high - altitude exposure has been considered a major cardiorespiratory , endocrine , metabolic , nutritional , thermal and psychological strain for the human body .
the atmospheric low oxygen partial pressure affects oxygen ( o2 ) cascade inducing metabolic adaptations , such as changes in cell oxidative metabolism .
acute , chronic or intermittent hypoxia ( ih ) exposure studies have been carried out with animals and humans in hypobaric chambers simulating high - altitude hypoxia conditions . as a rule , ih refers to discontinuous use of hypoxia to reproduce features of altitude acclimatization using different methods , protocols and devices .
specifically , ihh consists in temporary sessions expositions to acute hypobaric hypoxia conditions of a precise barometric pressure and thus to an equivalent altitude .
the ascent and descent of the chamber from ambient pressure to altitude occurred at a certain speed , and the oxyhemoglobin saturation of the patients is monitored at all times . a hypobaric chamber , also known as altitude chamber , is hence used during aerospace or high terrestrial altitude research or training to simulate the effects of high altitude on the human body , especially hypoxia ( low oxygen ) and hypobaria ( low ambient air pressure ) .
intermittent hypobaric hypoxia has been the focus of important research for recovery of post - myocardial infarction function over the past decades .
wang et al . observed that ihh improves post - ischaemic recovery of myocardial contractile function via redox signalling in rats 2011 .
in another recent investigation , xu et al . demonstrated that ihh attenuates progressive myocardial remodelling and improves overall myocardial contractility 2011 . in both studies ,
experimental animals were intermittently exposed to an equivalent altitude of 5000 m in a hypobaric chamber for 4 weeks , concluding that ihh might reveal as a promising therapeutic approach for ischaemic heart diseases .
cardiac protection by ihh has been associated with several mechanisms , including attenuated infarct size , myocardial fibrosis and apoptotic cardiomyocytes , elevated reactive oxygen species ( ros ) production during early reperfusion , preserved ca homeostasis , calcium / calmodulin - dependent protein kinase ii activity regulation , reduced myocardial apoptosis , induced opening of mitokatp channels , increased vascularization , as well as antiarrhythmic and antioxidant effects .
it has been thus suggested that ihh is a simple intervention , which may offer a thoughtful benefits to patients with acute myocardial infarction and with little side effects or adverse reactions .
it has been recently observed that hypoxia - inducible factor-1 alpha ( hif-1 ) , inducible nitric oxide synthase ( inos ) and phd are also involved in ihh induced cardioprotection , which can hence be considered potential therapeutic targets .
the transcription factor hif-1 is a key regulator responsible for the induction of genes that facilitate adaptation and survival of cells and the whole organism from normoxia ( 21% o2 ) to hypoxia ( 1% o2 ) .
inducible factor-1 is composed of hif-1 and hif-1. of these two subunits , hif-1 is constitutively expressed , whereas hif-1 is tightly regulated by oxygen tension in terms of its protein stability and activity . under continuous oxygen supply
, two distinct prolyl residues within the oxygen - dependent degradation domain of hif subunits are hydroxylated by prolyl-4-hydroxylase domain - containing enzymes ( phds ) .
it has also been described that the presence of high ros concentrations efficiently stabilizes hif-1 .
overall , ihh inhibits phd activity , increasing the stabilization of hif-1 and activating crucial adaptative genes for erythropoiesis , iron homeostasis and angiogenesis such as erythropoietin ( epo ) , transferrin , transferrin receptor and vascular endothelial growth factor [ 31,32,,33 ] , as well as genes that regulate vasomotor control , glucose and energy metabolism , ph regulation , cell proliferation and viability . hypoxia -
inducible factor-1 is also involved in the induction of cardioprotective molecules , such as inos and hemeoxygenase 1 .
nevertheless , several doubts exist as to whether ihh is a really safe technique , with little to no adverse effects in post - myocardial infarction patients .
intermittent hypobaric hypoxia might produce unfavourable biochemical changes , including decreased anti - oxidative capacity and increased lipid peroxidation , which would lead to suppression of vascular endothelial function and impairment of vascular hemodynamics .
moreover , ih causes oxidative stress that may limit bioavailability of the endothelium - derived vasodilator nitric oxide , and contribute to generate a hypertensive response .
cellular hypoxia is characterized by an increased levels of reduced equivalents as a result of insufficient availability of o2 to be reduced in the mitochondrial electron transport chain . in both the animal models and in humans exposed to different altitudes ( e.g. 30008500 m ) , an oxidative stress has been clearly shown , as reflected by increased lipid , protein and dna oxidation .
it has also been demonstrated that the activity of enzymes such as cyclooxygenase , nad(p)h oxidase and xanthine oxidase are crucial for the ros generation under hypoxic conditions . in this perspective , ros participate in cardioprotection induced by ischaemic conditioning [ , 41,,42 ] , and their generation might hence be beneficial after an acute myocardial infarction .
