Prevalence and Associated Factors of Obstructive Sleep Apnea in Patients with Resistant Hypertension

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1 Original Article Prevalence and Associated Factors of Obstructive Sleep Apnea in Patients with Resistant Hypertension Elizabeth S. Muxfeldt, 1 Victor S. Margallo, 1 Gleison M. Guimarães, 1 and Gil F. Salles 1 background Obstructive sleep apnea (OSA) syndromes are strongly associated with resistant hypertension, although this has not been systematically examined. The aim of our study was to investigate the prevalence of OSA and its associated factors in a large cohort of resistant hypertensive patients. methods A cross-sectional analysis with 422 resistant hypertensive patients (31.3% men; mean age = 62.4 ± 9.9 years) submitted to a full-night polysomnography. The presence of OSA was defined by an apnea-hypopnea index (AHI) >5 per hour and moderate/severe OSA was defined by an AHI >15. Statistical analysis included bivariable comparisons between patients with and without moderate/severe OSA and logistic regressions to assess the independent correlates of OSA severity. results Three-hundred forty-seven patients (82.2%) had OSA, and 234 patients (55.5%) had moderate/severe OSA. Patients with moderate/severe OSA were more frequently elderly and obese men with larger waist and neck Obstructive sleep apnea (OSA) is characterized by loud snoring, daytime sleepiness, and witnessed breathing interruptions with at least 5 obstructive respiratory events per hour of sleep. 1 Affecting 2% 4% of the adult population, 1 OSA is highly prevalent in patients with hypertension (range= 35% 80%) and other cardiovascular diseases, 1 3 and this association seems to be proportional to the severity of the disease. 2,3 Patients with resistant hypertension (RH), defined as an uncontrolled clinic blood pressure (BP) in spite of using at least 3 antihypertensive medications, 4 present high cardiovascular morbidity and mortality. 5 The first report on the relationships between OSA and RH was published more than a decade ago. 6 Although it seems that OSA contributes to development or persistence of antihypertensive treatment resistance, 2 it is not clear whether OSA should be considered a cause, 7 a risk factor for RH, 4,8 or just 2 associated diseases with similar phenotypes, such as obesity 2 4,8 11 and nocturnal nondipping pattern. 2,9,10 Moreover, RH and OSA also share common pathogenetic mechanisms, such as volume circumferences, had higher prevalences of diabetes and left ventricular hypertrophy, and had higher proteinuria than patients with no/mild OSA. No difference was found in plasma aldosterone and renin activity. Nighttime systolic blood pressures and pulse pressures were higher in moderate/severe OSA, with lower nocturnal blood pressure fall. In multivariable logistic regression, male sex, older age, diabetes, obesity, increased waist and neck circumferences, and nighttime systolic blood pressure were the independent correlates of moderate/severe OSA. conclusions Resistant hypertensive patients had a very high prevalence of OSA, and patients with moderate/severe OSA had an adverse ambulatory BP profile, with higher nighttime systolic blood pressures and pulse pressures and higher prevalence of nondipping patterns. Other correlates of OSA severity were mainly demographic-anthropometric variables. Keywords: blood pressure; hypertension; obstructive sleep apnea; polysomnography; resistant hypertension. doi: /ajh/hpu023 overload, 4,12 14 sympathetic activation, 2,3,15,16 and aldosterone excess. 3,4,14,17 Although it is generally accepted that there are strong associations between OSA and RH, this has not been systematically examined, and all previous studies evaluated rather small numbers of patients. 