Intermittent hypoxic trainingIntermittent hypoxic training

Intermittent hypoxic trainingIntermittent hypoxic training (or (or therapy) (IHT)therapy) (IHT)

is a non-invasive, drug-free technique aiming is a non-invasive, drug-free technique aiming to improve human performance and well-being to improve human performance and well-being using the phenomena of adaptation to reduced using the phenomena of adaptation to reduced oxygen.oxygen.

Consists of exposure to alternating periods of Consists of exposure to alternating periods of hypoxia (9 - 14% Ohypoxia (9 - 14% O22 inhaled through a mask) inhaled through a mask)

and reoxygenation with atmospheric airand reoxygenation with atmospheric air

An IHT session constitutes a few minutes An IHT session constitutes a few minutes interval of breathing low oxygen (hypoxic) air interval of breathing low oxygen (hypoxic) air alternated with an ambient or hyperoxic air alternated with an ambient or hyperoxic air over a 45- to 90-minute session per day. over a 45- to 90-minute session per day.

A full treatment course is 3–4 weeks A full treatment course is 3–4 weeks

IHT can be beneficialIHT can be beneficialchronic heart and lung diseases chronic heart and lung diseases

hypertension hypertension

asthma and chronic bronchitis asthma and chronic bronchitis

liver and pancreatic diseases liver and pancreatic diseases

anxiety and depression anxiety and depression

iron-deficiency anaemia iron-deficiency anaemia

lack of energy and fatiguelack of energy and fatigue

mitochondrial statusmitochondrial status

aerobic and anaerobic performanceaerobic and anaerobic performance

IHT is contra-indicated in case ofIHT is contra-indicated in case of

acute somatic and viral diseases acute somatic and viral diseases chronic obstructive pulmonary disease (COPD-chronic obstructive pulmonary disease (COPD-II and COPD-III) II and COPD-III) chronic diseases with symptoms of chronic diseases with symptoms of decompensation or terminal illness decompensation or terminal illness individual intolerance of oxygen insufficiency individual intolerance of oxygen insufficiency cancer, unless IHT is prescribed by a doctor cancer, unless IHT is prescribed by a doctor people with epilepsy, pacemakers or heart people with epilepsy, pacemakers or heart arrhythmias, unless treatment (including IHT) is arrhythmias, unless treatment (including IHT) is under direct medical supervisionunder direct medical supervision

Hypoxic Training indexHypoxic Training index (HTi) (HTi)

provides an objective measure of the hypoxic provides an objective measure of the hypoxic stress delivered during the Intermittent stress delivered during the Intermittent Hypoxic Training (IHT) session, Hypoxic Training (IHT) session,

compared to simple recording the inhaled compared to simple recording the inhaled fraction of oxygen (FiO2). HTi provides a fraction of oxygen (FiO2). HTi provides a figure (index) of dosage received by the figure (index) of dosage received by the individual at the end of the session.individual at the end of the session.

Knowledge of HTi can therefore be used to Knowledge of HTi can therefore be used to alter the training regime for different alter the training regime for different individuals, compensating for individual individuals, compensating for individual variability, and can be used in scientific variability, and can be used in scientific studies to ensure that subject exposure was studies to ensure that subject exposure was correctly controlled correctly controlled

Tissue hypoxia develops only when arterial Tissue hypoxia develops only when arterial oxygen saturation (SpO2) drops to 90% or oxygen saturation (SpO2) drops to 90% or below. This is due to the oxyhaemoglobin below. This is due to the oxyhaemoglobin dissociation curve. Saturations above 90% dissociation curve. Saturations above 90% produce very little effect or decrease of arterial produce very little effect or decrease of arterial oxygen partial pressure (PaO2)oxygen partial pressure (PaO2)

In order to obtain consistent and comparable values of In order to obtain consistent and comparable values of HTi for different individuals the following conditions HTi for different individuals the following conditions should be stipulated:should be stipulated:– The values of SpOThe values of SpO22 above 89% are not considered in the above 89% are not considered in the

calculation of HTi, as such saturation levels do not calculation of HTi, as such saturation levels do not contribute to the treatment. SpOcontribute to the treatment. SpO22 values below 75% count as values below 75% count as

75%. 75%.

– HTi is calculated as an integral value of SpOHTi is calculated as an integral value of SpO22 readings made readings made

with 1 s sampling frequency and divided by 60 in order to with 1 s sampling frequency and divided by 60 in order to produce a “per minute” value. produce a “per minute” value.

