.001). Subjects with higher NAE values were those with higher Hb concentration and lower pulse oxygen saturation. However, there was no association between NAEs and CMS score. Our results suggest that PEA and OEA could be involved in physiological regulation following long-term HA exposure.
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Altitude , Ácidos Graxos/sangue , Hemoglobinas/metabolismo , Hipóxia/sangue , Adulto , Doença da Altitude/sangue , Amidas , Doença Crônica , Endocanabinoides/sangue , Etanolaminas/sangue , Feminino , Humanos , Indígenas Sul-Americanos , Ácidos Linoleicos/sangue , Masculino , Ácidos Oleicos/sangue , Oxigênio/sangue , Ácidos Palmíticos/sangue , Peru , Alcamidas Poli-Insaturadas/sangue , Ácidos Esteáricos/sangueRESUMO
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.
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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
BACKGROUND: Chronic mountain sickness (CMS) is often associated with vascular dysfunction, but the underlying mechanism is unknown. Sleep-disordered breathing (SDB) frequently occurs at high altitude. At low altitude, SDB causes vascular dysfunction. Moreover, in SDB, transient elevations of right-sided cardiac pressure may cause right-to-left shunting in the presence of a patent foramen ovale (PFO) and, in turn, further aggravate hypoxemia and pulmonary hypertension. We speculated that SDB and nocturnal hypoxemia are more pronounced in patients with CMS compared with healthy high-altitude dwellers, and are related to vascular dysfunction. METHODS: We performed overnight sleep recordings, and measured systemic and pulmonary artery pressure in 23 patients with CMS (mean ± SD age, 52.8 ± 9.8 y) and 12 healthy control subjects (47.8 ± 7.8 y) at 3,600 m. In a subgroup of 15 subjects with SDB, we assessed the presence of a PFO with transesophageal echocardiography. RESULTS: The major new findings were that in patients with CMS, (1) SDB and nocturnal hypoxemia was more severe (P < .01) than in control subjects (apnea-hypopnea index [AHI], 38.9 ± 25.5 vs 14.3 ± 7.8 number of events per hour [nb/h]; arterial oxygen saturation, 80.2% ± 3.6% vs 86.8% ± 1.7%, CMS vs control group), and (2) AHI was directly correlated with systemic blood pressure (r = 0.5216; P = .001) and pulmonary artery pressure (r = 0.4497; P = .024). PFO was associated with more severe SDB (AHI, 48.8 ± 24.7 vs 14.8 ± 7.3 nb/h; P = .013, PFO vs no PFO) and hypoxemia. CONCLUSIONS: SDB and nocturnal hypoxemia are more severe in patients with CMS than in control subjects and are associated with systemic and pulmonary vascular dysfunction. The presence of a PFO appeared to further aggravate SDB. Closure of the PFO may improve SDB, hypoxemia, and vascular dysfunction in patients with CMS. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01182792; URL: www.clinicaltrials.gov.
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Doença da Altitude/epidemiologia , Altitude , Forame Oval Patente/epidemiologia , Hipertensão Pulmonar/epidemiologia , Hipóxia/epidemiologia , Síndromes da Apneia do Sono/epidemiologia , Adulto , Doença da Altitude/fisiopatologia , Pressão Sanguínea , Bolívia/epidemiologia , Estudos de Casos e Controles , Doença Crônica , Ecocardiografia Transesofagiana , Forame Oval Patente/diagnóstico por imagem , Forame Oval Patente/fisiopatologia , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/fisiopatologia , Hipóxia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polissonografia , Índice de Gravidade de Doença , Síndromes da Apneia do Sono/fisiopatologiaRESUMO
In the last few years, genetic and functional studies have provided important insight on the pathophysiology of excessive erythrocytosis (EE), the main sign of Chronic Mountain Sickness (CMS). The recent finding of the association of the CMS phenotype with a single-nucleotide polymorphism (SNP) in the Sentrin-specific Protease 1 (SENP1) gene, and its differential expression pattern in Andean highlanders with and without CMS, has triggered large interest in high-altitude studies because of the potential role of its gene product in the control of erythropoiesis. The SENP1 gene encodes for a protease that regulates the function of hypoxia-relevant transcription factors such as Hypoxia-Inducible Factor (HIF) and GATA, and thus might have an erythropoietic regulatory role in CMS through the modulation of the expression of erythropoietin (Epo) or Epo receptors. The different physiological patterns in the Epo-EpoR system found among Andeans, even among highlanders with CMS, together with their different degrees of erythropoietic response, might indicate specific underlying genetic backgrounds, which in turn might reflect different levels of adaptation to lifelong high-altitude hypoxia. This minireview discusses recent genetic findings potentially underlying EE and CMS, and their possible physiological mechanisms in Andean highlanders.
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Doença da Altitude/sangue , Doença da Altitude/genética , Policitemia/sangue , Policitemia/genética , Altitude , Doença da Altitude/complicações , Doença da Altitude/fisiopatologia , Doença Crônica , Humanos , Policitemia/complicações , Policitemia/fisiopatologia , América do SulRESUMO
BACKGROUND: Restless legs syndrome (RLS) and chronic mountain sickness (CMS) share physiological traits. Our objective was to explore a possible association between RLS and CMS. METHODS: We carried a cross-sectional study with male subjects living between 4100 and 4300 m above sea level. Participants underwent a clinical interview, physical examination, electrocardiographic (EKG) recording, and spirometry. We classified subjects into CMS, Limbo, and healthy high-altitude dwellers (hHAD), according to their Quinghai score and hematocrit levels. We applied the "Paradigm of questions for epidemiological studies of RLS," The International Restless Leg Syndrome Study Group Scale, and the Pittsburgh Sleep Quality Index. Logistic regression analysis was used to determine the association between variables. RESULTS: Seventy-eight male subjects were included. Forty subjects were hHAD, 23 were CMS patients, and 15 participants were considered as Limbo. CMS and Limbo subjects had a higher frequency of RLS (p <0.05). Limbo subjects had the highest severity score for RLS. There were no differences in age, body mass index (BMI), or tobacco use between RLS patients and non-sufferers. In the multivariate analysis, CMS was not associated with RLS diagnosis. Oxygen saturation (p = 0.019), poor sleep quality (p <0.01), and Quinghai score of ≥6 (p = 0.026) were independently associated with RLS diagnosis. CONCLUSIONS: Our results did not show a direct association between RLS and CMS; however, RLS was associated with reduced oxygen saturation. Hence, RLS could represent an early clinical manifestation of hypoxia, or, in CMS natural history, an early sign of maladaptation to high altitude.