HYPOXIC CONDITIONING IN REHABILITATION AND SECONDARY PREVENTION PROGRAMS IN CARDIAC PATIENTS WITH MULTIMORBIDITY: A REVIEW Текст научной статьи по специальности «Клиническая медицина»

Review article/Обзорная статья УДК: 616-03+616-008.3/5

DOI: https://doi.org/10.38025/2078-1962-2022-21-5-78-86

Hypoxic Conditioning in Rehabilitation and Secondary Prevention Programs in Cardiac Patients with Multimorbidity: a Review

o;

£ Nadezhda P. Lyamina*1, Galina K. Spirina2, Oleg S. Glazachev3

<

^ 'Moscow Centre for Research and Practice in Medical Rehabilitation, Restorative and Sports Medicine, Moscow, Russian Federation

^ 2 LLC "AsFor Group", Moscow, Russian Federation

^ 3I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation - ABSTRACT

c^ INTORDUCTION. Patients with multiple chronic diseases are at higher risk of premature death, hospitalization, longer hospital stays, X and reduced health-related quality of life compared to patients with a single disease. On the other hand, the presence of comorbid hi conditions limits the enrolment of traditional exercise-based cardiac rehabilitation programs. It is predicted that as life expectancy I increases, the level of multimorbidity will increase, making it even more important to find new additional methods and technologies ^ for the rehabilitation of cardiac patients with comorbidities.

X AIM. To analyze the data from the current publications or to define the validity and effectiveness of using different hypoxic conditioning regimens in cardiac patients with concomitant chronic pathology (arterial hypertension, obesity, diabetes mellitus, and chronic bronco chopulmonary diseases) as well as in multimorbid elderly patients.

MATERIAL AND METHODS. The search for relevant papers was carried out using the Medline, e-library, and Web of Science Core Collection databases, as well as the following keywords: "hypoxic conditioning", "hypoxic training", "hypoxic therapy", "interval hypoxic therapy", "intermittent hypoxia", "hypoxic conditioning", "interval hypoxia training", and "hypoxic exposure". The analysis included publications regarding the use of the hypoxic conditioning method in cardiac and elderly patients with multimorbid pathology, as well as publications on the use of the method in the rehabilitation of patients with certain nosologies to identify potential mechanisms in correcting bronchopulmonary violations and lipid and carbohydrate metabolism disorders. The last search date was April 05, 2022. RESULTS. Most of the analyzed studies proved that the hypoxic conditioning technology in passive interval exposure regimes is an effective method for non-pharmacological correction of cardiometabolic risks in cardiac patients with multimorbid pathology and can increase exercise tolerance, optimize hemodynamic parameters (HR, SBP and DBP), reduce the manifestations of bronchial obstruction and respiratory failure, and improve cognitive function and metabolic indicators. Personalized physical activity doses in oxygen-depleted ambient air appear to be promising, but require additional studies to establish optimal application protocols. CONCLUSION. The data presented may recommend hypoxic conditioning technologies for wider implementation in cardiac rehabilitation programs for patients with multimorbid pathologies.

KEYWORDS: Cardiac rehabilitation, comorbidity, hypoxic conditioning, interval hypoxic training

For citation: Lyamina N.P., Spirina G.K., Glazachev O.S. Hypoxic Conditioning in Rehabilitation and Secondary Prevention Programs in Cardiac Patients with Multimorbidity: a Review. Bulletin of Rehabilitation Medicine. 2022; 2' (5): 78-86. https://doi.org/10.38025/2078-1962-2022-21-5-78-86 *For correspondence: Nadezhda P. Lyamina, e-mail: lyana_n@mail.ru

Received: May 31, 2022 Revised: Jul 27, 2022 Accepted: Sep 20, 2022

© 2022, Nadezhda P. Lyamina, Galina K. Spirina, Oleg S. Glazachev /

Лямина Н.П., Спирина Г.К., Глазачев О.С.

Эта статья открытого доступа по лицензии CC BY.

This is an open article under the CC BY license.

Гипоксическое кондиционирование в программах реабилитации и вторичной профилактики кардиологических пациентов с коморбидной и мультиморбидной патологией: обзор

Лямина Н.П.*1, Спирина Г.К.2, Глазачев О.С.3

Московский научно-практический центр медицинской реабилитации, восстановительной и спортивной 2

медицины Департамента здравоохранения города Москвы, Москва, Россия >

ООО «АсФор Групп», Москва, Россия т

3Первый московский государственный медицинский университет им. И. М. Сеченова Минздрава России, Москва, н

Россия

РЕЗЮМЕ M

ВВЕДЕНИЕ. У пациентов с множественными хроническими заболеваниями риск преждевременной смерти, госпитализации, N длительного пребывания в стационаре и снижения качества жизни, связанного со здоровьем выше, чем у пациентов с одним E заболеванием. С другой стороны, наличие коморбидных заболеваний ограничивает охват традиционными программами кар- —I диологической реабилитации, основанными на физических упражнениях. Прогнозируется, что по мере увеличения продолжи- L тельности жизни уровень полиморбидности будет расти, что делает еще более важным поиск новых дополнительных методов — и технологий для реабилитации кардиологических пациентов с сопутствующими заболеваниями. E

ЦЕЛЬ. Проанализировать данные современных публикаций или определить обоснованность и эффективность использования 1 различных режимов гипоксического кондиционирования у кардиологических пациентов с сопутствующей хронической пато- W логией (артериальная гипертензия, ожирение, сахарный диабет и хронические бронхолегочные заболевания), а также пожилых ^ пациентов с полиморбидными заболеваниями. —

