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.


INTRODUCTION
With increasing altitude, the partial pressure of oxygen in the atmosphere falls along with the barometric pressure, leading to a gradually decreasing oxygen availability. Consequently, exposure to high-altitude results in diminished arterial blood oxygen content and initiates acclimatization processes consisting in a series of physiological responses of various organs and systems to maintain an adequate oxygen delivery to the tissues. Particularly, major changes occur in the cardiovascular system. While, the systemic vascular resistance may increase only up to 20%, there is more significant elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) due to hypoxic pulmonary vasoconstriction (HPV), against which the right ventricle (RV) should maintain its contractility (Baggish et al., 2014). HPV is a remarkable cardiovascular response to high-altitude hypoxia exposure (Sydykov et al., 2021). Although, the main purpose of the HPV is to maintain local ventilationperfusion matching and improve blood oxygenation, in the setting of global lung hypoxia during high-altitude exposure, diffuse HPV results in PAP and PVR increase (Swenson, 2013). The degree of the PAP elevation is usually mild-to-moderate and is not associated with serious adverse health consequences (Sydykov et al., 2021). If exposure to hypoxia persists, PAP may remain elevated Gaur et al., 2021) or become partially attenuated over the course of 2-3 weeks (Ghofrani et al., 2004;Baggish et al., 2010). However, a certain proportion of the population displays an exaggerated HPV (B?rtsch and Gibbs, 2007), which may predispose to high altitude pulmonary edema (HAPE), a potentially life-threatening condition that typically occurs in otherwise healthy individuals after rapid ascent to highaltitude (Sydykov et al., 2021). Importantly, alleviation of HPV by an immediate descent leads to a full recovery from HAPE.
A fall in arterial blood oxygen content initiates cardiac responses, including cardiac output increase, in order to maintain adequate oxygen delivery to the tissues (Naeije, 2010). The cardiac output enhancement observed upon high-altitude exposure is explained mainly by increased heart rate with maintained or decreased stroke volume (Naeije, 2010). In highaltitude hypoxia conditions with decreased oxygen availability, augmented cardiac output along with the enhanced load to the RV due to elevated PVR increases myocardial oxygen demand, thus predisposing the RV to myocardial dysfunction. In addition, cardiac performance may be hampered by various factors associated with the high-altitude exposure, such as increased blood viscosity, sympathetic nervous system activation and hypovolemia (Naeije, 2010). Thus, the RV not only should maintain or couple its contractility to increased afterload but also withstand other adverse challenges associated with high-altitude. All these factors together require RV functional and geometrical adaptation to maintain cardiac function and oxygen delivery to the tissues.
Available studies that evaluated the effects of acute highaltitude exposure on the RV produced conflicting results (Naeije and Dedobbeleer, 2013;Richalet and Pichon, 2014). While some studies demonstrated an augmented RV function in response to acute hypoxia-induced afterload increase Sareban et al., 2020), others found no change  or even an impaired RV function Hanaoka et al., 2011;Page et al., 2013). Furthermore, there is anecdotal evidence of acute RV failure due to increased RV pressure overload in a healthy individual upon highaltitude exposure . These discrepancies in the existing literature are poorly understood but might be related to the considerable differences in methods and research designs between the studies and lack of compliance with the guidelines for the assessment of the RV function and morphology (Rudski et al., 2010). In addition, gender , age , ethnicity , individual susceptibility  and some other factors can impact RV performance upon high-altitude hypoxia exposure. Further, at high altitude, RV might be subjected to hemodynamic load of variable severity in different individuals due to great interindividual variability in the HPV.
In lowlanders, prolonged high-altitude stay is associated with sustained HPV and pulmonary vascular remodeling Maggiorini et al., 2001;Luks et al., 2017). Depending on their severity, these changes can cause persistent elevation of PAP and PVR resulting in increased RV afterload, which may lead to RV remodeling and dysfunction . During prolonged stay at extreme high-altitudes (5800-6700 m), some healthy lowlanders might develop severe RV failure with peripheral congestion syndrome, which is fully reversible upon returning to low altitude (Anand et al., 1990). However, it remains unknown whether acute RV dysfunction affects subsequent development of RV remodeling and failure with prolonged stay at high-altitude.
