Background. Obesity and obstructive sleep apnea syndrome (OSAS) are associated with systemic inflammation, secondary cardiovascular comorbidities and low exercise capacity.
Aim. To assess the relations between obesity, exercise capacity and systemic inflammation in patients with severe OSAS. Method. Newly diagnosed severe OSAS patients (Apnea-Hypopnea Index [AHI] >30/hour, cardiorespiratory polygraphy), with no clinically significant cardio-respiratory comorbidities, were evaluated by anthropometric measurements (Body Mass Index [BMI]; neck, waist and hip circumference and ratio [WHR]); complete blood count and markers of systemic inflammation: erythrocyte sedimentation rate (ESR), fibrinogen (Fb), neutrophils and platelets to lymphocytes ratios (NLR, PLR). All subjects underwent a six-minute walk test, with measure of the 6-minute walk distance, and an incremental cardio-pulmonary exercise test with measurement of the peak oxygen uptake (peakVO2), in order to asses maximal exercise capacity. The relations between these parameters were analyzed.
Results. In a group of 30 severe OSAS patients (23 men), with mean/median values for age 45±9 years, BMI 34.9±4.7 kg/m2, WHR 1 (0.9-1.2), AHI 58.8/hour (26-113.5), Oxygen Desaturation Index (ODI) 46/hour (16.5-100.3), hemoglobin (Hb) 15 g/dl (11.6-17), ESR 8 mm/1 hour (1-39), FB 336 mg/ dl (232-652), NLR 2 (1-3.73), PLR 97.5 (55-166), we found a peakVO2 of 82.11±2.58% predicted value. A statistically significant negative correlation between BMI and peakVO2 (r=-0.493, p=0.006) was found. OSAS severity (AHI, ODI) also negatively correlated with VO2 peak (r=-0.477, p=0.008; r=-0.379, p=0.043). Surprisingly, BMI negatively correlated with PLR (r=-0.401, p=0.042). No correlation between peak exercise capacity and OSAS severity with PLR was identified.
Conclusion. Both obesity and severe OSAS are associated with decreased exercise capacity. In our study group, we did not find a relation between markers of systemic inflamation and OSAS severity or peak exercise capacity. Systemic inflammation may not be the main mechanism of reduced exercise capacity in severe OSAS, other mechanisms being probably involved (cardiac dysfunction).
Aerobic exercise maximal capacity depends on the integrity of the systems involved in the oxygen uptake, transport and utilization. Respiratory, cardio-vascular, hematological and peripheral muscle diseases may be, alone or combined, responsible for a low exercise capacity(1).
Chronic low grade systemic inflammation is cur-rently believed to be involved in the pathogenesis of cardiovascular disease, diabetes, muscle weakness, osteoporosis, weight loss and depression(2-7). Obesity is the main risk factor for obstructive sleep apnea syn-drome (OSAS) and both conditions are associated with systemic inflammation(8-10).
The anomalies that were identified in previous stud-ies during incremental exercise in unselected OSAS sub-jects were diverse: excessive increase in systemic blood pressure, blunted heart rate response, slow increase in cardiac output, or findings consistent with coronary artery disease, peripheral arterial disease, respiratory diseases or peripheral muscles dysfunction(11-20).
We aimed to evaluate the relation between obesity, exercise capacity and systemic inflammation in untreat-ed severe OSAS subjects, without other clinically sig-nificant diseases that could contribute to low exercise capacity. The patients with controlled systemic arterial hypertension and type 2 diabetes were not excluded from the research.
Study subjects. Subjects referred to a Pulmonology department for high clinical suspicion of obstructive sleep apnea underwent a cardio-respiratory polygraphy. Patients diagnosed with severe OSAS (Apnea Hypopnea Index [AHI] >30/hour) with no history of chronic car-diovascular or respiratory conditions were enrolled. Subjects were eligible if they were between 25 and 65 years old, capable of performing exercise testing on a cycle-ergometer, in good physical and mental health. The research protocol was approved by the Institutional Ethics Committee and written informed consent was obtained from all participants.
