Cardiovascular Regulation of the Elderly in Low Oxygenation Environments: A Narrative Review


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Introduction
Daily people all over the world (especially residents of places at sea level with some type of pre-existing comorbidity) are exposed to "hypoxic" regions (characterized by regions / environments of high altitude and/or with low oxygen availability), for the most diverse purposes such as housing, sports, travel, research, medical treatments and others. However, acute and long-term exposure in environments with these characteristics causes organic systems to be induced to adapt their physiological processes so that the systems last in a satisfactory and less harmful way in environments with low oxygenation. (1,2).
Studies have already shown that prolonged exposure to hypoxic environments with no previous experience or preparation can generate an atypical and possibly harmful physiological response to organ systems, especially in the elderly (3)(4)(5)(6). This is because, the aging process is linked to the dysfunction of several physiological parameters, in particular, to the cardiopulmonary and cardiovascular dysfunction (2). Thus, prolonged exposure to hypoxic environments can mediate possible physiological and pathophysiological complications in individuals with advanced age and / or with some type of cardiovascular or cardiopulmonary dysfunction, and these complications may be enhanced by the presence of any of these dysfunctions in old age.
Because the physiological responses induced by hypoxic environments vary widely, researchers have sought to understand how these physiological adaptations induced by hypoxity can impact global health, especially for subjects with the conditions listed above. In any case, acute or chronic exposure to hypoxic environments induces high levels of stress for the physiological systems, due to the conditions of hypothermia, hypohydration, hypoglycemia and more commonly hypobaric hypoxia, in which, subjects with the conditions mentioned above tend to be more responsive and harmed by this range of stressors (7,8).
Based on the presented panorama, this study aimed to describe the main adaptive effects on cardiovascular, myocardial and cardiorespiratory control in hypoxic environments in the elderly with some type of cardiovascular and / or cardiopulmonary dysfunction. So that the outcomes treated in this study can help to guide the subjects beforehand with any of these dysfunctions during exposure to hypoxic environments.

Study Search and Selection Strategy
The study is a narrative review, which was elaborated from the following steps: 1) de nition of the theme and question of the study; 2) selection of databases; 3) de nition of priority data for further analysis; 4) re ned comments and ltering of the studies and results found and 5) descriptive summary of the main ndings (9).
In order to carry out this study of narrative review, a bibliographic survey was carried out in June 2020 in the virtual database Medline via PubMed by two independent authors. The protocol used to search for the studies was done through the selection of previously de ned keywords (isolated and/or combined) in the English language, in which the following indexing terms and meSH terms were used: cardiovascular system and / or cardiovascular regulation and / or regulation of blood ow (cardiovascular system and / or cardiovascular control and / or blood ow control) and hypoxia and / or low availability of oxygen and / or altitude (hypoxia and / or low availability of oxygen and / or altitude). Thus, it was asked about the in uence of hypoxic environments on the cardiovascular regulation of the elderly, and how their behavior occurs from the permanence or passage in environments with these characteristics. Additionally, it is noteworthy that a search was also carried out on the references of the preliminary articles obtained from the indexing terms, however, none of the investigations met the selection criteria of the present study.

Study Selection Criteria and Data Analysis
After inserting the indexing terms and meSH terms in the database, the following screens were rst applied: clinical trials, controlled and randomized tests and publications from the last ve years. From this rst lter, a total of 210 articles were obtained, which were inserted in a spreadsheet and sent to two independent researchers, so that they could read the title and summary of the articles, and from this, indicate whether the work did or did not meet the criteria for inclusion in the present review. It should be noted that the independent evaluators did not start reading the summary of the studies when their titles were too different from the theme of the narrative review.
After carrying out this rst stage, the researchers responsible for the study started to read the selected works in full (111 studies), in which a second ltering was applied from the following screens: elderly population (with an average or median of 60 years) chronological age or older) and randomized longitudinal, cross-sectional or observational clinical trials. After reading and reviewing the studies from the added screens, a total of nine studies were obtained.
Finally, a third lter was applied, in which works published before 2015 were excluded, research projects, systematic review articles or meta-analysis, qualitative studies, expanded abstracts, dissertations, theses, book chapters, duplicate studies, studies with animal model, studies that did not directly investigate the in uence of hypoxic environments on cardiovascular control, studies involving sports modalities, studies with previously trained subjects, studies with athletes, case studies, studies with some type of pharmacological intervention and studies with some type of direct intervention of programmed and systematized physical exercise. From this, a total of four studies were obtained, which were reread and reviewed by the study researchers for further description of the results found.
