Systemic Vascular Dysfunction in Patients With Chronic Mountain Sickness

doi:10.1378/chest.11-0342

Chest

Volume 141, Issue 1, January 2012, Pages 139-146

https://doi.org/10.1378/chest.11-0342 Get rights and content

Background

Chronic mountain sickness (CMS) is a major public health problem characterized by exaggerated hypoxemia and erythrocytosis. In more advanced stages, patients with CMS often present with functional and structural changes of the pulmonary circulation, but there is little information on the systemic circulation. In patients with diseases associated with chronic hypoxemia at low altitude, systemic vascular function is altered. We hypothesized that patients with CMS have systemic vascular dysfunction that may predispose them to increased systemic cardiovascular morbidity.

Methods

To test this hypothesis, we assessed systemic endothelial function (by flow-mediated dilation [FMD]), arterial stiffness, and carotid intima-media thickness and arterial oxygen saturation (Sao₂) in 23 patients with CMS without additional classic cardiovascular risk factors and 27 age-matched healthy mountain dwellers born and permanently living at 3,600 m. For some analyses, subjects were classified according to baseline Sao₂ quartiles; FMD of the highest quartile subgroup (Sao₂ ≥ 90%) was used as a reference value for post hoc comparisons.

Results

Patients with CMS had marked systemic vascular dysfunction as evidenced by impaired FMD (CMS, 4.6% ± 1.2%; control subjects, 7.6% ± 1.9%; P < .0001), greater pulse wave velocity (10.6 ± 2.1 m/s vs 8.4 ± 1.0 m/s, P < .001), and greater carotid intima-media thickness (690 ± 120 μm vs 570 ± 110 μm, P = .001). A positive relationship existed between Sao₂ and FMD (r = 0.62, P < .0001). Oxygen inhalation improved (P < .001) but did not normalize FMD in patients with CMS, although it normalized FMD in hypoxemic control subjects (Sao₂ < 90%) and had no detectable effect in normoxemic control subjects (Sao₂ ≥ 90%).

Conclusions

Patients with CMS show marked systemic vascular dysfunction. Structural and functional alterations contribute to this problem that may predispose these patients to premature cardiovascular disease.

Trial registry

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

Section snippets

Study Subjects and Protocol

Between August 2008 and August 2010, 23 male patients with CMS (mean ± SD age, 52 ± 11 y) and 27 control subjects (49 ± 10 y) without traditional cardiovascular risk factors or a family history of premature cardiovascular events who were born and had been permanently living in La Paz, Bolivia (3,600 m above sea level) were included in the study. Inclusion criteria for patients with CMS were excessive erythrocytosis (hemoglobin concentration > 20 g/dL) in the presence of normal pulmonary

Results

The characteristics of the participants are shown in Table 1. As expected, Sao₂ was markedly lower and hemoglobin and hematocrit levels significantly higher in patients with CMS than in control subjects. Arterial BP and lung function, lipid and glucose plasma concentration, WBC count, and hsCRP level were normal and comparable between the two groups.

Discussion

CMS is a major public health problem in mountainous regions of the world, affecting many millions of high-altitude dwellers.1, 2 Although it is well established that this problem is associated with pulmonary vascular dysfunction and right-sided heart failure, there is little information on the systemic circulation. In the present study, we found that patients with CMS without additional cardiovascular risk factors have marked systemic vascular dysfunction as evidenced by impaired FMD, increased

Conclusions

To our knowledge, the present findings provide the first evidence that patients with CMS without additional cardiovascular risk factors have functional and morphological alterations of the systemic circulation. Some of these alterations also were found in hypoxemic high-altitude dwellers who did not experience CMS and were partially reversible during oxygen inhalation, suggesting that chronic hypoxemia may represent one of the underlying mechanisms.

Acknowledgments

Author contributions: Drs Allemann, Scherrer, and Sartorihad full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Rimoldi: contributed to the clinical examinations, study design, data analysis and interpretation, and writing of the first draft of the manuscript.

Dr Rexhaj: contributed to the clinical examinations, data analysis and interpretation, and final writing of the manuscript.

