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    Chronic mountain sickness in Tibet. Pei S X,Chen X J,Si Ren B Z,Liu Y H,Cheng X S,Harris E M,Anand I S,Harris P C The Quarterly journal of medicine A clinical syndrome identical to the chronic mountain sickness of the Andes occurs commonly in Lhasa, Tibet. It affects, almost exclusively, the immigrant Han population and develops after an average of 15 years' residence at high altitude. The early symptoms are attributable to polycythaemia--headache, dizziness, loss of memory and fatigue being prominent. In the later stages of the disease, dyspnoea and peripheral oedema develop. Haemodynamic investigations show pulmonary hypertension with a normal cardiac output and dilatation of the right ventricle in the long-established case. Respiratory gas studies provide evidence of alveolar underventilation and ventilation: perfusion inhomogeneity. Both clinical and investigatory data suggest that the earlier stages of the disease are dominated by polycythaemia, while cardiopulmonary involvement increases with the duration of the disease. The disease is rare in women and uncommon in Tibetans. Cigarette smoking appears to be a contributory factor.
    B-type natriuretic peptide, vascular endothelial growth factor, endothelin-1, and nitric oxide synthase in chronic mountain sickness. Ge Ri-Li,Mo Vivian Y,Januzzi James L,Jin Guan,Yang Yinzhong,Han Shufen,Wood Malissa J,Levine Benjamin D American journal of physiology. Heart and circulatory physiology The pathogenesis of chronic mountain sickness (CMS) may involve vasoactive peptides. The aim of this study was to investigate associations between CMS and levels of B-type natriuretic peptide (BNP), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and endothelial nitric oxide synthase (eNOS). A total of 24 patients with CMS and 50 control subjects residing at 4,300 m participated in this study. Mean pulmonary arterial pressure (mPAP) was measured by echocardiography. Serum BNP, VEGF, ET-1, and eNOS were measured. Receiver operator characteristic curves to assess the balance of sensitivity and specificity for CMS were constructed. As a result, patients with CMS had significantly greater mPAP compared with controls and had lower arterial O(2) saturation (Sa(O(2))). Both BNP and ET-1 correlated positively with mPAP and negatively with Sa(O(2)), whereas serum VEGF levels were inversely correlated with Sa(O(2)); eNOS correlated negatively with mPAP and positively with Sa(O(2)). Median concentrations of BNP were greater in patients with CMS compared with those without CMS: 369 pg/ml [interquartile range (IQR) = 336-431] vs. 243 pg/ml (IQR = 216-279); P < 0.001. Similarly, concentrations of VEGF [543 pg/ml (IQR = 446-546) vs. 243 pg/ml (IQR = 216-279); P < 0.001] and ET-1 [14.7 pg/ml (IQR = 12.5-17.9) vs. 11.1 pg/ml (IQR = 8.7-13.9); P = 0.05] were higher in those with CMS compared with those without, whereas eNOS levels were lower in those with CMS [8.90 pg/ml (IQR 7.59-10.8) vs. 11.2 pg/ml (9.13-13.1); P < 0.001]. The areas under the receiver operator characteristic curves for diagnosis of CMS were 0.91, 0.93, 0.77, and 0.74 for BNP, VEGF, ET-1, and eNOS, respectively. In age- and biomarker-adjusted logistic regression, BNP and VEGF were positively predictive of CMS, whereas eNOS was inversely predictive. In conclusion, severe chronic hypoxemia and consequent pulmonary hypertension in patients with CMS may stimulate release of natriuretic peptides and angiogenic cytokines. These vasoactive peptides may play an important role in the pathogenesis and clinical expression of CMS and may indicate potential prognostic factors in CMS that could serve as targets for therapeutic trials or clinical decision making. 10.1152/ajpheart.00366.2010
    [Multivariate analysis of changes of right heart function at high altitudes]. Zhu Q L,Deng X X,Cai Y N Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae
    Clinical, biochemical, electrocardiographic and noninvasive hemodynamic assessment of cardiovascular status in natives at high to extreme altitudes (3000m-5500m) of the Himalayan region. Sharma S Indian heart journal Cardiovascular status was studied in 500 natives living at high to extreme altitudes (3000m to 5500m) of the Himalayas. No case of congenital heart disease, rheumatic heart disease, coronary artery disease, primary myocardial disease or hypertension was found. A significant rise, however, was noted in both the systolic and diastolic systemic arterial pressure with age. Serum lipid and lipoprotein profile estimation in 148 subjects showed that with increasing altitude, the HDL cholesterol increased, while the LDL cholesterol, total cholesterol/HDL cholesterol ratio and the LDL cholesterol/HDL cholesterol ratio decreased. Electrocardiograms of 160 subjects (120 males and 40 females) above the age of 25 years showed right ventricular hypertrophy in 8 (5%), 6 of whom (17.6%) lived above the altitude of 4800m. Echocardiographic examination showed normal left ventricular function in all, while 27 per cent of the natives at an altitude of 4500m-5000m had evidence of pulmonary hypertension and rise of normalised right ventricular preejection period.
    Pulmonary pressure and cardiac function in chronic mountain sickness patients. Maignan Maxime,Rivera-Ch Maria,Privat Catherine,Leòn-Velarde Fabiola,Richalet Jean-Paul,Pham Isabelle Chest BACKGROUND:Chronic mountain sickness (CMS) is characterized by a loss of adaptation to hypoxia in high-altitude (HA) dwellers. Chronic hypoxemia, excessive erythrocytosis and frequently pulmonary hypertension (PH), which may lead to cardiac failure, develop in patients. We sought to assess the determinants of cardiac function in CMS patients with hypoxia-induced PH. METHODS:Fifteen healthy men living at sea level (SL) were compared to 15 healthy men living at HA and 55 patients with CMS from Cerro de Pasco, Peru (altitude, 4,300 m). Pulmonary pressures and cardiac function were estimated by echocardiography. RESULTS:None of the subjects had overt cardiac failure symptoms. CMS patients exhibited elevated mean pulmonary pressures as assessed by high-tricuspid pressure gradients (CMS patients, 34 +/- 10 mm Hg; HA subjects, 25 +/- 4 mm Hg [p = 0.002]; and SL subjects, 19 +/- 3 mm Hg [p < 0.001]). They also showed right ventricular (RV) dilation (mean end-diastolic RV area: CMS patients, 17 +/- 2 cm(2); HA subjects, 13 +/- 2 cm(2); SL subjects, 12 +/- 2 cm(2); p < 0.001) but did not display impaired systolic ventricular function. However, the RV Tei index was increased in CMS and HA subjects (CMS patients, 0.56 +/- 0.15; HA subjects, 0.52 +/- 0.12; SL subjects, 0.21 +/- 0.12; p < 0.001). CONCLUSION:Despite obvious pulmonary arterial hypertension and right heart dilation, CMS patients did not show any symptom or echocardiographic parameter of heart failure. TRIAL REGISTRATION:ClinicalTrials.gov. Identifier: NCT00424970. 10.1378/chest.08-1094
    Chronic mountain sickness: the reaction of physical disorders to chronic hypoxia. Zubieta-Castillo G,Zubieta-Calleja G R,Zubieta-Calleja L Journal of physiology and pharmacology : an official journal of the Polish Physiological Society Chronic mountain sickness (CMS) is a condition in which hematocrit is increased above the normal level in residents at high altitude. In this article we take issue with the "Consensus Statement On Chronic And Subacute High Altitude Diseases" of 2005 on two essential points: using a questionnaire to evaluate the symptoms of CMS to use the term "loss of adaptation" as opposed to "adaptation to disease in the hypoxic environment". We opine that CMS is rather an adaptive reaction to an underlying malfunction of some organs and no specific symptoms could be quantified. To substantiate our line of reasoning we reviewed 240 CMS cases seen at the High Altitude Pathology Institute in La Paz. Patients who had a high hematocrit (<58%) underwent pulmonary function studies in search for the cause of hypoxia: hypoventilation, diffusion alteration, shunts, and uneven ventilation-perfusion. The tests included arterial blood gas tests, chest x-rays, spirometry, hyperoxic tests, flow-volume curves, ventilation studies at rest and during exercise, ECG, exercise testing and doppler color echocardiography to assess heart structure and function. When correlated with clinical history these results revealed that CMS is practically always secondary to some type of anomaly in cardio-respiratory or renal function. Therefore, a questionnaire that tries to catalog symptoms common to many types of diseases that lead to hypoxia is flawed because it leads to incomplete diagnosis and inappropriate treatment. CMS, once again, was shown to be an adaptation of the blood transport system to a deficient organs' function due to diverse disease processes; the adaptation aimed at sustaining normoxia at the cellular level in the hypoxic environment at high altitude.