МАТЕРИАЛ И МЕТОДЫ. Поиск соответствующих работ проводился с использованием баз данных «Medline», «E-library» и «Core q Collection» (Web of Science), а также следующих ключевых слов: "гипоксическое кондиционирование", "гипоксическая трени- E ровка", "гипоксическая терапия", "интервальная гипоксическая терапия", "прерывистая гипоксия", "гипоксическое кондиционирование", "интервальная гипоксическая тренировка" и "гипоксическое воздействие". В анализ были включены публикации, касающиеся применения метода гипоксического кондиционирования у кардиологических и пожилых пациентов с полимор-бидной патологией, а также публикации об использовании метода в реабилитации пациентов с определенными нозологиями для выявления потенциальных механизмов в коррекции бронхолегочных нарушений и нарушений липидного и углеводного обмена. Дата последнего поиска - 05 апреля 2022 года.

РЕЗУЛЬТАТЫ. Большинство проанализированных исследований показали, что технология гипоксического кондиционирования в режимах пассивного интервального воздействия является эффективным методом нефармакологической коррекции кар-диометаболических рисков у кардиологических больных с полиморбидной патологией и позволяет повысить толерантность к физической нагрузке, оптимизировать гемодинамические параметры (ЧСС, SBP и DBP), уменьшить проявления бронхиальной обструкции и дыхательной недостаточности, улучшить когнитивные функции и метаболические показатели. Персонализированные дозы физической активности в обедненном кислородом окружающем воздухе представляются перспективными, но требуют дополнительных исследований для установления оптимальных протоколов применения.

ЗАКЛЮЧЕНИЕ. Представленные данные могут быть использованы для рекомендаций технологии гипоксического кондиционирования для более широкого внедрения в программы кардиологической реабилитации пациентов с полиморбидной патологией.

Для цитирования: Lyamina N.P., Spirina G.K., Glazachev O.S. Hypoxic Conditioning in Rehabilitation and Secondary Prevention Programs in Cardiac Patients with Multimorbidity: a Review. Bulletin of Rehabilitation Medicine. 2022; 21 (5): 78-86. https://doi.org/10.38025/2078-1962-2022-21-5-78-86

*Для корреспонденции: Лямина Надежда Павловна, e-mail: lyana_n@mail.ru

Статья получена: 31.05.2022 Поступила после рецензирования: 27.07.2022 Статья принята к печати: 20.09.2022

INTRODUCTION

The problem of rehabilitation of cardiac patients with multimorbidity

Cardiac rehabilitation (CR) has proven to be beneficial in reducing mortality, improving quality of life and preventing rehospitalization associated with cardiovascular disease (CVD) [1]. However, the level of participation and adherence to CR programs remains extremely low [2].

CR programs have traditionally been "single-disease" programs focusing on the needs of patients with

myocardial infarction (MI), and heart failure (HF) following cardiac and vascular surgery. Meanwhile, cardiac patients are increasingly suffering from two or more associated chronic diseases. According to an analysis by the British Heart Foundation National Audit of Cardiac Rehabilitation (NACR) Quality and Outcomes Report 2019, approximately 50% of the 6,502 patients receiving cardiac rehabilitation treatment had two or more comorbidities [3].

It is predicted that the level of multimorbidity will increase due to demographic changes (increased life expectancy and increased survival rates). It is important

to note that patients with multiple chronic diseases are at higher risk of premature death, hospitalization, longer hospital stays and reduced quality of life compared to patients with a single disease [3].

On the other hand, the number of comorbid conditions, such as neurological disorders (stroke, paraplegia and gait disturbances), restrictive lung diseases, obesity, connective tissue diseases, musculoskeletal disorders and ^ depression are often barriers to participation in traditional CR programs and increase the risk of dropping out of CR, ¡fi since not all programs consider the needs and capabilities ^ of patients with multimorbid pathology [3-6]. < It should also be noted that in patients with CVD, many J concomitant chronic conditions remain undiagnosed. This

0 applies to diseases such as chronic obstructive pulmonary g disease (COPD) and restrictive lung diseases, where symp-— toms like shortness of breath and reduced exercise tolerance "impersonate" cardiac pathology [5].

x Thus, the increasing burden and complexity of mul-q timorbidity makes it even more important to search for x additional, novel methods and technologies for the reha-

1 bilitation of cardiac patients with both comorbid and con-^ comitant pathologies.

^ AIM

To analyze the possibilities and effectiveness of hypoxic conditioning (interval hypoxic exposures at rest and physical activity in an oxygen-depleted ambient air) in rehabilitation programs for cardiac patients with comorbid and multimorbid pathologies. Previously, we provided data about the use of different protocols for interval hypoxic therapy in rehabilitation programs for patients with CVD, but without separate focus on comorbidities [7].