Dr Pratali: contributed to

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Early effects of acetazolamide on hemoglobin mass and plasma volume in chronic mountain sickness at 5100 m
2023, Pulmonology
Chronic Mountain Sickness (CMS) syndrome, combining excessive erythrocytosis and clinical symptoms in highlanders, remains a public health concern in high-altitude areas, especially in the Andes, with limited therapeutic approaches. The objectives of this study were to assess in CMS-highlanders permanently living in La Rinconada (5100–5300 m, Peru, the highest city in the world), the early efficacy of acetazolamide (ACZ) and atorvastatin to reduce hematocrit (Hct), as well as the underlying mechanisms focusing on intravascular volumes.
Forty-one males (46±8 years of age) permanently living in La Rinconada for 15 [10–20] years and suffering from CMS were randomized between ACZ (250 mg once-daily; N = 13), atorvastatin (20 mg once-daily; N = 14) or placebo (N = 14) uptake in a double-blinded parallel study. Hematocrit (primary endpoint) as well as arterial blood gasses, total hemoglobin mass (Hb_mass) and intravascular volumes were assessed at baseline and after a mean (±SD) treatment duration of 19±2 days.
ACZ increased PaO₂ by +13.4% (95% CI: 4.3 to 22.5%) and decreased Hct by -5.2% (95% CI: -8.3 to -2.2%), whereas Hct remained unchanged with placebo or atorvastatin. ACZ tended to decrease Hb_mass (-2.6%, 95% CI: -5.7 to 0.5%), decreased total red blood cell volume (RBCV, -5.3%, 95% CI: -10.3 to -0.3%) and increased plasma volume (PV, +17.6%, 95% CI: 4.9 to 30.3%). Atorvastatin had no effect on intravascular volumes, while Hb_mass and RBCV increased in the placebo group (+6.1%, 95% CI: 4.2 to 7.9% and +7.0%, 95%CI: 2.7 to 11.4%, respectively).
Short-term ACZ uptake was effective to reduce Hct in CMS-highlanders living at extreme altitude >5,000 m and was associated with both an increase in PV and a reduction in RBCV.
EPR spectroscopic evidence of iron-catalysed free radical formation in chronic mountain sickness: Dietary causes and vascular consequences
2022, Free Radical Biology and Medicine
Chronic mountain sickness (CMS) is a high-altitude (HA) maladaptation syndrome characterised by elevated systemic oxidative-nitrosative stress (OXNOS) due to a free radical-mediated reduction in vascular nitric oxide (NO) bioavailability. To better define underlying mechanisms and vascular consequences, this study compared healthy male lowlanders (80 m, n = 10) against age/sex-matched highlanders born and bred in La Paz, Bolivia (3600 m) with (CMS+, n = 10) and without (CMS-, n = 10) CMS. Cephalic venous blood was assayed using electron paramagnetic resonance spectroscopy and reductive ozone-based chemiluminescence. Nutritional intake was assessed via dietary recall. Systemic vascular function and structure were assessed via flow-mediated dilatation, aortic pulse wave velocity and carotid intima-media thickness using duplex ultrasound and applanation tonometry. Basal systemic OXNOS was permanently elevated in highlanders (P = <0.001 vs. lowlanders) and further exaggerated in CMS+, reflected by increased hydroxyl radical spin adduct formation (P = <0.001 vs. CMS-) subsequent to liberation of free ‘catalytic’ iron consistent with a Fenton and/or nucleophilic addition mechanism(s). This was accompanied by elevated global protein carbonylation (P = 0.046 vs. CMS-) and corresponding reduction in plasma nitrite (P = <0.001 vs. lowlanders). Dietary intake of vitamins C and E, carotene, magnesium and retinol were lower in highlanders and especially deficient in CMS + due to reduced consumption of fruit and vegetables (P = <0.001 to 0.028 vs. lowlanders/CMS-). Systemic vascular function and structure were also impaired in highlanders (P = <0.001 to 0.040 vs. lowlanders) with more marked dysfunction observed in CMS+ (P = 0.035 to 0.043 vs. CMS-) in direct proportion to systemic OXNOS (r = −0.692 to 0.595, P = <0.001 to 0.045). Collectively, these findings suggest that lifelong exposure to iron-catalysed systemic OXNOS, compounded by a dietary deficiency of antioxidant micronutrients, likely contributes to the systemic vascular complications and increased morbidity/mortality in CMS+.
ClinicalTrials.gov; No: NCT01182792; URL: www.clinicaltrials.gov.
Acute, subacute and chronic mountain sickness
2021, Revista Clinica Espanola
Más de 100 millones de personas ascienden cada año a áreas montañosas elevadas en todo el planeta y en altitudes no extremas (< 5.500 m) entre el 10 y el 85% se ven afectados por el denominado mal agudo de montaña, la enfermedad más frecuentemente inducida por una hipoxia hipobárica ligera-moderada. Asimismo, unos 140 millones de seres humanos viven de forma permanente en cotas comprendidas entre 2.500-5.500 m y hasta un 10% de ellos padecen la forma subaguda del mal de montaña (hipertensión pulmonar de la gran altitud) o la forma crónica (enfermedad de Monge), esta última especialmente frecuente en etnias andinas. La presente revisión expone los conceptos generales más relevantes en torno a estas 3 variantes clínicas, las cuales pueden ser incapacitantes, llegar a complicarse y ser potencialmente mortales, siendo esencial realizar una correcta prevención, diagnóstico, terapéutica y manejo de las mismas en un entorno hostil como es la alta montaña.
More than 100 million people ascend to high mountainous areas worldwide every year. At nonextreme altitudes (<5500 m), 10–85% of these individuals are affected by acute mountain sickness, the most common disease induced by mild-moderate hypobaric hypoxia. Approximately 140 million individuals live permanently at heights of 2500–5500 m, and up to 10% of them are affected by the subacute form of mountain sickness (high-altitude pulmonary hypertension) or the chronic form (Monge's disease), the latter of which is especially common in Andean ethnicities. This review presents the most relevant general concepts of these 3 clinical variants, which can be incapacitating and can result in complications and become life-threatening. Proper prevention, diagnosis, treatment and management of these conditions in a hostile environment such as high mountains are therefore essential.