    [Influence of high altitude environment on heart (author's transl)]. Deng X X,Cheng X S,Cai Y N,Yun J T,Li G,Liang Y,Li J X,Liao D H Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae
    Hormonal changes in normal and polycythemic high-altitude natives. Antezana A M,Richalet J P,Noriega I,Galarza M,Antezana G Journal of applied physiology (Bethesda, Md. : 1985) Acute and chronic exposure to high-altitude (HA) hypoxia inhibits the renin-angiotensin-aldosterone system and may modify the release of atrial natriuretic peptide (ANP) in sea-level (SL) natives. In HA natives, the release of these hormones could be influenced by changes in blood volume or pulmonary arterial pressure. Twenty-four men residing in La Paz, Bolivia, at 3,600 m were separated into two groups: one normocythemic (HAN; with hematocrit < 57%; n = 13) and the other polycythemic (HAP; with hematocrit > 57%; n = 11). A control group of 9 SL residents was studied in normoxia (SLN) as well as after 4 days spent at 4,350 m (SLH). The groups were tested for plasma active renin (PAR), plasma aldosterone concentration, ANP, and potassium and norepineprine concentrations at rest and after a maximal exercise. Pulmonary arterial systolic pressure was assessed by a Doppler technique. It was observed that PAR and plasma aldosterone concentration at rest and after exercise were lower in the SLH than in the SLN group. PAR and norepineprine concentration were higher among highlanders than in the SLN group. Renin response to exercise was normal among the HAN group and slightly decreased among the HAP group, and an exercise-induced increase in aldosterone was attenuated in both HA groups. Aldosterone response to renin was maintained among the SLH group but was attenuated in the HA groups, possibly owing to a protective mechanism against salt and water retention. Resting and exercise ANP was lower in the HA groups than in the SLN group.(ABSTRACT TRUNCATED AT 250 WORDS) 10.1152/jappl.1995.79.3.795
    Endothelin-1 in pulmonary hypertension associated with high-altitude exposure. Goerre S,Wenk M,Bärtsch P,Lüscher T F,Niroomand F,Hohenhaus E,Oelz O,Reinhart W H Circulation BACKGROUND:Endothelin-1 is involved in chronic pulmonary hypertension. Its role in acute pulmonary hypertension due to hypoxia in humans is not clear. We therefore studied the influence of hypoxia caused by exposure to high altitude on plasma endothelin-1 levels, arterial blood gases, and pulmonary arterial pressure in subjects taking nifedipine or placebo. METHODS AND RESULTS:Twenty-two healthy volunteers were investigated at low altitude (490 m) and high altitude (4559 m). Arterial blood gases were analyzed immediately, endothelin-1 was measured by radioimmunoassay, and pulmonary artery pressure was assessed by Doppler echocardiography. After baseline investigations, the mountaineers were allocated in a randomized double-blind fashion to receive either placebo or nifedipine (20 mg TID) during rapid ascent to high altitude within 22 hours. Tests were repeated at the high-altitude research laboratories located in the Capanna "Regina Margherita" (Italy, 4559 m). Plasma endothelin-1 was increased twofold at high altitude (5.9 +/- 2.2 pg/mL compared with 2.9 +/- 1.1 pg/mL, P < .05), was inversely related to arterial PO2 (r = -.46, P < .001), and correlated with pulmonary artery pressure (r = .52, P < .002). At high altitude, arterial endothelin-1 was lower (4.3 +/- 1.6 pg/mL) than venous endothelin-1 (5.9 +/= 2.2 pg/mL, P < .001), indicating either predominant production in the venous vasculature or pronounced clearance in the pulmonary circulation. The calcium antagonist nifedipine, which lowered pulmonary artery pressure at high altitude (32 +/- 5 versus 42 +/- 11 mm Hg, P < .05), had no influence on plasma endothelin-1 levels. The administration of 35% O2 at high altitude normalized arterial PO2, tended to decrease endothelin-1, and decreased pulmonary artery pressure accordingly. CONCLUSIONS:We conclude that plasma endothelin-1 is increased at high altitude, but whether or not it represents an important pathogenetic factor for pulmonary hypertension remains to be investigated. 10.1161/01.cir.91.2.359
    RV is doing well at high altitudes!--Always? Naeije Robert JACC. Cardiovascular imaging 10.1016/j.jcmg.2013.09.011
    Cardiac response to hypobaric hypoxia: persistent changes in cardiac mass, function, and energy metabolism after a trek to Mt. Everest Base Camp. Holloway Cameron J,Montgomery Hugh E,Murray Andrew J,Cochlin Lowri E,Codreanu Ion,Hopwood Naomi,Johnson Andrew W,Rider Oliver J,Levett Denny Z H,Tyler Damian J,Francis Jane M,Neubauer Stefan,Grocott Michael P W,Clarke Kieran, FASEB journal : official publication of the Federation of American Societies for Experimental Biology We postulated that changes in cardiac high-energy phosphate metabolism may underlie the myocardial dysfunction caused by hypobaric hypoxia. Healthy volunteers (n=14) were studied immediately before, and within 4 d of return from, a 17-d trek to Mt. Everest Base Camp (5300 m). (31)P magnetic resonance (MR) spectroscopy was used to measure cardiac phosphocreatine (PCr)/ATP, and MR imaging and echocardiography were used to assess cardiac volumes, mass, and function. Immediately after returning from Mt. Everest, total body weight had fallen by 3% (P<0.05), but left ventricular mass, adjusted for changes in body surface area, had disproportionately decreased by 11% (P<0.05). Alterations in diastolic function were also observed, with a reduction in peak left ventricular filling rates and mitral inflow E/A, by 17% (P<0.05) and 24% (P<0.01), respectively, with no change in hydration status. Compared with pretrek, cardiac PCr/ATP ratio had decreased by 18% (P<0.01). Whether the abnormalities were even greater at altitude is unknown, but all had returned to pretrek levels after 6 mo. The alterations in cardiac morphology, function, and energetics are similar to findings in patients with chronic hypoxia. Thus, a decrease in cardiac PCr/ATP may be a universal response to periods of sustained low oxygen availability, underlying hypoxia-induced cardiac dysfunction in healthy human heart and in patients with cardiopulmonary diseases. 10.1096/fj.10-172999
    Decrease of asymmetric dimethylarginine predicts acute mountain sickness. Tannheimer Markus,Hornung Kerstin,Gasche Matthias,Kuehlmuss Bernd,Mueller Matthias,Welsch Heiko,Landgraf Klaus,Guger Christoph,Schmidt Roland,Steinacker Jürgen Michael Journal of travel medicine INTRODUCTION:Each year, 40 million tourists worldwide are at risk of getting acute mountain sickness (AMS), because they travel to altitudes of over 2500 m. As asymmetric dimethylarginine (ADMA) is a nitric oxide synthase (NOS) inhibitor, it should increase pulmonary artery pressure (PAP) and raise the risk of acute mountain sickness and high-altitude pulmonary edema (HAPE). With this in mind, we investigated whether changes in ADMA levels (Δ-ADMA) at an altitude of 4000 m can predict an individual's susceptibility to AMS or HAPE. METHODS:Twelve subjects spent two nights in a hypobaric chamber, the first night without exposure to altitude conditions and the second night at a simulated altitude of 4000 m. At identical time points during both nights (after 2, 5, and 11 hours), we determined ADMA serum levels, PAP by Doppler echocardiography and estimated hypoxia related symptoms by Lake Louise Score (LLS). RESULTS:Contrary to our initial hypothesis, subjects with a marked increase in ADMA at 4000 m showed PAP levels below the critical threshold for HAPE and were not affected by AMS. By contrast, subjects with a decrease in ADMA suffered from AMS and had PAP levels above 40 mmHg. After 2 hours of hypoxia we found a significant relationship between Δ-PAP t(2) (Spearmans ρ = 0.30, p ≤ 0.05) respectively Δ-ADMA t(2) (ρ = -0.92, p ≤ 0.05) and LLS. CONCLUSION:After 2 hours of hypoxia, the Δ-ADMA (positive or negative) can predict an LLS of >5 with a sensitivity of 80% and a specificity of 100% and can help assess the risk of an increase in PAP to more than 40 mmHg and thus the risk of HAPE (ϕ coefficient: 0.69; p ≤ 0.05). 10.1111/j.1708-8305.2012.00652.x
    Epidemiological study of chronic mountain sickness in natives of Spiti Valley in the Greater Himalayas. Negi Prakash Chand,Asotra Sanjeev,V Ravi Kumar,Marwah Rajeev,Kandoria Arvind,Ganju Neeraj Kumar,Sharma Rajesh,Bhardwaj Rajeev High altitude medicine & biology AIMS:This study determined the prevalence of chronic mountain sickness (CMS) and its predisposing factors among natives of Spiti Valley in the northern state of Indian Himalayas. A cross-sectional survey study was conducted in natives of Spiti Valley aged ≥ 20 years residing at altitudes of 3000 to 4200 meters. CMS was diagnosed using Qinghai criteria. Demographics, behavioral characteristics, specified symptoms of CMS were recorded, including BP, anthropometrics, evidence of RHF, PAH, and severe cyanosis. ECG, echocardiography, PFT, and Sao2 were recorded, and Hb level was estimated with the cyanmethhemoglobin method. RESULTS:694 subjects free of cardiorespiratory diseases were analyzed. Prevalence of CMS was 28.7%, (95% C.I. of 25.9%-32.8%) and was higher in women than in men (36.6% vs. 15.7%, p<0.001). Erythrocythemia and hypoxemia were recorded in 10.5% and 7.5%, respectively. Age, truncal obesity, female gender, altitude of residence, and physical activity index were independent predictors of CMS with z statistics of 4.2, 2.29, -3.7, 2.8, and -2.8, respectively, and were statistically significant p<0.001. 6.2% of the surveyed population had HAPH. CONCLUSION:28.7% (95% C.I. of 25.9%-32.8%) of the natives of the Spiti Valley in the Indian Himalayas are affected with CMS. Higher prevalence of CMS amongst women needs further studies. Westernized lifestyle appears to have predisposition to CMS. 10.1089/ham.2012.1127