Although right heart catheterization is the gold standard method for the assessment of pulmonary hemodynamics and RV function, its application in healthy humans in highaltitude settings is challenging due to logistics (remote area) and its invasive nature. Alternatively, echocardiography has become a widely available and reliable method to study cardiovascular physiology (Soria et al., 2016(Soria et al., , 2019. It has been proven to be a valuable tool to characterize RV function and morphology in various cardiovascular conditions (Taleb et al., 2013;Greiner et al., 2014). Importantly, echocardiography allows measuring cardiac function serially over the specified time periods and altitude levels (Galie et al., 2016). Consequently, echocardiography has become a widely available and reliable method to study cardiovascular physiology in high-altitude research (Fagenholz et al., 2012;Feletti et al., 2018).
Recently emerged state-of-the-art echocardiography imaging modalities such as speckle-tracking and 3D echocardiography have significantly improved our understanding of the left ventricular (LV) physiology in lowlanders acutely exposed to high-altitude and in permanent high-altitude residents . However, these techniques remain underutilized for the in-depth characterization of the RV function and morphology in high-altitude settings. Understanding the physiology of the RV responses to acute hypoxia is of significant importance for gaining insights into mechanisms underlying acute RV dysfunction and failure in various cardiopulmonary diseases. Thus, this systematic review Frontiers in Physiology | www.frontiersin.org TRG, tricuspid regurgitation gradient; sPAP, systolic pulmonary artery pressure; mPAP, mean pulmonary artery pressure; PAAT, pulmonary artery acceleration time; PAAT/ET, pulmonary acceleration time to ejection time ratio; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; RV-E, tricuspid inflow early diastolic velocity; RV-A, tricuspid inflow late diastolic velocity; RV-E/A, tricuspid inflow early diastolic velocity to late diastolic velocity; aims to evaluate the RV responses to acute simulated altitude exposure and high-altitude ascent in healthy lowland individuals.

Data Sources and Search Strategy
A comprehensive literature search for the relevant articles was performed between January 2005 and May 2021 using online databases PubMed and Web of Science. The aim was to identify studies investigating the effects of acute simulated altitude or high-altitude exposure on RV systolic and diastolic function and morphologic parameters in healthy lowland adults. The search strategy was implemented using the following Boolean operators (AND/OR) and terms: "right ventricular function" OR "right ventricular dysfunction" OR "cardiac function" AND healthy subjects OR healthy individuals OR humans AND "echocardiography" OR "ultrasound imaging" AND hypoxia exposure OR "high altitude" OR hypoxia chamber OR hypoxia room. The search was refined by applying the limits "Humans" and "All adult: +19 years" in PubMed and searching within the subject areas of physiology, respiratory system, cardiovascular system and cardiology in the Web of Science. The exact search terms and Boolean operators used in PubMed and Web of Science are provided in the Supplementary Material. Additionally, manual searches were conducted using Google Scholar and reference lists of the eligible articles to retrieve further articles.

Inclusion and Exclusion Criteria
The inclusion criteria for the relevant studies were: (1) involving healthy lowland subjects aged ≥19 years that had not been exposed to altitudes over 2,500 m in the last 3 weeks before study inclusion; (2) simulated altitude or high-altitude field studies at elevations of 2,500 m and over; (3) reporting at least one of the echocardiographic parameters of the RV systolic or diastolic function or its morphology with numerical values or plots with indicated statistical changes; (4) measurements were performed at baseline (see level with normoxia breathing) and after hypoxia exposure for 15 min up to 1 month; (5) full-text in English; and (6) human subjects. Exclusion criteria were: (1) not reporting measurement results at baseline or after hypoxia exposure; (2) studies with unclear design; (3) case reports, reviews, abstracts, and editorials.

