Rodrigo P. Pedrosa

Obstructive Sleep Apnea The Most Common Secondary Cause of Hypertension Associated With Resistant Hypertension

Recognition and treatment of secondary causes of hypertension among patients with resistant hypertension may help to control blood pressure and reduce cardiovascular risk. However, there are no studies systematically evaluating secondary causes of hypertension according to the Seventh Joint National Committee. Consecutive patients with resistant hypertension were investigated for known causes of hypertension irrespective of symptoms and signs, including aortic coarctation, Cushing syndrome, obstructive sleep apnea, drugs, pheochromocytoma, primary aldosteronism, renal parenchymal disease, renovascular hypertension, and thyroid disorders. Among 125 patients (age: 52±1 years, 43% males, systolic and diastolic blood pressure: 176±31 and 107±19 mm Hg, respectively), obstructive sleep apnea (apnea-hypopnea index: >15 events per hour) was the most common condition associated with resistant hypertension (64.0%), followed by primary aldosteronism (5.6%), renal artery stenosis (2.4%), renal parenchymal disease (1.6%), oral contraceptives (1.6%), and thyroid disorders (0.8%). In 34.4%, no secondary cause of hypertension was identified (primary hypertension). Two concomitant secondary causes of hypertension were found in 6.4% of patients. Age >50 years (odds ratio: 5.2 [95% CI: 1.9–14.2]; P<0.01), neck circumference ≥41 cm for women and ≥43 cm for men (odds ratio: 4.7 [95% CI: 1.3–16.9]; P=0.02), and presence of snoring (odds ratio: 3.7 [95% CI: 1.3–11]; P=0.02) were predictors of obstructive sleep apnea. In conclusion, obstructive sleep apnea appears to be the most common condition associated with resistant hypertension. Age >50 years, large neck circumference measurement, and snoring are good predictors of obstructive sleep apnea in this population.

Characteristics and predictors of obstructive sleep apnea in patients with systemic hypertension.

Obstructive sleep apnea (OSA) is a secondary cause of hypertension and independently associated with target-organ damage in hypertensive patients. However, OSA remains largely underdiagnosed and undertreated. The aim of the present study was to evaluate the characteristics and clinical predictors of OSA in a consecutive series of patients followed up in a hypertension unit. A total of 99 patients (age 46 + or - 11 years, body mass index 28.8 kg/m(2), range 25.1 to 32.9) underwent polysomnography. The clinical parameters included age, gender, obesity, daytime sleepiness, snoring, Berlin Questionnaire, resistant hypertension, and metabolic syndrome. Of the 99 patients, 55 (56%) had OSA (apnea-hypopnea index >5 events/hour). Patients with OSA were older and more obese, had greater levels of blood pressure, and presented with more diabetes, dyslipidemia, resistant hypertension, and metabolic syndrome than the patients without OSA. Of the patients with OSA, 51% had no excessive daytime sleepiness. The Berlin Questionnaire and patient age revealed a high sensitivity (0.93 and 0.91, respectively) but low specificity (0.59 and 0.48, respectively), and obesity and resistant hypertension revealed a low sensitivity (0.58 and 0.44, respectively) but high specificity (0.75 and 0.91, respectively) for OSA. Metabolic syndrome was associated with high sensitivity and specificity for OSA (0.86 and 0.85, respectively). Multiple regression analysis showed that age of 40 to 70 years (odds ratio 1.09, 95% confidence interval 1.03 to 1.16), a high risk of OSA on the Berlin Questionnaire (odds ratio 8.36, 95% confidence interval 1.67 to 41.85), and metabolic syndrome (odds ratio 19.04, 95% confidence interval 5.25 to 69.03) were independent variables associated with OSA. In conclusion, more important than the typical clinical features that characterize OSA, including snoring and excessive daytime sleepiness, the presence of the metabolic syndrome is as an important marker of OSA among patients with hypertension.

Effects of OSA Treatment on BP in Patients With Resistant Hypertension: A Randomized Trial