    Images in cardiovascular medicine. High-altitude-induced right-heart failure. Huez Sandrine,Faoro Vitalie,Vachiéry Jean-Luc,Unger Philippe,Martinot Jean-Benoit,Naeije Robert Circulation 10.1161/CIRCULATIONAHA.106.650994
    Exercise pathophysiology in patients with chronic mountain sickness exercise in chronic mountain sickness. Groepenhoff Herman,Overbeek Marieke J,Mulè Massimiliano,van der Plas Mart,Argiento Paola,Villafuerte Francisco C,Beloka Sophia,Faoro Vitalie,Macarlupu Jose L,Guenard Herve,de Bisschop Claire,Martinot Jean-Benoit,Vanderpool Rebecca,Penaloza Dante,Naeije Robert Chest BACKGROUND:Chronic mountain sickness (CMS) is characterized by a combination of excessive erythrocytosis,severe hypoxemia, and pulmonary hypertension, all of which affect exercise capacity. METHODS:Thirteen patients with CMS and 15 healthy highlander and 15 newcomer lowlander control subjects were investigated at an altitude of 4,350 m (Cerro de Pasco, Peru). All of them underwent measurements of diffusing capacity of lung for nitric oxide and carbon monoxide at rest, echocardiography for estimation of mean pulmonary arterial pressure and cardiac output at rest and at exercise, and an incremental cycle ergometer cardiopulmonary exercise test. RESULTS:The patients with CMS, the healthy highlanders, and the newcomer lowlanders reached a similar maximal oxygen uptake at 32 1, 32 2, and 33 2 mL/min/kg, respectively, mean SE( P 5 .8), with ventilatory equivalents for C O 2 vs end-tidal P CO 2 , measured at the anaerobic threshold,of 0.9 0.1, 1.2 0.1, and 1.4 0.1 mm Hg, respectively ( P , .001); arterial oxygen content of 26 1, 21 2, and 16 1 mL/dL, respectively ( P , .001); diffusing capacity for carbon monoxide corrected for alveolar volume of 155% 4%, 150% 5%, and 120% 3% predicted, respectively( P , .001), with diffusing capacity for nitric oxide and carbon monoxide ratios of 4.7 0.1 at sea level decreased to 3.6 0.1, 3.7 0.1, and 3.9 0.1, respectively ( P , .05) and a maximal exercise mean pulmonary arterial pressure at 56 4, 42 3, and 31 2 mm Hg, respectively ( P , .001). CONCLUSIONS:The aerobic exercise capacity of patients with CMS is preserved in spite of severe pulmonary hypertension and relative hypoventilation, probably by a combination of increased oxygen carrying capacity of the blood and lung diffusion, the latter being predominantly due to an increased capillary blood volume. 10.1378/chest.11-2845
    [Study of hibernating myocardium with high altitude heart disease]. Peng Xian-bo,Mu Xin-bing,He Feng Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology
    The Effects of Sex on Cardiopulmonary Responses to Acute Normobaric Hypoxia. Boos Christopher John,Mellor Adrian,O'Hara John Paul,Tsakirides Costas,Woods David Richard High altitude medicine & biology UNLABELLED:Boos, Christopher John, Adrian Mellor, John Paul O'Hara, Costas Tsakirides, and David Richard Woods. The effects of sex on cardiopulmonary responses to acute normobaric hypoxia. High Alt Med Biol. 17:108-115, 2016.- BACKGROUND:Acute hypoxia leads to a number of recognized changes in cardiopulmonary function, including acute increase in pulmonary artery systolic pressure. However, the comparative responses between men and women have been barely explored. METHODS:Fourteen young healthy adult Caucasian subjects were studied at sea-level rest and then after >150-minute exposure to acute normobaric hypoxia (NH) equivalent to 4800 m and again at sea-level rest at 2 hours post-NH exposure. Cardiac function, using transthoracic echocardiography, physiological variables, and Lake Louise Scores for acute mountain sickness (AMS) were collected. RESULTS:All subjects completed the study, and there was an equal balance of men (n = 7) and women (n = 7) who were well matched for age (25.9 ± 3.2 vs. 27.3 ± 4.4; p = 0.51). NH exposure led to a significant increase in AMS scores and heart rate, as well as a fall in oxygen saturation, systolic blood pressure, and stroke volume. Stroke volumes and cardiac output were overall significantly higher in men than in women, and acute NH heart rate was higher in women (80.3 ± 10.2 vs. 69.7 ± 10.7/min; p < 0.05). NH led to a significant fall in the estimated left ventricular filling pressure (E/E'), an increase in the septal A' and S' and septal and lateral isovolumic contractile velocities (ICVs), and a fall in the E'A'S' ratio. The mitral E, lateral ICV, and E' velocities were all higher in men. Acute NH led to a significant increase in right ventricular systolic pressure and pulmonary vascular resistance. There was no interaction between NH exposure and sex for any parameters measured. CONCLUSION:Despite several baseline differences between men and women, the cardiopulmonary effects of acute NH are consistent between men and women. 10.1089/ham.2015.0114
    [Comparitive [Comparative] study of the indexes of pulmonary arterial pressure of healthy children at different altitudes by Doppler echocardiography]. Pang Ying,Ma Ru-Yan,Qi Hai-Ying,Sun Kun Zhonghua er ke za zhi = Chinese journal of pediatrics OBJECTIVE:Reduced oxygen availability at a high altitude is associated with increased pulmonary arterial pressure (PAP). With the altitude goes up the change of PAP in healthy children is still not clear. The difference of PAP in native Tibetan and Han children at a high altitude are also not clear. Many studies have shown that Doppler echocardiographic estimation of PAP correlates closely to the values obtained with the invasive measurement. Therefore the indexes of PAP in health children living at different altitudes were investigated and the indexes of PAP in Han and Tibetan children at the high altitude were compared by Doppler echocardiography. METHODS:A randomized survey was carried out on the indexes of PAP with Doppler echocardiography (HP-8500 and CAL-163 echocardiographic machine) by two doctors of Qinghai Provincial Women and Children Hospital from June 1998 to July 2002. The survey covering Jiuzhi Qinghai (at 3700 m above the sea level), Xining Qinghai (at 2260 m above the sea level) and Shanghai (at 16 m above the sea level) included a population of 1061 children aged 0 - 14 years. The population of 1061 composed of 218 Han children at Shanghai, 567 Han children at Xining Qinghai and 276 children at Jiuzhi, Qinghai including 118 migrated Han and 148 native Tibetan children. The physical, EKG and chest X-ray examination of each child were carried out to ensure all the subjects were healthy. A pulse oximeter was placed on each child's foot to provide measurements of arterial oxygen saturation (SO2) distal to the ductus arteriosus. The indexes of PAP included right ventricular systolic time interval (RSTI) and mean of pulmonary arterial pressure (mPAP) which was assessed by a multiple regression equation (mPAP=27.79 + 35.42 x PEP/AT-50.85 x AT/ETc). The AT/ETc was that AT/ET was divided by R-R. The RSTI included previous ejection period (PEP), ascending time (AT), ejection time (ET), PEP/AT and AT/ET. All subjects were divided into 7 age groups. The data of PAP indexes were compared among three different altitude groups and age groups. The data of PAP indexes were also compared in Han and Tibetan children living over 3700 m sea level in each age group. RESULTS:With the altitude increase the SO2 of the subjects obviously reduced and the indexes of PAP changed. The SO2 correlated closely with the PEP, AT, PEP/A, AT/ET and mPAP (r = 0.352, 0.144, -0.394, -0.166 and -0.363, respectively; P < 0.01). The AT and AT/ET in the groups of 2260 m and 3700 m were shorter than those in the group of 16 m (P = 0.03-0.000) in each age group. The PEP and PEP/AT in 3700 m group were longer than those in 2260 m and 16 m groups (P=0.006-0.000) in each age group. The mPAP in 3700 m group was higher than that in 2260 m and 16 m groups in each age group (mean [+/-SE] mmHg, 35.23 +/- 8.72 vs 17.99 +/- 8.78 and 15.86 +/- 8.96 aged 0 - 28 d, 32.06 +/- 13.38 vs 20.72 +/- 5.71 and 14.64 +/- 8.19 aged to 6 mo, 31.83 +/- 10.53 vs 20.89 +/- 10.12 and 14.69 +/- 5.89 aged to 1 yr, 27.58 +/- 13.55 vs 19.12 +/- 9.75 and 17.36 +/- 6.71 aged to 3 yr, 24.19 +/- 8.38 vs 19.64 +/- 9.36 and 16.43 +/- 4.68 aged to 6 yr, 23.90 +/- 11.35 vs 16.77 +/- 6.79 and 14.42 +/- 6.50 aged to 10 yr, 23.08 +/- 7.31 vs 18.53 +/- 7.25 and 15.45 +/- 6.12 aged to 14 yr, P=0.000). With the growth of the children the reduction of PAP was remarkable at 3700 m above sea level (F=5.638 P=0.000), the mPAP indexes of the first, second and third age groups were evidently higher than those of the other age groups. The SO2, RSTI and mPAP in the native Tibetan children were not different from those in the migrated Han children (P > 0.05) in each age group. CONCLUSION:The PAP of healthy children at the high altitude was different from that of healthy children at the low altitude. The PAP of the healthy children at 3700 m above sea level was remarkably increased. At 3700 m above sea level the PAP of newborns and infants increased much more compared with that of juvenile. The race may not significantly affect the PAP at the high altitude. The high altitude hypoxic environment might play a major role in the increase of PAP.
