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Bailey D.M.,University of South Wales | Bailey D.M.,CNRS Institute of Radical Chemistry | Rimoldi S.F.,University of Bern | Rexhaj E.,University of Bern | And 11 more authors.
Chest | Year: 2013

Background: Acute exposure to high altitude stimulates free radical formation in lowlanders, yet whether this persists during chronic exposure in healthy, well-adapted and maladapted highlanders suffering from chronic mountain sickness (CMS) remains to be established. Methods: Oxidative-nitrosative stress (as determined by the presence of the biomarkers ascorbate radical [A •- ], via electron paramagnetic resonance spectroscopy, and nitrite [NO 2 2 ], via ozonebased chemiluminescence) was assessed in venous blood of 25 male highlanders in Bolivia living at 3,600 m with CMS (n 5 13, CMS 1 ) and without CMS (n 5 12, CMS 2 ). Twelve age- and activitymatched, healthy, male lowlanders were examined at sea level and during acute hypoxia. We also measured fl ow-mediated dilatation (FMD), arterial stiffness defi ned by augmentation index normalized for a heart rate of 75 beats/min (AIx-75), and carotid intima-media thickness (IMT). Results: Compared with normoxic lowlanders, oxidative-nitrosative stress was moderately increased in the CMS 2 group ( P , .05), as indicated by elevated A •- (3,191 - 457 arbitrary units [AU] vs 2,640 - 445 AU) and lower NO 2 2 (206 - 55 nM vs 420 - 128 nM), whereas vascular function remained preserved. This was comparable to that observed during acute hypoxia in lowlanders in whom vascular dysfunction is typically observed. In contrast, this response was markedly exaggerated in CMS 1 group (A •- , 3,765 - 429 AU; NO 2 2 , 148 - 50 nM) compared with both the CMS 2 group and lowlanders ( P , .05). This was associated with systemic vascular dysfunction as indicated by lower ( P , .05 vs CMS 2 ) FMD (4.2% - 0.7% vs 7.6% - 1.7%) and increased AIx-75 (23% - 8% vs 12% - 7%) and carotid IMT (714 - 127 m M vs 588 - 94 m M). Conclusions: Healthy highlanders display a moderate, sustained elevation in oxidative-nitrosative stress that, unlike the equivalent increase evoked by acute hypoxia in healthy lowlanders, failed to affect vascular function. Its more marked elevation in patients with CMS may contribute to systemic vascular dysfunction. © 2013 American College of Chest Physicians.

Pratali L.,CNR Institute of Neuroscience | Allemann Y.,University of Bern | Rimoldi S.F.,University of Bern | Faita F.,CNR Institute of Neuroscience | And 11 more authors.
JACC: Cardiovascular Imaging | Year: 2013

Objectives The aim of this study was to evaluate right ventricular (RV) and left ventricular function and pulmonary circulation in chronic mountain sickness (CMS) patients with rest and stress echocardiography compared with healthy high-altitude (HA) dwellers. Background CMS or Monge's disease is defined by excessive erythrocytosis (hemoglobin >21 g/dl in males, 19 g/dl in females) and severe hypoxemia. In some cases, a moderate or severe increase in pulmonary pressure is present, suggesting a similar pathogenesis of pulmonary hypertension. Methods In La Paz (Bolivia, 3,600 m sea level), 46 CMS patients and 40 HA dwellers of similar age were evaluated at rest and during semisupine bicycle exercise. Pulmonary artery pressure (PAP), pulmonary vascular resistance, and cardiac function were estimated by Doppler echocardiography. Results Compared with HA dwellers, CMS patients showed RV dilation at rest (RV mid diameter: 36 ± 5 mm vs. 32 ± 4 mm, CMS vs. HA, p = 0.001) and reduced RV fractional area change both at rest (35 ± 9% vs. 43 ± 9%, p = 0.002) and during exercise (36 ± 9% vs. 43 ± 8%, CMS vs. HA, p = 0.005). The RV systolic longitudinal function (RV-S′) decreased in CMS patients, whereas it increased in the control patients (p < 0.0001) at peak stress. The RV end-systolic pressure-area relationship, a load independent surrogate of RV contractility, was similar in CMS patients and HA dwellers with a significant increase in systolic PAP and pulmonary vascular resistance in CMS patients (systolic PAP: 50 ± 12 mm Hg vs. 38 ± 8 mm Hg, CMS vs. HA, p < 0.0001; pulmonary vascular resistance: 2.9 ± 1 mm Hg/min/l vs. 2.2 ± 1 mm Hg/min/l, p = 0.03). Both groups showed comparable systolic and diastolic left ventricular function both at rest and during stress. Conclusions Comparable RV contractile reserve in CMS and HA suggests that the lower resting values of RV function in CMS may represent a physiological adaptation to chronic hypoxic conditions rather than impaired RV function. (Chronic Mountain Sickness, Systemic Vascular Function [CMS]; NCT01182792).