For the analysis of the data, the method of integral description of the results of the selected works was adopted, due to the low number of studies that contemplated the theme, in which such description was delineated from general topics

Results And Discussion
Adaptive Responses of the cardiovascular and Cardiopulmonary System to Hypoxic Environments At high altitudes (above 1000 meters above sea level) it is common to install hypoxia hypoxia, this condition occurs due to the reduction in the partial pressure of atmospheric oxygen when compared to sea level, which in turn causes a signi cant reduction arterial oxygen saturation. This condition induces cardiovascular chemoreceptors to adjust pulmonary ventilation in an attempt to reestablish normal levels of oxygen supply to organic systems (10). This process mediated by the chemoreceptors directly in uences the heart rate modulation during exposure to hypoxia situations, this modulation occurs autonomously, which modi es the heart rate control by means of the cardiac barore ex and the sympathetic activity, as well as in the modi cation of the heart rate. vasoconstrictive (sympathetic) activity (10,11). In addition, from the moment that arterial oxygen saturation decreases, the organic systems, in response, induce increases in mechanical ventilation in order to reduce the stressor effects originating from hypoxity, and also to maintain the integrality of the energy supply system (aerobic) myocardium. Magalhães et al., (2002) found that the ventilatory values can be 2 to 5 times higher in hypoxic environments, this elevation being responsible for the satisfactorily satisfactory functioning of the organic systems. In addition, in the same study it was also observed that blood ow tends to become more selective in hypoxic environments, in which tissues considered vital have priority in the supply of arterial blood.
However, even with the imposition of these adaptations in order to maintain a satisfactory organic functioning, studies such as Wilmore and Costill, (13) demonstrate that the maximum oxygen consumption (VO2máx) does not undergo signi cant reductions up to an altitude of 1600 meters, in the which, oxygen saturation shows a decreasing tendency from altitudes higher than indicated, in addition, it was observed that for every 1000 meters of increase in altitude the value of VO2max presents a decreasing tendency of 11%. Therefore, these ndings help to foster the need for the process of prior adaptation of organic systems so that it can perform its functions properly when exposed to hypoxic environments.
Another important aspect when it comes to hypoxity is the modulation of blood ow, which undergoes signi cant changes when it comes to high altitudes and / or hypoxic environments, as these situations present an induction of loss of body water, which induces the increased blood viscosity. With more dense blood, the ejection volume decreases, causing signi cant increases in cardiac output and, consequently, in heart rate, to try to temporarily remedy this drop in ejection volume. In addition, increases in blood density also cause an overload on the heart due to the increased resistance exerted by the blood (more dense) on the vessel wall, which may increase the risk of atherosclerotic injury and cardiac events (14, 15).
The brief overview presented above was evidenced in a study by Lang et al., (16), in which it was possible to identify that hypertensive individuals (age 52.2 ± 9.7) when subjected to a six-minute walk test at altitude elevated (3260 m), had an increased blood pressure (BP) response during rest and, mainly, shortly after the test, in which it was possible to observe that BP remained elevated throughout the recovery period. This nding is noteworthy, given the apparent di culty in controlling blood pressure in hypertensive patients when exposed to environments with low oxygenation, especially when subjected to light activities that require a satisfactory acute response from the cardiovascular system.
However, it has been demonstrated that exposure to high altitudes and / or hypoxic environments can generate long-term bene ts, as evidenced in the study by Rostrup, (1998), in which it was demonstrated that the increase in sympathetic activity can be a re ex to not an increase in the concentrations of circulating catecholamines, but an increase in the stimulation of their nerve terminals. However, prolonged exposure to this type of environment tends to promote a signi cant decrease in plasma volume and, simultaneously, a reduction in maximum heart rate (17,18), which in turn implies a reduction in maximum cardiac output, which can directly affect the supply of arterial blood to the tissues, mainly through moderate to high intensity situations (8, 17 In the same sense, in a more recent study developed by Park et al., (2) with obese elderly (66.5 ± 0.8 years) submitted to physical exercises in high altitude environments (3000 m), it was possible to observe that the body composition, lung function and heart rate variability improved signi cantly, even higher when compared to elderly people in the same condition, however, trained in normoxic locations. Thus, new studies should be carried out to verify in a concrete way the possible bene ts or harms caused by short and long term exposure in regions of great hypoxity.
Blood pressure and myocardial behavior in relation to altitude in elderly people with COPD Chronic Obstructive Pulmonary Disease (COPD) is mainly characterized by air ow limitation due to its chronic obstruction. Which results from the dysfunction of the gas diffusion between the airways and the bronchi, together with in ammation and later, possible destruction of the lung parenchyma (20). This condition is aggravated during physical exertion or when staying in hypoxic environments such as places with more than 1600m of altitude due to the low atmospheric pressure of oxygen (2). This condition, when not congenital, is more commonly found in subjects over 50 years of age due to a prospective accumulation of bad behavioral habits such as active or passive use of nicotine, too much permanence in environments with excess of gaseous pollutants and among others (21,22).