6,7,18,19 Therefore, the objective of this study was to evaluate the prevalence of OSA in a large cohort of patients with well-characterized RH and to identify clinic-laboratorial covariables associated with its presence and severity. METHODS Patients and baseline procedures From a total of 451 consecutive patients within a cohort of RH patients, 422 patients agreed to participate in this crosssectional study from September 2010 to January 2013 in the hypertension outpatient clinic of our tertiary-care University Correspondence: Elizabeth Silaid Muxfedlt (bethmux@globo.com). Initially submitted August 25, 2013; date of first revision October 13, 2013; accepted for publication January 18, 2014; online publication April 4, Hypertension Program, University Hospital Clementino Fraga Filho, School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. American Journal of Hypertension, Ltd All rights reserved. For Permissions, please journals.permissions@oup.com American Journal of Hypertension 27(8) August

2 Muxfeldt et al. Hospital. Twenty-nine patients (6%) refused to perform polysomnography (PSG; 66% of them considered at high risk for OSA by Berlin Questionnaire previously applied, similar to those who accepted). All participants gave written informed consent, and the local ethics committee had previously approved the study protocol. All patients fulfilled criteria for RH (clinic BP 140/90 mm Hg using 3 antihypertensive drugs in full dosages or using 4 drugs regardless of clinic BP levels, ideally including a diuretic) 4 and were considered at least moderately adherent by a validated questionnaire. 20 The exclusion criteria were patients aged >80 years, with poor therapy adherence, any cognitive impairment, or any severe concurrent disease in the last 6 months. A database, which included demographic characteristics, cardiovascular risk factors (diabetes, dyslipidemia, smoking, physical inactivity, and obesity), and target-organ damage (coronary heart disease, heart failure, cerebrovascular disease, advanced retinopathy, and peripheral arterial disease), was developed at the entrance of each patient into the cohort. 21 Snoring and daytime sleepiness were evaluated by Berlin Questionnaire. 22 All patients were submitted to a standard protocol, including a thorough clinical examination, a laboratory evaluation, 24-hour ambulatory BP monitoring (ABPM), carotid-femoral (aortic) pulse wave velocity measurement, 2-dimensional echocardiogram, and full-night PSG. Anthropometric measurements (height, weight, and abdominal and neck circumference), and antihypertensive therapeutic scheme were registered. Body mass index (BMI) was calculated (weight/(height) 2 ). 21 Waist and neck circumferences were considered increased if >88 cm and >41 cm in women or if >102 cm and >43 cm in men, respectively. 2,21 The laboratory evaluation included fasting glycemia, serum creatinine and lipids, plasma aldosterone and renin activity, and albuminuria and proteinuria in a sterile 24-hour urine collection. The use of mineralocorticoid receptor blocker (spironolactone) was interrupted for at least 4 weeks before aldosterone and renin assays. Patients with high aldosterone-to-renin ratio (>30, calculated with renin activities <0.5 ng/dl/h corrected to 0.5) were further investigated for primary aldosteronism by measuring 24-hour urinary sodium and aldosterone excretion on a high-salt diet. Echocardiographic left ventricular mass was calculated by the Devereux formula and indexed to body surface area. Left ventricular hypertrophy was defined as left ventricular mass index >125 g/ m 2 in men and >110 g/m 2 in women. 23 Carotid femoral pulse wave velocity was measured in the morning just after the ABPM with the Complior equipment (Artech-Medical, Paris, France). 24 Three consecutive measurements were performed, and the mean value was used. Direct carotid femoral distance was corrected by a factor of 0.8, as recently recommended. 24 BP measurements Clinic BP was measured twice on 2 occasions with suitably sized cuffs, with patients in the sitting position, using a digital BP monitor (HEM-907 XL; Omron Healthcare, Kyoto, Japan). The mean between the 4 readings was registered. The ABPM was recorded using Mobil O graph 1070 American Journal of Hypertension 27(8) August 2014 (version 12) equipment (DYNAMAPA, Cardios, São Paulo, Brazil) approved by the British Society of Hypertension. 