Browne V.A.,University of Colorado at Denver | Julian C.G.,University of Colorado at Denver | Toledo-Jaldin L.,Instituto Boliviano Of Biologia Of Altura | Cioffi-Ragan D.,University of Colorado at Denver | And 2 more authors.
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2015

Evolutionary trade-offs required for bipedalism and brain expansion influence the pregnancy rise in uterine artery (UtA) blood flowand, in turn, reproductive success. We consider the importance of UtA blood flow by reviewing its determinants and presenting data from 191 normotensive (normal, n = 125) or hypertensive (preeclampsia (PE) or gestational hypertension (GH), n = 29) Andean residents of very high (4100-4300 m) or low altitude (400 m, n = 37). Prior studies showthat UtA blood flowis reduced in pregnancies with intrauterine growth restriction (IUGR) butwhether the IUGRis due to resultant fetal hypoxia is unclear. We found higher UtA blood flow and Doppler indices of fetal hypoxia in normotensive women at high versus low altitude but similar fetal growth. UtA blood flow was markedly lower in early-onset PE versus normal high-altitude women, and their fetuses more hypoxic as indicated by lower fetal heart rate, Doppler indices and greater IUGR. We concluded that, despite greater fetal hypoxia, fetal growth was well defended by higher UtA blood flows in normal Andeans at high altitude butwhen compounded by lower UtAblood flowin early-onsetPE, exaggerated fetal hypoxia caused the fetus to respond by decreasing cardiac output and redistributing blood flow to help maintain brain development at the expense of growth elsewhere. We speculate that UtAblood flowis not onlyan important supply line but also a trigger for stimulating the metabolic and other processes regulating feto-placentalmetabolismand growth. Studies using the natural laboratory of high altitude are valuable for identifying the physiological and genetic mechanisms involved in human reproductive success. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Soria R.,Instituto Boliviano Of Biologia Of Altura | Julian C.G.,University of Colorado at Denver | Vargas E.,Instituto Boliviano Of Biologia Of Altura | Moore L.G.,University of Colorado at Denver | Giussani D.A.,University of Cambridge
Pediatric Research | Year: 2013

Background: We present a cohort of ca. 25,000 birth records from Bolivia of men and women who are currently adults. We used this cohort to test the hypothesis that high altitude reduces birth weight and that highland ancestry confers graduated protection against this effect. Methods: Birth records were obtained from obstetric clinics and hospitals in La Paz (3,600 m) and Santa Cruz (420 m). Only singleton, healthy term (>37 wk) pregnancies of nonsmoking mothers were included. Andean, Mestizo, or European ancestry was determined by validated analysis of parental surnames. Results: High altitude reduced body weight (3,396 ± 3 vs. 3,090 ± 6 g) and length (50.8 ± 0 vs. 48.7 ± 0 cm) at birth (P < 0.001). Highland ancestry partially protected against the effects of high altitude on birth weight (Andean = 3,148 ± 15 g; Mestizo = 3,081 ± 6 g; and European = 2,957 ± 32 g; trend P < 0.001) but not on birth length. The effects of high-altitude pregnancy on birth size were similar for male and female babies. Conclusion: High altitude reduces birth weight and highland native ancestry confers graduated protection. Given previous studies linking reduced birth weight with increased risk of cardiovascular disease, further study is warranted to test whether adults from high-altitude pregnancy are at increased risk of developing cardiovascular disease. Copyright © 2013 International Pediatric Research Foundation, Inc.