As previously mentioned, COPD is more prevalent in the elderly, to whom the combination of these two conditions is closely linked with some comorbidities, mainly cardiovascular diseases, with emphasis on changes in blood pressure values, often resulting from endothelial dysfunction resulting from the natural process. and irreversible aging, with this, subjects conditioned to such characteristics are more responsive to changes in the cardiovascular system induced by hypoxia, with emphasis on pressure values (23,24). Additionally, COPD also seems to be associated with impaired autonomic regulation of blood ow, thus, subjects conditioned to the characteristics listed above are exceptionally more susceptible to changes in cardiovascular regulation induced by hypoxia and / or high altitude environments (20,25).
In view of this, in a randomized and eld study conducted by Schwarz et al., (20) it was identi ed that, after a group of subjects with an average age of 64 years old and living in low-altitude regions spent 48 hours in a at an altitude of more than 2500m, their heart rate and blood pressure values have been greatly altered. Since, in the rst 24 hours, the mean values of morning diastolic BP in the group increased by + 5.0 mmHg. The same occurred with mean morning systolic BP, however, the increase was twice as large + 10 mmHg. On the second day, mean BP values were slightly reduced, however, systolic BP was still signi cantly higher when compared to baseline values. Additionally, it was also identi ed that 48 hours of stay in a high altitude environment was su cient to cause signi cant decreases in barore ex sensitivity (-3.0 msec / mmHg) and a progressive and signi cant increase in cardiac variability (+ 1.8%).
From this perspective, pulmonary hypertension is also one of the characteristic complications of COPD, which is linear in the severity of the in ammation and destruction of the lung parenchyma. This speci c condition is often linked to cardiovascular complications, and in this case in particular, with ventricular dysfunction (26,27). Faced with this, in a randomized and eld study conducted by Lichtblau et al. (26) it was identi ed that, after a group of people with a median age of 66 years (all with COPD and some cardiovascular dysfunction and residents of regions of low altitude) to spend a night in an environment of 2590m of altitude, was enough to cause alterations in the cardiovascular parameters. In which, one night in this environment was enough to cause a signi cant decrease in partial oxygen pressure (9.0 kPa to 6.6 kPa) together with a 7% decrease in oxygen saturation in arterial blood (from 94-87%). The high altitude also caused morphological changes in the myocardial function of the right ventricle, to which there was an increase in the systolic speed of the tricuspid regurgitation peak (TRV) as well as in the tricuspid pressure gradient (TPG) (2.4 m / s TRV for 2.8 m / s and 23mm HG TPG for 32mm Hg). The right ventricular out ow tract together with its nais systolic area and right atrial pressure also increased with exposure to altitude (26).
In addition, all study participants had normal left ventricular systolic function at an altitude of 490 m.
However, the participants' rise to an altitude of 2590m was su cient to cause a signi cant increase in heart rate together with an increase in systolic BP, in addition to a slight increase in the diameter of the aortic root and a slight reduction in the ejection fraction. of the left ventricle (26).
Thus, it can be said that elderly individuals with COPD are more vulnerable to acute exposure to hypoxic and / or high altitude environments, in which this exposure acts directly and negatively on autonomic and cardiovascular regulation, leading to clinically signi cant increases in blood pressure and heart rate values (20). These changes can be explained due to the fact that the external stimuli that guide the cardiovascular autonomic regulation receive a cascade of adverse reactions, since the scarcity of oxygen stimulates the chemoreceptors and, consequently, the metaboreceptors, to a misinterpretation of not supplying the demand metabolic, interfering directly and systemically in cardiovascular control during rest. In addition, high altitude environments are linked to low temperatures, therefore, exposure to this type of place makes the thermoreceptors gain more prominence during cardiovascular regulation, which can also interfere with cardiovascular homeostasis during rest (28).
Therefore, the exposure of the elderly to hypoxic environments leads to a cascade of disproportionate peripheral stimuli, which directly interfere with central cardiovascular regulation, and may even overlap it, which generates blood ow dysregulation, and, consequently, blood pressure and heart rate values at rest or during light physical activities. In addition, although these increases are a natural response to such conditions, the study also identi ed that such consequences were perpetuated longer in elderly subjects and with COPD when compared to young subjects without COPD exposed to the same condition (20). Thus, exposure to hypoxic and / or high altitude environments proved to be harmful and possibly harmful to the cardiovascular health of elderly people with COPD.
