Introduction In this issue of the Journal of Hypertension, an article by Haider et al.[1] provides evidence on the possibility to apply a respiratory training technique, based on intermittent respiration of a gas mixture exposing patients to normobaric hypoxia, in the nonpharmacological treatment of patients with chronic obstructive pulmonary disease (COPD). These patients are characterized by a low ventilatory drive to carbon dioxide and thus are at increased risk of developing hypercapnia, hypoxemia at night and elevated pulmonary artery pressure. An intervention aimed at improving their cardiorespiratory regulation would thus be welcome. The approach proposed by the authors, termed interval hypoxic training (IHT), was originally developed in the former Soviet Union in the 1990s, after which time it has been largely overlooked until recently. According to the hypothesis made by Haider et al., IHT may represent an alternative or supplementary form of rehabilitation, besides the traditional physical training, for COPD patients. In patients with chronic pulmonary disease, in whom the same investigators demonstrated the possibility to obtain favorable results with regular performance of a slow breathing exercise [2], the conventional training of respiratory muscles has worthy but limited results [1]. According to the data obtained by Haider et al., intermittent breathing of hypoxic gas mixtures could offer a better outcome in terms of cardiovascular regulation. Hereafter, a brief description of this technique and of the putative mechanisms involved in its effects is provided for the nonfamiliar reader. Development of the techniques for interval hypoxic training IHT was developed in the former Soviet Union in the 1990s [3–8] and consists of repeated short periods (5–7 min each) of steady (9–12% O2 concentration in inspired air) or progressive hypoxia (down to 5–7% O2), interrupted by equal periods of rest/recovery [9] characterized by respiration of ambient air. Pioneering research on the effects of exposure to hypoxia, carried out between years 1939 and 1943 [10], showed that even exposure to mild hypoxia, similar to that associated to ascent to a small altitude, produces favorable adaptation effects, improving lung ventilation, increasing hemoglobin concentration and, in the end, arterial oxygen saturation. Initially, IHT was used to increase resistance to ionizing radiation exposure [3] in the training of competitive athletes [4] and to improve adaptation to high altitude [5]. Over time, research was oriented to the putative therapeutic application of IHT, and its use was extended to the management of a variety of disorders, including asthma [6] and chronic bronchitis [7]. In Russia and Ukraine, in the past 30 years, a number of IHT protocols and equipments have been designed and manufactured [11] and, due to the absence of negative side effects, their use has become quite common [11]. However, as many of the scientific publications addressing the possible benefits of IHT were in Russian or Ukrainian languages, they were not made widely available elsewhere, and these potentially interesting findings have remained largely unknown. Technical aspects Two methods are currently being used for IHT in former Soviet Union countries that are as follows: exposure to hypobaric hypoxia through a barochamber (simulating altitude hypoxia) and exposure to normobaric hypoxia. Historically, IHT was first performed using a barochamber. A number of observations were made in both animals and humans using this method [12,13] despite the negative side effects of the repeated compression/decompression sequence that were often accompanying the immediate favorable effects of hypobaric therapy. The disadvantages of hypobaric chambers initially used (headache, chest pain and cardiac rhythm disturbances [14]) prompted the development and investigation of methods for normobaric hypoxia training. Indeed, in recent years, intermittent breathing of normobaric hypoxic gas mixtures has become a practical and more common approach for IHT. Three main methods to produce normobaric hypoxia are currently available are as follows: A method based on use of a hermetically sealed cabin able to host five to seven patients, in which oxygen concentration is maintained between 12 and 14%. Single 30–60 min sessions are applied daily for 15–20 days [15]. A method based on a hypoxic training device intended to be used in one individual patient at a time, operating on the open breathing system principle. The patient breathes a hypoxic gas mixture (12–16% O2) through a mask into an open circuit [16,17] for 3–10 min. Inspiration of the hypoxic air mixture is alternated with 3–10 min inspiration of room air. The procedure is repeated five to 10 times a day over 15–20 days. A method based on respiration of gas mixtures progressively poorer of O2, leading to gradually intensifying hypoxia, by using a rebreathing technique with CO2 elimination [18,19] also in this case through a system designed to be used by one patient at a time. The patient breathes into a spirometer in which the O2 concentration progressively falls while CO2 is absorbed by soda lime. Rebreathing proceeds for 5–6 min until an inspired air with O2 concentration of 7–8% is reached, then the