Circulating Microparticles Are Differentially Increased in Lowlanders and Highlanders with High Altitude Induced Pulmonary Hypertension during the Cold Season.

The role of microparticles (MPs) and cold in high altitude pulmonary hypertension (HAPH) remains unexplored. We investigated the impact of long-term cold exposure on the pulmonary circulation in lowlanders and high-altitude natives and the role of MPs. Pulmonary hemodynamics were evaluated using Doppler echocardiography at the end of the colder and warmer seasons. We further examined the miRNA content of MPs isolated from the study participants and studied their effects on human pulmonary artery smooth muscle (hPASMCs) and endothelial cells (hPAECs). Long-term exposure to cold environment was associated with an enhanced pulmonary artery pressure in highlanders. Plasma levels of CD62E-positive and CD68-positive MPs increased in response to cold in lowlanders and HAPH highlanders. The miRNA-210 expression contained in MPs differentially changed in response to cold in lowlanders and highlanders. MPs isolated from lowlanders and highlanders increased proliferation and reduced apoptosis of hPASMCs. Further, MPs isolated from warm-exposed HAPH highlanders and cold-exposed highlanders exerted the most pronounced effects on VEGF expression in hPAECs. We demonstrated that prolonged exposure to cold is associated with elevated pulmonary artery pressures, which are most pronounced in high-altitude residents. Further, the numbers of circulating MPs are differentially increased in lowlanders and HAPH highlanders during the colder season.

Right Ventricular Response to Acute Hypoxia Exposure: A Systematic Review.

Background: Acute hypoxia exposure is associated with an elevation of pulmonary artery pressure (PAP), resulting in an increased hemodynamic load on the right ventricle (RV). In addition, hypoxia may exert direct effects on the RV. However, the RV responses to such challenges are not fully characterized. The aim of this systematic review was to describe the effects of acute hypoxia on the RV in healthy lowland adults. Methods: We systematically reviewed PubMed and Web of Science and article references from 2005 until May 2021 for prospective studies evaluating echocardiographic RV function and morphology in healthy lowland adults at sea level and upon exposure to simulated altitude or high-altitude. Results: We included 37 studies in this systematic review, 12 of which used simulated altitude and 25 were conducted in high-altitude field conditions. Eligible studies reported at least one of the RV variables, which were all based on transthoracic echocardiography assessing RV systolic and diastolic function and RV morphology. The design of these studies significantly differed in terms of mode of ascent to high-altitude, altitude level, duration of high-altitude stay, and timing of measurements. In the majority of the studies, echocardiographic examinations were performed within the first 10 days of high-altitude induction. Studies also differed widely by selectively reporting only a part of multiple RV parameters. Despite consistent increase in PAP documented in all studies, reports on the changes of RV function and morphology greatly differed between studies. Conclusion: This systematic review revealed that the study reports on the effects of acute hypoxia on the RV are controversial and inconclusive. This may be the result of significantly different study designs, non-compliance with international guidelines on RV function assessment and limited statistical power due to small sample sizes. Moreover, the potential impact of other factors such as gender, age, ethnicity, physical activity, mode of ascent and environmental factors such as temperature and humidity on RV responses to hypoxia remained unexplored. Thus, this comprehensive overview will promote reproducible research with improved study designs and methods for the future large-scale prospective studies, which eventually may provide important insights into the RV response to acute hypoxia exposure.

Circulating Apoptotic Signals During Acute and Chronic Exposure to High Altitude in Kyrgyz Population.

Background: Circulating apoptotic signals (CASs) have been described in the pathologies associated with dysregulated apoptosis, such as cancer, heart diseases, and pulmonary hypertension (PH). However, nothing is known about the expression profiles of these markers in the circulation of humans exposed to acute and chronic effects of high altitude (HA). Methods: Gene expression levels of different apoptotic signals (ASs) were analyzed in human pulmonary artery smooth muscle cells (PASMCs) upon hypoxia incubation. In addition, we measured the plasma values of relevant CAS in Kyrgyz volunteers during acute and chronic exposure to HA. Finally, we analyzed the effects of pro-apoptotic mediator Fas ligand (FasL) on apoptosis and proliferation of human PASMCs. Results: Several cellular AS were increased in PASMCs exposed to hypoxia, in comparison to normoxia condition. Among analyzed CAS, there was a prominent reduction of FasL in lowlanders exposed to HA environment. Furthermore, decreased circulatory levels of FasL were found in highlanders with HA-induced PH (HAPH), as compared to the lowland controls. Furthermore, FasL concentration in plasma negatively correlated with tricuspid regurgitant gradient values. Finally, FasL exerted pro-apoptotic and anti-proliferative effects on PASMCs. Conclusion: Our data demonstrated that circulating levels of FasL are reduced during acute and chronic exposure to HA environment. In addition, dysregulated FasL may play a role in the context of HAPH due to its relevant functions on apoptosis and proliferation of PASMCs.