From all the data presented so far, it is not possible to state that the changes and dysfunctions of cardiovascular parameters were exclusively derived from exposure to altitude, since COPD can be a possible confounding factor in these results. However, such changes only occurred when the study participants were exposed to hypoxic and / or high altitude environments, since the cardiovascular parameters were not altered when the subjects were evaluated in an environment with less than 500m of altitude.

Final Considerations
The study aimed to describe the main adaptive effects on cardiovascular, myocardial and cardiorespiratory control in hypoxic environments in the elderly with some type of cardiovascular and / or cardiopulmonary dysfunction. From this, it can be concluded that, exposure to hypoxic environments directly and negatively in uenced the cardiovascular regulation and cardiac behavior of the elderly, in which this episode worsened in the presence of comorbidities, such as COPD.
It is a fact that the aging process has become a public health problem nowadays, since some factors such as psychosocial, cultural, medicinal and economic factors have contributed to the increase in the longevity of humanity, culminating in the largest population of the elderly age group, that in the year 2050, it will represent 16.7% of the world population, with almost 1.6 billion elderly people all over the planet (29). Therefore, such an episode needs attention, since, concurrently with the aging process, there is a deterioration of the tissues and physiological processes of the human body, which are closely linked to the inevitable aging process. Such a circumstance leads to a decline in physical, functional and physiological capacities, in which some of these processes directly interfere with cardiovascular regulation, such as skeletal and cardiovascular muscle dysfunction (30).
The aging process alone is already a risk factor for cardiovascular events, in which, within this process, the increased stiffness of the vascular endothelium stands out (31). The vascular endothelium has a direct role in the regulation of vascular tone, coagulation, blood circulation homeostasis, and mediation of vasodilating substances, in addition to producing anti-in ammatory responses, and being the link between the cardiovascular system. With aging, this whole system involved in the control of endothelial function suffers great deterioration, leading to endothelial dysfunction, which is inherent and common in the elderly population (32). Such condition is also closely associated with the occurrence of cardiac events and deaths in the elderly, being responsible for a large percentage of deaths in this public, so that such circumstances can be aggravated when there is exposure to hypoxic environments or with low concentrations of oxygen (33).
Therefore, exposure to hypoxic stimuli can generate a cascade of deleterious reactions in elderly subjects, which can be aggravated if there is the presence of some type of comorbidity. Since exposure to hypoxic environments causes disruptions in the central system responsible for cardiovascular regulation, thus overloading the peripheral systems, generating increases in resting heart rate, BP and cardiac variability, in which, the acute increase in these factors may precede cardiac events and in a chronic way, death. Another important point to highlight is the fact that exposure to hypoxic environments generates an oscillatory hemodynamic shear stress, to which this process is an atherosclerotic risk factor, since the increase in hypoxia-induced stress increases the chances of developing lesions in the endothelium wall (34).
In addition, exposure to hypoxic stimuli can also cause homeostatic and metabolic dysregulations that are detrimental to the cardiovascular health of the elderly. Since, in order to maintain body homeostasis, constant and standardized contractions of all body muscles are necessary, especially cardiac muscles (35). For the operation of these systems to take place in a speci c and e cient manner, the presence of oxygen is essential, therefore, prolonged exposure to hypoxic environments can cause an inversion of the metabolism responsible for supplying the metabolic demand of the homeostasis maintenance process, which may lead to an increase in the production of metabolites and peripheral fatigue, which when in excess, induce acute low-grade in ammation, which directly stimulates the increase in the chances of lethal cardiac events in subjects conditioned to the scenarios presented previously (36, 37).
In addition, endothelial dysfunction also causes less responsiveness to nitric oxide-mediated vasodilation, which can lead to the development of atherosclerotic lesions and lethal cardiac events (16, 38). As already mentioned, exposure to hypoxic environments can mediate the increase in metabolites and peripheral fatigue, which in excess, induce the deterioration of cardiovascular integrity, however, many of the subjects classi ed under the conditions presented above are unaware of the potential risks of exposure to hypoxic environments. therefore, it is recommended that the exposure of subjects with these conditions to hypoxic environments be measured, especially if aggravating comorbidities are present. And if possible, that such exposure is made after the intervention and release of a specialist doctor, or, after the subject's physiological familiarization, the conditions to which he will be exposed, so that the consequences of this exposure are not so severe on cardiovascular health. Thus, the present study helped to consolidate that hypoxia is harmful to endothelial function, body homeostasis and cardiovascular health of elderly subjects with some type of comorbidity.