MATERIAL AND METHODS

The search for related works was carried out using the Medline, e-library, and Web of Science Core Collection databases, as well as the following keywords: "hypoxic conditioning", "hypoxic training", "hypoxic therapy", "interval hypoxic therapy", "intermittent hypoxia", "hypoxic conditioning", "interval hypoxia training", and "hypoxic exposure". Considering the results of recent clinical studies and individual experimental studies, we analyzed the data on the use of different modes of hypoxic conditioning in cardiac patients with the most commonly diagnosed conditions: arterial hypertension (AH), obesity, diabetes mellitus (DM) and chronic bronchopulmonary diseases, as well as in elderly patients, which contained data from controlled clinical trials, experimental studies explaining pathogenetic mechanisms, and systematic reviews through meta-anal-ysis and publications review performed over the past 5 years. In the absence of studies of a specific nosology in the last 5 years, we included earlier studies. The analysis included publications regarding the use of the method in the previously mentioned areas in cardiac patients, as well as publications on the use of the method in individual nosologies to identify potential mechanisms in correcting bronchopulmonary violation, as well as lipid and carbohydrate metabolism disorder.

Abstracts of conferences and studies with incomplete data were excluded from the analysis. In accordance with the narrative style of this review, a search was

also conducted for additional publications concerning the physiological mechanisms of hypoxic effects.

The results of the studies selected for analysis are summarized in Table 1 (see Appendix).

Hypoxic conditioning as a therapeutic factor

The therapeutic effect of air with reduced oxygen content can be understood from the works of Hippocrates, descriptions of Marco Polo's mountain travels and other sources. Observations of the Andean population (~4260 m, FiO ~11%) indicate that coronary heart disease (CHD) and, in particular, myocardial infarctions are quite rare among residents living at high altitudes. In consecutive autopsy series, not a single case of MI or even CAD was found [8]. In Switzerland, age-standardized mortality rates (per 100,000 person-years) for coronary artery disease were significantly higher in men (289) and women (104) living below 300 m above sea level compared to men (242) and women (74) living at altitudes above 1500 m [9]. Burtscher pointed out that, from a biological point of view, it is the hypoxia-in-ducible factor (HIF)-mediated mechanisms that can contribute to the reduction of cardiovascular mortality in residents of medium-high mountainous areas [8]. Activation of the HIF protein family under the action of various stressors, particularly periodic hypoxia, is used to explain a wide range of hematological and other effects from the molecular to organ and systemic levels. In this case, the degree of tissue hypoxia related to the frequency of stress-stimulating effects and recovery/reoxygenation periods is not that much, which justifies the techniques of interval hypoxic exposure [10, 11].

The most commonly used protocols in clinical practice are interval hypoxic therapy at rest (IHT - hypoxia-nor-moxia regimen, IHHT - hypoxia-hyperoxia regimen) and physical training with individual doses in oxygen-deprived ambient air.

Hypoxic conditioning in arterial hypertension patients

A recently published systematic review analyzed available data on the effectiveness of incorporating IHT/IHT courses in the rehabilitation of patients with CVD [12]. Of the 320 patients included in the study, the vast majority were elderly patients with comorbid pathologies: CAD/ CHF and AH. The analysis revealed a significant decrease in heart rate (MD = -5.35 bpm, p = 0.006), systolic blood pressure (SBP) (MD = -13.72, p < 0.001) mm Hg and diastolic blood pressure (DBP) (MD = -7.88 mm Hg, p = 0.003) in patients after a course of IHHT/IHT compared to the control group. Moreover, the course of hypoxic therapy has been shown to determine the trend towards lower total cholesterol and low-density lipoprotein (LDL) levels [12].

In 2019, Ignatenko et al. [13] comparatively analyzed the effect of two modes of hypoxic conditioning (IHT with timed dosing and IHHT with calculated procedural parameters based on individual sensitivity to hypoxia) on the clinical manifestations of ischemia and hypertensive syndrome in 219 patients with stable angina pectoris together with arterial hypertension. For the first time, this work evaluates the overall long-term (within one year) effectiveness of 4 courses of hypoxic training. The authors showed that the use of IHT/IHHT can potentiate the antihypertensive effect of the underlying drug therapy: the frequency of achieving

the optimal blood pressure level was observed in 40% of patients receiving drug therapy, 50% of patients receiving a combination of drug therapy and IHT, and 63.4% of patients receiving a combination of drug therapy and IHHT. In the IHHT group, normalization of diurnal BP variability was achieved in 50.7% of patients. The antianginal effect of IHT/IHT techniques was manifested by a significant reduction in angina attacks and a lower incidence of painless myocardial ischemia [13].

In 2020, Muangritdech et al. [14] provided data from a randomized clinical trial (RCT) aimed at evaluating the effectiveness of two IHT regimens (at rest and in combination with exercise) in patients with grade I AH, who were regularly taking antihypertensive medications. The patients, who received antihypertensive drugs without any physical intervention, were in the control group. A significant decrease in SBP was found in both groups that received a course of IHT at rest (-12.0±8.0 mm Hg, P = 0.004 and -9.9±8.8 mm Hg, P = 0.028, mean±95%) and in combination with exercise (-13.0±7.8 mmHg, P = 0.002 and -10.0±8.4 mmHg, p = 0.016) on the 2nd and 28th day after the end of the intervention, respectively. Furthermore, these changes were accompanied by an increase in values of the nitric oxide metabolites NOx and HIF-1a, compared to the control group, as well as a significant increase in the distance covered during a 6-minute walk test [13].

The presented results confirm one of the proposed mechanisms to lower blood pressure by increasing the bioavailability of NO, which leads to vasodilation and a decrease in total peripheral resistance. Previously, similar results were obtained by Lyamina et al. [15]. The authors found that 20 daily sessions of IHT (FiO2 - 0.10) increased NO synthesis and reduced BP to a level healthy for patients with stage I AH, while the decrease in BP persisted for at least 3 months.