A <sup>1</sup>H NMR spectroscopic metabolomic study of the protective effects of irbesartan in a rat model of chronic mountain sickness
2021, Journal of Pharmaceutical and Biomedical Analysis
Chronic mountain sickness (CMS) is a significant pathology in most high-altitude regions globally, affecting the cardiopulmonary system and its mechanism is largely unknown. A metabonomic approach using ¹H nuclear magnetic resonance spectroscopy allows for detecting differential metabolites, which provides a global view and mechanisms during CMS development. In this study, we simulated a high-altitude environment to establish a rat model of CMS. Irbesartan was administered to CMS rats at three doses (6.75, 13.5, and 27 mg/kg) once a day for 15 days. HE staining and transmission electron microscopy were used to evaluate the effect of changes on the lung. Based on ¹H NMR spectra obtained from serum samples, partial least squares-discriminant analysis (PLS-DA) and its variant orthogonal PLS-DA (OPLS-DA) models were applied to distinguish the different groups. Histopathological sections showed that the alveolar structure was abnormal, inflammatory infiltration occurred in CMS rats, and CMS induced notable metabolic disorder according to the ¹H NMR result. However, irbesartan reversed the imbalanced metabolites via energy metabolism, amino acid metabolism, and taurine metabolism pathways, and its effect was also confirmed by the general signs and morphology of the lung. The results revealed that irbesartan as an effective therapeutic agent to improve CMS is warranted.
Irbesartan ameliorates chronic mountain sickness in a rat model via the cholesterol metabolism: An iTRAQ -based proteomics analysis
2021, Biomedicine and Pharmacotherapy
To study the effects of irbesartan on pulmonary artery lesions in a rat model with chronic mountain sickness (CMS) and identify the biomarkers involved.
In this study, we used a rat model of CMS to evaluate the therapeutic effect of irbesartan by measuring pulmonary artery pressure and evaluating the histopathology of the pulmonary artery. We also used proteomics technology to identify differentially expressed proteins (DEPs) in the serum and performed bioinformatics analysis. Results were then verified by enzyme linked immunosorbent assay (ELISA) and immunohistochemistry (IHC).
Irbesartan treatment induced a significant decrease (P < 0.05) in the pulmonary artery pressure of CMS rats. Histopathological and electron microscope further confirmed that high altitude hypoxia induced changes in the structure of the pulmonary artery tissue and caused ultrastructural lesions. Proteomics analysis identified 40 DEPs; bioinformatics analysis further revealed that the cholesterol metabolism pathway plays a crucial role in the occurrence of CMS. ELISA and IHC verified that several DEPs (Apo-A1, Apo-C1, Apo-E, IGF-1, Profilin1, and Col1a1) represent critical biological markers in pulmonary artery disease caused by CMS.
Irbesartan significantly improved pulmonary artery damage in a rat model of CMS possibly by impacting on the cholesterol metabolism pathway and by reducing damage to vascular endothelial cells. Irbesartan also inhibited the expression levels of IGF-1, Profilin1 and Col1a1 to relieve pulmonary artery pressure and improve lung function by inhibiting vascular remodeling. Several proteins were identified as potential biomarkers of CMS, including Apo-A1, Apo-C1, Apo-E, IGF-1, Profilin1, and Col1a1.
Markers of cardiovascular risk and their reversibility with acute oxygen therapy in Kyrgyz highlanders with high altitude pulmonary hypertension
2021, Pulmonology
Citation Excerpt :
Unfortunately, excessive reactive oxygen species concentration can cause vascular endothelial dysfunction, the major underlying factor promoting atherogenesis and CVD.9 Well acclimatized, healthy highlanders have elevated reactive oxygen species concentration without evidence of vascular dysfunction, which is in contrast to observations in highlanders with chronic mountain sickness (CMS).10,11 CMS is characterized by polycythemia, pulmonary hypertension and severe chronic hypoxemia.12
High altitude pulmonary hypertension (HAPH), a chronic altitude related illness, is associated with hypoxemia, dyspnea and reduced exercise performance. We evaluated ECG and pulse wave-derived markers of cardiovascular risk in highlanders with HAPH (HAPH+) in comparison to healthy highlanders (HH) and lowlanders (LL) and the effects of hyperoxia.
We studied 34 HAPH+ and 54 HH at Aksay (3250 m), and 34 LL at Bishkek (760 m), Kyrgyzstan. Mean pulmonary artery pressure by echocardiography was mean ± SD 34 ± 3, 22 ± 5, 16 ± 4 mmHg, respectively (p < 0.05 all comparisons). During quiet rest, breathing room air or oxygen in randomized order, we measured heart-rate adjusted QT interval (QTc), an ECG-derived marker of increased cardiovascular mortality, and arterial stiffness index (SI), a marker of cardiovascular disease derived from pulse oximetry plethysmograms.
Pulse oximetry in HAPH+, HH and LL was, mean ± SD, 88 ± 4, 92 ± 2 and 95 ± 2%, respectively (p < 0.05 vs HAPH+, both comparisons). QTc in HAPH+, HH and LL was 422 ± 24, 405 ± 27, 400 ± 28 ms (p < 0.05 HAPH+ vs. others); corresponding SI was 10.5 ± 1.9, 8.4 ± 2.6, 8.5 ± 2.0 m/s, heart rate was 75 ± 8, 68 ± 8, 70 ± 10 bpm (p < 0.05, corresponding comparisons HAPH+ vs. others). In regression analysis, HAPH+ was an independent predictor of increased QTc and SI when controlled for several confounders. Oxygen breathing increased SI in HH but not in HAPH+, and reduced QTc in all groups.
Our data suggest that HAPH+ but not HH may be at increased risk of cardiovascular mortality and morbidity compared to LL. The lack of a further increase of the elevated SI during hyperoxia in HAPH+ may indicate dysfunctional control of vascular tone and/or remodelling.