BACKGROUND OSA is extremely common among patients with resistant hypertension (HTN). However, the impact of the treatment of OSA with CPAP on BP in patients with resistant HTN is not well established. METHODS In the current study, 40 patients with confirmed resistant HTN and moderate to severe OSA confirmed by full polysomnography were randomized to medical therapy or to medical treatment plus CPAP for 6 months. Patients were evaluated at study baseline and after 6 months by 24-h ambulatory BP monitoring (ABPM). RESULTS Thirty-five patients (77% men; age, 56 ± 1 years; BMI, median 32 kg/m² [25%-75%, 28-39 kg/m²]; apnea-hypopnea index, 29 events/h [24-48 events/h]; Epworth Sleepiness Scale, 10 ± 1; systolic/diastolic office BP, 162 ± 4/97 ± 2 mm Hg; taking four [four to five] antihypertensive drugs) completed the study. CPAP was used for 6:01 ± 0:20 h/night (3:42-7:44 h/night). Compared with the control group, awake systolic/diastolic ABPM decreased significantly in the CPAP group (Δ: +3.1 ± 3.3 /+2.1 ± 2.7 mm Hg vs -6.5 ± 3.3/-4.5 ± 1.9 mm Hg, respectively, P < .05). Interestingly, the BP changes were observed only while patients were awake, but not during nocturnal ABPM (Δ: +2.8 ± 4.5/+1.8 ± 3.5 mm Hg vs +1.6 ± 3.5/+0.8 ± 2.9 mm Hg, P = NS). CONCLUSIONS The treatment of OSA with CPAP significantly reduces daytime BP in patients with resistant HTN. Therefore, our study reinforces the importance of recognizing and treating OSA in patients with resistant HTN. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00812695; URL: www.clinicaltrials.gov.

The Effects of Continuous Positive Airway Pressure on Prehypertension and Masked Hypertension in Men With Severe Obstructive Sleep Apnea

Obstructive sleep apnea and hypertension are common conditions that frequently coexist. Continuous positive airway pressure (CPAP) reduces blood pressure in patients with obstructive sleep apnea and sustained hypertension. However, the impact of CPAP on patients with obstructive sleep apnea and prehypertension and masked hypertension, conditions associated with increased cardiovascular risk, is unknown. Thirty-six male patients (age, 43±7 years; body mass index, 28.8±3.0 kg/m2) with untreated severe obstructive sleep apnea (apnea–hypopnea index, 56±22 events/hr on polysomnography) with diagnostic criteria for prehypertension and/or masked hypertension, based on office and 24-hour ambulatory blood pressure monitoring, respectively, were studied. The patients randomized to no treatment (control; n=18) or CPAP (n=18) for 3 months had similar frequency of prehypertension and masked hypertension at study entry. There were no significant changes in blood pressure in patients randomized to the control group. In contrast, patients randomized to CPAP presented significant reduction in office systolic (from 126±5 to 121±7 mm Hg; P=0.001) and a trend for diastolic blood pressure (from 75±7 to 73±8 mm Hg; P=0.08) as well as a significant decrease in daytime and nighttime systolic and diastolic blood pressure (P<0.05 for each comparison). There was a significant reduction in the frequency of prehypertension (from 94% to 55%; P=0.02) and masked hypertension (from 39% to 5%; P=0.04) only in the CPAP group. In conclusion, effective CPAP therapy promotes significant reduction in the frequency of prehypertension and masked hypertension by promoting significant blood pressure reductions in patients with severe obstructive sleep apnea.

Obstructive sleep apnea, masked hypertension, and arterial stiffness in men.

BACKGROUND Obstructive sleep apnea (OSA) is an established cause of hypertension. However, it is not clear whether the frequency of masked hypertension in patients with OSA and whether OSA have an independent role on arterial stiffness taking into account ambulatory blood pressure (BP) monitoring (ABPM). METHODS We evaluated 61 male normotensive participants as determined by casual clinic BP level <140/90 mm Hg without clinical evidence of cardiovascular disease and on no medications (43 patients with moderate-to-severe OSA (apnea-hypopnea index (AHI) > or = 15 events/hour by polysomnography) and 18 age- and body mass index-matched controls without OSA (AHI <5 events/hour)). Pulse wave velocity (PWV), an index of arterial stiffness, and 24-h ABPM were performed in a blinded fashion. Masked hypertension was defined when abnormal daytime ABPM was > or = 135 or > or = 85 mm Hg. RESULTS The AHI and lowest oxygen saturation were 2.6 +/- 1.6 and 90 +/- 2 vs. 52.8 +/- 21.0 events/hour and 75 +/- 10% for controls and OSA patients, respectively; P < 0.001. Compared with controls, patients with OSA had higher office systolic BP (113 +/- 9 vs. 118 +/- 10 mm Hg; P = 0.05) and a higher unadjusted proportion of masked hypertension (2 controls (11.1%) vs. 13 patients (30.2%); P < 0.05). PWV was 8.7 +/- 0.7, 9.4 +/- 1.0, and 10.6 +/- 1.1 m/s in the control, OSA without and with masked hypertension groups, respectively (P < 0.01 for each comparison). Multiple regression showed that systolic daytime ABPM and the lowest oxygen saturation were independently related to PWV (adjusted R2 = 0.34; P < 0.01). CONCLUSIONS Patients with OSA presented a higher unadjusted rate of masked hypertension than matched controls. Lowest oxygen saturation has an independent association with arterial stiffness.