Study Selection and Data Extraction
Two authors (Argen Mamazhakypov and Meerim Sartmyrzaeva) independently screened the retrieved articles by titles and abstracts according to the inclusion and exclusion criteria. Then, the full-texts of the relevant articles were obtained, and the same two authors independently screened the full-text of the articles. Disagreements were resolved by discussions between all the authors. Two authors (Argen Mamazhakypov and Meerim Sartmyrzaeva) independently extracted the following data (Tables 1, 2): publication details (authors, publication year), sample characteristics (sample size, gender, age), hypoxia exposure profile (simulated altitude or high-altitude field study, hypoxia exposure duration, altitude elevation), mode of ascent (staged acclimatization or without preacclimatization), and summarized the outcome measures (RV function and morphology parameters) and the changes in RV parameters upon simulated altitude or high-altitude exposure (Tables 4, 6).

Study Selection
Using electronic searches of the databases PubMed and Web of Science, the initial search retrieved 160 records. Additional 19 articles were identified through other sources. After excluding duplicates and articles in languages other than English, we screened the remaining 151 articles by their title and abstract and excluded animal experiments, case reports, review articles, editorials, conference abstracts and articles on irrelevant topics. The remaining 76 records were evaluated for eligibility by full-text assessment, of which 37 studies fulfilled the inclusion criteria and thus were selected for systematic review. The selection process is shown in the PRISMA flow diagram in Figure 1.

Study Characteristics
The characteristics of the selected 37 studies are summarized in Tables 1, 2. The studies differed in their design (e.g., mode of ascent, altitude level, and measurement time-points at high-altitude), simulated altitude characteristics (e.g., hypoxia breathing, normobaric or hypobaric hypoxia chamber exposure), reported RV parameters, and subject characteristics (number, gender, and age). The marked methodological heterogeneity across these studies and the small number of papers prevented meta-analysis. Hence, we provide a descriptive analysis of the results.
According to the mode of hypoxia exposure the selected studies were divided into simulated altitude and high-altitude field studies. Twelve studies exploited simulated altitude using normobaric or hypobaric hypoxia chambers or hypoxia breathing, and 25 studies were conducted in high-altitude field conditions.

Effects of Simulated Altitude on the Right Ventricle
Twelve studies explored effects of simulated altitude and included a total of 199 healthy adults    Indicates that the echocardiographic parameter was provided in the corresponding studies; empty cell indicate that the echocardiographic parameter is not provided in the corresponding studies. Reichenberger et al., 2007;Hanaoka et al., 2011;Pavelescu and Naeije, 2012;Boos et al., 2013Boos et al., , 2016Goebel et al., 2013;Netzer et al., 2017;Seccombe et al., 2017;Pezzuto et al., 2018;Ewalts et al., 2021). Study participants were exposed to various degrees of hypoxia from 9.9 to 12.5% fraction of inspired oxygen (FiO 2 ), which correspond to altitude levels ranging from 4,000 to 5,500 m. Altitude was simulated by either hypobaric or normobaric hypoxic chamber exposure or hypoxia breathing. Duration of the hypoxia exposure varied from 15 to 150 min. In the majority of the studies, a single echocardiography investigation was performed at high altitude, but in few of them, serial investigations were done. Echocardiographic parameters assessed systolic and diastolic RV function and RV morphology. The summary of the assessed RV parameters is presented in Table 3 and the changes of the parameters upon hypoxia exposure are summarized in Table 4.