patient breathes room air for 10–15 min. Generally, three sessions are administered each day at 10–20 min intervals for 2 weeks. The availability of so many different methods and the lack of standardization in their use have unfortunately introduced considerable variability in the data collected by studies focusing on this issue, leading to important differences in their results, which has so far made the comparison of conclusions on the clinical benefit of this approach difficult. Mechanisms of the possible beneficial effects of interval hypoxic training When dealing with physiologic and clinical aspects related to hypoxia, two points of view are competing. Western scientists tend to focus on the potential damage that hypoxia may induce, whereas a number of former Soviet Union scientific groups consider that 'hypoxia (provided that is brief and intermittent) can cause beneficial effects to an organism' [11]. According to this interpretation, IHT would be beneficial because it induces increased ventilatory sensitivity to hypoxia and other hypoxia-related physiological changes. Following IHT, cellular membranes become more stable with an improvement of O2 transportation in tissues. Moreover, IHT induces changes in mitochondria, involving nicotinamide adenine dinucleotide (NAD)-dependent metabolism, which increases the efficiency of oxygen utilization in ATP production [20]. These effects are mediated partly by nitric oxide (NO)-dependent reactions [13,21]. Different hemodynamic and autonomic responses to obstructive sleep apnea and to intermittent hypoxia: the two sides of the coin Obstructive sleep apnea (OSA) represents a common chronic form of sleep-disordered breathing afflicting millions of patients worldwide, which has been shown to be characterized by repeated episodes of apnea-induced blood oxygen desaturation during sleep. OSA, which therefore represents a pathologic type of intermittent exposure to hypoxia, has been indicated as an independent risk factor for a variety of cardiovascular problems, including hypertension, stroke, coronary artery disease and cardiac arrhythmias [22,23]. In particular, among these comorbidities, consistent evidence is available demonstrating a strong relationship between OSA and hypertension [24–27], current hypertension management guidelines indicating OSA as one of the identifiable causes of hypertension and a frequent reason for resistant hypertension. Such a relationship is due to a number of mechanisms, including OSA-induced chemoreflex activation responsible for an increase in sympathetic activity. Indeed, the main hallmark of OSA is represented by recurrent episodes of arterial hypoxemia during the brief asphyxiations caused by repeated upper airway collapse during sleep. This leads to an apparent paradox: on one side OSA, which is the predominant pathological cause of chronic, intermittent hypoxemia affecting the adult population, appears to favor the appearance of arterial hypertension. On the other side, a number of experimental and clinical studies, conducted primarily in the nations of the former Soviet Union, have shown that intermittent hypoxia can be applied therapeutically to lower blood pressure, both in hypertensive animals and patients [28]. While during acute episodes of hypoxia, chemoreceptor-mediated sympathetic activation leads to an increase in heart rate and systemic arterial pressure, different patterns of intermittent hypoxia are in fact responsible for remarkably divergent effects on systemic arterial pressure in the posthypoxic chronic state. These divergent results are typically exemplified by the hypertensive effects of OSA vs. the depressor effects of therapeutic exposure to intermittent hypoxia (Table 1). OSA is characterized by a series of brief, intense episodes of hypoxia and hypercapnia, associated with sleep fragmentation and changes in intrathoracic pressure, leading to persistent, maladaptive chemoreflex-mediated activation of the sympathetic nervous system which contributes to a reduction in arterial baroreflex sensitivity (BRS) and to the appearance of chronic arterial hypertension. Conversely, controlled intermittent hypoxia-conditioning programs appear to be safe, efficacious modalities for prevention and treatment of hypertension. The mechanisms responsible for the discrepant chronic effects of these two types of intermittent hypoxia exposure are multifold. In OSA patients, during acute episodes of nocturnal hypoxia induced by repeated airways collapse, chemoreceptor-mediated sympathetic activity increases, with a resulting increase in heart rate, cardiac output, peripheral resistance and systemic arterial pressure. Such an often frequent sequence of hypoxia–hypercapnia episodes is associated with sleep fragmentation and with repeated fluctuations in intrathoracic pressure (the Mueller maneuver), all contributing to the negative hemodynamic effects of OSA. During individual apneic events, the chemoreflex-mediated increase in sympathetic nerve activity (SNA) is directly related to the duration of the apnea and the magnitude of hemoglobin O2 desaturation. The increase in SNA is accompanied by increases in systemic arterial pressure, often 50 mmHg or more, occurring in the hyperventilating phase following apnea, that subside