25 All patients were using their prescribed antihypertensive medications, including spironolactone, during ABPM. A reading was taken every 15 minutes throughout the day and every 30 minutes at night. The nighttime period was ascertained for each individual patient from registered diaries. Parameters evaluated were mean 24-hour, daytime, nighttime, and early morning (first 2 hours after awakening) systolic BP (SBP), diastolic BP, and pulse pressure. The nocturnal BP fall was calculated as (((daytime BP nighttime BP) / daytime BP) 100), and patients were classified according to the dipping pattern as: dippers (nocturnal reduction 10% and <20%), extreme dippers (nocturnal reduction 20%), nondippers (nocturnal reduction <10% and 0%), and risers (nocturnal reduction <0%). 26 Patients were also divided into controlled ambulatory BP (daytime BP <135/85 mm Hg and nighttime BP <120/70 mm Hg) or uncontrolled ambulatory BP (daytime BP 135/85 mm Hg or nighttime BP 120/70 mm Hg). 4,10,27 Considering clinic and ambulatory BPs at the enrollment for this study, the prevalences of true, white-coat, masked, and sustained controlled RH were 43%, 27%, 13%, and 17%, respectively. 27 Polysomnography All patients underwent a full-night attended diagnostic PSG recorded in BrainNet BNT 36 device and analyzed by Poliwin XP software (EMSA, Rio de Janeiro, Brazil). All patients were using their prescribed antihypertensive medications during PSG. During all PSG studies, airflow, respiratory effort, and oxyhemoglobin saturation were monitored. Electrocardiogram, electroencephalogram, electrooculogram, and submental/anterior tibial electromyogram were simultaneously recorded with surface electrodes according to the American Academy of Sleep Medicine standards. 1 Sleep stages, oxygen desaturation, breathing events, and periodic limb movement were scored by an experienced physician blinded to other patients data. Apnea and hypopnea were respectively defined as a 90% and 30% decrease of airflow for at least 10 seconds associated with oxyhemoglobin desaturation 4%. Obstructive and central apneas were diagnosed according to the presence or absence of accompanying respiratory effort. The apnea-hypopnea index (AHI) was calculated as the number of apnea-hypopnea events per hour of sleep. The presence of OSA was defined by an AHI >5 events/hour and each severity category by the following criteria: mild OSA (AHI 5 14), moderate OSA (AHI 15 30), and severe OSA (AHI >30). 1 Statistical analysis Statistical analyses were performed with SPSS statistical package version 19.0 (SPSS, Chicago, IL). Continuous data were described as means (SD) if normally distributed or as medians (interquartile range) if asymmetrically distributed. Bivariable comparisons between patients with moderate/severe OSA and patients with no or mild OSA were performed by unpaired t test (for continuous normal

3 Sleep Apnea in Resistant Hypertension variables), Mann Whitney test (for continuous asymmetric variables), and χ 2 test (for categorical variables). To assess the independent correlates of each severity grade of OSA, multivariable logistic regressions were performed with total OSA, moderate/severe OSA, and severe OSA as the dependent variables. Candidate variables to enter the models were age, sex, obesity, increased neck and waist circumferences, presence of diabetes and cardiovascular diseases, nighttime SBP, nondipping pattern (nondippers and risers), snoring, left ventricular hypertrophy, and 24-hour proteinuria and albuminuria. A stepwise forward procedure was used to select the independent covariables (P < 0.10 was necessary to enter and to remain into the models). Hosmer Lemeshow goodness-of-fit test and the area under the receiver operating characteristics curve of estimated probabilities were used to assess models calibration and