Academic Editors: Osama Hamdy and Joanna Mitri
Cardiovascular diseases (CVDs) are recognized as one of the major causes of morbidity and mortality worldwide. Generally, most CVDs can be prevented by addressing behavioral risk factors, including smoking, unhealthy diet and obesity, lack of physical activity, and alcohol abuse. Therefore, it is important to have a healthy lifestyle by performing regular physical activity to improve cardiovascular health and diseases. However, a majority of adults worldwide do not meet the minimum recommendations for regular aerobic exercise, and overweight and obesity ratio continues to rise. In addition, obese individuals, with a high prevalence of CVDs, have a lower participation rate for exercise because of the strain on the musculoskeletal system. Hypoxic therapy, including exposure or exercise intervention under hypoxia, has been utilized as a new therapeutic modality for cardiovascular benefit and amelioration of CVDs. Hypoxic therapy shows various physiological and pathophysiological properties, including increased appetite suppression and dietary intake reduction, increased energy consumption, improved glycogen storage, enhanced fatty acid oxidation, improved myocardial angiogenesis or ventricular remodeling, augmentation of blood flow within the skeletal muscle vascular beds, and reduction of the burden on the musculoskeletal system making it applicable to patients with CVDs and obesity with attenuated cardiovascular function. In particular, hypoxic therapy is very effective in improving cardiovascular benefits and preventing CVDs by enhancing arterial function, vascular endothelial function, and hemorheological properties. These observations indicate that hypoxic therapy may be an important and essential strategy for improving cardiovascular health and reducing cardiovascular morbidity and mortality.
Cardiovascular diseases (CVDs) are the leading cause of death globally [1]. An estimated 17.9 million people died from CVDs in 2019, representing 32% of all global deaths [2, 3]. Of these deaths, 85% were due to heart attack and stroke [2, 3]. Of the 17 million premature deaths (under the age of 70 years) due to noncommunicable diseases in 2019, 38% were caused by CVDs [4]. Most CVDs can be prevented by addressing behavioral risk factors such as tobacco use, unhealthy diet and presence of obesity, physical inactivity, and alcohol abuse [5]. It is important to detect CVDs as early as possible so that management with lifestyle modification and medication can be initiated [6].
Among the several behavioral modification therapies, physical activity or exercise is recognized as a representative strategy for reducing, preventing, and treating CVD risk factors [6, 7, 8, 9]. Physical inactivity is a significant risk factor for CVDs [10]. Sedentary individuals have a 150–240% higher risk and prevalence for CVD than physically active individuals [7]. The main benefit of being physically active in reducing the risk of CVDs is that the individuals who are even slightly physically active, regardless of the amount of physical activity, have lower morbidity and mortality rates than those who are not physically active [9]. These findings suggest that a relatively small increase in physical activity can lead to a remarkable reduction in CVDs [6, 9]. In addition, increasing the amount of physical activity also reduces the risk of stroke and heart failure due to a dose-dependent relationship [6]. Regular exercise is especially effective in lowering the risk of CVDs by improving body composition, cardiovascular parameters, and arterial function [11].
However, a majority of adults do not meet the minimum recommendations for regular aerobic exercise [6, 10, 12]. The proportion of overweight/obese individuals is increasing in both sexes and across all age groups [13]. In particular, obesity is linked to numerous diseases of the cardiovascular system and increases CVD prevalence and mortality independently of other cardiovascular risk factors [14, 15, 16]. Recent research results emphasize abdominal obesity, which is determined by waist circumference, as a representative cardiovascular risk parameter [14]. It is important to note that overweight individuals have difficulty performing exercise due to musculoskeletal problems, and thus, they suffer a vicious cycle of continuously increasing cardiovascular risk and disease prevalence [17, 18].