– During the treatment target SpODuring the treatment target SpO22 values are in the range of values are in the range of

75% - 89%. 75% - 89%.

where:HTi : Hypoxic Training index,t : period of time, andSpO2 (t) : SpO2 (%), arterial oxygen saturation value measured at one-second intervals

How the HTi is calculated: Only part of the IHT session is shown, the targeted SpO2 value is 80% as an example. The filled part of the SpO2 graph represents the amount of hypoxia delivered, “dosage”.This image shows a typical SpO2 curve during a full biofeedback-controlled IHT session. (FiO2 is altered automatically using biofeedback controlled hypoxicator to attain and sustain the desired SpO2 target value

IHT Effects on the brainIHT Effects on the brain

dopamine and seratonin, dopamine and seratonin, associated with positive associated with positive mood and calmness, mood and calmness, showed quite a significant showed quite a significant increase in people who increase in people who underwent a three-week underwent a three-week course of intermittent course of intermittent hypoxic acclimatisation. hypoxic acclimatisation.

Norepinephrine, Norepinephrine, sympathetic nervous system sympathetic nervous system and the so-called 'fight ' and the so-called 'fight ' response, was decreased.response, was decreased.

NeurotransmitterNeurotransmitter (n= 5)(n= 5) (n=10(n=10))

pp

Norepinephrine Norepinephrine DopamineDopamine

SeratoninSeratonin

186186

132132

108108

150150

167167

238238

<0.05<0.05

<0.05<0.05

<0.01<0.01

A study showed that after twice daily sessions of A study showed that after twice daily sessions of IHT lasting 60 to 90 min, athletes‘ performance IHT lasting 60 to 90 min, athletes‘ performance improved by 2.9%improved by 2.9%

Physiological Responses to IHTPhysiological Responses to IHT

Increase capillary densityIncrease capillary density

Shift SpOShift SpO22 curve to the right curve to the right

Increase EPO Increase EPO

Development of Red Blood CellsDevelopment of Red Blood Cells

CommonMyeloid Progenitor

First red cells are produced in the yolk sac. Later red cell First red cells are produced in the yolk sac. Later red cell production shifts to the liver, spleen and then the bone production shifts to the liver, spleen and then the bone marrow.marrow.Feedback control of RBC Production is through Feedback control of RBC Production is through Erythropoietin (Epo). Erythropoietin (Epo). – Necessary to prevent death and promote proliferation of Necessary to prevent death and promote proliferation of

committed precursorscommitted precursors– Shifts non-committed progenitor cells into the erythroid lineageShifts non-committed progenitor cells into the erythroid lineage– Produced in renal tubular epithelial cells and more widely in the Produced in renal tubular epithelial cells and more widely in the

growing embryogrowing embryo– Feedback control targets the first committed cell in the erythroid Feedback control targets the first committed cell in the erythroid

lineage.lineage.

Feedback control loop

EPO geneEPO gene

In humans and other mammals, hypoxia In humans and other mammals, hypoxia modulates EPO levels by increasing modulates EPO levels by increasing expression of the EPO geneexpression of the EPO gene

mechanism is the transcription factor complex mechanism is the transcription factor complex hypoxia-inducible factor (HIF)-1hypoxia-inducible factor (HIF)-1

It plays an essential role in cellular and It plays an essential role in cellular and systemic responses to hypoxiasystemic responses to hypoxia

This is one of the class of hypoxia inducible This is one of the class of hypoxia inducible factors, a family that includes Hif1a, Hif2a, factors, a family that includes Hif1a, Hif2a, and Hif3aand Hif3a

What regulates Erythropoietin (Epo) What regulates Erythropoietin (Epo) ProductionProduction??

Epo is regulated Epo is regulated transcriptionally by an transcriptionally by an regulatory region near the regulatory region near the genegeneThis regulatory region binds This regulatory region binds HIF (Hypoxia Induced HIF (Hypoxia Induced Factor) Factor) Hypoxia regulates HIFHypoxia regulates HIFHIF also activates VEGF and HIF also activates VEGF and induces vasculogenesis- a induces vasculogenesis- a problem in pregnancyproblem in pregnancy

Semenza G.L.Cell. 2001 Oct 5;107(1):1-3

HIF-1HIF-1

Hypoxia-inducible factor Hypoxia-inducible factor 1, alpha subunit (basic 1, alpha subunit (basic helix-loop-helix helix-loop-helix transcription factor) transcription factor)