    RV contractility and exercise-induced pulmonary hypertension in chronic mountain sickness: a stress echocardiographic and tissue Doppler imaging study. Pratali Lorenza,Allemann Yves,Rimoldi Stefano F,Faita Francesco,Hutter Damian,Rexhaj Emrush,Brenner Roman,Bailey Damian M,Sartori Claudio,Salmon Carlos Salinas,Villena Mercedes,Scherrer Urs,Picano Eugenio,Sicari Rosa JACC. Cardiovascular imaging 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). 10.1016/j.jcmg.2013.08.007
    Pulmonary artery pressure in healthy subjects at 4250 m measured by Doppler echocardiography. Dubowitz Gerald,Peacock Andrew J Wilderness & environmental medicine OBJECTIVE:Acute hypoxia causes vasoconstriction in the pulmonary arteries. This hypoxic pulmonary vasoconstriction (HPV) has been reported to be common in subjects exposed to high altitude. In the past, it has been difficult to directly measure this HPV because of the invasive nature of tests, but the recent availability of portable color flow Doppler ultrasound has enabled measurements of pulmonary artery systolic pressure (PASP) in the field. We set out to study the feasibility of this method to detect changes related to HPV at 4250 m. We hypothesized that significant changes in the cardiopulmonary circulation are seen at high altitude and are detectable with Doppler echocardiography. In addition, we hypothesized that detected changes are related to the syndrome of acute mountain sickness (AMS) and could be reversed using 100% oxygen. METHODS:Over a 10-week period in the spring of 1998, 56 healthy lowlanders not normally residing at altitude were studied while visiting 4250 m in Nepal having walked from 2774 m. This was a cross-sectional observational study conducted by a single experienced observer at high altitude, using transthoracic color flow continuous wave Doppler echocardiography. Subjects were initially assessed for significant tricuspid regurgitation (TR) to measure PASP. After estimating PASP under ambient conditions at altitude, oxygen was delivered and PASP remeasured. RESULTS:Of 56 subjects, 36 had Doppler signals appropriate for estimation of pulmonary artery systolic pressure. In these 36, a wide range of PASP was observed (mean 25 mm Hg, range 18-36 mm Hg), but none fell outside of the normal range. After oxygen administration, PASP was reduced (from mean 25 mm Hg to mean 18 mm Hg, P<.0001) suggesting that a degree of hypoxic pulmonary vasoconstriction was present. No subjects in the study group reported clinical AMS. CONCLUSIONS:We found PASP at 4250 m to be within the normal range but higher than would be expected at sea level; however, unlike previous reports, we found such increases to be mild and reversible with oxygen. In addition, the observed incidence of AMS was low when compared with earlier studies, perhaps related to adequate acclimatization. 10.1580/07-WEME-OR-094R1.1
    High altitude pulmonary hypertension with severe right ventricular dysfunction. Maripov Abdirashit,Mamazhakypov Argen,Karagulova Gulnura,Sydykov Akylbek,Sarybaev Akpay International journal of cardiology 10.1016/j.ijcard.2013.07.129
    High-altitude pulmonary hypertension. Xu X-Q,Jing Z-C European respiratory review : an official journal of the European Respiratory Society High-altitude pulmonary hypertension (HAPH) is a specific disease affecting populations that live at high elevations. The prevalence of HAPH among those residing at high altitudes needs to be further defined. Whereas reduction in nitric oxide production may be one mechanism for the development of HAPH, the roles of endothelin-1 and prostaglandin I₂ pathways in the pathogenesis of HAPH deserve further study. Although some studies have suggested that genetic factors contribute to the pathogenesis of HAPH, data published to date are insufficient for the identification of a significant number of gene polymorphims in HAPH. The clinical presentation of HAPH is nonspecific. Exertional dyspnoea is the most common symptom and signs related to right heart failure are common in late stages of HAPH. Echocardiography is the most useful screening tool and right heart catheterisation is the gold standard for the diagnosis of HAPH. The ideal management for HAPH is migration to lower altitudes. Phosphodiesterase 5 is an attractive drug target for the treatment of HAPH. In addition, acetazolamide is a promising therapeutic agent for high-altitude pulmonary hypertension. To date, no evidence has confirmed whether endothelin-receptor antagonists have efficacy in the treatment of high-altitude pulmonary hypertension. 10.1183/09059180.00011104
    Anatomical and hemodynamic evaluations of the heart and pulmonary arterial pressure in healthy children residing at high altitude in China. Qi Hai-Ying,Ma Ru-Yan,Jiang Li-Xia,Li Shu-Ping,Mai Shu,Chen Hong,Ge Mei,Wang Mei-Ying,Liu Hai-Ning,Cai Yue-Hong,Xu Su-Ya,Li Jia International journal of cardiology. Heart & vasculature OBJECTIVES:Altitude-hypoxia induces pulmonary arterial hypertension and altered cardiac morphology and function, which is little known in healthy children at high altitude. We compared the cardiopulmonary measurements between the healthy children at 16 m and those at 3700 m in China and between the Hans and the Tibetans at 3700 m. METHODS:Echocardiography was assessed in 477 children (15 day-14 years) including 220 at 16 m and 257 at 3700 m. The dimensions and wall thickness of the left- and right-sided heart, systolic and diastolic functions including cardiac output index (CI) were measured using standard methods. Mean pulmonary arterial pressure (mPAP) was estimated by the Doppler waveforms in the main pulmonary artery. RESULTS:Compared to the 16 m-group, 3700 m-group had higher mPAP, increasing dilatation of the right heart, and slower decrease in right ventricular hypertrophy in 14 years (p < 0.05). The left heart morphology was not different (p > 0.20). Systolic and diastolic functions of both ventricles were significantly reduced, but CI was higher (p < 0.0001). There was no difference in any measurement between the Hans and the Tibetans (p > 0.05). CONCLUSIONS:Children living at high altitude in China have significantly higher mPAP, dilated right heart and slower regression of right ventricular hypertrophy in the first 14 years of life. Systolic and diastolic functions of both ventricles were reduced with a paradoxically higher CI. There was no significant difference in these features between the Hans and the Tibetans. These values provide references for the care of healthy children and the sick ones with cardiopulmonary diseases at high altitude. 10.1016/j.ijcha.2014.10.015
    Chronic intermittent hypoxia at high altitude exposure for over 12 years: assessment of hematological, cardiovascular, and renal effects. Brito Julio,Siqués Patricia,León-Velarde Fabiola,De La Cruz Juan José,López Vasthi,Herruzo Rafael High altitude medicine & biology The aim of this cross-sectional study was to assess the health status of subjects weekly commuting between sea level and 3550-m altitude for at least 12 yr (average 22.1 +/- 5.8). We studied 50 healthy army men (aged 48.7 +/- 2.0) working 4 days in Putre at 3550-m altitude, with 3 days rest at sea level (SL) at Arica, Chile. Blood pressure, heart rate, Sa(O(2) ), and altitude symptoms (AMS score and sleep status) were measured at altitude (days 1, 2, and 4) and at SL (days 1, 2, and 3). Hematological parameters, lipid profile, renal function, and echocardiography were performed at SL on day 1. The results showed signs of acute exposure to hypoxia (tachycardia, high blood pressure, low Sa(O(2) )), AMS symptoms, and sleep disturbances on day 1, which rapidly decreased on day 2. In addition, echocardiographic findings showed pulmonary hypertension (PAPm > 25 mmHg, RV and RA enlargement) in 2 subjects (4%), a PAPm > 20 mmHg in 14%, and a right ventricle thickness >40 mm in 12%. Hematocrit (45 +/- 2.7) and hemoglobin (15 +/- 1.0) were elevated, but lower than in permanent residents. There was a remarkably high triglyceride level (238 +/- 162) and a mild decrease of glomerular filtration rate (34% under 90 mL/min and 8% under 80 mL/min of creatinine clearance). In conclusion, in these preliminary results, in chronic intermittent hypoxia exposure even over longer periods, most subjects still show symptoms of acute altitude illnesses, but a faster recovery. Findings in triglycerides, in the pulmonary circulation and in renal function, are also a matter of concern. 10.1089/ham.2007.8310