Currently, several researchers have widely used hypoxic conditions for cardiovascular benefit and amelioration of CVDs based on studies showing that high-altitude populations have lower rates of obesity and CVD than those who live at sea level [17, 19, 20]. Hypoxic therapy such as hypoxic exposure and hypoxic training is being used as a novel therapeutic modality to effectively reduce cardiovascular risk and obesity, which is highly associated with numerous CVDs [18, 21, 22, 23, 24, 25, 26]. In addition, hypoxic therapy is being used effectively to promote the health of various populations by improving various physiological and pathophysiological properties [23, 24, 25, 26]. Acute exercise under hypoxia reduces joint loading and improves functional ability by decreasing exercise load, especially in the same expenditure. Chronic exercise intervention under hypoxia also improves body composition, aerobic fitness, muscle function, cardiometabolic parameters, and arterial endothelial function [17, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37]. Several previous studies have investigated the effects of hypoxic therapy such as exposure or exercise under high altitude and hypoxia on cardiovascular benefits and improvement of CVDs [24, 27, 28, 29, 30, 31, 32, 33, 34].
Therefore, this narrative review summarizes recent evidence and any possible benefits of hypoxic therapy under hypoxia in cardiovascular function and CVDs.
Short-term and/or long-term hypoxic exposure induces various physiological and pathologic changes [17, 21, 23]. Acute exposure to hypoxia activates the sympathetic nervous system among the components of the autonomic nervous system (ANS) as a compensatory response leading to increases in heart rate and minute ventilation, which leads to an increase in cardiac output [27, 38]. Hyperventilation under hypoxia is regulated by peripheral chemoreceptors in the carotid arteries in response to reduced arterial oxygen partial pressure and is an essential process for supplying sufficient oxygen to tissues [38, 39, 40]. These ventilation and cardiovascular physiological responses to hypoxia allow the metabolic needs of tissues to be met at rest and during exercise under hypoxia. Prolonged exposure to hypoxia leads to erythropoiesis, which increases erythrocyte mass, leads to an adaptation of the respiratory response, and decreases cardiac output to a level similar to that in normoxia [17, 18, 41, 42].
In addition, acute exposure to hypoxia induces appetite loss and reduced dietary intake due to anorexia [43, 44, 45]. Several studies have reported that hypoxemia caused by hypoxia induces a decrease in appetite and those changes in appetite-regulating hormones under hypoxia have a particularly significant effect [22, 46, 47, 48, 49, 50]. Leptin and ghrelin are considered the most representative dietary regulating hormones that show positive changes under hypoxic exposure, and changes in several appetite-related hormones and adipokines such as glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), and peptide YY (PYY) have been demonstrated to be associated with hypoxic exposure [17, 22, 44, 45, 46, 47, 48, 49, 50]. Several previous studies have demonstrated that exposure and exercise intervention under hypoxia induces decreased appetite and energy intake by decreasing ghrelin and increasing leptin, GLP-1, PP, PYY, and norepinephrine [46, 47, 48, 51, 52, 53]. This means that appetite reduction by hypoxia is considered to have physiological and pathologic properties in showing the potential to prevent obesity and thereby reducing the morbidity and mortality rates in people with CVDs [17].
The most representative methods of hypoxic therapy are exposure and/or exercise
intervention under hypoxia, and they are known to induce various physiological
changes [17, 21, 23, 27, 38, 39, 40, 41, 42, 43, 44, 45]. Environmental control chamber equipment for
various hypoxic therapies, including exposure and exercise intervention under
hypoxia, is shown in Fig. 1. Previous studies summarized the compensatory
mechanisms and physiological responses to hypoxic therapy, including bodyweight
responses (i.e., decreased resting leptin level, increased adrenergic response,
resting norepinephrine remains post-treatment, increased serotonin level and
suppressed appetite), cellular and metabolic responses (i.e., increased hypoxic
inducible factor-1 and vascular endothelial growth factor expression, increased
angiogenesis, increased glycolytic enzyme and number of mitochondria, improved
insulin sensitivity, and increased glucose transporter-4), cardiovascular
responses (i.e., increased resting and maximal heart rate, increased peripheral
vasodilation, increased diameter of arterioles, increased affinity of hemoglobin
to oxygen, normalized blood pressure (BP), and improved cardiovascular
protection), and respiratory responses (i.e., hyperventilation, increased lung
diffusion capacity for carbon monoxide and oxygen, increased carbon dioxide
reserve in sleeping, decreased arterial oxygen saturation (S
Environmental control chamber equipment for various hypoxic therapies including exposure and exercise intervention under hypoxia. (A) External view of the environmental control chamber. (B) Front view of the inside of the environmental control chamber. (C) Posterior view of the inside of the environmental control chamber. (D) Emergency oxygen supply equipment. (E) Vacuum toilet system. (F) Vacuum pump device for hypobaric hypoxia. (G) Nitrogen generator for normobaric hypoxia. (H) Vacuum pump panel.