Right Ventricular Systolic Function
In all of the studies, at least one of the following RV systolic function parameters was reported: tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (RV-FAC), tissue Doppler-derived peak tricuspid annulus systolic velocity (RV-S ′ ), RV myocardial performance index (RV-MPI) and RV global longitudinal strain (RV-GLS). The most frequently measured RV systolic parameter was TAPSE, which was evaluated in 10 studies Kjaergaard et al., 2007;Reichenberger et al., 2007;Pavelescu and Naeije, 2012;Boos et al., 2013Boos et al., , 2016Goebel et al., 2013;Netzer et al., 2017;Seccombe et al., 2017;Pezzuto et al., 2018). In 7 of these studies, TAPSE values remained unchanged upon exposure to acute hypoxia Pavelescu and Naeije, 2012;Boos et al., 2013Boos et al., , 2016Goebel et al., 2013;Seccombe et al., 2017;Pezzuto et al., 2018). One study reported significant elevation of TAPSE following 1 h of hypoxia breathing (FiO 2 = 12.5%) suggesting augmented RV function . Significantly decreased TAPSE values upon hypoxia breathing (FiO 2 = 10%), suggesting RV systolic dysfunction, were observed in one study . One more study evaluating TAPSE at several time points over the course of 150 min hypoxia showed that TAPSE decreased after 1 h of hypoxia breathing . Other frequently reported RV systolic function parameters included RV-MPI Reichenberger et al., 2007;Hanaoka et al., 2011;Boos et al., 2013;Netzer et al., 2017;Seccombe et al., 2017) and RV-S ′ Kjaergaard et al., 2007;Pavelescu and Naeije, 2012;Boos et al., 2013;Netzer et al., 2017;Pezzuto et al., 2018), which were evaluated in 6 studies each. RV-MPI was not changed in 3 studies Boos et al., 2013;Seccombe et al., 2017), while its values were significantly increased in one study . In addition, RV-MPI values increased in subjects susceptible to HAPE  and in those who were exposed to hypoxia for more than 100 min . RV-S ′ values remained unchanged in 4 studies Kjaergaard et al., 2007;Pavelescu and Naeije, 2012;Pezzuto et al., 2018) and were increased in one study  or decreased in another study after 1 h hypoxia exposure (Netzer   Frontiers in Physiology | www.frontiersin.org  Indicates that the echocardiographic parameter was provided in the corresponding studies; empty cell indicate that the echocardiographic parameter is not provided in the corresponding studies.

Right Ventricular Systolic Function
In all studies, at least one of the following RV systolic function parameters was reported: TAPSE, RV-S ′ , RV-FAC or RV-MPI. In addition, RV free wall or global strain were assessed in 8 studies Stembridge et al., , 2019Maufrais et al., 2017;Sareban et al., 2020;Yang et al., 2020a,b;Ewalts et al., 2021). The most frequently reported RV systolic function parameter TAPSE was assessed in 18 studies

Right Ventricular Systolic Function
Only a few studies followed the international guidelines and assessed multiple parameters for the comprehensive RV evaluation (Pavelescu and Naeije, 2012;Boos et al., 2013;Maufrais et al., 2017;Netzer et al., 2017;Stewart et al., 2020;Tian et al., 2020;Yang et al., 2020a;Gaur et al., 2021;Yuan et al., 2021). Most of the studies have evaluated only one or 2 or 3 of the following RV systolic function parameters: TAPSE, RV-S ′ , RV-FAC, RV-MPI or RV-GLS. Assessment of multiple parameters revealed inconsistent changes in RV systolic function parameters at different timepoints and altitude levels. More specifically, TAPSE and RV-S ′ remained unchanged upon exposure to high-altitude in the majority of the studies Page et al., 2013;Hilty et al., 2016;Maufrais et al., 2017;Gaur et al., 2021). However, in a few studies, RV function assessed by TAPSE was augmented at earlier time-points of exposure (with 24 h) Sareban et al., 2020) and then decreased at later stages of highaltitude stay Gaur et al., 2021). Similarly, RV-S ′ values were increased at certain time-points of high-altitude exposure in several studies De Boeck et al., 2018;Sareban et al., 2020;Stewart et al., 2020;Yang et al., 2020a). Notably, assessment of RV-FAC and RV-MPI revealed augmented RV systolic function in none of the studies Page et al., 2013;Dedobbeleer et al., 2015;Maufrais et al., 2017;Berger et al., 2018;De Boeck et al., 2018;Stembridge et al., 2019;Sareban et al., 2020;Stewart et al., 2020;Tian et al., 2020;Yang et al., 2020a;Ewalts et al., 2021;He et al., 2021;Lichtblau et al., 2021;Yuan et al., 2021). In fact, in several studies, the changes of RV-FAC and RV-MPI values indicated diminished RV systolic function Page et al., 2013;Dedobbeleer et al., 2015;Hilty et al., 2016;Qiu et al., 2017;Stewart et al., 2020;Tian et al., 2020;Yang et al., 2020a;He et al., 2021;Yuan et al., 2021). Moreover, serial assessment of the RV systolic function parameters within the same study showed inconsistent changes over the course of high-altitude acclimatization Stewart et al., 2020;Gaur et al., 2021). Taken together, in the majority of the studies conventional echocardiography demonstrated maintained RV systolic function upon acute highaltitude exposure, although with variations in the directions of changes in RV systolic parameters and measurement points over the course of high-altitude acclimatization.