Obstructive Sleep Apnea Is Common and Independently Associated With Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy

BACKGROUND Hypertrophic cardiomyopathy (HCM) is associated with arrhythmias and cardiovascular death. Left atrial enlargement and atrial fibrillation (AF) are considered markers for death due to heart failure in patients with HCM. Obstructive sleep apnea (OSA) is independently associated with heart remodeling and arrhythmias in other populations. We hypothesized that OSA is common and is associated with heart remodeling and AF in patients with HCM. METHODS We evaluated 80 consecutive stable patients with a confirmed diagnosis of HCM by sleep questionnaire, blood tests, echocardiography, and sleep study (overnight respiratory monitoring). RESULTS OSA (apnea-hypopnea index [AHI] > 15 events/h) was present in 32 patients (40%). Patients with OSA were significantly older (56 [41-64] vs 38.5 [30-53] years, P < .001) and presented higher BMI (28.2 +/- 3.5 vs 25.2 +/- 5.2 kg/m(2), P < .01) and increased left atrial diameter (45 [42-52.8] vs 41 [39-47] mm, P = .01) and aorta diameter (34 [30-37] vs 29 [28-32] mm, P < .001), compared with patients without OSA. Stepwise multiple linear regression showed that the AHI (P = .05) and BMI (P = .06) were associated with left atrial diameter. The AHI was the only variable associated with aorta diameter (P = .01). AF was present in 31% vs 6% of patients with and without OSA, respectively (P < .01). OSA (P = .03) and left atrial diameter (P = .03) were the only factors independently associated with AF. CONCLUSIONS OSA is highly prevalent in patients with HCM and it is associated with left atrial and aortic enlargement. OSA is independently associated with AF, a risk factor for cardiovascular death in this population.

Left atrial diameter is independently associated with arterial stiffness in patients with obstructive sleep apnea: Potential implications for atrial fibrillation

BACKGROUND Obstructive sleep apnea (OSA) is associated with increased risk for the occurrence and recurrence of atrial fibrillation. However, the mechanisms involved are poorly understood. METHODS We studied 73 middle-aged subjects divided in two groups: with moderate-to-severe OSA (apnea-hypopnea index [AHI] ≥ 15 events/h) or without OSA (AHI ≤5 events/h) by polysomnography. The groups were matched for age, sex, body mass index and hypertension diagnosis. Carotid-femoral pulse wave velocity (a non invasive measurement of arterial stiffness of the aorta) and transthoracic echocardiography were performed in all participants. RESULTS As expected, patients with OSA presented higher AHI than patients without OSA (49.6 ± 21.5 vs. 3.3 ± 1.4 events/h; P<0.001). Compared with subjects without OSA, pulse wave velocity (9.6 ± 1.5 vs. 10.7 ± 1.8 m/s; P<0.001) and left atrial diameter (34.7 ± 3.2 vs. 37.6 ± 3.3 mm; P<0.001) were significantly increased in patients with OSA. Pulse wave velocity significantly correlated with left atrial diameter (r=0.45; P<0.001). Multivariate regression analysis showed that AHI and systolic blood pressure were the only independent determinants of pulse wave velocity (F=30.5; r(2)=0.48; P<0.01). The only independent variable associated with left atrial diameter was pulse wave velocity. CONCLUSIONS Left atrial diameter is significantly increased and independently associated with arterial stiffness in patients with OSA. This potential mechanism of atrial remodeling may contribute to explain the increase risk of atrial fibrillation in these patients.

Obstructive sleep apnea is common among patients referred for coronary artery bypass grafting and can be diagnosed by portable monitoring.

BackgroundObstructive sleep apnea (OSA) is common among patients with coronary artery disease. However, OSA remains largely under recognized. The lack of clinical suspicion and difficulties to access full polysomnography (PSG) are limiting factors. The aim of this study was to evaluate, among patients referred to coronary artery bypass grafting (CABG): (i) the prevalence of OSA, (ii) the association of OSA with clinical symptoms, (iii) the performance of overnight unattended portable monitoring (PM) as an alternative method for the diagnosis of OSA. MethodsConsecutive patients referred for CABG were evaluated by standard physical evaluation and validated questionnaires (Berlin questionnaire and Epworth Sleepiness Scale) and underwent full PSG and PM (Stardust II). ResultsWe studied 70 consecutive patients (76% men), age 58±7 years (mean±SD), BMI [median (interquartile range)] 27.6 kg/m2 (25.8–31.1). The prevalence of OSA (full PSG) using an apnea–hypopnea index of at least 5 events/h was 87%. Commonly used clinical traits for the screening of OSA such as the Epworth Sleepiness Scale and neck circumference had low sensitivities to detect OSA. In contrast, the Berlin questionnaire showed a good sensitivity (72%) to detect OSA. PM showed good sensitivity (92%) and specificity (67%) for the diagnosis of OSA. ConclusionOSA is strikingly common among patients referred for CABG. The Berlin questionnaire, but not symptom of excessive daytime sleepiness is a useful tool to screen OSA. PM is useful for the diagnosis of OSA and therefore is an attractive tool for widespread use among patients with coronary artery disease.