    Pulmonary capillary blood volume and membrane conductance in Andeans and lowlanders at high altitude: a cross-sectional study. de Bisschop Claire,Kiger Laurent,Marden Michael C,Ajata Alfredo,Huez Sandrine,Faoro Vitalie,Martinot Jean-Benoit,Naeije Robert,Guénard Hervé Nitric oxide : biology and chemistry Lung carbon monoxide (CO) transfer and pulmonary capillary blood volume (Vc) at high altitudes have been reported as being higher in native highlanders compared to acclimatised lowlanders but large discrepancies appears between the studies. This finding raises the question of whether hypoxia induces pulmonary angiogenesis. Eighteen highlanders living in Bolivia and 16 European lowlander volunteers were studied. The latter were studied both at sea level and after acclimatisation to high altitude. Membrane conductance (Dm(CO)) and Vc, corrected for the haemoglobin concentration (Vc(cor)), were calculated using the NO/CO transfer technique. Pulmonary arterial pressure and left atrial pressures were estimated using echocardiography. Highlanders exhibited significantly higher NO and CO transfer than acclimatised lowlanders, with Vc(cor)/VA and Dm(CO)/VA being 49 and 17% greater (VA: alveolar volume) in highlanders, respectively. In acclimatised lowlanders, Dm(CO) and Dm(CO)/VA values were lower at high altitudes than at sea level. Echocardiographic estimates of cardiac output and pulmonary arterial pressure were significantly elevated at high altitudes as compared to sea level. The decrease in Dm(CO) in lowlanders might be due to altered gas transport in the airways due to the low density of air at high altitudes. The disproportionate increase in Vc in Andeans compared to the change in Dm(CO) suggests that the recruitment of capillaries is associated with a thickening of the blood capillary sheet. Since there was no correlation between the increase in Vc and the slight alterations in haemodynamics, this data suggests that chronic hypoxia might stimulate pulmonary angiogenesis in Andeans who live at high altitudes. 10.1016/j.niox.2010.05.288
    Echocardiographic and tissue Doppler imaging of cardiac adaptation to high altitude in native highlanders versus acclimatized lowlanders. Huez Sandrine,Faoro Vitalie,Guénard Herve,Martinot Jean-Benoit,Naeije Robert The American journal of cardiology High-altitude exposure is a cause of pulmonary hypertension and decreased exercise capacity, but associated changes in cardiac function remain incompletely understood. The aim of this study was to investigate right ventricular (RV) and left ventricular function in acclimatized Caucasian lowlanders compared with native Bolivian highlanders at high altitudes. Standard echocardiography and tissue Doppler imaging studies were performed in 15 healthy lowlanders at sea level; <24 hours after arrival in La Paz, Bolivia, at 3,750 m; and after 10 days of acclimatization and ascent to Huayna Potosi, at 4,850 m, and the results were compared with those obtained in 15 age- and body size-matched inhabitants of Oruro, Bolivia, at 4,000 m. Acute exposure to high altitude in lowlanders caused an increase in mean pulmonary arterial pressure, to 20 to 25 mm Hg, and altered RV and left ventricular diastolic function, with prolonged isovolumic relaxation time, an increased RV Tei index, and maintained RV systolic function as estimated by tricuspid annular plane excursion and the tricuspid annular S wave. This profile was essentially unchanged after acclimatization and ascent to 4,850 m, except for higher pulmonary arterial pressure. The native highlanders presented with relatively lower pulmonary arterial pressures but more pronounced alterations in diastolic function, decreased tricuspid annular plane excursion and tricuspid annular S waves, and increased RV Tei indexes. In conclusion, cardiac adaptation to high altitude was qualitatively similar in acclimatized Caucasian lowlanders and in Bolivian native highlanders. However, lifelong exposure to high altitude may be associated with different cardiac adaptation to milder hypoxic pulmonary hypertension. 10.1016/j.amjcard.2009.02.006
    Can patients with pulmonary hypertension travel to high altitude? Luks Andrew M High altitude medicine & biology With the increasing popularity of adventure travel and mountain activities, it is likely that many high altitude travelers will have underlying medical problems and approach clinicians for advice about ensuring a safe sojourn. Patients with underlying pulmonary hypertension are one group who warrants significant concern during high altitude travel, because ambient hypoxia at high altitude will trigger hypoxic pulmonary vasoconstriction and cause further increases in pulmonary artery (PA) pressure, which may worsen hemodynamics and also predispose to acute altitude illness. After addressing basic information about pulmonary hypertension and pulmonary vascular responses to acute hypoxia, this review discusses the evidence supporting an increased risk for high altitude pulmonary edema in these patients, concerns regarding worsening oxygenation and right-heart function, the degree of underlying pulmonary hypertension necessary to increase risk, and the altitude at which such problems may occur. These patients may be able to travel to high altitude, but they require careful pre-trip assessment, including echocardiography and, when feasible, high altitude simulation testing with echocardiography to assess changes in PA pressure and oxygenation under hypoxic conditions. Those with mean PA pressure > or =35 mm Hg or systolic PA pressure > or =50 mm Hg at baseline should avoid travel to >2000 m; but if such travel is necessary or strongly desired, they should use supplemental oxygen during the sojourn. Patients with milder degrees of pulmonary hypertension may travel to altitudes <3000 m, but should consider prophylactic measures, including pulmonary vasodilators or supplemental oxygen. 10.1089/ham.2009.10306
    Reliability of echocardiographic speckle-tracking derived bi-atrial strain assessment under different hemodynamic conditions. Sareban Mahdi,Perz Tabea,Macholz Franziska,Reich Bernhard,Schmidt Peter,Fried Sebastian,Mairbäurl Heimo,Berger Marc M,Niebauer Josef The international journal of cardiovascular imaging The aim of this study was to assess intra- and inter-observer variability of left (LA) and right atrial (RA) strain indices obtained by two-dimensional speckle-tracking echocardiography (2D-STE) in a healthy group of individuals at low-altitude and after rapid ascent to high-altitude in order to provoke altered systemic and pulmonary hemodynamics otherwise seen in various cardiac diseases. Twenty healthy subjects underwent transthoracic echocardiography during a baseline examination at low-altitude (424 m) as well as 7, 20 and 44 h after arrival at high-altitude (4559 m). Atrial strain indices (i.e. reservoir, conduit and contractile strain) were determined off-line by two independent observers. Intra- and inter-observer reproducibility of variables was assessed by intra-class correlation coefficients (ICCs), coefficients of variation and Bland Altman plots. Heart rate, systemic blood pressure and pulmonary artery pressure increased significantly from low-altitude to the first examination at high-altitude. Intra-observer ICCs were ≥0.90 except for RA conduit strain with an ICC of 0.86. The mean intra-observer differences were small and limits of agreement of relative differences were narrow for all atrial strain parameters (<3 and <16%, respectively). Inter-observer ICCs (0.80-0.90), mean biases and limits of agreement (<4 and <20%, respectively) were greater than intra-observer results for all parameters. Intra- and inter-obserer ICCs for all atrial strain variables did not differ between low- and high-altitude. 2D-STE-derived bi-atrial strain indices have excellent intra- and moderate inter-observer reproducibility with no effect of high-altitude-induced hemodynamic changes on reliability results. 10.1007/s10554-017-1154-7
    Right ventricular morphology and function in chronic obstructive pulmonary disease patients living at high altitude. Güvenç Tolga Sinan,Erer Hatice Betül,Kul Seref,Perinçek Gökhan,Ilhan Sami,Sayar Nurten,Yıldırım Binnaz Zeynep,Doğan Coşkun,Karabağ Yavuz,Balcı Bahattin,Eren Mehmet Heart, lung & circulation INTRODUCTION:Pulmonary vasculature is affected in patients with chronic pulmonary obstructive disease (COPD). As a result of increased pulmonary resistance, right ventricular morphology and function are altered in COPD patients. High altitude and related hypoxia causes pulmonary vasoconstriction, thereby affecting the right ventricle. We aimed to investigate the combined effects of COPD and altitude-related chronic hypoxia on right ventricular morphology and function. MATERIALS AND METHODS:Forty COPD patients living at high altitude (1768 m) and 41 COPD patients living at sea level were enrolled in the study. All participants were diagnosed as COPD by a pulmonary diseases specialist depending on symptoms, radiologic findings and pulmonary function test results. Detailed two-dimensional echocardiography was performed by a cardiologist at both study locations. RESULTS:Oxygen saturation and mean pulmonary artery pressure were higher in the high altitude group. Right ventricular end diastolic diameter, end systolic diameter, height and end systolic area were significantly higher in the high altitude group compared to the sea level group. Parameters of systolic function, including tricuspid annular systolic excursion, systolic velocity of tricuspid annulus and right ventricular isovolumic acceleration were similar between groups, while fractional area change was significantly higher in the sea level groups compared to the high altitude group. Indices of diastolic function and myocardial performance index were similar between groups. CONCLUSION:An increase in mean pulmonary artery pressure and right ventricular dimensions are observed in COPD patients living at high altitude. Despite this increase, systolic and diastolic functions of the right ventricle, as well as global right ventricular performance are similar in COPD patients living at high altitude and sea level. Altitude-related adaptation to chronic hypoxia could explain these findings. 10.1016/j.hlc.2012.08.004