Hypoxic conditioning and obesity

The World Health Organization (WHO) has recognized obesity as a new non-communicable "epidemic of the 21st century". According to the Russian epidemiological study ESSE-RF, the prevalence of obesity in various regions of Russia varies between 22.5% and 44.5%, when measured by BMI and between 43% and 67% in terms of waist circumference [16]. Obesity is an important risk factor for the development of cardiovascular diseases (CVD), being responsible for more than 23% of CAD cases and one of the leading risk factors for the development of fatal cardiovascular events. Obesity is closely associated with other risk factors (AH, dyslipidemia, physical inactivity, etc.) that affect the survival of cardiac patients, contributing to early disability and a decrease in both overall life expectancy and quality of life due to the development of concomitant diseases. Therefore, it is essential to correct metabolic disorders and BMI during CR.

Back in 2010, clinical studies were conducted to evaluate the effectiveness of IHHT in patients with metabolic syndrome (MS) who received basic therapy to resolve comorbidities without the use of drugs for correcting eating behaviour and body weight. A course of 15 IHHT procedures in passive mode alone or in combination with moderate systemic hyperthermia (one of the groups of patients received hypoxic conditioning procedures in combination

with alpha-capsule) has been demonstrated to lead to a significant reduction in body weight, mainly due to a reduction in fat mass, accompanied by a decrease in the level of total cholesterol, LDL, optimization of BP, increased hypoxic resistance, physical endurance and improved psychological status [17].

In a review by New Zealand colleagues, Lizamore and Hamlin [18], based on their analysis of 22 studies involv- z ing subjects leading a sedentary lifestyle, showed that D a 4-week course of IHT at rest improved submaximal exer- Z cise tolerance and reduced sympathetic predominance in D the dynamics of heart rate variability parameters. >

Results of one study conducted in 2020 at the Univer- L sity of Grenoble showed that in obese patients with low > levels of physical activity (less than 2 hours per week), pas- I sive hypoxic exposures in interval or continuous regimens > without individual dosing caused a decrease in SBP and m DBP. However, in this mode, IHT in patients does not con- > tribute to significant changes in anthropometric indices or | lipid profiles [19]. E

Bestavashvili et al. [20] evaluated the efficacy of IHHT E in passive mode, but with individual dosing, based on the ^ results of a hypoxic test in 65 CVD patients with MS. After > completing a course of 15 IHHT procedures, a significant I decrease in SBP and DBP (p <0.001), a decrease in TC, LDL L (p = 0.03), as well as anthropometric indices, NT-proBNP, m liver fibrosis and steatosis indices, ALT and AST enzymes were observed (p = 0.001). The degree of reduction in SBP, DBP and resting heart rate correlated significantly with the degree of reduction in arterial stiffness indices.

Recent studies have shown that low-intensity exercise in a hypoxic environment increases metabolic load and oxidative stress, similar to high-intensity exercise, with lower walking speed being more accessible and less traumatic to muscles and joints in obese patients with underlying orthopedic conditions. [21-23]. Ramos-Campo et al. [24], in a systematic review of a meta-analysis, showed that in obese and overweight patients, physical activity under hypoxic conditions led to lower body weight, fat mass, WC/ OB index, LDL, SBP and DBP, as well as a more pronounced reduction in the level of triglycerides and an noticeable increase in muscle mass during physical training in hypoxia compared with a normoxic environment.

A group of Korean researchers developed an original protocol for a course of Pilates classes in a hypoxic environment (FiO2 = 14.5%), the implementation of which for 12 weeks (3 times a week) in obese patients led to a significant reduction in the values of SBP and DBP, TC, TG, elimination of signs of endothelial dysfunction, increased aggregation, improvement of erythrocyte deformability and rheological properties of the blood, compared with the control group of patients exercising in the same mode, but in normoxia [25].

In 2021, De Groote and Deldicque [26], in a descriptive review, presented data from 17 RCTs that assessed the effectiveness of exercise in hypoxia. Although some RCTs did not show weight loss in patients, an improvement in body composition was demonstrated by a reduction in body fat and an increase in lean body mass. The results for the dynamics of physical performance were ambiguous: both a significant increase in maximal oxygen consumption (VO2max) and maximal aerobic capacity after

an 8-week course of hypoxic training with less pronounced effects, especially in elderly multimorbid patients. The authors conclude that the benefits of hypoxic training depend on the type of exercise, exercise regimen, and factors contributing to weight loss after hypoxic training, including increased energy expenditure, decreased appetite coupled with reduced food intake and increased levels of ghrelin and leptin.

^ Hypoxic conditioning and diabetes mellitus

¡fi Experimental studies have shown that HIF-1a

^ plays a significant role in the pathogenesis of p-cell

< dysfunction and DM, as well as in the development of both

J macrovascular and microvascular complications of DM. In

0 turn, hyperglycemia destabilizes HIF-1a, thereby disrupting g the physiological response to hypoxia [27].

— Given the complexity of molecular cascade regulation involving HIF-1a, currently, there is no consensus among

x researchers on the validity of the HIF-1a level induction

q strategy for the treatment of diabetes itself and its

x complications. There are few clinical studies on this topic.

1 Serebrovskaya et al. [28] demonstrated that a 3-week ^ course of IHT increased insulin sensitivity and reduced ck fasting glucose levels in patients with pre-diabetes, which

correlated with the increase in HIF-1 a mRNA in blood leukocytes.

