Mast Cells in Cardiac Remodeling: Focus on the Right Ventricle.

In response to various stressors, cardiac chambers undergo structural remodeling. Long-term exposure of the right ventricle (RV) to pressure or volume overload leads to its maladaptive remodeling, associated with RV failure and increased mortality. While left ventricular adverse remodeling is well understood and therapeutic options are available or emerging, RV remodeling remains underexplored, and no specific therapies are currently available. Accumulating evidence implicates the role of mast cells in RV remodeling. Mast cells produce and release numerous inflammatory mediators, growth factors and proteases that can adversely affect cardiac cells, thus contributing to cardiac remodeling. Recent experimental findings suggest that mast cells might represent a potential therapeutic target. This review examines the role of mast cells in cardiac remodeling, with a specific focus on RV remodeling, and explores the potential efficacy of therapeutic interventions targeting mast cells to mitigate adverse RV remodeling.

Osteopontin in Pulmonary Hypertension.

Pulmonary hypertension (PH) is a pathological condition with multifactorial etiology, which is characterized by elevated pulmonary arterial pressure and pulmonary vascular remodeling. The underlying pathogenetic mechanisms remain poorly understood. Accumulating clinical evidence suggests that circulating osteopontin may serve as a biomarker of PH progression, severity, and prognosis, as well as an indicator of maladaptive right ventricular remodeling and dysfunction. Moreover, preclinical studies in rodent models have implicated osteopontin in PH pathogenesis. Osteopontin modulates a plethora of cellular processes within the pulmonary vasculature, including cell proliferation, migration, apoptosis, extracellular matrix synthesis, and inflammation via binding to various receptors such as integrins and CD44. In this article, we provide a comprehensive overview of the current understanding of osteopontin regulation and its impact on pulmonary vascular remodeling, as well as consider research issues required for the development of therapeutics targeting osteopontin as a potential strategy for the management of PH.

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.

An Exaggerated Rise in Pulmonary Artery Pressure in a High-Altitude Dweller during the Cold Season.

Chronic hypoxia-induced sustained pulmonary vasoconstriction and vascular remodeling lead to mild-to-moderate elevation of pulmonary artery pressure in high-altitude residents. However, in some of them, severe pulmonary hypertension may develop. Besides hypoxia, high-altitude residents also face other environmental challenges such as low ambient temperatures. We describe a case of a 49-year-old woman of Kyrgyz ethnicity with abnormally increased pulmonary artery pressure, revealed by Doppler echocardiography. Significantly elevated pulmonary artery pressure was detected in late winter and this was not associated with right ventricular hypertrophy or right ventricular dysfunction. Repeat echocardiography performed in late summer disclosed a significant attenuation of pulmonary artery pressure elevation, with no changes in right ventricular performance parameters. This case illustrates that, in susceptible individuals, long-term cold exposure could induce an abnormal pulmonary artery pressure rise, which can be reversed during warm seasons as in our patient. In certain circumstances, however, additional factors could contribute to a sustained pulmonary artery pressure increase and the development of persistent pulmonary hypertension, which often leads to right heart failure and premature death.

Pulmonary Hypertension in Acute and Chronic High Altitude Maladaptation Disorders.

Alveolar hypoxia is the most prominent feature of high altitude environment with well-known consequences for the cardio-pulmonary system, including development of pulmonary hypertension. Pulmonary hypertension due to an exaggerated hypoxic pulmonary vasoconstriction contributes to high altitude pulmonary edema (HAPE), a life-threatening disorder, occurring at high altitudes in non-acclimatized healthy individuals. Despite a strong physiologic rationale for using vasodilators for prevention and treatment of HAPE, no systematic studies of their efficacy have been conducted to date. Calcium-channel blockers are currently recommended for drug prophylaxis in high-risk individuals with a clear history of recurrent HAPE based on the extensive clinical experience with nifedipine in HAPE prevention in susceptible individuals. Chronic exposure to hypoxia induces pulmonary vascular remodeling and development of pulmonary hypertension, which places an increased pressure load on the right ventricle leading to right heart failure. Further, pulmonary hypertension along with excessive erythrocytosis may complicate chronic mountain sickness, another high altitude maladaptation disorder. Importantly, other causes than hypoxia may potentially underlie and/or contribute to pulmonary hypertension at high altitude, such as chronic heart and lung diseases, thrombotic or embolic diseases. Extensive clinical experience with drugs in patients with pulmonary arterial hypertension suggests their potential for treatment of high altitude pulmonary hypertension. Small studies have demonstrated their efficacy in reducing pulmonary artery pressure in high altitude residents. However, no drugs have been approved to date for the therapy of chronic high altitude pulmonary hypertension. This work provides a literature review on the role of pulmonary hypertension in the pathogenesis of acute and chronic high altitude maladaptation disorders and summarizes current knowledge regarding potential treatment options.

Cardiac Acclimatization at High Altitude in Two Different Ethnicity Groups.