Recently, the advent of speckle-tracking echocardiography and its utilization to assess myocardial strain allowed less angle-dependent and load-independent insights into intrinsic myocardial function (Salvo et al., 2015). Speckle-tracking echocardiography has been shown to be a reliable technique in the analysis of RV myocardial mechanics (Kossaify, 2015). In addition, it enables assessment of additional alterations of myocardial mechanics such as contraction dyssynchrony (Badagliacca et al., 2015). Using this technique, RV dyssynchrony was shown in various cardiopulmonary conditions associated with an increased RV pressure overload (Kalogeropoulos et al., 2008;Badagliacca et al., 2017;Pezzuto et al., 2018). Speckletracking echocardiography was utilized to evaluate RV-GLS in two simulated altitude studies Ewalts et al., 2021) and in several high-altitude studies Maufrais et al., 2017;Stembridge et al., 2019;Sareban et al., 2020;Yang et al., 2020a;Ewalts et al., 2021;Yuan et al., 2021). Although, the RV-GLS values remained unchanged upon hypoxia exposure in most of the studies Maufrais et al., 2017Maufrais et al., , 2019Stembridge et al., 2019;Sareban et al., 2020;Ewalts et al., 2021), three studies demonstrated RV dyssynchrony in healthy adults upon exposure to acute simulated altitude and high-altitude Ewalts et al., 2021;Yuan et al., 2021).
Augmented RV afterload predisposes the RV to myocardial dysfunction. Although, there is significant amount of information on the pressure overload-induced RV dysfunction, hypoxia itself induces activation of several molecular pathways that could contribute to RV remodeling and dysfunction (Pena et al., 2020). In addition, preclinical studies have demonstrated that hypoxia can directly exert negative inotropic effects in intact animal preparations (Tucker et al., 1976) and in isolated cardiomyocytes (Silverman et al., 1997). The depressive effects of hypoxia on embryonic mouse cardiomyocytes may be related to hypoxia-inducible factor-1 mediated sarcoplasmic reticulum Ca 2+ -ATPase downregulation (Ronkainen et al., 2011). Direct negative inotropic effects of hypoxia were corroborated in a recent study that demonstrated preservation of the RV contractile function by improved oxygen delivery to the hypoxic myocardium in lambs exposed to acute hypoxia (Boehme et al., 2018).
Besides the direct effects of hypoxia on the myocardium, reduced venous return due to plasma volume contraction might also be responsible for the RV dyssynchrony as increasing venous return to the right heart alleviates it . In addition, in a recent study, high-altitude-induced RV dyssynchrony was associated with a lower degree of oxygen saturation and higher PAP  suggesting its relationship with hypoxemia and increased RV afterload. Interestingly, there were no differences in the conventional echocardiography systolic function parameters between subjects with RV dyssynchrony and those without . Taken together, while conventional echocardiography-derived parameters suggest maintained RV systolic function upon exposure to hypoxia, subtle changes can be revealed by speckletracking echocardiography. Interestingly, the findings derived by the latter suggested that these changes might be driven not only by increased afterload but also by other factors such as decreased preload and direct effects of hypoxia.