once regular ventilation resumes [28]. The heart rate response varies as a function of the chemoreflex activation and the lack of ventilation. Intermittent breathing of a hypoxic gas mixture conversely seems to acutely lead to increases in heart rate mostly mediated by vagal withdrawal [29,30]. This condition is quite different also from the effects of long-lasting apnea occurring during prolonged water immersion, in which chemoreflex stimulation by hypoxia is associated with stimulation of skin and mucosal receptors innervated by afferent parasympathetic fibers, which determines concomitant and significant peripheral sympathetic and cardiac vagal activation resulting in bradycardia and hypertension [31].Table 1: Pro-hypertensive and antihypertensive features of obstructive sleep apnea and interval hypoxic training, respectivelyOSA-related hypoxia is also likely to exert direct neuromodulation on circumventricular sites of central sympathetic regulation, including the subfornical organ and the hypothalamic paraventricular nucleus [32]. Indeed, initial reports suggested that the same molecular mechanisms involving these neuromodulators [including increased angiotensin II [33] and endothelin-1 [34] and decreased NO formation [32,35]] may influence peripheral chemoreflex sensitivity and central sympathetic activity. Although the above effects of OSA-induced acute hypoxia are well known and may explain a sympathetic nervous system-mediated blood pressure increase [36,37], the effects of IHT on the autonomic nervous system are largely unknown. One hypothesis suggests that adaptation to hypoxia after IHT is associated with an increased ventilatory response and with a more favorable sympathovagal balance [38]. The data provided by Haider et al.[1] in their article appear to support this suggestion and provide evidence of a significant increase in baroreflex sensitivity up to normal levels in mild COPD patients after IHT. Such an increase in BRS was accompanied by a selective increase in hypercapnic ventilatory response without changes in hypoxic ventilatory response. Role of autonomic nervous system in human adaptation to hypoxia From 1938 to 1943, repeated exposure of Soviet pilots to hypoxia in hypobaric chambers was shown to dampen the increases in heart rate and arterial pressure during acute hypoxia [39,40] suggesting that such training was able to modulate the autonomic nervous system responsiveness. In the late 1990s, Gazenko and Grigor'ev's studies on the sympathetic response to IHT in humans and animals led to recommend IHT for conditioning pilots of high-altitude flights [41]. Sirotinin et al.[42] considered the changes induced by hypoxia and IHT on the autonomic control to be the key factors in adaptation and came to the paradoxical conclusion that in these conditions 'between sympathetic and parasympathetic systems there is not antagonism but synergism' [43]. The autonomic nervous system plays a role in the modulation of the oscillatory behavior of the cardiovascular system [44,45]. Spectral analysis of variability in the R–R interval is a recognized tool allowing quantification of its oscillatory components, which in short-term recordings appear to be frequently organized into two frequency regions of pathophysiologic interest, respectively called low-frequency (0.04–0.14 Hz) and high-frequency (0.15–0.35 Hz) regions, the latter including the contribution of respiratory modulation in regularly breathing patients. Whereas high-frequency components of R-R interval variability primarily reflect the respiration-driven vagal modulation of sinus rhythm [45], the low-frequency components appear to have a more widespread neural genesis [46] and reflect both the sympathetic and parasympathetic modulation of the heart [44–46] as well as the baroreflex responsiveness to the beat-to-beat variations in arterial blood pressure [47,48]. To understand how IHT might affect autonomic function in healthy individuals, Bernardi et al.[38] performed power spectral analysis of heart rate variability too. IHT nearly abolished the increase in heart rate and in the low-frequency component of heart rate variability (HRV) during hypoxic exposure, whereas sham training did not alter the hypoxia-induced tachycardia. This indicates that IHT increased parasympathetic cardiac modulation during the hypoxic challenge and suggests that long-lasting IHT may simulate other conditions of prolonged exposure to hypoxia, such as acclimatization to high altitude [35]. A similar activation of the parasympathetic nervous system by IHT was later confirmed by studies in rats [49,50] and humans [51–53]. The differences between the effects of acute hypoxia and chronic IHT appear to resemble those between acute and chronic exposure to high altitude. During acute exposure to high altitude, R–R variability is reduced, with a relative increase in the low-frequency component [35,53,54] suggesting an increased sympathetic modulation of the sinus node in response to hypobaric hypoxia. Conversely, an antihypertensive effect of chronic exposure to high-altitude hypoxia has been suggested in former studies [55]. In permanent high-altitude residents, arterial pressure was reported to be 10–15 mmHg lower, and aging-related blood pressure increases seem