discrimination. Results were presented as odds ratios and their 95% confidence intervals (CIs). Also, a multiple linear regression was carried out to assess the independent correlates of continuous AHI (log 10 transformed because of its asymmetric distribution). The candidate variables and selection criteria were the same as in the logistic regression analyses, except that obesity, increased waist and neck circumferences and left ventricular hypertrophy were substituted for BMI, continuous waist and neck circumferences, and left ventricular mass index, respectively. Results were presented as B coefficients (with their SEs), standardized beta and partial correlation coefficients, and adjusted r 2 of the final model. A subgroup multivariable analysis (logistic and linear) was undertaken exclusively with patients with uncontrolled ambulatory BPs. In all analyses, a 2-tailed P value <0.05 was regarded as significant. RESULTS A total of 422 patients (31% men; mean age = 62.4 ± 9.9 years) were enrolled. PSG identified OSA in 347 patients (82.2%; 95% CI = 74.0% 91.3%) and moderate or severe OSA in 234 patients (55.5%; 95% CI = 48.8% 63.0%). Thirteen patients (2.8%) had central sleep apnea. Tables 1 and 2 outline the baseline characteristics of all patients and those with and without moderate/severe OSA. Moderate/severe OSA was more frequent in male, elderly, obese (with increased waist and neck circumferences), and diabetic patients. Antihypertensive treatment was similar in number of drugs and drugs taken at bedtime, although patients with moderate/severe OSA were using more calcium channel blockers and less centrally acting alpha-agonists than those with no/mild OSA (Table 1). Patients with moderate/severe OSA also presented higher fasting glycemia and proteinuria and a higher prevalence of left ventricular hypertrophy. No difference was found in relation to renal function, serum lipids, or plasma aldosterone and renin activity. Aortic arterial stiffness was also similar in the two groups (Table 1). Furthermore, the nocturnal BP profile was worse in patients with moderate/severe OSA. They presented higher nighttime systolic BP and pulse pressure and lower nocturnal systolic BP fall, with a higher prevalence of nondipping patterns (both the riser and the nondipper pattern) than patients with no/mild OSA (Table 2). Figures 1 and 2 present the results of multivariable logistic regression analyses for the independent covariables associated with the presence of OSA, moderate/severe OSA, and severe OSA in all patients and in patients with uncontrolled ambulatory BPs, respectively. Older age, male sex, obesity, increased waist and neck circumferences, higher nighttime Table 1. Baseline characteristics of patients grouped according to obstructive sleep apnea diagnosed by polysomnography Characteristics All patients (n = 422) No/mild OSA (n = 188) Moderate/severe OSA (n = 234) Clinical and demographic data Sex, % male * Age, years 62.4 (9.9) 61.2 (10.4) 63.4 (9.4)*** Age >65 years *** Snoring *** Daytime sleepiness Weight, kg 79.8 (16.5) 74.4 (13.8) 84.2 (17.3)* BMI, kg/m (5.7) 29.5 (5.2) 32.5 (5.7)* Obesity, BMI 30 kg/m * Waist circumference, cm (12.1) 97.5 (11.3) (11.6)* Increased waist circumference a ** Neck circumference, cm 37.8 (3.7) 36.3 (3.1) 39.1 (3.6)* Increased neck circumference b ** Cardiovascular risk factors Diabetes *** Physical inactivity (Continued) American Journal of Hypertension 27(8) August