Gaur, Priya, Meerim Sartmyrzaeva, Abdirashit Maripov, Kubatbek Muratali Uulu, Supriya Saini, Koushik Ray, Krishna Kishore, Almaz Akunov, Akpay Sarybaev, Bhuvnesh Kumar, Shashi Bala Singh, and Praveen Vats. Cardiac acclimatization at high altitude in two different ethnicity groups. High Alt Med Biol. 22:58-69, 2021. Introduction: High altitude (HA) exposure causes substantial increase in pulmonary artery pressure (PAP) and resistance. However, the effects of HA hypoxia exposure on cardiac function remain incompletely understood. Studies evaluating interethnic differences in cardiac functions in response to HA exposure are lacking. We aimed to compare the cardiac performance in Indian versus Kyrgyz healthy lowland subjects over the course of a 3-week HA exposure at 4,111 m. Methodology: Ten Indians and 20 Kyrgyz subjects were studied to assess cardiac acclimatization noninvasively by echocardiography in two different ethnic groups for 3 weeks of stay at HA. Pulmonary hemodynamics, right and left ventricular functions were evaluated at basal and on days 3, 7, 14, and 21 of HA exposure and on day 3 of deinduction. Results: HA exposure significantly increased PAP, pulmonary vascular resistance, cardiac output (CO), and heart rates (HRs) in both groups. Tricuspid regurgitant gradient increased significantly in both the group at day 3 versus basal; 38.9 mmHg (31.8, 42.9) versus 21.9 mmHg (19.5, 22.6) in Kyrgyz; and 34.1 mmHg (30.2, 38.5) versus 20.4 mmHg (19.7, 21.3) in Indians. HR increased significantly in Indians at day 3 and 7, whereas in Kyrgyz throughout exposure. CO increased significantly in both groups at day 3 versus basal with 5.9 L/min (5.5, 6.4) versus 5.1 L/min (4.4, 5.9) in Kyrgyz, and 5.7 L/min (5.56, 5.98) versus 4.9 L/min (4.1, 5.3) in Indians. Both groups exhibited preserved right ventricular diastolic and systolic functions at HAs. HA exposure changed the left ventricular diastolic parameters only in Kyrgyz subjects with impaired mitral inflow E/A, but not in Indian subjects. All cardiac changes induced at HAs have been recovered fully upon deinduction in both, except lateral-septal A', which remained low in Indians. Conclusion: Although pulmonary hemodynamics responses were similar in both groups, there were differences in cardiac functional parameters between the two in response to HA exposure that may be accounted to ethnic variation.

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.

Temporal transcriptome analysis suggest modulation of multiple pathways and gene network involved in cell-cell interaction during early phase of high altitude exposure.

High altitude (HA) conditions induce several physiological and molecular changes, prevalent in individuals who are unexposed to this environment. Individuals exposed towards HA hypoxia yields physiological and molecular orchestration to maintain adequate tissue oxygen delivery and supply at altitude. This study aimed to understand the temporal changes at altitude of 4,111m. Physiological parameters and transcriptome study was conducted at high altitude day 3, 7, 14 and 21. We observed changes in differentially expressed gene (DEG) at high altitude time points along with altered BP, HR, SpO2, mPAP. Physiological changes and unsupervised learning of DEG's discloses high altitude day 3 as distinct time point. Gene enrichment analysis of ontologies and pathways indicate cellular dynamics and immune response involvement in early day exposure and later stable response. Major clustering of genes involved in cellular dynamics deployed into broad categories: cell-cell interaction, blood signaling, coagulation system, and cellular process. Our data reveals genes and pathways perturbed for conditions like vascular remodeling, cellular homeostasis. In this study we found the nodal point of the gene interactive network and candidate gene controlling many cellular interactive pathways VIM, CORO1A, CD37, STMN1, RHOC, PDE7B, NELL1, NRP1 and TAGLN and the most significant among them i.e. VIM gene was identified as top hub gene. This study suggests a unique physiological and molecular perturbation likely to play a critical role in high altitude associated pathophysiological condition during early exposure compared to later time points.

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 Chronic Thromboembolic Pulmonary Hypertension in a High-Altitude Dweller.

Chronic hypoxia causes sustained pulmonary vasoconstriction and vascular remodeling leading to development of pulmonary hypertension in high-altitude residents. Although pulmonary hypertension is of mild to moderate degrees in most cases, some high-altitude residents may develop severe pulmonary hypertension. We report a case of a 47-year-old female highlander of Kyrgyz ethnicity who presented with exertional breathlessness and echocardiographic signs of severe pulmonary hypertension, who was diagnosed as having chronic thromboembolic pulmonary hypertension (CTEPH). To the best of our knowledge, this is the first documented case of severe CTEPH in a high-altitude dweller. This case illustrates that causes other than hypoxia may underlie and/or contribute to severe pulmonary hypertension in residents of high altitude.

A Temporal Study on Learning and Memory at High Altitude in Two Ethnic Groups.