it is also noteworthy that erythropoiesis stimulation with an increase in epo concentration , thereby enhancing red blood cells mass , hematocrit , blood viscosity and platelet count , have significant effect on blood rheology and blood pressure , exposing patients with high risk of cardiovascular events to hemoconcentration and thrombosis , especially during episodes of dehydration .
elevated systemic hematocrit increases the risk of cardiovascular disorders , such as stroke and myocardial infarction .
moreover , erythrocytosis predisposes to a prothrombotic state and hematocrit is a prognostic marker in patients with st - segment elevation mi .
patients with elevated hematocrit are at increased risk of short - term mortality , as arterial thrombi usually forms under high blood flow conditions .
although it has been suggested that the ih - induced , adverse myocardial consequences might be reversed by epo administration , this appears rather unlikely , considering the previously mentioned mechanisms . in this perspective
, it should considered that systemic effects of hypoxia exposure are also dependent upon the so - call 
hypoxic dose , especially in terms of time of exposure , level of simulated altitude , type of hypoxic strategy .
for instance , it has been shown that natural versus artificial hypoxia can produce very different haematological results [ 54,55,,56 ] .
conversely , there is trustworthy evidence in the current scientific literature to show that the most effective method to stimulate accelerated erythropoiesis with the  living high - training low ' strategy requires 2500 m altitude , 22 hr a day for at least 28 days .
the empirical evidence regarding the efficacy of ih is , however , still partially unclear .
several studies , have failed to demonstrate significant alterations in the erythropoietic response after different protocols [ 58,59,,60 ] .
. also showed that normobaric ih ( 3000 m ) was insufficient to enhance erythropoiesis 2007 , whereas exposure to more elevated simulated altitude ( i.e. 4000 m ) through intermittent normobaric hypoxia , or up to 50006300 m through ihh , induced a significant increase in several haematological parameters .
obstructive sleep apnoea is associated with increased risk of atherosclerosis and , therefore , myocardial infarction and stroke , essential and resistant hypertension , cardiac rhythm perturbations ( e.g. atrial fibrillation , bradyarrhythmias , supraventricular and ventricular arrhythmias ) and heart failure . as this condition
is characterized by episodic cycles of hypoxia and normoxia during the sleep , park and suzuki observed that ih increases the susceptibility of the heart to oxidative stress , thereby worsening the risk of ischaemia - reperfusion - induced myocardial injury 2007 . in obese or diabetic patients , ih exacerbates the insulin resistance and induces steatohepatitis , suggesting that it might account for the metabolic dysfunction in obesity .
considering the original findings of wang et al . 2011 , and xu et al .
2011 , who reported that prolonged exposure of mice to an equivalent altitude of 5000 can initiate the cardioprotective response , and even of other authors who tested the cardioprotection effects of ihh to an equivalent altitude of 7000 m , the acute exposure to similar or equivalent altitude might induce pulmonary oedema in susceptible or nonacclimatized patients [ 69,70,,71 ] .
although intermittent and chronic exposures have been demonstrated to be effective in increasing coronary vasculature , decreasing infarction size and providing more efficient metabolism and better cardiac functional recovery post - ischaemia , ihh safety issues have been mostly overlooked , so that assorted concerns should be raised about the opportunity to use ihh in the post - myocardial infarction period at this point in time .
several ihh protocols used in some studies were also aggressive , which would hamper their introduction within the clinical practice .
as such , further research is needed before ihh can be widely advocated in myocardial infarction prevention and recovery .
 abstractintermittent hypobaric hypoxia ( ihh ) has been the focus of important research in cardioprotection , and it has been associated with several mechanisms . intermittent hypobaric hypoxia inhibits prolyl hydroxylases ( phd ) activity , increasing the stabilization of hypoxia - inducible factor-1 ( hif-1 ) and activating crucial adaptative genes . 
 it has been hence suggested that ihh might be a simple intervention , which may offer a thoughtful benefits to patients with acute myocardial infarction and no complications . 
 nevertheless , several doubts exist as to whether ihh is a really safe technique , with little to no complications in post - myocardial infarction patients . 
 intermittent hypobaric hypoxia might produce instead unfavourable changes such as impairment of vascular hemodynamics and hypertensive response , increased risk of hemoconcentration and thrombosis , cardiac rhythm perturbations , coronary artery disease and heart failure , insulin resistance , steatohepatitis and even high - altitude pulmonary oedema in susceptible or nonacclimatized patients . 
 although intermittent and chronic exposures seem effective in cardioprotection , ihh safety issues have been mostly overlooked , so that assorted concerns should be raised about the opportunity to use ihh in the post - myocardial infarction period . 
 several ihh protocols used in some studies were also aggressive , which would hamper their widespread introduction within the clinical practice . 
 as such , further research is needed before ihh can be widely advocated in myocardial infarction prevention and recovery . 
Introduction
Conflict of interest