High-altitude exposure causes major changes in various functions of the cardiovascular system (Naeije, 2010). In addition to HPV and an associated increase in PAP and PVR, other initial cardiovascular responses include an increase in cardiac output along with tachycardia (Naeije, 2010). Of note, non-cardiovascular factors might contribute to the cardiovascular responses at high-altitude. For example, previous studies demonstrated plasma volume contraction upon high-altitude exposure (Singh et al., 1990), which can remain below sea level values even for up to 4-6 months above 4,000 m (Pugh, 1964). Reduced plasma volume causes, in turn, alterations in the LV function . These findings are supported by recent studies with plasma volume expansion . In healthy lowlanders, plasma volume expansion during acclimatization to 3,800 m restored LV end-diastolic volume, mitral inflow velocities and stroke volume .
Differences in ethnicity , age , gender  and exposure duration  and physical activity might account for the discrepancies between the study results. The magnitude of the RV response to high-altitude exposure might also be related to the susceptibility to HAPE. For example, exposure to normobaric hypoxia was associated with RV dysfunction in Japanese HAPE-susceptible subjects, while HAPE-resistant subjects displayed maintained RV function . In line with these findings, in healthy subjects at highaltitude, the degree of RV dysfunction was associated with subclinical pulmonary edema . Importantly, HAPE-susceptible individuals exhibit an exaggerated HPV and display higher PAP values at high-altitude compared to HAPEresistant subjects . There is anecdotal evidence of severe acute hypoxic PH with RV dilatation in a previously healthy lowlander upon arrival to 3,700 m within 24 h . All these findings suggest that lowland apparently healthy HAPE-susceptible subjects are also prone to develop RV dysfunction, most probably due to an augmented HPV. However, direct effects of the gene-variants associated with HAPE susceptibility on the RV cannot be ruled out yet.

Right Ventricular Diastolic Function
It should be noted that only a few studies followed the international guidelines to evaluate multiple parameters for full characterization of the RV diastolic function. Most of the studies provided only a few RV diastolic function parameters. Thus, 7 out of 12 simulated altitude and 15 out of 24 high-altitude exposure studies reported at least one of the following RV diastolic function parameters: RV-E, RV-A, RV-E/A, RV-E ′ , RV-A ′ , and RV-E ′ /A ′ .
Hypoxia has been shown to alter myocardial relaxation (Tucker et al., 1976;Gibbs, 2007). However, LV and RV intrinsic relaxation estimated by TDI echocardiography derived E ′ remained unchanged upon acute exposure to high-altitude suggesting that ventricular early filling may be unaffected by hypoxia . Interventricular interaction between the RV and LV may impair LV filling through the septal shift toward the LV due to RV pressure overload (B?rtsch and Gibbs, 2007). Alterations in the traditional LV diastolic function markers such as E/A ratio at high-altitude may not be associated with an impairment in myocardial relaxation but might rather reflect lower LV filling pressure (Holloway et al., 2011). Impairment of the LV relaxation seems less likely because pulmonary capillary wedge pressure, which is considered as a surrogate marker of left atrial pressure, is not elevated upon exposure to high-altitude . Moreover, increased LV untwist velocity upon acute high-altitude exposure despite attenuated LV filling Stembridge et al., 2015;Osculati et al., 2016), suggests preserved or even augmented LV relaxation. Increased sympathetic activation may contribute to the enhanced LV untwisting (Rademakers et al., 1992). Likewise, changes in RV diastolic filling patterns upon hypoxia exposure may develop due to increased RV afterload and sympathetic nervous system activation but not due to altered RV relaxation Naeije, 2010).