to be more gradual than in lowlanders [56]. Indeed, hypertension and ischemic heart disease are reported to be less prevalent and less severe in highlanders [57]. According to some authors, the hypotensive effect of chronic exposure to high altitude could be ascribed to suppression of sympatho-adrenal and renin–angiotensin systems [28]. These hypotensive responses in people chronically exposed to high-altitude hypoxia are in sharp contrast with the marked and sustained increases in blood pressure (BP) and circulating catecholamines reported in lowlanders subjected to 4 [58] or 9 week [59] sojourns at 5260 m, in whom a severe hypobaric hypoxic stress was responsible for intense sympathetic activation that was very likely a major factor contributing to their hypertensive responses. Possible clinical applications Scientists in the former Soviet Union have studied and applied IHT for treatment and prevention of a number of human diseases. The majority of clinical studies assessing the use of IHT for disease treatment have been carried out in Bronchial Asthma and COPD [11]. Demonstration that IHT increases the hypoxic ventilatory response may be potentially useful in clinical conditions associated with a low ventilatory drive, such as COPD [60,61], asthma [62] and autonomic diseases such as familial dysautonomia [63], in addition to improving adaptation to high altitude. In general, available clinical studies have shown that IHT increases exercise tolerance, hypoxic ventilatory response, hematocrit and blood hemoglobin content; dampens exercise-induced tachycardia and produces a rightward shift in the lactate–exercise load relationship [5,10,64–70]. Its use in COPD patients, as suggested in the present study conducted by Haider et al.[1], thus has a reasonable background. In COPD, baroreflex sensitivity is decreased [71], and HRV is reduced at rest and also during exercise [72,73]. In addition, these patients show a marked increase in efferent muscle sympathetic nerve activity (MSNA), another marker of sympathetic activation [74]. The improvement in BRS showed in the present article following IHT, in spite of some limitations such as the relatively small sample size of this study and the possible confounding effects of drug treatment, suggests that at an early stage of COPD these abnormalities are to a great extent functional and could be reversed. This observation should be considered aganist the background of previous studies on this issue, although most previous reports of IHT clinical applications have typically consisted of repetitive, brief bouts of steady or progressive hypoxia, interrupted by similar or prolonged periods of normoxic recovery. However, it should be considered that substantial variations in the intensity of hypoxia, in duration and number of hypoxic exposures per session, and in the number and frequency of sessions may make the comparison of results of different studies more difficult. Conclusion The repeated hypoxemia induced at night by OSA has relevant negative effects on arterial blood pressure control, favoring the appearance of arterial hypertension. The opposite seems to occur in case of intermittent respiration of hypoxic gas mixtures. On the basis of previous evidence, the demonstration of an improved sympatho-vagal balance in the study by Haider et al. further supports the suggestion that IHT might represent a promising new approach in the prevention and treatment of many diseases. A number of methodological issues, however, still need to be properly addressed before recommending a widespread use of this technique. Among them is the proper choice of the intensity and frequency of the hypoxic stimulus to be applied, which may depend on an individual patient's reactivity and should thus be individually titrated for each patient to avoid negative side effects and to increase the probability of a favorable outcome [11]. Studies on the most suitable approach to optimal titration of IHT are currently being performed, and specific criteria are being developed to assess the individual adaptability and responsiveness to IHT. Moreover, safe, portable and inexpensive IHT devices are being developed and tested. Their availability, together with the reported absence of negative side effects, which are, conversely, often associated with drug therapies, might thus promote the adoption of IHT as a new approach to rehabilitation of patients with a number of chronic cardiorespiratory diseases. [28]. However, similarly to what has happened for other nonconventional methods of training, such as slow breathing exercises, small studies like the one by Haider et al. need to be confirmed by the results of further investigations on a larger scale. Indeed, though respiratory training was initially used to train patients with COPD only, it has been subsequently shown to positively affect the clinical conditions also of patients with heart failure or arterial hypertension [2,75–77]. Because of its preconditioning effect, this might well be the case also for IHT, which may turn out to be useful not only in COPD patients but also in those with cardiovascular disease. Controlled, randomized intervention trials are now needed to test this interesting possibility in a sufficiently large number of patients.