Two clinical studies reviewed in a systematic review by Neuhoff [29] showed a reduction in blood glucose levels by 0.74-2.1 mmol after a one hour of exposure to moderate hypoxia. However, two other clinical studies into the effects of exposure to 10 sessions of hypoxic conditioning failed to demonstrate a sustainable decrease in fasting blood glucose levels.

In an analytical review, a group of authors from South Korea confirmed that the short- and long-term effects of exercise in a hypoxic environment were associated with improved glucose uptake and insulin sensitivity in patients with T2DM to a greater extent than with exercises done under normoxic conditions [30]. Meanwhile, there is limited evidence suggesting the efficacy and safety of the long-term effects of such exposure in patients with metabolic disorders.

Hypoxic conditioning and respiratory diseases

In 2018, Ignatenko et al. [31] presented the results of a study that included 90 patients with multimorbid pathology: stable angina II-III functional class and COPD stages 1-2, aged between 40 and 60 years. The inclusion of IHT in the standard therapy led to a reduction in the frequency of intermittent and persistent cough (by 11.1% and 22.2%, respectively) and of dyspnea after moderate and strenuous exercises (by 15.5% and 4.5%, respectively). Regarding the cardiovascular system, an increase in exercise tolerance was noted, as evidenced by the increase in distance in the 6-minute walk test (+66.8 m vs. +36.3 m in patients with FC II and +34.5 m vs. +22.5 m in patients with FC III) and reclassification of the functional class of angina in the direction of its decrease (FC I +15.6 - control and +22.2% - exposure and FC II -15.6 and -15.5%, FC III - 0 and -6.6%, respectively).

The work of Borukaeva [32] revealed changes in parameters of external respiratory function. After a course

of IHT in patients with mild to moderate asthma, there was a significant improvement in bronchial patency, an increase in respiratory volume and alveolar ventilation, and a decrease in minute respiratory volume. The share of alveolar ventilation in the minute respiratory volume increased due to improved pulmonary ventilation and reduced functional dead space, leading to an increase in the efficiency of gas exchange between alveolar air and venous blood.

Hypoxic Conditioning in Elderly Patients with Polymorbidity

The results of a placebo-controlled study (conducted by U. Bayer et al. in 2017) involving elderly patients with multimorbid pathology (dementia and concomitant cardiac pathology, such as IHD, CHF, AH, and atrial fibrillation) showed the following: an increase in exercise tolerance, i.e., a significant increase in the distance covered during the 6-minute walking test (6MWT) in patients, who received 15 IHHT treatments at rest, as part of a multimodal exercise-based rehabilitation program compared to the control group [33]. A significant improvement in cognitive functions was also observed in this group of patients according to the results of dementia definition test (Dem-Tect) and clock drawing (Clock-drawing Test). The increase in values in the dementia test was +16.7% (in the control group +0.39%, p < 0.001) and in the clock drawing test was +10.7% (in the control group +8%, p=0.031). It should be noted that the hypoxic load was administered individually, based on the results of a 10-minute hypoxic test, where the degree and rate of blood oxygen desaturation and heart rate were assessed.

Wang et al. [34] studied the safety and therapeutic efficacy of this method in elderly cardiac patients with mul-timorbidity. Patients with moderate cognitive impairment were diagnosed with CVD (CHD, AH), chronic bronchitis, degenerative arthritis, and other age-related diseases. A course of 3 sessions of IHT per week for 8 weeks resulted in a significant improvement in MMSE test results from 25.7+0.4 to 27.7+0.6 (P=0.038) and a 5-7 mmHg reduction in SBP. Art. (P < 0.05).

A systematic review with a meta-analysis published in 2020 (M. Jung et al.) showed that exercise under hypoxic conditions had a significant effect on improving cognitive functions in older adults (SMD = 0.3, 95% confidence interval: 0.14±0.45, I2 = 54%, p<0.001) [35]. Various characteristics (age, type of cognitive task, exercise intensity, type of training and hypoxia level) significantly influenced the effectiveness of complex training and the degree of compensation for cognitive dysfunction.

CONCLUSION

Hypoxic conditioning of cardiac patients with multimorbid pathologies can be considered as a universal, path-ogenically substantiated method of non-drug intervention during cardiac rehabilitation and secondary prevention, which increases exercise tolerance, optimizes hemodynamic parameters (HR, SBP, and DBP), corrects metabolic disorders, reduces manifestations of bronchial obstruction, respiratory failure and improves cognitive function.

The data presented in the review demonstrate that passive hypoxic conditioning in IHT/IHHT regimens is an

effective alternative approach to non-drug correction of and improved patient adherence to rehabilitation and pre-

cardiometabolic risks in cardiac patients with obesity and ventive programs. This is necessary for cardiac patients of

metabolic disorders. all age categories with comorbid and concomitant pathol-

The use of a course of individually dosed physical activ- ogy. However, additional large-scale controlled studies

ity performed by patients in a hypoxic gas environment are needed to establish optimal protocols for the use of

(hypoxic rooms or breathing with a hypoxic gas mixture hypoxic exposure, to substantiate the criteria for choos-

through a mask) has certain prospects. Due to the syner- ing the intensity of hypoxic stimulation and the duration of

gistic effects of hypoxia and exercise hypoxia, the phys- training courses, depending on the comorbid "burden" of z

ical exertion stress of high-intensity training is reduced, the underlying cardiac disease. D

allowing for faster comprehensive rehabilitation results Z

H

ADDITIONAL INFORMATION >

Information about the authors: >

Nadezhda P. Lyamina, Dr. Sci. (Med.), Professor, Head of the Medical Rehabilitation Department, Moscow Centre for I