Pulmonary Vascular Pressure Response to Acute Cold Exposure in Kyrgyz Highlanders.

Background/Aims: Long-term high altitude residence leads to a sustained increase in pulmonary vascular resistance and elevation of pulmonary artery pressure due to chronic alveolar hypoxia. However, living at high altitude is also associated with other environmental factors such as cold. There is still little experimental evidence suggesting detrimental effects of low temperatures on the pulmonary vasculature. Therefore, our objective was to investigate acute effects of cold exposure on the pulmonary circulation in Kyrgyz high altitude natives. Methods: Responses of the pulmonary circulation during acute exposure to controlled cold conditions (4°C-6°C) for 60 minutes were measured in highlanders using Doppler echocardiography. Based on the Doppler echocardiography-derived tricuspid regurgitant systolic pressure gradient (TRG), subjects with TRG ≥40 mmHg were allocated into the pulmonary hypertension (PH) group. Participants from the PH group were compared with volunteer control subjects with TRG <40 mmHg. All baseline measurements were evaluated in a warm room during 60 minutes (22°C-28°C). Following baseline echocardiography, the subjects were assigned to either warm or cold exposure for an additional 60 minutes. Results: Acute cold exposure significantly increased TRG both in the control (ΔTRG, 4.93 mmHg) and in the PH (ΔTRG, 8.15 mmHg) group, compared to the respective warm exposure conditions (ΔTRG, -0.14 and -0.05 mmHg). No changes in cardiac output were observed upon cold exposure. Conclusion: Thus, acute exposure to cold leads to elevation of pulmonary artery pressure in high altitude residents.

A Case of Subacute Infantile Mountain Sickness in a Kyrgyz Child.

Muratali Uulu, Kubatbek, Meerim Cholponbaeva, Melis Duishobaev, Aidana Toktosunova, Abdirashit Maripov, Akylbek Sydykov, and Akpay Sarybaev. A case of subacute infantile mountain sickness in a Kyrgyz child. High Alt Med Biol. 19:208-210, 2018.-Subacute infantile mountain sickness (SIMS) is a syndrome of severe pulmonary hypertension and right heart failure that develops in infants born in the lowlands and subsequently brought to live at high altitudes. Earlier postmortem studies have demonstrated significant remodeling of small pulmonary arteries as well as right ventricular hypertrophy and dilatation. In this report, we present a case of SIMS in a Kyrgyz child born to a native highlander mother evaluated by conventional echocardiography and tissue Doppler imaging. An echocardiogram showed severe pulmonary hypertension, a markedly dilated right ventricle with flattening of interventricular septum, and right ventricular dysfunction. To our knowledge, this is the first report of noninvasive imaging of pulmonary circulation and right ventricle in an infant with SIMS and confirmed the diagnosis using echocardiography.

Right Ventricular Remodeling and Dysfunction in Obstructive Sleep Apnea: A Systematic Review of the Literature and Meta-Analysis.

BACKGROUND: Recent studies have reported that obstructive sleep apnea (OSA) patients present alterations in right ventricular (RV) structure and function. However, large randomized controlled trials evaluating the impact of OSA on the right ventricle are lacking. METHODS: A comprehensive electronic database (PubMed, Web of Science, and Google Scholar) and reference search up to October 30, 2016, was performed. A systematic review and meta-analysis were performed to assess RV structure and function in OSA patients based on conventional echocardiography and tissue Doppler imaging. RESULTS: Twenty-five studies with 1,503 OSA patients and 796 controls were included in this study. OSA patients exhibited an increase in RV internal diameter (weighted mean difference (WMD) (95% confidence intervals (CIs)) 2.49 (1.62 to 3.37); p = 0.000) and RV wall thickness (WMD (95% CIs) 0.82 (0.51 to 1.13); p = 0.000). Furthermore, OSA patients had a significantly elevated RV myocardial performance index (WMD (95% CI) 0.08 (0.06 to 0.10); p = 0.000), decreased RV S' (WMD (95% CI) -0.95 (-1.59 to -0.32); p = 0.003), tricuspid annular plane systolic excursion (WMD (95% CI) -1.76 (-2.73 to -0.78); p = 0.000), and RV fractional area change (WMD (95% CI) -3.16 (-5.60 to -0.73); p = 0.011). CONCLUSION: OSA patients display RV dilatation, increased wall thickening, and altered RV function.