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Drs Allemann, Scherrer, and Sartori contributed equally to this work.

Funding/Support: This work was supported by grants from the Swiss National Science Foundation, the Placide Nicod Foundation, and the Leenards Foundation.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

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Chest

Original ResearchOccupational And Environmental Lung DiseasesSystemic Vascular Dysfunction in Patients With Chronic Mountain Sickness

Background

Methods

Results

Conclusions

Trial registry

Section snippets

Study Subjects and Protocol

Results

Discussion

Conclusions

Acknowledgments

Am J Med

Chest

Chest

J Am Soc Echocardiogr

Chest

J Am Coll Cardiol

Consensus statement on chronic and subacute high altitude diseases

High Alt Med Biol

The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness

Circulation

Endothelial function in obstructive sleep apnea and response to treatment

Am J Respir Crit Care Med

Effects of hematocrit changes on flow-mediated and metabolic vasodilation in humans

Hypertension

Endothelial function and dysfunction. Part I: methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension

J Hypertens

Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia

Circulation

Comparison of two automatic methods for the assessment of brachial artery flow-mediated dilation

J Hypertens

A system for real-time measurement of the brachial artery diameter in B-mode ultrasound images

IEEE Trans Med Imaging

Expert consensus document on arterial stiffness: methodological issues and clinical applications

Eur Heart J

Original Research
Occupational And Environmental Lung Diseases
Systemic Vascular Dysfunction in Patients With Chronic Mountain Sickness