Julian C.G.,University of Colorado at Denver | Hageman J.L.,University of Colorado at Denver | Wilson M.J.,University of Colorado at Denver | Vargas E.,Instituto Boliviano Of Biologia Of Altura | And 2 more authors.
American Journal of Human Biology | Year: 2011

Objective: Maternal physiologic responses to pregnancy promoting fetal oxygen and nutrient delivery are important determinants of reproductive success. Incomplete physiologic compensation for reduced oxygen availability at high altitude (≥2,500 m) compromises fetal growth. Populations of highland (e.g., Andeans, Tibetans) compared with lowland origin groups (e.g., Europeans, Han Chinese) are protected from this altitude-associated decrease in birth weight; here we sought to determine whether maternal development at high altitude-rather than highland ancestry-contributed to the protection of birth weight and uterine artery (UA) blood flow during pregnancy. Methods: In women of lowland ancestry who were either raised at high altitude in La Paz, Bolivia (3,600-4,100 m) ("lifelong," n = 18) or who had migrated there as adults ("newcomers," n = 40) we compared maternal O2 transport during pregnancy and their infant's birth weight. Results: Pregnancy raised maternal ventilation and arterial O2 saturation equally, with the result that arterial O2 content was similarly maintained at nonpregnant levels despite a fall in hemoglobin. UA blood flow and uteroplacental O2 delivery were lower in lifelong than newcomer residents (main effect). Birth weight was similar in lifelong residents versus newcomers (2,948 ± 93 vs. 3,090 ± 70 gm), with both having values below those of a subset of eight high-altitude residents who descended to deliver at low altitude (3,418 ± 133 gm, P < 0.05). Conclusion: Lifelong compared with newcomer high-altitude residents have lower uteroplacental O2 delivery and similar infant birth weights, suggesting that developmental factors are likely not responsible for the protective effect of highland ancestry. © 2011 Wiley-Liss, Inc.

Bigham A.W.,University of Michigan | Julian C.G.,University of Colorado at Denver | Wilson M.J.,University of Colorado at Denver | Wilson M.J.,Western State Colorado University | And 4 more authors.
Physiological Genomics | Year: 2014

Low birth weight and intrauterine growth restriction (IUGR) increase the risk of mortality and morbidity during the perinatal period as well as in adulthood. Environmental and genetic factors contribute to IUGR, but the influence of maternal genetic variation on birth weight is largely unknown. We implemented a gene-by-environment study wherein we utilized the growth restrictive effects of high altitude. Multigenerational high altitude residents (Andeans) are protected from altitude-associated IUGR compared with recent migrants (Europeans). Using a combined cohort of low- and high-altitude European and Andean women, we tested 63 single nucleotide polymorphisms (SNPs) from 16 natural selection-nominated candidate gene regions for associations with infant birth weight. We identified significant SNP associations with birth weight near coding regions for two genes involved in oxygen sensing and vascular control, PRKAA1 and EDNRA, respectively. Next, we identified a significant association for the PRKAA1 SNP with an intermediate phenotype, uterine artery diameter, which has been shown to be related to Andean protection from altitude-associated reductions in fetal growth. To explore potential functional relationships for the effect of maternal SNP genotype on birth weight, we evaluated the relationship between maternal PRKAA1 SNP genotype and gene expression patterns in general and, in particular, of key pathways involved in metabolic homeostasis that have been proposed to play a role in the pathophysiology of IUGR. Our observations suggest that maternal genetic variation within genes that regulate oxygen sensing, metabolic homeostasis, and vascular control influence fetal growth and birth weight outcomes and hence Andean adaptation to high altitude. © 2014 the American Physiological Society.

PubMed | Instituto Boliviano Of Biologia Of Altura, Center for Investigation and Research in Sleep, University of Bern, University of Tarapacá and CNR Institute of Clinical Physiology
Type: Journal Article | Journal: Chest | Year: 2016

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.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.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.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.ClinicalTrials.gov; No.: NCT01182792; URL: www.clinicaltrials.gov.