One of the new therapeutic alternatives to increase cardiovascular benefits resolve CVDs is hypoxic therapy, which was recently used as a common medical modality and is positioned in the field of alternative medicine [21, 23, 24, 25]. Hypoxic therapy such as hypoxic exposure or hypoxic exercise intervention can be used to increase cardiovascular benefits and to treat or prevent CVDs (Fig. 2). Therefore, this review focuses on the effectiveness and potential applications of hypoxia therapy.
Efficacy of hypoxic therapy in enhancing cardiovascular benefits
and in the treatment and prevention of cardiovascular diseases. CVDs,
cardiovascular diseases; FMD, flow-mediated dilation; NO, nitric oxide; NOx,
nitric oxide metabolites; HIF-1
The initial data used to evaluate the relationship between hypoxic exposure and CVDs were derived from epidemiological studies. These studies compared high-altitude and low-altitude populations, and several studies showed that the risk of CVDs decreased with increasing altitude, but other studies have reported the opposite [54, 55, 56, 57, 58, 59, 60, 61]. Most of these conflicting findings result from confounding factors (i.e., ethnicity, race, sex, physical activity, and nutritional status), which were not adequately addressed in the study design and analysis. Faeh et al. [62] evaluated the effect of altitude on CVDs using the Swiss National Cohort Study Group data. They analyzed the relationship between altitude (e.g., hypoxia degree) and CVDs using data from 1.64 million German and Swiss residents and found a highly beneficial effect on coronary artery disease (CAD) and stroke. In addition, they reported that individuals who were born at high altitudes also had an independent protective effect for CAD [29, 62]. The beneficial effects of high altitude on CVDs have been consistently reported in other studies [63, 64, 65]. Faeh et al. [63] conducted a follow-up study of the Swiss National Cohort using data from 4.2 million individuals. They reported that mortality from CVDs decreased linearly with increasing altitude. Ezzati et al. [64] confirmed a beneficial dose-response relationship between altitude and CVDs using a variety of data sources, including the National Center for Health Statistics, the National Elevation Dataset, and the U.S. Census Estimates. In addition, Winkelmayer et al. [65] reported a lower mortality rate for myocardial infarction, stroke, and CVDs among dialysis patients in people living at high altitudes.
Previous studies have evaluated the efficacy of hypoxic exposure as a potential
therapeutic modality for increasing cardiovascular benefits and treating or
preventing CVDs based on the beneficial relationship between altitude and CVDs
[66, 67, 68, 69, 70, 71]. Vedam et al. [66] examined the effects of hypoxia corresponding
to 80% S
Additionally, Lyamina et al. [69] examined the effect of a 20-day,
intermittent, normobaric, intermittent hypoxia conditioning program on BP and NO
production in patients with stage 1 arterial hypertension. They reported that the
intermittent hypoxia conditioning program increased NO synthesis and decreased BP
in hypertensive patients, and the reduction in BP persisted for at least 3 months
in 28 of 33 hypertensive patients. Burtscher et al. [70] investigated
the effectiveness of intermittent hypoxic exposure (IHE) (inspired oxygen
fraction; F
Based on the previous studies discussed above, hypoxic exposure enhances arterial endothelial function through activation of NO-mediated mechanisms to increase cardiovascular benefit and shows promise as a potential therapeutic modality for treating or preventing CVDs.
The addition of physical activity to hypoxia results in compensatory
vasodilatation where there is increased blood flow to the activated skeletal
muscles, compensating for reduced oxygen content in arteries and keeping oxygen
delivery to active muscles relatively constant [72]. Acute exercise and/or
exercise interventions are independent and highly potent metabolic stressors
[73]. Acute hypoxic exposure reduces S
Regarding acute exercise under hypoxia, Jung et al. [36] investigated
the effect of an acute pilates program under hypoxia on metabolic, cardiac, and
vascular functions in healthy women. They concluded that, compared to normoxic
conditions, the acute pilates program under hypoxia (F
Exercise intervention under hypoxic conditions has been studied and has shown a
clear therapeutic effect on cardiovascular health. Nishiwaki et al. [33]
examined the effects of exercise training under hypobaric hypoxia (600.1–608.3
mmHg; simulated 2000 m altitude) on arterial stiffness and FMD in 16
postmenopausal women (56
In previous studies conducted with patients with CVDs, Korkushko et al.