4 Muxfeldt et al. Table 1. Continued Characteristics All patients (n = 422) No/mild OSA (n = 188) Moderate/severe OSA (n = 234) Current smoking Dyslipidemia Target organ damage Any cardiovascular disease Coronary heart disease Heart failure Cerebrovascular disease Peripheral arterial disease Antihypertensive treatment No. of drugs 4 (3 5) 4 (3 5) 4 (3 5) No. of drugs at bedtime 2 (1 3) 2 (1 3) 2 (1 3) ACE inhibitor AR blockers Beta-blockers Calcium channel blockers ** Direct vasodilators Central alpha agonists *** Spironolactone Laboratory exams Fasting glucose, mmol/l 6.5 (2.9) 6.1 (2.7) 6.7 (3.0)*** Serum creatinine, µmol/l 80 (71 97) 80 (68 97) 83 (71 97) Creatinine clearance c, ml/min/1.73 m 2 83 (31) 80 (31) 85 (32) Total cholesterol, mmol/l 5.29 (1.23) 5.37 (1.23) 5.23 (1.22) HDL cholesterol, mmol/l 1.17 (0.33) 1.19 (0.32) 1.16 (0.34) Triglycerides, mmol/l 1.85 (1.23) 1.85 (1.42) 1.86 (1.06) Plasma aldosterone, ng/dl 11.0 ( ) 11.0 ( ) 10.2 ( ) Plasma renin activity, ng/dl/h 1.5 ( ) 1.4 ( ) 1.5 ( ) Aldosterone-renin ratio >30 d Proteinuria, mg/24 h 132 (76 233) 114 (65 196) 153 (87 273)** Albuminuria, mg/24 h 18 (8 53) 17 (7 52) 19 (10 54) Microalbuminuria 30 mg/24 h Aortic pulse wave velocity, m/s 9.5 (2.1) 9.4 (2.2) 9.7 (2.0) Aortic pulse wave velocity >10 m/s Dimensional echocardiogram LV mass index, g/m (49) 133 (39) 144 (55)*** LVH *** Values are presented as percentages or as means (SD), except for number of antihypertensive drugs, serum creatinine, plasma aldosterone and renin activity, proteinuria, and albuminuria, which are presented as medians (interquartile range). Abbreviations: ACE, angiotensin-converting enzyme; AR, angiotensin II receptor; BMI, body mass index; HDL, high-density lipoprotein; IQR, interquartile range; LV, left ventricular; LVH, left ventricular hypertrophy; OSA, obstructive sleep apnea. a Increased waist circumference: >88 cm in women and >102 cm in men. b Increased neck circumference: >41 cm in women and >43 cm in men. c Creatinine clearance calculated by Cockroft Gault formula. d To calculate aldosterone-to-renin ratio, plasma renin activity <0.5 was corrected to 0.5 ng/dl/h. *P < 0.001, **P < 0.01, ***P < 0.05 for bivariable comparisons between groups with and without moderate-severe OSA American Journal of Hypertension 27(8) August 2014

5 Sleep Apnea in Resistant Hypertension Table 2. Clinic and ambulatory blood pressures of patients grouped according to obstructive sleep apnea diagnosed by polysomnography Characteristics All patients (n = 422) No/mild OSA (n = 188) Moderate/severe OSA (n = 234) Clinic blood pressures, mm Hg Systolic BP 155 (28) 158 (30) 153 (27) Diastolic BP 85 (17) 86 (18) 84 (17) Pulse pressure 70 (21) 72 (21) 69 (21) 24-Hour blood pressures, mm Hg Systolic BP 130 (18) 128 (17) 130 (18) Diastolic BP 75 (13) 75 (12) 75 (13) Pulse pressure 55 (10) 53 (10) 55 (11) Daytime blood pressures, mm Hg Systolic BP 132 (18) 131 (18) 133 (19) Diastolic BP 77 (13) 77 (12) 77 (13) Pulse pressure 55 (10) 54 (10) 56 (11) Nighttime blood pressures, mm Hg Systolic BP 121 (19) 119 (18) 123 (20)* Diastolic BP 70 (13) 69 (13) 70 (13) Pulse pressure 51 (11) 50 (10) 53 (12)* Early morning blood pressures, mm Hg Systolic BP 134 (21) 133 (21) 135 (21) Diastolic BP 79 (14) 78 (14) 79 (15) Pulse pressure 55 (14) 55 (14) 56 (14) Uncontrolled ambulatory BP Isolated nocturnal RH Nocturnal BP reduction Systolic BP 8.1 (8.6) 9.1 (8.1) 7.3 (8.9)* Diastolic BP 9.8 (10.1) 10.4 (9.5) 9.3 (10.5) Non-dipping pattern * Categories of dipping a Riser, % * Nondipper, % * Dipper, % Extreme dipper, % Values are presented as means (SD) or percentages. Abbreviations: BP, blood pressure; OSA, obstructive sleep apnea; RH, resistant hypertension. a Categories of dipping were compared using the dipper pattern as reference. *P < 0.05 for bivariable comparisons between groups with and without moderate-severe OSA. SBP, and diabetes were almost universal correlates of any severity grade of OSA. Age, sex, and obesity were the strongest correlates of OSA. Each 10 mm Hg increment in nighttime SBP increased the odds of having any OSA or moderate/ severe OSA by 18% but not the odds of having only severe OSA. Table 3 presents the results of multiple linear regression for the independent correlates of continuous AHI in all patients and in those with uncontrolled ambulatory BPs. Age, waist and neck circumferences, nighttime SBP, fasting glycemia, and presence of snoring (only in all patients) were the independently associated variables. Discussion Our study has two main findings. First, it confirms the very high prevalence rate of OSA in the largest sample of patients with RH ever evaluated. Second, it demonstrates that over and beyond demographic-anthropometric characteristics known to be associated with OSA (older age, male sex, obesity, and increased waist and neck circumferences), the presence of diabetes and a worse nocturnal BP profile are also independently associated with moderate/severe OSA in RH patients. Whether this cluster of adverse risk factors implies a higher risk of future American Journal of Hypertension 27(8) August