Research and Practice in Medical Rehabilitation, Restorative and Sports Medicine of Moscow Healthcare Department, >

Russia. T

E-mail: lyana_n@mail.ru, ORCID ID: http://orcid.org/0000-0001-6939-3234 >

Galina K. Spirina, Director General, LLC "AsFor Group'; Russia. I

E-mail: g.spirina@aimediq.com, ORCID ID: http://orcid.org/0000-0002-9574-5931 e Oleg S. Glazachev, Dr. Sci. (Med.), Professor, Professor of the Department of Normal Physiology, N.V. Sklifosovskiy E

Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University, Russia. W

E-mail: glazachev@mail.ru, ORCID ID: http://orcid.org/0000-0001-9960-6608 >

XI

Authors' contribution: >

All authors confirm their authorship according to the ICMJE criteria (all authors contributed significantly to the con- m ception, study design and preparation of the article, read and approved the final version before publication). Special Contributions:

Lyamina N.P. - development of the structure of the manuscript, writing and scientific revision of the text of the manuscript, verification of critical content, approval of the manuscript for publication;

Spirina G.K. - review of publications on the topic of the article, writing and revision of the text of the manuscript; Glazachev O.S. - developing a strategy of searching for relevant sources and the manuscript structure, analysis and interpretation of the data, writing and scientific revision of the text of the manuscript and verification of critical content.

Funding Source:

This study was not supported by any external sources of funding. Disclosure:

Galina K. Spirina is LLC "AsFor Group" director, the company, distributing hypoxic machines in Russia. She did not participate in the development of the strategy of search for relevant sources, nor in the interpretation of data. All other authors declare that there are no apparent and potential conflicts of interest related to the publication of this article. However, there are no brands or trademarks of devices for hypoxic therapy mentioned in the paper, and review analysed different approaches for hypoxic training, not only those, implemented by the company in its products. Ethics Approval: Not applicable.

Consent for Publication:

Not applicable.

REFERENCES

1. Sawan M.A., Calhoun A.E., Fatade Y.A., Wenger N.K. Cardiac rehabilitation in women, challenges and opportunities. Progress in Cardiovascular Diseases. 2022; (70): 111-118. https://doi.org/10.1016Zj.pcad.2022.01.007

2. Ades P.A., Khadanga S., Savage P.D., Gaalema D.E. Enhancing participation in cardiac rehabilitation: Focus on underserved populations. Progress in Cardiovascular Diseases. 2022; (70): 102-110. https://doi.org/10.1016/j.pcad.2022.01.003

3. Taylor R.D., Dalal H.M., McDonagh S. The role of cardiac rehabilitation in improving cardiovascular outcomes. Nature Reviews Cardiology. 2022; 19(3): 180-194. https://doi.org/10.1038/s41569-021-00611-7

4. Chockalingam A., Chan A., Kanaley J.A., Aggarwal K. Home-Based Arm Cardiac Rehabilitation in Disabled Veterans: A Pilot Study. Mo Med. 2021; 118(4): 387-392.

5. Bauldoff G.S., Carlin B.W. Pulmonary comorbidities in cardiac rehabilitation. Progress in Cardiovascular Diseases. 2022; (70): 190-194. https://doi.org/10.1016/j.pcad.2022.01.009

6. Tang L.H., Harrison A., Skou S.T., Doherty P. To what extent are comorbidity profiles associated with referral and uptake to cardiac rehabilitation. International Journal of Cardiology. 2021; (15): 343:85-91. https://doi.org/10.1016/jjjcard.2021.09.016

7. Glazachev O.S., Lyamina N.P., Spirina G.K. Intermittent hypoxic conditioning: experience and potential in cardiac rehabilitation programs. Russian Journal of Cardiology. 2021; 26(5): 4426 p. https://doi.org/10.15829/1560-4071-2021-4426

8. Burtscher M. Effects of living at higher altitudes on mortality: a narrative review. Aging and Disease. 2013; 5(4): 274-280. https://doi.org/10.14336/AD.2014.0500274

9. Faeh D., Gutzwiller F., Bopp M. Swiss National Cohort Study Group. Lower mortality from coronary heart disease and stroke at higher altitudes in Switzerland. Circulation. 2009; 120(6): 495-501. https://doi.org/10.1161/aRCULATI0NAHA.108.819250

10. Serebrovskaya T., Lei Xi. Intermittent hypoxia training as non-pharmacologic therapy for cardiovascular diseases: Practical analysis on methods and equipment. Experimental Biology and Medicine. 2016; 241(15): 1708-1823. https://doi.org/10.1177/1535370216657614

11. Tobin B., Costalat G., Renshaw G.M.C. Intermittent not continuous hypoxia provoked haematological adaptations in healthy seniors: hypoxic pattern may hold the key. European Journal of Applied Physiology. 2020; 120(3): 707-718. https://doi.org/10.1007/s00421-020-04310-y

12. Glazachev O.S., Kryzhanovskaya S.Y., Zapara M.A., Dudnik E.N., Samartseva V.G., Susta D. Safety and Efficacy of Intermittent Hypoxia Conditioning as a New Rehabilitation/ Secondary Prevention Strategy for Patients with Cardiovascular Diseases: A Systematic Review and Meta-analysis. Current Cardiology Reviews. 2021; 17(6): e051121193317. https://doi.org/10.2174/1573403X17666210514005235

