The aim of the study is to evaluate the effects of intermittent

hypoxic-hyperoxic training (IHHT) to protect myocardium against perioperative

myocardial injury during cardiac surgery using cardiopulmonary bypass.

This is a prospective, single-center, randomized controlled clinical trial, which will involve patients over 18 years old who would be recruited consecutively during pre-admission consultation at the I.M Sechenov First Moscow State Medical University Cardiac Surgery Department. All patients with a diagnosis of valvular heart disease, or aortic arch disease and indications for cardiac surgery, according to the European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines.

Five days before the operation, patients will be randomly assigned into two groups using a computer-generated randomization table: intermittent hypoxic-hyperoxic training and an intermittent hypoxic-hyperoxic training control group. For both groups laboratory testing (specific biomarkers - C-reactive protein, troponin I, fatty acid-binding protein (FABPs) and lactate) will be performed before training and after the surgery, and the hypoxic-inducible factor (HIF 1 alpha) would be implemented before and after the trainings.

Patients in the intermittent hypoxic-hyperoxic training group will undergo four daily procedures of interval hypoxic-hyperoxic training before cardiac surgery, using a normobaric device to obtain hypoxic and hyperoxic gas mixtures (ReOxy Cardio; Aimediq S.A., Luxemburg, Registration certificate in RU P3H 2014/1486). Before the start of the training, each patient would undergo a hypoxic test to assess the individual response to hypoxia, and to determine the rate of reduction of blood oxygen saturation (SpO2) with a finger pulse oximeter (Masimo SET, measurement accuracy ±2%). During 5 minutes the patient will receive air with reduced oxygen content (12%), through a mask under constant monitoring of the heart rate (HR) and SpO2. As a safety measure, minimal SpO2 would be set at 82% and maximal accepted increase of heart rate would be set to +50% of the initial heart rate. When these values would be reached, the supply of oxygen automatically would be switched to a hyperoxic gas mixture (35%-40% O2), inhaling of which would be continued until SpO2 reached 100% (even if SpO2 was lower before the procedure), therefore depending on the rate of saturation reduction, will be taken 1 to 3 minutes (mean 1 min and 50 seconds). The intention is to create hyperoxic arterial oxygen tension and not to simply reduce the time required to recover from hypoxia. Intermittent hypoxic hyperoxic training would be considered successful if there were no significant side effects during the procedure such as angina pain, loss of consciousness, severe dizziness or other variants of significant subjective deterioration of the patient's condition. In the case of successfully passing the test, patients will proceed to the basic intermittent hypoxic hyperemic training. During the training, the hypoxic gas mixture will be given to the patient again in intermittent mode, based on the individual test parameters and alternating with the supply of a hyperoxic gas mixture. One cycle of the procedure consists of hypoxic and hyperoxygenated intervals, the duration of which will be regulated automatically according to the biofeedback principle, based on monitoring of individual values of SpO2 and heart rate. The duration of the hypoxic period ranges from 3 to 5 minutes, and the duration of the hyperoxic period ranges from 1 to 3 minutes, depending on the SpO2 recovery rate. The total time of the hypoxic gas mixture inhaled during one procedure will be 20-30 min. A final training would be conducted in the evening before the surgery. Patients in the intermittent hypoxic-hyperoxic training - control group also will undergo four daily procedures before surgery, using 40 min training periods with simulation of intermittent hypoxic-hyperoxic training by using the same equipment, the patient receives moistened air through a placebo mask under constant monitoring of heart rate and SpO2. Only the person who will conduct the training would know about the patient's allocation to a particular intervention group, the anesthesiologists and cardiac surgeons will not have access to this information. Episodes of cardiac arrhythmias, hypotension with a need for inotropic drug prescription, changes in electrocardiogram, pulse values and blood pressure levels will be recorded during surgery and the postoperative period.

Patients will be monitored for 7 days in the hospital, and 30 days after discharge to evaluate the complications.

Differences between groups will be assessed using the unpaired Student's t-test or the one-tailed Anova test followed by the Bonferroni post-test. Baseline corrected logistic regression models will be used to estimate the training effect in relation to primary and secondary endpoints. Statistical significance will be set at 0.05 to test hypotheses.

Inclusion Criteria:

• 1. Written consent to participate in the study 2. Male or female patients over 18 years 3. Indications for planned replacement of the aortic or mitral valves or operations on the aortic arch.

Exclusion Criteria:

• 1. Individual intolerance to the intermittent hypoxic-hyperoxic training

  2. Acute coronary syndrome after hospitalization and before the surgery

  3. The presence of an acute infectious process after hospitalization and before the surgery (fever, leukocytosis with a shift leukocyte formula to the left, increased erythrocyte sedimentation rate (ESR), increased C-reactive protein)

  4. Uncompensated hypertension at the time of the procedure (systolic blood pres-sure more than 160 mm Hg, diastolic blood pressure more than 110 mm Hg)

  5. Loss of consciousness, severe dizziness

Non-inclusion criteria:

1. Occlusive atherosclerotic disease of lower limbs,
2. Acute coronary syndrome within 4 weeks before entry
3. Preoperative renal insufficiency (serum creatinine higher than 200 mmol/L),
4. Acute infectious diseases
5. Partial and secondary generalized forms of epilepsy,
6. Uncompensated hypertension (Blood pressure at the time of the procedure: systolic blood pressure more than 160 mm Hg, diastolic blood pressure more than 110 mm Hg)
7. Severe bronchial asthma with the development of respiratory failure of the II-III degree and individual intolerance to oxygen deficiency.

9. Severe hepatic impairment (class C child-Pugh) Intervention type

10. Mental illness (if patients are not capable of understanding the nature, significance and implications of the clinical trial)

11. Myocardial insufficiency as a component of multiple organ failure in decompensation of liver and kidney diseases

Data disclosure is not permitted by the local ethics committee. For more information about the study, you need to contact the principal investigator.