6 Muxfeldt et al. 422; 347 Older age (n = 422; 234 (n = 422; 140 P < P < 0.01 Figure 1. Results (odds ratios and 95% confidence intervals (CIs)) for the independent covariables associated with the presence of (a) total obstructive sleep apnea (OSA), (b) moderate/severe OSA, (c) severe OSA in all patients. Candidate variables to enter models were the following: age, sex, obesity, increased neck and waist circumferences, presence of diabetes and cardiovascular diseases, nighttime systolic blood pressure (SBP) and nondipping pattern, snoring, left ventricular hypertrophy, and 24-hour proteinuria. Abbreviation: ROC, receiver operating characteristics American Journal of Hypertension 27(8) August 2014

7 Sleep Apnea in Resistant Hypertension a Odds ratio (95% CI) Presence of OSA (n = 246; 206 patients with OSA) Older age (>65 years) Male sex Obesity Increased waist circumference Nighttime SBP (10 mm Hg) 3.28 ( ) 2.54 ( ) 3.22 ( ) 2.82 ( ) 1.17 ( ) P = P = 0.03 P = P = 0.03 P = 0.07 b Male sex Older age (>65 years) Obesity Nighttime SBP (10 mm Hg) Increased waist circumference Diabetes Increased neck circumference c Older age (>65 years) Obesity Male sex Diabetes Increased neck circumference Odds ratio (95% CI) 3.70 ( ) 2.58 ( ) 2.46 ( ) 1.18 ( ) 2.88 ( ) 1.28 ( ) 2.18 ( ) Odds ratio (95% CI) 3.51 ( ) 3.81 ( ) 2.80 ( ) 2.52 ( ) 2.34 ( ) Hosmer-Lemeshow goodness-of-fit test: P = 0.43 Area under ROC curve: (95% CI: ) Presence of moderate/severe OSA (n = 246; 143 patients with mod/sev OSA) Hosmer Lemeshow goodness-of-fit test: P = 0.47 Area under ROC curve: (95% CI: ) Presence of severe OSA (n = 246; 84 patients with severe OSA) P = P = P = 0.01 P = 0.03 P = 0.03 P = 0.44 P = 0.14 P < P < P = P = P = 0.07 Snoring 1.57 ( ) P = Hosmer-Lemeshow goodness-of-fit test: P = 0.84 Area under ROC curve: (95% CI: ) Figure 2. Results (odds ratios and 95% confidence intervals (CIs)) for the independent covariables associated with the presence of (a) total obstructive sleep apnea (OSA), (b) moderate/severe OSA, (c) severe OSA in patients with uncontrolled ambulatory blood pressures. Candidate variables to enter models were the following: age, sex, obesity, increased neck and waist circumferences, presence of diabetes and cardiovascular diseases, nighttime systolic blood pressure (SBP) and nondipping pattern, snoring, left ventricular hypertrophy, and 24-hour proteinuria. Abbreviation: ROC, receiver operating characteristics. American Journal of Hypertension 27(8) August

8 Muxfeldt et al. Table 3. Multiple linear regression results for variables independently correlated with the apnea-hypopnea index (log 10 transformed) in patients with resistant hypertension Covariable Β coefficient (SE) Standardized beta Partial correlation P value All patients (n = 422) R 2 of the model = 0.30 Age, 1 year (0.003) <0.001 Neck circumference, 1 cm (0.009) <0.001 Waist circumference, 1 cm (0.003) <0.001 Nighttime SBP, 10 mm Hg (0.014) Fasting glycemia, 1 mmol/l (0.009) Snoring, 0 = no, 1 = yes (0.057) Patients with uncontrolled ambulatory BPs (n = 244) R 2 of the model = 0.28 Age, 1 year (0.003) <0.001 Neck circumference, 1 cm (0.010) <0.001 Waist circumference, 1 cm (0.003) <0.001 Nighttime SBP, 10 mm Hg (0.015) Fasting glycemia, 1 mmol/l (0.010) Snoring, 0 = no, 1 = yes (0.069) Candidate variables to enter the model were the following: age, sex, body mass index, neck and waist circumferences, previous cardiovascular diseases, nighttime systolic blood pressure (SBP) and nocturnal SBP fall, snoring, left ventricular mass index, fasting glycemia and 24-hour proteinuria. Abbreviation: BP, blood pressure. major cardiovascular events in patients with RH and whether OSA treatment is capable of reverting, at least in part, this excess cardiovascular risk, particularly regarding the unfavorable nocturnal BP profile, is presently unknown and should be examined in future prospective studies and randomized trials. The high prevalence of OSA has been previously reported in smaller samples of RH patients. 