Introduction: Cognitive function has been compromised during high-altitude (HA) exposure due to slowing of mental processing. Materials and Methods: A total of 20 Indian and 20 Kyrgyz soldiers were studied at 4111 m to assess cognitive function in two different ethnic groups. Paired associate learning, pattern recognition memory, spatial span (SSP), spatial working memory (SWM), choice reaction time (CRT), and simple reaction time (SRT) were evaluated at sea level and on days 3, 7, 14, and 21 of HA stay and on day 3 of deinduction. Results: All the parameters were significantly affected at HA. Indian soldiers were acclimatized by 7 days but Kyrgyz soldiers required 21 days for acclimatization. A slow impairment in SWM, CRT, and SRT was observed in Kyrgyz soldiers than in Indian soldiers and it continues throughout 21 days of HA stay, but for Indian soldiers the deterioration was maximum on day 7 and improvement in SWM, CRT, and SRT was observed on day 14 and close to baseline value on day 21. After deinduction, although Indian soldiers attained the normal value, Kyrgyz soldiers had higher value than baseline in SSP, SWM, CRT, and SRT. Conclusion: Difference in the cognitive performances of Indian and Kyrgyz soldiers may be due to the ethnogenetic diversity of these two groups.

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.

Global expression profiling and pathway analysis in two different population groups in relation to high altitude.

High altitude (HA) is associated with number of stresses. Response of these stresses may vary in different populations depending upon altitude, duration of residency, ancestry, geographical variation, lifestyle, and ethnicities. For understanding population variability in transcriptome, array-based global gene expression profiling was performed on extracted RNA of male volunteers of two different lowland population groups, i.e., Indians and Kyrgyz, at baseline and day 7 of HA exposure (3200 m). A total of 97 genes were differentially expressed at basal in Kyrgyz as compared to Indians (82 downregulated and 15 upregulated), and 196 were differentially expressed on day 7 of HA (118 downregulated and 78 upregulated). Ingenuity Pathway Analysis and gene ontology highlighted eIF2 signaling with most significant negative activation z score at basal in Kyrgyz compared to Indians with downregulation of various L- and S-ribosomal proteins indicating marked translational repression. On day 7, cAMP-mediated signaling is most enriched with positive activation z score in Kyrgyz compared to Indians. Plasma cAMP levels were higher in Kyrgyz on day 7 compared to Indians. Extracellular adenosine levels were elevated in both the groups upon HA, but higher in Kyrgyz compared to Indians. Valedictory qRT-PCR showed upregulation of ADORA2B and CD73 along with downregulation of ENTs in Kyrgyz compared to Indians indicating elevated levels of extracellular nucleotides mainly adenosine and activation of extracellular cAMP-adenosine pathway which as per literature triggers endogenous protective mechanisms under stress conditions like hypoxia. Thus, transcriptome changes at HA are population-specific, and it may be necessary to take care while interposing similar results in different populations.

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.

High Altitude Pulmonary Edema in a Mining Worker With an Abnormal Rise in Pulmonary Artery Pressure in Response to Acute Hypoxia Without Prior History of High Altitude Pulmonary Edema.

High altitude pulmonary edema (HAPE) is a potentially life-threatening form of noncardiogenic pulmonary edema that may develop in otherwise healthy individuals upon ascent to high altitude. A constitutional susceptibility has been noted in some individuals, whereas others appear not to be susceptible at all. In our report, we present a case of HAPE triggered by concurrent respiratory tract infection and strenuous exercise in a mining worker with an abnormal rise in pulmonary artery pressure in response to acute hypoxia, without a prior history of HAPE during almost a year of commuting between high altitude and lowland areas.

Effects of intermittent exposure to high altitude on pulmonary hemodynamics: a prospective study.

Chronic alveolar hypoxia due to disease or low atmospheric pressure at high altitude results in the development of hypoxic pulmonary hypertension. The effects of intermittent hypoxia on pulmonary hemodynamics in healthy men have not been studied. We aimed to investigate, prospectively, pulmonary hemodynamics in workers commuting between an elevation of 3700 and 4200 m (4-week working shift) and lowland, below 500 m (4 weeks of holiday). Pulmonary hemodynamics has been investigated by Doppler echocardiography in 26 healthy Caucasian males, mean age 42 +/- 9 yr. First at lowland (760 m) and next during the fourth week of work at high altitude. Investigations were repeated in 21 subjects 1 year later at the end of the high-altitude exposure. The third series of investigations was performed 2 yr after the initial ones in 10 subjects who earlier had shown the strongest hypoxic vasoconstriction. At lowland, subjects presented with normal pulmonary hemodynamics. At high altitude, mean pulmonary artery pressure (PAPm) rose from 14.7 +/- 2.7 mmHg to 25.8 +/- 8.3 mmHg. One year later the PAPm remained unchanged in hypoxic conditions (25.0 +/- 7.3 mmHg). At the end of a 2-year follow-up of 10 "hyperreactors," PAPm measured at the end of the hypoxic exposure was the same as at the initial investigation, averaging 28 +/- 4.0, 28 +/- 3.5, and 29 +/- 2.5 mmHg at the beginning and at 1 and after 2 yr of intermittent exposure to high altitude. We concluded that intermittent exposure to 4000 m lasting 3 yr does not lead to development of permanent pulmonary hypertension.