    Comparison of Echocardiographic Parameters Between Healthy Highlanders in Tibet and Lowlanders in Beijing. Yang Ying,Zha-Xi Duo-Ji,Mao Wei,Zhi Guang,Feng Bin,Chen Yun-Dai High altitude medicine & biology Yang, Ying, Duo-Ji Zha-Xi, Wei Mao, Guang Zhi, Bin Feng, and Yun-Dai Chen. Comparison of echocardiographic parameters between healthy highlanders in Tibet and lowlanders in Beijing. High Alt Med Biol. 19:259-264, 2018.-The hearts of highlanders exhibit distinct features compared with the hearts of lowlanders. However, previous findings have not been verified in a large-scale Tibetan population study. The aim of this study was to present differences in echocardiography results among healthy native Tibetans, acclimatized Han highlanders, and Han lowlanders at sea level. A total of 1820 healthy Tibetans and 224 healthy Han highlanders were drawn from a representative sample of residents in Tibet. Echocardiography was performed on each participant at the sampled local medical centers. Echocardiographic data from 2332 healthy Han lowlanders were obtained from a database of a medical examination center in Beijing. Using propensity score matching to balance differences in demographic features, we evaluated the effects of altitude and ethnicity in three paired comparisons. The results revealed that the great arteries were larger in the Han population than in the Tibetan population regardless of altitude (all p < 0.05). No differences were found in the right atrium between different altitudes and ethnicities. The diameters and thicknesses of the right ventricle (RV) were larger in the Tibetans than in the Han lowlanders (i.e., 30.0 mm (26.0, 34.0) versus 28.6 mm (25.5, 31.8) for the basal right ventricular linear dimension). The left heart in diastole was largest in the Han lowlanders (i.e., 46.3 ± 3.9 mm versus 43.0 mm [40.0, 44.0] in Han highlanders and 45.8 mm [43.0, 48.8] versus 42.0 mm [39.0, 45.0] in Tibetans for the diameter of the left ventricle [LV] at end-diastole). Moreover, the interventricular septum was thicker in the high-altitude population than in the low-altitude population (all p < 0.05). Compared with the Tibetans, the Han highlanders exhibited enhanced ventricular functions (65.0% [60.0, 69.0] versus 68.0% [63.0, 69.0] for LV ejection fraction and 22.0 mm [20.0, 26.0] versus 24.0 mm [21.0, 27.0] for tricuspid annular plane systolic excursion, both p < 0.05). In conclusion, a small left heart and a large RV may be consequences of hypoxic exposure at high altitudes irrespective of ethnic origin. 10.1089/ham.2017.0094
    Cardiac structure and function in adolescent Sherpa; effect of habitual altitude and developmental stage. Stembridge Mike,Ainslie Philip N,Donnelly Joseph,MacLeod Nicholas T,Joshi Suchita,Hughes Michael G,Sherpa Kami,Shave Rob American journal of physiology. Heart and circulatory physiology The purpose of this study was to examine ventricular structure and function in Sherpa adolescents to determine whether age-specific differences in oxygen saturation (SpO2 ) and pulmonary artery systolic pressure (PASP) influence cardiac adaptation to chronic hypoxia early in life. Two-dimensional, Doppler, and speckle-tracking echocardiography were performed on adolescent (9-16 yr) highland Sherpa (HLS; 3,840 m; n = 26) and compared with age-matched lowland Sherpa (LLS; 1,400 m; n = 10) and lowland Caucasian controls (LLC; sea level; n = 30). The HLS were subdivided into pre- and postadolescence; SpO2 was also recorded. Only HLS exhibited a smaller relative left ventricular (LV) end-diastolic volume; however, both HLS and LLS demonstrated a lower peak LV untwisting velocity compared with LLC (92 ± 26 and 100 ± 45 vs. 130 ± 43°/s, P < 0.05). Although SpO2 was similar between groups, PASP was higher in post- vs. preadolescent HLS (30 ± 5 vs. 25 ± 5 mmHg, P < 0.05), which negatively correlated with right ventricular strain rate (r = 0.50, P < 0.01). Much like their adult counterparts, HLS and LLS adolescents exhibit slower LV diastolic relaxation, despite residing at different altitudes. These findings suggest fundamental differences exist in the diastolic function of Sherpa that are present at an early age and may be retained after migration to lower altitudes. The higher PASP in postadolescent Sherpa is in contrast to previous reports of lowland children at high altitude and, unlike that in lowlanders, was not explained by differences in SpO2 ; thus different regulatory mechanisms seem to exist between these two distinct populations. 10.1152/ajpheart.00938.2015
    Cardiac biomarkers at high altitude. Mellor Adrian,Boos Christopher,Holdsworth David,Begley Joe,Hall David,Lumley Andrew,Burnett Anne,Hawkins Amanda,O'Hara John,Ball Stephen,Woods David High altitude medicine & biology BACKGROUND:Classically, biomarkers such as the natriuretic peptides (NPs) BNP/NT-proBNP are associated with the diagnosis of heart failure and hs-cTnT with acute coronary syndromes. NPs are also elevated in pulmonary hypertension. High pulmonary artery systolic pressure (PASP) is a key feature of high altitude pulmonary edema (HAPE), which may be difficult to diagnose in the field. We have previously demonstrated that NPs are associated with high PASP and the presence of acute mountain sickness (AMS) in a small cohort at HA. We aimed to investigate the utility of several common cardiac biomarkers in diagnosing high PASP and AMS. METHODS:48 participants were assessed post-trekking and at rest at three altitudes: 3833 m, 4450 m, and 5129 m. NPs, hs-cTnT and hsCRP, were quantified using immunoassays, PASP was measured by echocardiography, and AMS scores were recorded. RESULTS:Significant changes occurred with ascent in NPs, hs-cTnT, hsCRP (all p<0.001) and PASP (p=0.006). A high PASP (≥40 mm Hg) was associated with higher NPs, NT-proBNP: 137±195 vs. 71.8±68 (p=0.001); BNP 15.3±18.1 vs. 8.7±6.6 (p=0.001). NPs were significantly higher in those with AMS or severe AMS vs. those without (severe AMS: NT-proBNP: 161.2±264 vs. 76.4±82.5 (p=0.008)). The NPs correlated with hsCRP. cTnT increased with exercise at HA and was also higher in those with a high PASP (13.8±21 vs. 7.8±6.5, p=0.018). CONCLUSION:The NPs and hs-cTnT are associated with high PASP at HA and the NPs with AMS. 10.1089/ham.2014.1035
    Long-Term Intermittent Work at High Altitude: Right Heart Functional and Morphological Status and Associated Cardiometabolic Factors. Brito Julio,Siques Patricia,López Rosario,Romero Raul,León-Velarde Fabiola,Flores Karen,Lüneburg Nicole,Hannemann Juliane,Böger Rainer H Frontiers in physiology Living at high altitude or with chronic hypoxia implies functional and morphological changes in the right ventricle and pulmonary vasculature with a 10% prevalence of high-altitude pulmonary hypertension (HAPH). The implications of working intermittently (day shifts) at high altitude (hypobaric hypoxia) over the long term are still not well-defined. The aim of this study was to evaluate the right cardiac circuit status along with potentially contributory metabolic variables and distinctive responses after long exposure to the latter condition. A cross-sectional study of 120 healthy miners working at an altitude of 4,400-4,800 m for over 5 years in 7-day commuting shifts was designed. Echocardiography was performed on day 2 at sea level. Additionally, biomedical and biochemical variables, Lake Louise scores (LLSs), sleep disturbances and physiological variables were measured at altitude and at sea level. The population was 41.8 ± 0.7 years old, with an average of 14 ± 0.5 (range 5-29) years spent at altitude. Most subjects still suffered from mild to moderate symptoms of acute mountain sickness (mild was an LLS of 3-5 points, including cephalea; moderate was LLS of 6-10 points) (38.3%) at the end of day 1 of the shift. Echocardiography showed a 23% mean pulmonary artery pressure (mPAP) >25 mmHg, 9% HAPH (≥30 mmHg), 85% mild increase in right ventricle wall thickness (≥5 mm), 64% mild right ventricle dilation, low pulmonary vascular resistance (PVR) and fairly good ventricle performance. Asymmetric dimethylarginine (ADMA) (OR 8.84 (1.18-66.39); < 0.05) and insulin (OR: 1.11 (1.02-1.20); < 0.05) were associated with elevated mPAP and were defined as a cut-off. Interestingly, the correspondence analysis identified association patterns of several other variables (metabolic, labor, and biomedical) with higher mPAP. Working intermittently at high altitude involves a distinctive pattern. The most relevant and novel characteristics are a greater prevalence of elevated mPAP and HAPH than previously reported at chronic intermittent hypobaric hypoxia (CIHH), which is accompanied by subsequent morphological characteristics. These findings are associated with cardiometabolic factors (insulin and ADMA). However, the functional repercussions seem to be minor or negligible. This research contributes to our understanding and surveillance of this unique model of chronic intermittent high-altitude exposure. 10.3389/fphys.2018.00248