[78] investigated the efficacy of exercise training under hypoxia in the elderly
with CAD, and they confirmed that hypoxic training is a non-pharmacological
therapy that can effectively improve CAD through the economic function of the
cardiovascular system, optimization of oxygen consumption, improvement of
vasomotor endothelial function due to increased NO formation, and normalization
of microcirculation. Serevrovskaya and Xi [24] conducted a review study on the
practical effectiveness of exercise intervention under hypoxia as a
non-pharmacological treatment for CVDs by synthesizing several studies. Based on
evidence accumulating from studies of the last 50 years in healthy populations
and patients with CVDs, hypoxic therapy modality, composed of 3–4 bouts of 5–7
min exposures to 12–10% oxygen alternating with normoxic durations for 2–3
weeks, can result in remarkable beneficial effects on cardiovascular health and
the treatment of CVDs such as hypertension, coronary heart disease, and heart
failure. Muangritdech et al. [32] examined the effects of 6-week
exercise interventions under hypoxia (F
In summary, hypoxic therapy, such as acute exercise and/or exercise intervention under hypoxia, induces greater reductions in BP and improves vascular endothelial function and hemorheological properties, thereby reducing cardiovascular risk and improving various aspects of cardiovascular function compared to circumstances under normoxia [24, 33, 36, 37, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 75, 77, 78, 79]. This evidence confirms that hypoxic therapy is a promising modality for improving cardiovascular benefits and in preventing and treating CVDs.
Hypoxic therapy is a novel therapeutic modality that may improve cardiovascular benefit and be utilized in the prevention and treatment of CVDs, but further clinical trials and thorough evaluation are needed to standardize various hypoxic therapies and utilize hypoxic devices [24]. Levine [80] reported that there are several considerations associated with taking patients with CVDs to hypoxia as follows: (1) the decrease in available oxygen in hypoxia can cause or worsen the symptoms of CVDs; (2) hypoxia and various environmental conditions (exercise, dehydration, changes in diet, thermal stress, and emotional stress from personal danger or conflict) can cause acute CVDs; (3) occasionally, sudden death from CVDs may occur; (4) ensuring optimal health, allowing adequate compliance for at least 5 days, and optimizing the intake of medications such as statins and aspirin are important in reducing the risk of side effects; (5) evaluation of exercise capacity and ischemia through a graded exercise test in normoxia is needed, and the decision of a specialist is warranted for participation in hypoxic therapy. These considerations mean that first aid and medical systems must be thoroughly equipped when hypoxic therapy is used for patients with CVDs.
Hypoxic therapy, including exposure or exercise interventions under hypoxic
conditions, can be utilized as a novel therapeutic modality for cardiovascular
benefit and improvement of CVDs based on a variety of physiologic and pathologic
responses. In particular, with regard to cardiovascular health and CVDs, many
previous studies have reported that various hypoxic therapies have positive
effects on BP, cardiovascular risk factors, arterial stiffness, FMD,
hemorheological properties, NO, NOx, and HIF-1
CVDs, cardiovascular diseases; CAD, coronary artery disease; GLP-1,
glucagon-like peptide-1; PP, pancreatic polypeptide; PYY, peptide YY;
S
HYP and KL conceptualized the study. HYP, JK, and KL designed the content. HYP, SWK, and WSJ wrote and prepared the original draft. HYP, JK, and KL reviewed and edited the manuscript. SWK and WSJ were in charge of visualization. SWK, WSJ, JK, and KL supervised the writing of the manuscript. All authors have read and agreed to the final version of the manuscript.
Not applicable.
This study was supported by the Konkuk University Research Professor Program.
This work was supported by the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea (NRF-2019S1A5B8099542).
The authors declare no conflict of interest.