Brenner R.,University of Bern | Pratali L.,CNR Institute of Clinical Physiology | Rimoldi S.F.,University of Bern | Murillo Jauregui C.X.,Instituto Boliviano Of Biologia Of Altura | And 9 more authors.
Chest | Year: 2015

BACKGROUND: There is considerable interindividual variability in pulmonary artery pressure among high-altitude (HA) dwellers, but the underlying mechanism is not known. At low altitude, a patent foramen ovale (PFO) is present in about 25% of the general population. Its prevalence is increased in clinical conditions associated with pulmonary hypertension and arterial hypoxemia, and it is thought to aggravate these problems. METHODS: We searched for a PFO (transesophageal echocardiography) in healthy HA dwellers (n = 22) and patients with chronic mountain sickness (n = 35) at 3,600 m above sea level and studied its effects (transthoracic echocardiography) on right ventricular (RV) function, pulmonary artery pressure, and vascular resistance at rest and during mild exercise (50 W), an intervention designed to further increase pulmonary artery pressure. RESULTS: The prevalence of PFO (32%) was similar to that reported in low-altitude populations and was not different in participants with and without chronic mountain sickness. Its presence was associated with RV enlargement at rest and an exaggerated increase in right-ventricularto-right-atrial pressure gradient (25 ± 7 mm Hg vs 15 ± 9 mm Hg, P < 001) and a blunted increase in fractional area change of the right ventricle (3% [ 2 1%, 5%] vs 7% [3%, 16%], P =.008) during mild exercise. CONCLUSIONS: These findings show, we believe for the first time, that although the prevalence of PFO is not increased in HA dwellers, its presence appears to facilitate pulmonary vasoconstriction and RV dysfunction during a mild physical eff ort frequently associated with daily activity. © 2015 American College of Chest Physicians.

Stuber T.,University of Bern | Sartori C.,University of Lausanne | Schwab M.,University of Lausanne | Jayet P.-Y.,University of Lausanne | And 8 more authors.
Chest | Year: 2010

Background: Chronic mountain sickness (CMS) is an important public health problem and is characterized by exaggerated hypoxemia, erythrocytosis, and pulmonary hypertension. While pulmonary hypertension is a leading cause of morbidity and mortality in patients with CMS, it is relatively mild and its underlying mechanisms are not known. We speculated that during mild exercise associated with daily activities, pulmonary hypertension in CMS is much more pronounced. Methods: We estimated pulmonary artery pressure by using echocardiography at rest and during mild bicycle exercise at 50 W in 30 male patients with CMS and 32 age-matched, healthy control subjects who were born and living at an altitude of 3,600 m. Results: The modest, albeit significant difference of the systolic right-ventricular-to-right-atrial pressure gradient between patients with CMS and controls at rest (30.3 ± 8.0 vs 25.4 ± 4.5 mm Hg, P 5.002) became more than three times larger during mild bicycle exercise (56.4 ± 19.0 vs 39.8 ± 8.0 mm Hg, P<.001). Conclusions: Measurements of pulmonary artery pressure at rest greatly underestimate pulmonary artery pressure during daily activity in patients with CMS. The marked pulmonary hypertension during mild exercise associated with daily activity may explain why this problem is a leading cause of morbidity and mortality in patients with CMS. © 2010 American College of Chest Physicians.

Jayet P.-Y.,University of Lausanne | Rimoldi S.F.,University of Bern | Stuber T.,University of Bern | Salinas Salmon C.,Instituto Boliviano Of Biologia Of Altura | And 11 more authors.
Circulation | Year: 2010

Background-Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. Methods and Results-We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean±SD, 32.1±5.6 versus 25.3±4.7 mm Hg; P<0.001) and flow-mediated dilation was 30% smaller (6.3±1.2% versus 8.3±1.4%; P<0.0001) in offspring of mothers with preeclampsia than in control subjects. A strong inverse relationship existed between flow-mediated dilation and pulmonary artery pressure (r=-0.61, P<0.001). The vascular dysfunction was related to preeclampsia itself because siblings of offspring of mothers with preeclampsia who were born after a normal pregnancy had normal vascular function. Augmented oxidative stress may represent an underlying mechanism because thiobarbituric acid-reactive substances plasma concentration was increased in offspring of mothers with preeclampsia. Conclusions-Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life. © 2010 American Heart Association, Inc.

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