Metabolic syndrome (MS) is a constellation of obesity, hyperglycemia, decreased high-density lipoprotein (HDL), increased triglyceride, and high blood pressure. Thus, MS represents a group of risk factors that increases the risk of heart disease and other health problems, such as diabetes mellitus (DM) and stroke [1]. The associations of these factors with each other and with health problems have been recognized for decades. The frequencies of these risk factors have clearly demonstrated that MS is common and has a rising prevalence worldwide, which relates largely to increasing obesity and sedentary lifestyles [2], with different regions having individual clusters of epidemic risk factors [3]. As a result, MS is now in the spotlight as both a public health and a clinical problem.

Physical activity is widely acknowledged to reduce the risk of cardiovascular disease in individuals with established disorders such as obesity, hypertension, DM, and hyperlipidemia [4-9]. Meanwhile, new alternatives for traditional altitude training regimes have been proposed, known as “living low and training high”, and the effects on endurance performance have been demonstrated extensively in athletes [10-12]. Recently, several studies have reported the effects of hypoxia training on physical fitness not only in athletes but also in nonathletes [13-17]. In obese subjects, body weight was significantly decreased in subjects with hypoxia training compared with that in subjects with normoxia training [14]. Recent studies have also reported that hypoxic training could more effectively reduce arterial stiffness in postmenopausal women compared with that in normoxic training [17]. However, although body weight changes during high-altitude mountain expeditions have been described in several studies for healthy subjects [18,19], there have been very few reports on hypoxic training effects under controlled experimental conditions. The purpose of this study was to investigate the influence of hypoxic physical exercise on metabolic risk markers and to compare the effects on maximum oxygen uptake (VO_2max), arterial stiffness, and several blood parameters related to MS to a control group training under normoxic conditions.

Demographic and physiological baseline characteristics for both training groups are shown in Table 1. Before training, no significant differences in any values were identified between groups. Measurements for several parameters according to group and before/after training are shown in Table 2. Significant interactions were observed for the ABI [F(1, 7) = 7.88, P = 0.03]. No significant main effects or interactions were observed for body weight, BMI, body fat, waist circumference, S_min, P_max, and laboratory parameters. Despite no significant main effects among the groups, a significant main effect for before/after training was observed for S_max [F(1, 7) = 7.99, P = 0.03] and VO_2max [F(1, 7) = 18.99, P <

Table 1 . Subjects characteristics.

Table 2. Physical and laboratory parameters of the subjects before and after training.

BMI: Body mass index, S_min: minimum thickness of subcutaneous fat; P_max: Maximum thickness of preperitoneal fat; S_max: Maximum thickness of subcutaneous fat; ABI: Ankle brachial index; PWV: Brachial ankle pulse wave velocity; VO_2max: Maximum oxygen uptake; HOMA: Homeostasis model assessment; TG: Triglycerides; TCHO: Total cholesterol; HDL: High-density lipoprotein cholesterol; LDL: Low-density lipoprotein cholesterol; TG: Triglycerides; NS: Not significant.

0.001]. For PWV, significant main effect for the groups were observed [F(1, 7) = 8.43, P = 0.02].

Subsequently, the PWV after training was signifycantly lower in the hypoxic group than in the normoxic group (P = 0.02, Figure 1). The VO_2max in the hypoxic group was significantly higher after training than before training (P = 0.04, Figure 2).

The present study concerns the influence of hypoxic physical exercise on metabolic risk markers, VO_2max, and arterial stiffness in healthy subjects and, to our knowledge, is the first study with a same-subject repeatedmeasures design in controlled laboratory conditions. Although there were no effects on MS-related blood-test markers such as glucose and lipid parameters, we found a significant decrease in PWV, and a significant increase in VO_2max. Our results suggest regular hypoxic exercise is not only associated with cardiorespiratory improvement but also prevention of arteriosclerosis.