13. Ignatenko G.A., Mukhin I.V., Gavrilyak V.G., Chebotareva E.N., Dzuban A.S., Panieva N.J., Paniev D.S. Hypoxia Hyperoxitherapy in the treatment of ^ patients with comorbid cardiac pathology. University Clinic. 2019; 1(30): 5-10. https://doi.org/10.26435/UC.V0I1(30).219

I— 14. Muangritdech N., Hamlin M.J., Sawanyawisuth K. et al. Hypoxic training improves blood pressure, nitric oxide and hypoxia-inducible factor-1 alpha in hypertensive patients. European Journal of Applied Physiology. 2020; 120(8): 1815-1826. https://doi.org/10.1007/s00421-020-04410-9 15. Lyamina N.P., Lyamina S.V., Senchiknin V.N. et al. Normobaric hypoxia conditioning reduces blood pressure and normalizes nitric oxide synthesis in I patients with arterial hypertension. Journal of Hypertension. 2011; 29(11): 2265-2272. https://doi.org/10.1097/HJH.0b013e32834b5846

q 16. Zhernakova Y.V., Zheleznova E.A., Chazova I.E., Oshchepkova E.V., Dolgusheva Yu.A., YArovaya E.B., Blinova N.V., Orlovskij A.A., Konosova I.D., co Shalnova S.A., Rotar' O.P., Konradi A.O., Shlyahto E.V., Bojcov S.A. The prevalence of abdominal obesity and the association with socioeconomic

q status in regions of the Russian Federation, the results of the epidemiological study-ESSE-RF. TerapevticheskiiArkhiv. 2018; 90(10): 14-22.

_ 17. Glazachev O.S., Zvenigorodskaia L.A., Dudnik E.N., Iartseva L.A., Mishchenkova T.V., Platonenko A.V., Spirina G.K. Interval hypoxic-hyperoxic training

CL in the treatment of the metabolic syndrome. Eksperimental'naia iklinicheskaiagastroenterologiia. 2010; (7): 51-6.

^ 18. Lizamore C.A., Hamlin M.J. The Use of Simulated Altitude Techniques for Beneficial Cardiovascular Health Outcomes in Nonathletic, Sedentary, and

Clinical Populations: A Literature Review. High Altitude Medicine & Biolology. 2017; 18(4): 305-321. https://doi.org/10.1089/ham.2017.0050 CI 19. Chacaroun S., Borowik A., Doutreleau S., Belaidi E., Wuyam B., Tamisier R., Pépin J.L., Flore P., Verges S. Cardiovascular and metabolic responses to I passive hypoxic conditioning in overweight and mildly obese individuals. American Journal of Physiology - Regulatory, Integrative and Comparative

< Physiology. 2020; 319(2): 211-222. https://doi.org/10.1152/ajpregu.00311.2019

^^ 20. Bestavashvili A., Glazachev O., Suvorov A, Zhang Y., Zhang X., Rozhkov A., Kuznetsova N., Pavlov C., Glushenkov D., Kopylov P. Intermittent Hypoxic-^ Hyperoxic Exposures Effects in Patients with Metabolic Syndrome: Correction of Cardiovascular and Metabolic Profile. Biomedicines. 2022; 10(3): 566

^E p. https://doi.org/10.3390/biomedicines10030566

21. Balestra C., Lambrechts K., Mrakic-Sposta S., Vezzoli A., Levenez M., Germonpré P., Virgili F., Bosco G., Lafère P. Hypoxic and Hyperoxic Breathing as a Complement to Low-Intensity Physical Exercise Programs: A Proof-of-Principle Study. International Journal of Molecular Sciences. 2021; 22(17): 9600 p. https://doi.org/10.3390/ijms22179600

22. Brinkmann C., Bloch W., Brixius K. Exercise during short-term exposure to hypoxia or hyperoxia - novel treatment strategies for type 2 diabetic patients? Scandinavian Journal of Medicine and Science in Sports. 2018; 28(2): 549-564. https://doi.org/10.1111/sms.12937

23. Park H.Y., Jung W.S., Kim J., Lim K. Twelve weeks of exercise modality in hypoxia enhances health-related function in obese older Korean men: A randomized controlled trial. Geriatrics and Gerontology International. 2019; (19): 311-316. https://doi.org/10.1111/ggi.13625

24. Ramos-Campo D.J., Girard O., Pérez A., Rubio-Arias J.Á. Additive stress of normobaric hypoxic conditioning to improve body mass loss and cardiometabolic markers in individuals with overweight or obesity: A systematic review and meta-analysis. Physiology & Behavior. 2019; (207): 28-40. https://doi.org/10.1016Zj.physbeh.2019.04.027

25. Jung K., Kim J., Park H.Y., Jung W.S., Lim K. Hypoxic Pilates Intervention for Obesity: A Randomized Controlled Trial. International Journal of Environmental Research and Public Health. 2020; 17(19): 7186 p. https://doi.org/10.3390/ijerph17197186

26. De Groote E., Deldicque L. Is Physical Exercise in Hypoxia an Interesting Strategy to Prevent the Development of Type 2 Diabetes? A Narrative Review. Diabetes, Metabolic Myndrome and Obesity: Targets and Therapy. 2021; (14): 3603-3616. https://doi.org/10.2147/DMSO.S322249