Gene Code: Chr.14:q23.2Gene Code: Chr.14:q23.2

Induces EPO synthesisInduces EPO synthesis

Blocked by HIF prolyl-Blocked by HIF prolyl-hydroxylasehydroxylase

In hypoxic conditions, HIF In hypoxic conditions, HIF prolyl-hydroxylaseprolyl-hydroxylase is inhibited, since is inhibited, since itit utilizes oxygen as a co- utilizes oxygen as a co-substratesubstrateHypoxia also results in a buildup of succinate, Hypoxia also results in a buildup of succinate, due to inhibition of the electron transport chain due to inhibition of the electron transport chain in the mitochondria in the mitochondria The buildup of succinate further inhibits HIF The buildup of succinate further inhibits HIF prolyl-hydroxylase action, since it is an end-prolyl-hydroxylase action, since it is an end-product of HIF hydoxylationproduct of HIF hydoxylationBy inhibiting HIF prolyl-hydroxylase, the By inhibiting HIF prolyl-hydroxylase, the activity of HIF-1α in the bloodstream is activity of HIF-1α in the bloodstream is prolonged, which results in an increase in prolonged, which results in an increase in endogenous production of erythropoetinendogenous production of erythropoetin

Hypoxia Prevents Degradation of HIF-1Hypoxia Prevents Degradation of HIF-1

If HIF-1 Controls Epo, what Controls HIF-1?

PHD = proline hydroxylase

CapillaryCapillary network formation under Hypoxia network formation under Hypoxia

Capillary network formation. Cells seeded formed Capillary network formation. Cells seeded formed capillary-like structure at approximately 4–5 h, which capillary-like structure at approximately 4–5 h, which was more prominent in was more prominent in hypoxiahypoxia (b) as compared to (b) as compared to normoxia (a). When HIF-2 clone was cultured in normoxia (a). When HIF-2 clone was cultured in hypoxia (c), network formation was even more evident hypoxia (c), network formation was even more evident than hypoxic, control endothelial cells. A magnified than hypoxic, control endothelial cells. A magnified view (d) shows representative vascular sprouting view (d) shows representative vascular sprouting (arrows), which was larger in number in order of (arrows), which was larger in number in order of (c)>(b)>(a). The capillary network formation was (c)>(b)>(a). The capillary network formation was enumerated after 24 h of hypoxic incubation by enumerated after 24 h of hypoxic incubation by measuring the length of capillary structures (e). measuring the length of capillary structures (e).

Hypoxia alone promoted network formation, which Hypoxia alone promoted network formation, which became even more evident by overexpressing HIF-2became even more evident by overexpressing HIF-2

Vascular endothelial growth factor Vascular endothelial growth factor (VEGF)(VEGF)

is a signal protein produced by cells that is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen is part of the system that restores the oxygen supply to tissues when blood circulation is supply to tissues when blood circulation is inadequate.inadequate.

VEGF's normal function is to create new blood VEGF's normal function is to create new blood vessels during embryonic development, vessels during embryonic development, new new blood vesselsblood vessels after injury, after injury, muscle following muscle following exerciseexercise, and new vessels (collateral , and new vessels (collateral circulation) to bypass blocked vesselscirculation) to bypass blocked vessels

Hypoxia induced VEGFHypoxia induced VEGF

When a cell is deficient in oxygen, it produces When a cell is deficient in oxygen, it produces hypoxia-inducible factor, a transcription factor. hypoxia-inducible factor, a transcription factor. HIF stimulates the release of VEGF, among HIF stimulates the release of VEGF, among other functions (including modulation of other functions (including modulation of erythropoeisis). erythropoeisis).

Circulating VEGF then binds to VEGF Circulating VEGF then binds to VEGF Receptors on endothelial cells, triggering a Receptors on endothelial cells, triggering a Tyrosine Kinase Pathway leading to Tyrosine Kinase Pathway leading to angiogenesis.angiogenesis.

SpOSpO2 2 CurveCurveoxygen saturation refers to oxygenation, or oxygen saturation refers to oxygenation, or when oxygen molecules (Owhen oxygen molecules (O22) enter the tissues ) enter the tissues of the body. of the body. In this case blood is oxygenated in the lungs, In this case blood is oxygenated in the lungs, where oxygen molecules travel from the air where oxygen molecules travel from the air and into the blood. and into the blood. As a result of this oxygenation, the color of the As a result of this oxygenation, the color of the blood changes from dark purple to red. blood changes from dark purple to red.

Oxygen saturation, or OOxygen saturation, or O22 sats measure the sats measure the percentage of hemoglobin binding sites in the percentage of hemoglobin binding sites in the bloodstream occupied by oxygenbloodstream occupied by oxygen

DiscussionDiscussionWhich athletic sport may be the most suitable Which athletic sport may be the most suitable implementing iHTs and why?implementing iHTs and why?

What is intermittent hypoxic training and it’s What is intermittent hypoxic training and it’s strengths, weakness, opportunity, threat on strengths, weakness, opportunity, threat on athlete in practicing.athlete in practicing.

Why iHTs is so important onto HIF and Why iHTs is so important onto HIF and VEGF. How these substances can beneficial VEGF. How these substances can beneficial on functional capacity of body.on functional capacity of body.