    Exaggerated hypoxic pulmonary vasoconstriction without susceptibility to high altitude pulmonary edema. Dehnert Christoph,Mereles Derliz,Greiner Sebastian,Albers Dagmar,Scheurlen Fabian,Zügel Stefanie,Böhm Thomas,Vock Peter,Maggiorini Marco,Grünig Ekkehard,Bärtsch Peter High altitude medicine & biology BACKGROUND:Abnormally high pulmonary artery pressure (PAP) in hypoxia due to exaggerated hypoxic pulmonary vasoconstriction (HPV) is a key factor for development of high-altitude pulmonary edema (HAPE). It was shown that about 10% of a healthy Caucasian population has an exaggerated HPV that is comparable to the response measured in HAPE-susceptible individuals. Therefore, we hypothesized that those with exaggerated HPV are HAPE-susceptible. METHODS AND RESULTS:We screened 421 healthy Caucasians naïve to high altitude for HPV using Doppler echocardiography for assessment of systolic PAP in normobaric hypoxia (PASPHx; Po2 corresponding to 4500 m). Subjects with exaggerated HPV and matched controls were exposed to 4559 m with an identical protocol that causes HAPE in 62% of HAPE-S. Screening revealed 39 subjects with exaggerated HPV, of whom 33 (PASPHx 51±6 mmHg) ascended within 24 hours to 4559 m. Four (13%) of them developed HAPE during the 48 h-stay. This incidence is significantly lower than the recurrence rate of 62% previously observed in HAPE-S in the same setting. None of the control subjects (PASPHx 33±5 mmHg) developed HAPE. CONCLUSION:An exaggerated HPV cannot be considered a surrogate maker for HAPE-susceptibility although excessively elevated PAP is a hallmark in HAPE, while a normal HPV appears to protect from HAPE in this study. 10.1089/ham.2014.1117
    Association between serum concentrations of hypoxia inducible factor responsive proteins and excessive erythrocytosis in high altitude Peru. Painschab Matthew S,Malpartida Gary E,Dávila-Roman Victor G,Gilman Robert H,Kolb Todd M,León-Velarde Fabiola,Miranda J Jaime,Checkley William High altitude medicine & biology Painschab, Matthew S., Gary E. Malpartida, Victor G. Davila-Roman, Robert H. Gilman, Todd M. Kolb, Fabiola Leon-Velarde, J. Jaime Miranda, and William Checkley. Association between serum concentrations of hypoxia inducible factor responsive proteins and excessive erythrocytosis in high altitude Peru. High Alt Med Biol 16:26-33, 2015.-Long-term residence at high altitude is associated with the development of chronic mountain sickness (CMS), which is characterized by excessive erythrocytosis (EE). EE occurs under chronic hypoxia, and a strongly selected mutation in hypoxia-inducible factor 2α (HIF2A) has been found in native Tibetans that correlates with having a normal hemoglobin at high altitude. We sought to evaluate differences in plasma levels of four HIF-responsive proteins in 20 participants with EE (hemoglobin >21 g/dL in men and >19 in women) and in 20 healthy, age- and sex-matched participants without EE living at high altitude in Puno, Peru. We performed ELISA to measure plasma levels of the four HIF-responsive proteins: vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGF-R1), endothelin-1, and erythropoietin. As a secondary aim, we evaluated the association between HIF-responsive proteins and echocardiography-estimated pulmonary artery systolic pressure (PASP) in a subset of 26 participants. sVEGF-R1 was higher in participants with vs. without EE (mean 107 pg/mL vs. 90 pg/mL; p=0.007). Although plasma concentrations of endothelin-1, VEGF, and erythropoietin were higher in participants with vs. without EE, they did not achieve statistical significance (all p>0.25). Both sVEGF-R1 (p=0.04) and erythropoietin (p=0.04) were positively associated with PASP after adjustment for age, sex, and BMI. HIF-responsive proteins may play a pathophysiological role in altitude-related, chronic diseases but our results did not show consistent changes in all measured HIF-responsive proteins. Larger studies are needed to evaluate for additional genetic and environmental risk factors. 10.1089/ham.2014.1086
    Transpulmonary plasma catecholamines in acute high-altitude pulmonary hypertension. Berger Marc M,Luks Andrew M,Bailey Damian M,Menold Elmar,Robotti Guido C,Mairbäurl Heimo,Dehnert Christoph,Swenson Erik R,Bärtsch Peter Wilderness & environmental medicine OBJECTIVE:High altitude leads to an increase in sympathetic nervous system (SNS) activity and pulmonary arterial pressure (PAP). We assessed whether the SNS contributes to this increase in PAP. METHODS:Sympathetic discharge to the pulmonary vasculature was assessed by measuring plasma norepinephrine concentrations in central venous blood entering the lung and systemic arterial blood leaving the lung (arterial-central venous difference; a - cv(diff)). Sympathetic activity in the adrenal gland was assessed by measuring systemic plasma epinephrine concentrations. The a - cv(diff) of epinephrine was assessed to investigate its metabolism across the lung. The measurements were performed in 34 mountaineers during both rest and exercise at low altitude and after 20 hours at high altitude (4559 m). Norepinehrine and epinephrine concentrations were measured by high-performance liquid chromatography. Pulmonary blood flow was assessed by inert gas rebreathing, and systolic PAP (PASP) by transthoracic Doppler-echocardiography. RESULTS:Exercise and high altitude increased PASP and increased arterial and central venous plasma norepinephrine. In contrast, exercise but not high altitude increased arterial and central venous epinephrine. There was no significant a - cv(diff) for norepinephrine and epinephrine during rest and exercise at low altitude, nor during rest at high altitude. However, during exercise at high altitude the a - cv(diff) for norepinephrine was positive. There was no correlation between the a - cv(diff) of both norepinephrine and epinephrine with PASP during exercise, high altitude or during a combination of both. CONCLUSIONS:The degree of pulmonary hypertension that occurs upon high-altitude exposure is largely independent of the SNS activity in the pulmonary vasculature and adrenal gland. 10.1016/j.wem.2010.11.011
    High altitude-induced borderline pulmonary hypertension impaired cardiorespiratory fitness in healthy young men. Yang Te,Li Xiangjun,Qin Jun,Li Shuangfei,Yu Jie,Zhang Jihang,Yu Shiyong,Wu Xiaojing,Huang Lan International journal of cardiology OBJECTIVE:High altitude exposure has been suggested to cause borderline elevation of pulmonary artery pressure (PAP) in quite a few healthy individuals. This cohort study was to investigate the impact of altitude induced borderline pulmonary hypertension (PH) on cardiorespiratory fitness in healthy subjects. METHODS:299 healthy Chinese young men with normal PAP were consecutively studied between July 2011 and September 2013. Among these subjects 114 kept living at low altitude (450m), 91 ascended to high altitude (3700m) from low altitude within 24h (acute exposure), and 94 resided at 3700m for more than 1year (chronic exposure). Mean PAP and cardiac function were examined by echocardiography, and cardiorespiratory fitness was determined by predicted work capacity at a heart rate of 170beats per minute (PWC170). RESULTS:Mean PAP remained within normal range (<20mmHg) in 113 of 114 participants (99%) at low altitude. In contrast, the incidence of borderline PH (mPAP between 20 and 25mmHg) was 29% and 37% for respective acute and chronic exposures. Compared to the subjects with normal mPAP within each of the exposure groups, the subjects with borderline PH had increased right ventricular Tei index (RV-Tei), which correlated with the decline of PWC170 (acute exposure: r=-0.296, p=0.004; chronic exposure: r=-0.247, p=0.016). However, these changes were relatively milder than those with confirmed PH (mPAP>25mmHg). CONCLUSION:Borderline PH compromised cardiorespiratory fitness in healthy young men. The decline of cardiorespiratory fitness was related at least in part with the impaired right ventricular function, which was correlated with the elevated mPAP. 10.1016/j.ijcard.2014.12.044
    Pulmonary vascular reserve and exercise capacity at sea level and at high altitude. Pavelescu Adriana,Faoro Vitalie,Guenard Hervé,de Bisschop Claire,Martinot Jean-Benoit,Mélot Christian,Naeije Robert High altitude medicine & biology It has been suggested that increased pulmonary vascular reserve, as defined by reduced pulmonary vascular resistance (PVR) and increased pulmonary transit of agitated contrast measured by echocardiography, might be associated with increased exercise capacity. Thus, at altitude, where PVR is increased because of hypoxic vasoconstriction, a reduced pulmonary vascular reserve could contribute to reduced exercise capacity. Furthermore, a lower PVR could be associated with higher capillary blood volume and an increased lung diffusing capacity. We reviewed echocardiographic estimates of PVR and measurements of lung diffusing capacity for nitric oxide (DL(NO)) and for carbon monoxide (DL(CO)) at rest, and incremental cardiopulmonary exercise tests in 64 healthy subjects at sea level and during 4 different medical expeditions at altitudes around 5000 m. Altitude exposure was associated with a decrease in maximum oxygen uptake (VO2max), from 42±10 to 32±8 mL/min/kg and increases in PVR, ventilatory equivalents for CO2 (V(E)/VCO2), DL(NO), and DL(CO). By univariate linear regression VO2max at sea level and at altitude was associated with V(E)/VCO2 (p<0.001), mean pulmonary artery pressure (mPpa, p<0.05), stroke volume index (SVI, p<0.05), DL(NO) (p<0.02), and DL(CO) (p=0.05). By multivariable analysis, VO2max at sea level and at altitude was associated with V(E)/VCO2, mPpa, SVI, and DL(NO). The multivariable analysis also showed that the altitude-related decrease in VO2max was associated with increased PVR and V(E)/VCO2. These results suggest that pulmonary vascular reserve, defined by a combination of decreased PVR and increased DL(NO), allows for superior aerobic exercise capacity at a lower ventilatory cost, at sea level and at high altitude. 10.1089/ham.2012.1073