6,7,18,19,28 The pioneering study of Logan and colleagues 6 evaluated 41 patients with RH and found a prevalence of 83% for total OSA, defined as an AHI 10. Subsequently, 4 other studies 7,18,19,28 reported OSA prevalences in RH ranging from 64% (AHI 15, thus moderate/severe OSA) 7 to 81% (AHI 10). 18 The largest of these studies, the recently published RESIST-POL study, 28 evaluated 204 patients with true RH (uncontrolled ambulatory BPs) and reported a prevalence of 72% for total OSA (AHI 5) and a prevalence of 45% for moderate/severe OSA. Our study evaluated the largest group of RH patients (422 individuals, more than the double the largest previous study) and confirmed the very high prevalence of total OSA (82%) and of moderate/severe OSA (55%). The main risk factors for general RH (defined by the classic clinical criteria) 4 are female sex, older age, diabetes, obesity, left ventricular hypertrophy, and chronic kidney disease. 4,9,10 Those patients also present a high prevalence of nondipping patterns 4,9,10 and increased arterial stiffness. 5 On the other hand, OSA shared some of these same characteristics, such as older age (particularly in postmenopausal women), 2,29 obesity (high BMI and neck circumference), 2,3 diabetes and insulin resistance, 2,3 left ventricular hypertrophy, 2,3,29 nondipping pattern, 2,30 and increased arterial stiffness. 2,29,31 So the strong association between these 2 conditions is not unexpected at all. The prevalence of OSA was significantly higher in men than in women, and this male predominance had also been previously described in general populations, 29,32 hypertensive patients, 2 and RH patients, 6,7,28 although the reason for sex differences are not clear. Although older age is a well-known risk factor for OSA, 2,3,11 the association of OSA and hypertension is stronger in young to middle-aged adults (<50 years) than in elderly individuals. 2,3,6,32,33 In our cohort, the mean age was 62.4 years, and older age (>65 years) tripled the risk of having OSA. Obesity seems to be the most important link between OSA and hypertension. 2,3 Our patients with moderate/severe OSA were more obese, with higher BMI and increased waist and neck circumferences. Small pharyngeal airway is the principle abnormality found in patients with OSA and results from obesity and increased neck circumference. 3 Diabetes is also a common characteristic of the 2 diseases, reinforcing the pivotal role of obesity. In our study, the presence of diabetes increased by 63% the risk of having moderate/severe OSA but more than tripled the odds of having severe OSA, suggesting that worsening insulin resistance and glucose intolerance may be associated with OSA severity. 2,3,11 In our study, left ventricular hypertrophy was more prevalent in patients with moderate/severe OSA than in patients with no/mild OSA, which supports previous reports. 2,3,29 Otherwise, we did not find differences in aortic stiffness. It is generally accepted that OSA is associated with increased arterial stiffness, 31 although none of the previous studies specifically evaluated patients with RH. Furthermore, we did not find any associations between aldosterone status (evaluated as plasma aldosterone concentration, renin activity, and aldosterone-to-renin ratio) and presence or severity of OSA, although aldosterone excess is recognized to be associated with both conditions, OSA and RH. 17,34,35 Previously, it has been shown that aldosterone levels correlate with severity of OSA, 35,36 perhaps because of a fluid retention within the neck, increasing the upper airway resistance, and that the 1076 American Journal of Hypertension 27(8) August 2014