Study protocol. Severe OSAS diagnosis was made through an unattended (ambulatory or in-hospital) six-channel cardio-respiratory polygraphy (AliceNightOne and Porti 7 poligraphs), which included measurements of nasal airflow via nasal pressure cannula, monitoring of respiratory effort with chest and abdominal band, continuous pulse oximetry, body position and snoring. The tests were manually scored in accordance with American Academy of Sleep Medicine standards by a trained medical doctor.
All patients underwent clinical examination – blood tests, including complete blood count and inflammatory markers: erythrocyte sedimentation rate (ESR) and fibrinogen (Fb); standard chest X-ray and pulmonary function tests (lung volumes and flows, lung diffusion test).
Exercise capacity was assessed through a standard 6 -minute walk test (6MWT, ERS/ATS Technical Standard, 2014(21)), and an incremental cardiopulmo-nary exercise test (CPET, ATS/ACCP Statement 2003(22)), using a cycle-ergometer. The predicted value for the six-minute walk distance (6MWD) was calculated using Enright and Sherrill equations(23) and peak oxygen uptake (peakVO2) was calculated using Wasserman equation(24,25). The results were expressed as percent predicted for both the 6MWD (6MWDpp) and peakVO2 (peakVO2pp).
The data were analyzed using a SPSS20 trial version. We performed the Kolmogorov-Smirnov normality dis-tribution test for all the data and then reported the subjects’ characteristics and findings as mean±SD, or median [IQR]. We searched for relations between obe-sity, exercise capacity and systemic inflammation using bi-variate correlation tests. A p value of less than 0.05 was considered significant.
We split the patients into different groups, as follows: a) the overweight and mildly obese (BMI<35 kg/ m2) and those with moderate to severe obesity; b) men and women; c) subjects with low exercise capacity and those with normal exercise capacity; d) subjects aged less or more than 40. We searched for significant differences for the parameters of interest in these groups using Man Whitney U test.
Results and discussions
Thirty severe OSAS patients (23 men) were included. The cardio-respiratory polygraphy data are presented in Table 1. Twenty-nine patients had an estimated total sleep time (eTST) of more than 4 hours.
Baseline characteristics. Baseline characteristics are presented in Table 2 and Table 3. Four patients were overweight, four patients were morbidly obese (BMI≥40 kg/m2), the rest of the subjects having grade I or grade II obesity. Eleven patients had a significant smoking history (more than 5 pack-years), with two being active smokers, all with normal pulmonary function tests. Two patients with controlled type 2 diabetes mellitus were enrolled.
ESR and fibrinogen values were higher than the upper limit of normal in two cases (ESR >20 mm/1 hour, Fb>450 mg/dl), in the diabetic patients. In the rest of the patients, these parameters commonly used to assess systemic inflammation were in the normal range, despite the fact that subjects were obese and had severe OSAS. This sug-gests that in subjects without manifest cardiovascular or respiratory impairment, these classic parameters have a low accuracy in detecting systemic inflammation.
The Platelets to Lymphocytes Ratio (PLR) and Neutrophil to Lymphocytes Ratio (NLR) were in the normal range of reference values(26-28). Six patients had NLR value of >3 and three of them also had a PLR >137.3, both cut-offs associated with higher risk of heart fail-ure(29,30). This findings weren’t associated with a low exercise capacity at the 6MWT (all with normal 6MWDpp), but the maximal exercise capacity was impaired in four of them (low peakVO2pp).
Exercise capacity was evaluated using the six-min-ute walk test and an incremental cardiopulmonary exer-cise test (CPET). All patients completed the tests without incidents.
The patient’s physical performance at the 6MWT (6MWDpp) was lower than expected (<85% predicted value) in 6 subjects (20%) (Figure 1).
The maximal (peak) exercise capacity observed at the incremental CPET was lower than expected (VO2 peak of less than 80% predicted value) in 14 subjects (46.66%) (Figure 2).
The exercise capacity data are showed in Table 4. The majority (28) of the patients ended the exercise test because of leg fatigue with only two cases of excessive increase in blood pressure (at 240/120 mmHg).