    Cardiovascular medicine at high altitude. Whayne Thomas F Angiology Altitude physiology began with Paul Bert in 1878. Chronic mountain sickness (CMS) was defined by Carlos Monge in the 1940s in the Peruvian Andes as consisting of excess polycythemia. Hurtado et al performed studies in the Peruvian Andes in the 1950s to 1960s which defined acclimatization in healthy altitude natives, including polycythemia, moderate pulmonary hypertension, and low systemic blood pressure (BP). Electrocardiographic changes of right ventricular hypertrophy (RVH) were noted. Acclimatization of newcomers to altitude involves hyperventilation stimulated by hypoxia and is usually benign. Acute mountain sickness (AMS) in travelers to altitude is characterized by hypoxia-induced anorexia, dyspnea, headache, insomnia, and nausea. The extremes of AMS are high-altitude cerebral edema and high-altitude pulmonary edema. The susceptible high-altitude resident can lose their tolerance to altitude and develop CMS, also referred to as Monge disease. The CMS includes extreme polycythemia, severe RVH, excess pulmonary hypertension, low systemic BP, arterial oxygen desaturation, and hypoventilation. 10.1177/0003319713497086
    Pulmonary artery pressure and arterial oxygen saturation in people living at high or low altitude: systematic review and meta-analysis. Soria Rodrigo,Egger Matthias,Scherrer Urs,Bender Nicole,Rimoldi Stefano F Journal of applied physiology (Bethesda, Md. : 1985) More than 140 million people are living at high altitude worldwide. An increase of pulmonary artery pressure (PAP) is a hallmark of high-altitude exposure and, if pronounced, may be associated with important morbidity and mortality. Surprisingly, there is little information on the usual PAP in high-altitude populations. We, therefore, conducted a systematic review (MEDLINE and EMBASE) and meta-analysis of studies published (in English or Spanish) between 2000 and 2015 on echocardiographic estimations of PAP and measurements of arterial oxygen saturation in apparently healthy participants from general populations of high-altitude dwellers (>2,500 m). For comparison, we similarly analyzed data published on these variables during the same period for populations living at low altitude. Twelve high-altitude studies comprising 834 participants and 18 low-altitude studies (710 participants) fulfilled the inclusion criteria. All but one high-altitude studies were performed between 3,600 and 4,350 m. The combined mean systolic PAP (right ventricular-to-right atrial pressure gradient) at high altitude [25.3 mmHg, 95% confidence interval (CI) 24.0, 26.7], as expected was significantly (P < 0.001) higher than at low altitude (18.4 mmHg, 95% CI 17.1,19.7), and arterial oxygen saturation was significantly lower (90.4%, 95% CI 89.3, 91.5) than at low altitude (98.1%; 95% CI 97.7, 98.4). These findings indicate that at an altitude where the very large majority of high-altitude populations are living, pulmonary hypertension appears to be rare. The reference values and distributions for PAP and arterial oxygen saturation in apparently healthy high-altitude dwellers provided by this meta-analysis will be useful to future studies on the adjustments to high altitude in humans. 10.1152/japplphysiol.00394.2016
    Physiological Changes to the Cardiovascular System at High Altitude and Its Effects on Cardiovascular Disease. Riley Callum James,Gavin Matthew High altitude medicine & biology Riley, Callum James, and Matthew Gavin. Physiological changes to the cardiovascular system at high altitude and its effects on cardiovascular disease. High Alt Med Biol. 18:102-113, 2017.-The physiological changes to the cardiovascular system in response to the high altitude environment are well understood. More recently, we have begun to understand how these changes may affect and cause detriment to cardiovascular disease. In addition to this, the increasing availability of altitude simulation has dramatically improved our understanding of the physiology of high altitude. This has allowed further study on the effect of altitude in those with cardiovascular disease in a safe and controlled environment as well as in healthy individuals. Using a thorough PubMed search, this review aims to integrate recent advances in cardiovascular physiology at altitude with previous understanding, as well as its potential implications on cardiovascular disease. Altogether, it was found that the changes at altitude to cardiovascular physiology are profound enough to have a noteworthy effect on many forms of cardiovascular disease. While often asymptomatic, there is some risk in high altitude exposure for individuals with certain cardiovascular diseases. Although controlled research in patients with cardiovascular disease was largely lacking, meaning firm conclusions cannot be drawn, these risks should be a consideration to both the individual and their physician. 10.1089/ham.2016.0112
    Can patients with coronary heart disease go to high altitude? Dehnert Christoph,Bärtsch Peter High altitude medicine & biology Tourism to high altitude is very popular and includes elderly people with both manifest and subclinical coronary heart disease (CHD). Thus, risk assessment regarding high altitude exposure of patients with CHD is of increasing interest, and individual recommendations are expected despite the lack of sufficient scientific evidence. The major factor increasing cardiac stress is hypoxia. At rest and for a given external workload, myocardial oxygen demand is increased at altitude, particularly in nonacclimatized individuals, and there is some evidence that blood-flow reserve is reduced in atherosclerotic coronary arteries even in the absence of severe stenosis. Despite a possible imbalance between oxygen demand and oxygen delivery, studies on selected patients have shown that exposure and exercise at altitudes of 3000 to 3500 m is generally safe for patients with stable CHD and sufficient work capacity. During the first days at altitude, patients with stable angina may develop symptoms of myocardial ischemia at slightly lower heart rate x  blood-pressure products. Adverse cardiac events, however, such as unstable angina coronary syndromes, do not occur more frequently compared with sea level except for those who are unaccustomed to exercise. Therefore, training should start before going to altitude, and the altitude-related decrease in exercise capacity should be considered. Travel to 3500 m should be avoided unless patients have stable disease, preserved left ventricular function without residual capacity, and above-normal exercise capacity. CHD patients should avoid travel to elevations above 4500 m owing to severe hypoxia at these altitudes. The risk assessment of CHD patients at altitude should always consider a possible absence of medical support and that cardiovascular events may turn into disaster. 10.1089/ham.2010.1024
    [A correlation study of Tei index and N-terminal pro-brain natriuretic peptide in patients with high-altitude heart disease]. Li Gao-yuan,Liu Zheng-jian,Chen Hai-jun,Zhang Xue-hong,Jiang Jun-jie,Hu An-zhong Zhonghua nei ke za zhi OBJECTIVE:To explore the diagnostic value of Tei index of right ventricle and serum level of NT-proBNP in patients with high-altitude heart disease (HAHD). METHODS:Right ventricle Tei index and serum NT-proBN level were calculated and tested in 32 local healthy volunteers and 34 cases of HAHD patients hospitalized in our hospital in Golmud city (2808 meters above sea level) from 2008 to 2010, and a correlation study was conducted thereafter. RESULTS:The pulmonary arterial systolic pressure and right ventricle Tei index, elevated significantly in HAHD patients compared with the control group [(86.61 vs 9.72) mm Hg (1 mm Hg = 0.133 kPa) and (0.90 vs 0.33) respectively, P < 0.05]. Patients diagnosed as mild pulmonary hypertension without alteration in cardiac structure showed higher pulmonary arterial systolic pressure and the Tei index compared with the control group [(57.1 vs 9.72) mm Hg and (0.78 vs 0.33) respectively, P < 0.05]. In addition, the level of serum NT-proBNP was significantly higher in HAHD group than that of control group [(1246.8 ± 512.6) ng/L and (98.6 ± 21.7) ng/L respectively, P < 0.05]. CONCLUSION:Right ventricle Tei index and serum NT-proBNP level are sensitive indicators for right ventricular function and thus of favorable clinical significance for the diagnosis of HAHD.