Atrial contraction is the final component of the ventricular diastole and contributes ∼15-20% of stroke volume , and thus is intricately related to cardiac performance. As atria actively participate in the ventricular filling, atrial function is considered as a part of ventricular diastolic function. Atrial function can be affected by a number of factors such as decreased energy supply and preload, increased afterload, and altered ventricular mechanics observed upon exposure to highaltitude Ewalts et al., 2021;He et al., 2021). However, despite its importance, literature on atrial function at high-altitude remains scarce. Only a few studies evaluated atrial function upon exposure to high-altitude using speckle-tracking echocardiography He et al., 2021). Thus, unchanged left atrial and enhanced RA contractile function was reported a few hours following an ascent to 4,559 m . In contrast, a more recent study revealed a slightly impaired left atrial function and a prominent RA dysfunction at high-altitude . More specifically, acute high-altitude exposure led to a decrease of the reservoir and conduit functions of both atria and reduced RA contractility . Notably, atrial dyssynchrony occurred only to the RA and was associated with worse RV performance . Taken together, in addition to conventional RV diastolic indices, evaluating RA function by means of speckletracking echocardiography can provide additional insights into the RV diastolic function in response to high-altitude exposure. However, exploitation of such methods remains underutilized.

Clinical Implication of Acute Hypoxia Induced Right Ventricular Dysfunction
Understanding the physiology of the RV responses to acute hypoxia is important for gaining insights into mechanisms underlying acute RV dysfunction and failure in some diseases encountered at low-altitude. For example, acute RV dysfunction associated with HPV is common during exacerbation of respiratory diseases such as chronic obstructive pulmonary disease and diffuse fibrotic lung diseases (Weitzenblum, 1994;Judge et al., 2012;Swenson, 2013). Further, episodes of transient hypoxemia accompany sleep-disordered breathing. The most common type of sleep-disordered breathing is obstructive sleep apnea. HPV contributes to transient increases in PAP during sleep in obstructive sleep apnea patients (Kholdani et al., 2015). Taken together, acute hemodynamic load exerted on the RV due to HPV is common during exacerbation in diverse cardiopulmonary conditions and understanding of its pathophysiology may lead to the development of better management strategies.
Therapeutic approaches that could potentially improve RV performance upon acute high-altitude exposure should either reduce RV afterload or improve RV oxygenation. Decreased aerobic exercise capacity observed upon exposure to highaltitude is ascribed to both a decrease in arterial oxygen content and a limitation in maximal cardiac output (Fulco et al., 1998). Combined effects of several factors such as decreased blood volume, hypocapnia, increased blood viscosity, alterations of autonomic nervous system have been shown to limit maximal cardiac output (Wagner, 2000). A limitation in RV flow output due to HPV has also been shown to contribute to reduced maximal cardiac output and exercise capacity . Indeed, several vasodilators such as sildenafil (Ghofrani et al., 2004;Richalet et al., 2005), bosentan ) and sitaxsentan  have been shown to improve maximal exercise capacity along with decreasing PAP in humans upon acute high-altitude exposure. Sitaxsentan , sildenafil  and epoprostenol (Pavelescu and Naeije, 2012) also improved RV function in healthy volunteers upon acute high-altitude exposure or hypoxic breathing. Although, their direct impact on the RV cannot be excluded, these beneficial effects on the RV were probably due to lowering PAP and PVR. Taken together, vasodilators can improve RV function and exercise capacity at least in part due to reduction of RV afterload.
Another strategy to improve RV function is to improve RV oxygenation. Artificial oxygen carriers initially developed as "blood substitutes" are now considered also for other therapeutic concepts as "oxygen therapeutics" (Spahn, 2018). Recently, a beneficial effect of a novel cross-linked hemoglobinbased oxygen carrier was demonstrated in an experimental model of acute mountain sickness in rabbits and goats (Zhang et al., 2021). Application of a carbon monoxide-saturated hemoglobin-based oxygen carrier significantly improved cardiac performance in mice exposed to high-altitude (Wang et al., 2017). Furthermore, in lambs exposed to acute hypoxia, administration of a novel oxygen delivery biotherapeutic Omniox-cardiovascular was associated with preserved RV contractile function despite elevated PVR (Boehme et al., 2018). Thus, artificial oxygen carriers might be useful in improving RV function in conditions of acute hypoxia exposure. Similarly, agents improving cardiomyocyte tolerance to hypoxia may also help to maintain cardiac function and exercise capacity at highaltitude. For example, trimetazidine has been shown to prevent cardiorespiratory fitness impairment and improve left ventricular systolic function in healthy volunteers during acute high-altitude exposure . However, it remains unknown whether trimetazidine can improve RV function upon acute exposure to high-altitude.