Among patients with DM, increased physical activity or cardiorespiratory endurance capability is associated with substantially reduced risk of cardiovascular events [23-25]. A recent study demonstrated that higher levels of cardiorespiratory fitness protect against MS in older individuals [26]. Kumagai et al. [27] reported a high degree of cardiorespiratory fitness positively contributed to

the low prevalence of MS in patients with impaired glucose tolerance and type 2 DM. VO_2max is commonly used in exercise testing to assess an individual’s endurance capacity. Lakka et al. [28] investigated associations of recreational physical activity and cardiorespiratory fitness with MS the associations of VO_2max with the components of MS were stronger than those of physical activity. They emphasized that metabolic disorders may be suppressed by regular physical activity and maintenance of high VO_2max values. Our results indicate that VO_2max after 4 weeks of regular training increased significantly under the hypoxic condition compared with the normoxic condition; therefore, hypoxic training effected improvement of cardiorespiratory function. However, several investigators found unremarkable effects of hypoxic training on VO_2max in nonathletes. Wiesner et al. [15] evaluated the influence of normobaric hypoxia training on physical fitness in obese subjects; hypoxic exposure term was 60 min. Meanwhile, in 10-hour simulated altitude conditions of 3000 m overnight, a significant increase in VO_2max was observed in the altitude group compared with the control [29]. Thus, we hypothesized that improvement of cardiorespiratory function was affected not only by exercise intensity but also by hypoxic exposure term.

The development of atherosclerosis increases the incidence of cardiovascular events such as heart attack or stroke. Hirai et al. [30] have shown strong associations between aortic stiffness and the degree of coronary artery disease, and similar associations have been reported between PWV and independently assessed cardiovascular risk scores [31]. PWV is generally assessed by measureing the time that the pulse wave takes to travel a given distance along the blood vessel; thus, it is an objective measurement of atherosclerosis. Nishiwaki et al. [17] demonstrated a significant increase in the percentage of flow-mediated vasodilation and a significant reduction in PWV after training in the hypoxic group in postmenopausal women. Their results indicate that hypoxic training may induce vascular functional adaptation. Our results also showed that PWV was significantly decreased in the post-hypoxic-training group compared with that in the normoxic-training group; these findings are in agreement with those previously reported. Meanwhile, reduced percentage of body fat, and values of laboratory parameters considered metabolic risk markers, were not observed after training. Several authors have investigated whether hypoxic training can induce MS-related marker reduction [13-15]. Netzer et al. [14] found no significant effect on lipids and HbA1c after normobaric hypoxic training (15 Vol% O₂) using a low intensity physical exercise (60% VO_2max), which resembled our study. Wiesner et al. [15] also investigated the hypoxic training effect on MS risk markers in obese subjects; their results showed no significant influence on blood pressure or LDL cholesterol. Our findings are also in agreement with previous studies that examined the effect of hypoxic training on MS risk markers. However, a few studies have reported decreased TG or insulin after short-term regular hypoxic training [13,15]. Further study with larger numbers of participants is needed for confirmation.

Our study has several limitations. First, the subjects were healthy young men, and our study did not include patients with metabolic disorders. Hence, we did not evaluate the pathological process and potential reduction of MS risk markers during regular hypoxic training. Second, the number of subjects was small, and our study design included before/after measurements with a control not a crossover study design. Third, the training duration was only 4 weeks; such short-term study does not provide information about long-term cardiorespiratory effects. To validate our findings, further studies are warranted with a larger number of participants and long-term monitoring using a crossover design. Further investigation is needed to confirm whether hypoxic training is related to MS risk marker reduction.

We found significant decreases in preperitoneal fat and PWV, and a significant increase in VO_2max, in the hypoxic group compared with the normoxic group. Our results suggest that regular hypoxic training may more effectively reduce arterial stiffness and improve cardiorespiratory parameters compared with training performed at the same relative exercise intensity under normoxic conditions.