OSA Is Common and Independently Associated With Hypertension and Increased Arterial Stiffness in Consecutive Perimenopausal Women

BACKGROUND Perimenopause is associated with increased cardiovascular risk. OSA is an emerging risk factor for cardiovascular disease, particularly among men, but the independent contribution of OSA to cardiovascular risk in climacteric women is not clear. METHODS We evaluated 277 consecutive women (age, 56 [52-61] years; BMI, 28 [25-32] kg/m2) without manifest cardiovascular disease (heart failure, coronary disease, or stroke). All women underwent 24-h ambulatory BP monitoring, arterial stiffness evaluation (pulse wave velocity), and portable sleep study. RESULTS OSA (apnea-hypopnea index ≥ 5 events/h) and moderate to severe OSA (apnea-hypopnea index ≥ 15 events/h) were diagnosed in 111 (40.1%) and 31 (11.1%) women, respectively. None of the participants had received a previous diagnosis of OSA. Women with moderate to severe OSA vs those without OSA had a higher prevalence of hypertension, were prescribed more medications for hypertension, had higher awake BP (systolic, 133 [125-142] vs 126 [119-134] mm Hg [P < .01]; diastolic, 82 [78-88] vs 79 [74-85] mm Hg [P = .07]), higher nocturnal BP (systolic, 125 [118-135] vs 115 [109-124] mm Hg [P < .01]; diastolic, 73 [69-79] vs 69 [62-75] mm Hg [P < .01]), and more arterial stiffness (pulse wave velocity, 11.5 [10.1-12.3] m/s vs 9.5 [8.6-10.8] m/s, P < .001). Oxygen desaturation index during the night was independently associated with 24-h arterial BP and arterial stiffness (per five-unit increase in oxygen desaturation index, β = 1.30 [95% CI, 0.02-2.54; P = .04] vs 0.22 [95% CI, 0.03-0.40; P = .02] in women with vs without OSA, respectively). CONCLUSIONS OSA is common, underdiagnosed, and independently associated with high BP and increased arterial stiffness in perimenopausal women.

Lysyl Oxidase as a Serum Biomarker of Liver Fibrosis in Patients with Severe Obesity and Obstructive Sleep Apnea

STUDY OBJECTIVES Obstructive sleep apnea (OSA) is associated with the progression of nonalcoholic fatty liver disease (NAFLD). We hypothesized that the hypoxia of OSA increases hepatic production of lysyl oxidase (LOX), an enzyme that cross-links collagen, and that LOX may serve as a biomarker of hepatic fibrosis. DESIGN Thirty-five patients with severe obesity underwent liver biopsy, polysomnography, and serum LOX testing. A separate group with severe OSA had serum LOX measured before and after 3 mo of CPAP or no therapy, as did age-matched controls. LOX expression and secretion were measured in mouse hepatocytes following exposure to hypoxia. SETTING The Johns Hopkins Bayview Sleep Disorders Center, and the Hypertension Unit of the Heart Institute at the University of São Paulo Medical School. MEASUREMENTS AND RESULTS In the bariatric cohort, the apnea-hypopnea index was higher in patients with hepatic fibrosis than in those without fibrosis (42.7 ± 30.2 events/h, versus 16.2 ± 15.5 events/h; P = 0.002), as was serum LOX (84.64 ± 29.71 ng/mL, versus 45.46 ± 17.16 ng/mL; P < 0.001). In the sleep clinic sample, patients with severe OSA had higher baseline LOX than healthy controls (70.75 ng/mL versus 52.36 ng/mL, P = 0.046), and serum LOX decreased in patients with OSA on CPAP (mean decrease 20.49 ng/mL) but not in untreated patients (mean decrease 0.19 ng/mL). Hypoxic mouse hepatocytes demonstrated 5.9-fold increased LOX transcription (P = 0.046), and enhanced LOX protein secretion. CONCLUSIONS The hypoxic stress of obstructive sleep apnea may increase circulating lysyl oxidase (LOX) levels. LOX may serve as a biomarker of liver fibrosis in patients with severe obesity and nonalcoholic fatty liver disease.