LIMITATIONS
Our systematic review has several limitations. As with any systematic review, publication bias and the possibility of missing potentially relevant articles cannot be excluded. However, we attempted to minimize such issues by using a robust search strategy including checking bibliography of original and review articles on the relevant topics.
In general, heterogeneity and small sample size limit the conclusions that can be drawn from the systematic analysis of the studies. Our systematic review identified considerable heterogeneity between study results. In the majority of the studies, RV function and morphology parameters were underreported. Studies also differed significantly in terms of mode of altitude ascent. In studies with a staged acclimatization, participants spent nights at intermediate altitudes, while in other studies, subjects were brought to high-altitude by vehicles within a short time. In addition, results of acute altitude simulation studies cannot be fully extrapolated to the high-altitude field conditions. For example, reduction of total blood volume that occurs at high-altitude is not observed during acute simulated altitude . Moreover, the debate about the potential differences in modalities of hypoxia challenge remains unresolved (Savourey et al., 2003;Mounier and Brugniaux, 2012). Furthermore, echocardiography examinations were performed at different time-points of exposure to hypoxia. All these factors might have influenced the changes in the RV function parameters at a target altitude. Moreover, only very few studies considered other factors potentially influencing the RV response to acute hypoxia such as gender , age  and ethnicity .
With the advent of speckle-tracking echocardiography, detection of subtle cardiac abnormalities might have been improved. However, only in a few of the included studies such a sensitive technique was employed. In addition, in most of the studies, participants were middle-aged males; thus, our results probably are not applicable to other groups such as females and other age groups. Since we considered studies only on healthy subjects, our conclusions cannot be extended to individuals with underlying diseases. Conventional echocardiography and Doppler echocardiography are considered as less accurate noninvasive methods to assess pulmonary hemodynamics and cardiac function compared to invasive techniques (Fisher et al., 2009). Invasive methods, such as right heart catheterization, are less suitable due to ethical considerations in healthy individuals and challenging logistics in remote areas (Fagenholz et al., 2012;Feletti et al., 2018). Nevertheless, numerous studies have validated echocardiography by comparing it with invasive measurements of pulmonary hemodynamics at high-altitude (Allemann et al., 2000;Fagenholz et al., 2012).
Some studies included in the review reported similar number of subjects from the same authors, which might be the case that the same subject's data might have been used twice in two different publications. Although, we did not contact the authors regarding this issue, we have been very careful to screen the included studies if the authors have mentioned that the data presented in their studies had been used in previous publications.

CONCLUSION
This systematic review demonstrated that the reports on the effects of acute exposure to hypoxia on the RV are controversial and inconclusive. This may be due to significantly different study designs and non-optimal reporting of multiple RV parameters as recommended by international guidelines. Moreover, the potential impact of other factors such as gender, age, mode of ascent and physical activity on RV responses to hypoxia largely remained neglected. Larger-scale studies and longer follow-up are needed to explore RV adaptation to hypoxia and associated increased afterload and its clinical relevance. Future research should study RV physiology by assessing multiple conventional echocardiography parameters along with the recently developed techniques, such as speck-tracking and 3D echocardiography. Thus, this comprehensive overview will promote reproducible research with improved study design and methods for the future large-scale prospective studies assessing RV function in accordance with the international guidelines, which eventually may provide important insights into the RV response to acute hypoxia exposure.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.