27. Gunton J.E. Hypoxia-inducible factors and diabetes. The Journal of Clinical Investigation. 2020; 130(10): 5063-5073. https://doi.org/10.1172/JCI137556

28. Serebrovska T.V., Portnychenko A.G., Portnichenko V.I., Xi Lei, Egorov E., Antoniuk-Shcheglova I., Naskalova S., Shatylo V.B. Effects of intermittent hypoxia training on leukocyte pyruvate dehydrogenase kinase 1 (PDK-1) mRNA expression and blood insulin level in prediabetes patients. European Journal of Applied Physiology. 2019; 119(3): 813-823. https://doi.org/10.1007/s00421-019-04072-2

29. Neuhoff C.G., Zhou S., Broadbent S. Intermittent Hypoxia as an Interventional Strategy for Impaired Fasting Blood Glucose: a Systematic Review. International Journal of Health Sciences. 2018; (6): 17-28.

30. Kim S.W., Jung W.S., Chung S., Park H.Y. Exercise intervention under hypoxic condition as a new therapeutic paradigm for type 2 diabetes mellitus: A narrative review. World Journal of Diabetes. 2021; 12(4): 331-343. https://doi.org/10.4239/wjd.v12.i4.331

31. Ignatenko G.A., Kontovsky E.A., Dubovik A.V., Milner I.A., Smirnova Ya.Yu., Bryzhataya Yu.O., Sergienko N.V., Rakitov B.L. Tsyganok T.V. The use of interval normobaric hypoxic therapy in patients with cardiopulmonary pathology. Bulletin of Hygiene and Epidemiology. 2018; 22(4): 22-25.

32. Borukaeva I.K., Abazova Z.K., Ragimbekova M.R., Temirzhanova F.K. Effect of interval hypoxytherapy and enteral oxygenotherapy on immunological reactivity in patients with bronchial asthma. Russian Journal of Immunology. 2019; 13(22): 174-176.

33. Bayer U., Likar R., Pinter G. et al. Intermittent hypoxic-hyperoxic training on cognitive performance in geriatric patients. Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2017; 3(1): 114-122. https://doi.org/10.1016/j.trci.2017.01.002

34. Wang H., Shi X., Schenck H., Hall J.R., Ross S.E., Kline G.P., Chen S., Mallet R.T., Chen P. Intermittent Hypoxia Training for Treating Mild Cognitive Impairment: A Pilot Study. American Journal of Alzheimer's Disease & Other Dementias. 2020; (35): 1533317519896725. https://doi.org/10.1177/1533317519896725

35. Jung M., Zou L., Yu J.J., Ryu S., Kong Z., Yang L., Kang M., Lin J., Li H., Smith L., Loprinzi P.D. Does exercise have a protective effect on cognitive function under hypoxia? A systematic review with meta-analysis. Journal of Sport and Health Science. 2020; 9(6): 562-577. https://doi.org/10.1016/jjshs.2020.04.004

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Jung K, 2020 [25] Obesity RCT 32 PE under hypoxic condition J.SBP and DBP J. total cholesterol, triglycerides elimination of signs of endothelial dysfunction and improvement of rheological properties of blood

De Groote E, 2021 [26] Obesity Diabetes mellitus SR 17 RCT PE under hypoxic condition conflicting data on weight loss, fat mass and exercise tolerance the effectiveness of hypoxic training depends on the type of exercise and the mode of hypoxic load

SerebrovskaTV, 2019 [28] Prediabetes CT 18 IHTat rest t insulin sensitivity J. fasting glycemia t tolerance to hypoxia t HIF-la mRNA in blood leukocytes Maximum effect one month after the completion of the course

Neuhoff CG, 2018 [29] Diabetes mellitus SR 4 RCT Hypoxic Exposure and IHTat rest conflicting data on lowering fasting glucose levels

Kim SW, 2021 [30] Diabetes mellitus Descriptive review 4 RCT PE under hypoxic condition improved glucose uptake and insulin sensitivity

Ignatenko GA, 2018 [31] IHD: stable angina NYHA 11-111 +COPD RCT 90 IHHTat rest ¿frequency of non-permanent/persistent cough, J. frequency of dyspnea at rest/after exercise reclassification to less heavy NYHA class t tolerance to PE

Borukaeva IK, 2019 [32] Bronchial asthma mild to moderate RCT 46 IHTat rest t tidal volume, alveolar ventilation t efficiency of gas exchange between alveolar air and venous blood

Bayer U, 2017 [33] Dementia + IHD, CHF, AH RCT 34 IHHTat rest t 6 MWT distance t cognitive functions

Wang H, 2020 [34] Mild Cognitive Impairment + IHD, AH, DM Pilot study 7 IHTat rest t cognitive functions J.SBP, DBP

Jung M, 2020 [35] Dementia Multimorbidity patients Healthy SR with meta-analysis 18 PE under hypoxic condition t cognitive functions

Note: IHD - Ischemic Heart Disease, CHF- Chronic Heart Failure, AH - Arterial Hypertension, COPD-Chronic Obstructive Pulmonary Disease, RCT-randomized clinical trial, IHT/IHHT-Interval Hypoxia Treatment/- Interval Hypoxia Hyperoxia Treatment, PE-physical exercise, CHE- Continuous Hypoxia Exposure, SR - systematic review, CT-clinical trial, HR - Heart Rate, SBP/DBP - Systolic/Diastolic Blood Pressure, LDL - low density lipid, ALT- alanine aminotransferase, AST- aspartate aminotransferase

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