9 Sleep Apnea in Resistant Hypertension mineraloreceptor blockade might reduce the severity of sleep apnea. 17,34 36 In our study, a total of 39% of patients were using spironolactone, and AHI was similar in patients using or not using this drug (24 vs. 26 events/hour; P = 0.36). Possibly, the greater use of spironolactone may have weakened the possible associations between aldosterone excess and presence of OSA. The relationships between OSA and ambulatory BP levels in RH are still a matter of debate. Although it is generally accepted that OSA increases the likelihood of having a nocturnal nondipping pattern and that the blunted nocturnal BP fall is related to OSA severity, 2,3,30 some previous reports failed to show significant influences of OSA on nocturnal BP levels or on dipping patterns. 6,7,28 We found higher nighttime SBP and pulse pressure and higher prevalences of nondipping patterns (both the nondipper and riser patterns) in patients with moderate/severe OSA in comparison with those with no or mild OSA. Otherwise, it should be recognized that the magnitude of the differences in nocturnal SBP and pulse pressure was rather modest (4 and 3 mm Hg, respectively). Nevertheless, we have previously demonstrated that the nocturnal BPs are better risk predictors than the daytime BPs and that the nondipping patterns provide additive prognostic information beyond 24-hour mean BP levels in patients with RH. 37,38 Hence, even these rather small nocturnal BP differences between RH patients with and without OSA may have implications for cardiovascular outcomes. On the other hand, we did not find any association between the presence of OSA and clinic, 24-hour, or daytime BPs. This suggests that nighttime BP alterations might be a result of the sleep disturbance itself rather than a contributor or consequence of shared risk factors. Moreover, these small BP differences may also explain the seemingly small effect of continuous positive airway pressure treatment on ambulatory BP levels in patients with RH and OSA. 39,40 This study has some limitations that should be discussed. It has a cross-sectional design; hence no cause-and-effect relationship should be inferred, only simple associations. It included only RH patients, so the high OSA prevalence and its associated factors should not be generalized to the less severe general hypertension population. Otherwise, the main strengths of the study are the large number of RH patients evaluated, all of whom submitted to full-night complete PSG, considered the gold standard, and the blinded analysis of PSG. In conclusion, RH patients have a very high prevalence of OSA and patients with moderate/severe OSA present an increased cardiovascular risk with a high prevalence of diabetes, obesity, and left ventricular hypertrophy. They also have an adverse ABPM profile with higher nighttime systolic BP, wider pulse pressure, and higher prevalence of nondipping patterns than patients with no or mild OSA. Whether OSA treatment will be capable of reverting this adverse nocturnal BP profile and prevent worse cardiovascular outcomes shall be the focus of future interventional studies. Acknowledgments This work was supported by research grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico; Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro; FINEP (Ministry of Science and Tecnology); and DECIT (Ministry of Health). DISCLOSURE The authors declared no conflict of interest. REFERENCES 1. Epstein MD, Kristo D, Strollo PJ, Friedman N, Malhotra A, Patil SP, Ramar K, Rogers R, Schwab RJ, Weaver EM, Weinstein MD. Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine. Clinical guideline for the evaluation, management and longterm care of obstructive sleep apnea in adults. 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