As we expected, according to data from literature, the 6MWT was less accurate in identifying patients with impaired exercise capacity than the CPET.
When looking at the entire group of patients, we found significant negative correlations between obesity and exercise capacity, as we expected.
The absolute value of the 6MWD correlated with the BMI (r=-0.465, p=0.011) (Figure 3). At the CPET, the peakVO2pp negatively correlated with neck perimeter (r=-0.528, p=0.003) (Figure 4), but not with waist or hip ratio. Self-reported diurnal somnolence (Epworth Sleepiness Scale Score) also had no correlation with OSAS severity and exercise capacity.
BMI had a significant negative correlation with the mean average nocturnal SaO2 (r=-0.496, p=0.006), which represents the result of both intermittent hypoxemia induced by OSAS and continuous hypoxemia secondary to obesity-associated chronic hypoventilation.
The PLR was negatively correlated with obesity, especially with the neck perimeter (r=-0.559, p=0.003, (Figure 5) and weight (r=-0.536, p=0.005). In severe OSAS, obesity seems to be less contributive to systemic inflammation than OSAS itself and/or other contributive factors (smoking, insulin-resistance).
Peak exercise capacity (peakVO2pp) was negatively correlated with OSAS severity (AHI, r=-0.474, p=0.008 and ODI, r=-0.472, p=0.010), which was not the case for the 6MWT (6MWDpp), probably due to the fact that more intense exercise is needed to reveal a subclinical cardiovascular impairment.
As expected, the maximal exercise capacity (peakVO2pp) had a negative correlation with ESR and a positive one with the hemoglobin level.
Age had a positive correlation with markers of systemic inflammation, but only with ESR and Fb; the tobacco exposure and the fasting glucose level weren’t correlated with those param-eters. No correlation between PLR and OSA severity or maximal exercise capacity (peakVO2pp) was found.
We also analyzed the impact of some characteristics of the studied subjects (age, sex) on the exercise capacity and systemic inflammation.
When comparing subjects according to age (less or more 40 years), we found that older patients had a better perfor-mance at the 6MWT (the difference between median values of 6MWDpp was 10%, p=0.025), despite the fact that the groups were similar in terms of BMI and OSAS severity. This could be explained by different response modalities to systemic inflammation.
When looking for gender-related differences, we found that women had a better exercise performance at the 6MWT (p=0.022), even though they had higher values of inflammatory markers (ESR, p=0.046, and PLR, p=0.019), possibly associated with older age and loss of hormonal protection (p=0.037). There was no significant difference in BMI between men and women.
When comparing the subjects according to the exercise capacity (e.g., the ability to achieve at peak exercise a VO2 of more than 80% predicted value), the only parameter related to exercise tolerance was the oxygen desaturation index (ODI), a higher ODI being associated with lower exer-cise capacity. Median values of ODI in the two groups were: 36/hour in subjects with VO2peak of >80% predicted, and 69/hour in subjects with VO2peak of <80% predicted (Man-Whitney U = 52.5, n0=16, n1=14, p=0.024).
The study evaluated a selected OSAS population – e.g., subjects without clinically significant cardiovascular comorbidities. It was revealed that an important proportion of these subjects had a low exercise capacity. As we expect-ed, the peak exercise performance (peakVO2pp) correlated negatively with both obesity and OSAS severity. The sub-maximal exercise performance (6MWDpp) had a negative correlation with obesity and no correlation with OSAS severity, probably due to the fact that more intense exercise is needed to reveal a subclinical cardiovascular impairment. The CPET is more sensitive than the 6MWT in identifying incipient impairment of exercise capacity.
PLR (as marker of systemic inflammation) was higher in subjects with a lower BMI. So, in obese subjects with severe OSAS, obesity seems to be less contributory to systemic inflam-mation than OSAS itself and/or other factors (smoking, insu-lin-resistance). Systemic inflammation may not be the main mechanism of reduced exercise capacity in severe OSAS with-out clinically significant cardiovascular comorbidities, other mechanisms being probably involved (cardiac dysfunction).
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