Prevalence and associated factors of obstructive sleep apnea in refractory hypertension.

BACKGROUND: Refractory hypertension (RfHT) and obstructive sleep apnea (OSA) share common pathophysiological mechanisms and probably are intrinsically associated, but their prevalence, clinical profile, and polysomnography (PSG) pattern remain misunderstood. OBJECTIVE: To describe OSA prevalence and PSG pattern of patients with RfHT in a large cohort of resistant hypertension (RHT). METHODS: This is a cross-sectional study involving 418 RHT patients (30.9% male; mean age of 62.5 ±â€Š9.9 years) who were submitted to full-night PSG. RfHT was defined as uncontrolled ambulatory blood pressure monitoring using five or more antihypertensive drugs, including spironolactone. Bivariate analysis compared RHT and RfHT and multivariate analysis was performed to assess the independent correlates of OSA. RESULTS: A total of 90 patients (21.5%) were diagnosed with RfHT (26.7% male; mean age of 58.5 ±â€Š8.3 years). In comparison with resistant ones, RfHT patients were younger, with higher smoking and previous cardiovascular diseases prevalence, especially stroke. There was no difference regarding anthropometric measures. OSA prevalence (80.0 vs. 82.9%) and moderate/severe OSA (51.1 vs. 57.0%) were similar in both groups as well as apnea-hypopnea index. In its turn, refractory hypertensive patients presented better sleep efficiency (78 vs. 71%), with higher total sleep time (315 vs. 281 min) and lower sleep latency (11 vs. 17 min). There was no difference regarding rapid eye movement sleep, oxygen saturation, microarousals index, and periodic limb movement. CONCLUSION: In this large RHT cohort, resistant and refractory hypertensive patients have similar OSA prevalence, although refractory ones, which by definition use spironolactone, are younger and apparently have a better sleep pattern.

Impact of Metabolic Risk Factors on COVID-19 Clinical Outcomes: An Extensive Review.

BACKGROUND: Cardiovascular (CV) risk factors, particularly cardiometabolic, seem to be associated with heightened severity and increased morbimortality in patients infected with the novel Coronavirus disease-2019 (COVID-19). METHODS: A thorough scoping review was conducted to elucidate and summarize the latest evidence for the effects of adverse cardiac metabolic profiles on the severity, morbidity, and prognosis of COVID-19 infection. RESULTS: The pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is complex, being characterized by viral-induced immune dysregulation and hypercytokinemia, particularly in patients with critical disease, evolving with profound endothelial dysfunction, systemic inflammation, and prothrombotic state. Moreover, cardiovascular comorbidities such as diabetes are the most prevalent amongst individuals requiring hospitalization, raising concerns towards the clinical evolution and prognosis of these patients. The chronic proinflammatory state observed in patients with cardiovascular risk factors may contribute to the immune dysregulation mediated by SARS-CoV-2, favoring more adverse clinical outcomes and increased severity. Cardiometabolism is defined as a combination of interrelated risk factors and metabolic dysfunctions such as dyslipidemia, insulin resistance, impaired glucose tolerance, and central adiposity, which increase the likelihood of vascular events, being imperative to specifically analyze its clinical association with COVID-19 outcomes. CONCLUSION: DM and obesity appears to be important risk factors for severe COVID-19. The chronic proinflammatory state observed in patients with excess visceral adipose tissue (VAT) possibly augments COVID-19 immune hyperactivity leading to more adverse clinical outcomes in these patients.

A review of Covid-19 and acute kidney injury: from pathophysiology to clinical results / Uma revisão da Covid-19 e lesão renal aguda: da fisiopatologia aos resultados clínicos

Abstract Acute kidney injury (AKI) in hospitalized patients with COVID-19 is associated with higher mortality and a worse prognosis. Nevertheless, most patients with COVID-19 have mild symptoms, and about 5% can develop more severe symptoms and involve hypovolemia and multiple organ dysfunction syndrome. In a pathophysiological perspective, severe SARS-CoV-2 infection is characterized by numerous dependent pathways triggered by hypercytokinemia, especially IL-6 and TNF-alpha, leading to systemic inflammation, hypercoagulability, and multiple organ dysfunction. Systemic endotheliitis and direct viral tropism to proximal renal tubular cells and podocytes are important pathophysiological mechanisms leading to kidney injury in patients with more critical infection, with a clinical presentation ranging from proteinuria and/or glomerular hematuria to fulminant AKI requiring renal replacement therapies. Glomerulonephritis, rhabdomyolysis, and nephrotoxic drugs are also associated with kidney damage in patients with COVID-19. Thus, AKI and proteinuria are independent risk factors for mortality in patients with SARS-CoV-2 infection. We provide a comprehensive review of the literature emphasizing the impact of acute kidney involvement in the evolutive prognosis and mortality of patients with COVID-19.

Resumo A lesão renal aguda (LRA) em pacientes hospitalizados com COVID-19 está associada a maior mortalidade e um pior prognóstico. No entanto, a maioria dos pacientes com COVID-19 tem sintomas leves e cerca de 5% podem desenvolver sintomas mais graves e envolver hipovolemia e síndrome de disfunção de múltiplos órgãos. Em uma perspectiva fisiopatológica, a infecção grave por SARS-CoV-2 é caracterizada por numerosas vias dependentes desencadeadas por hipercitocinemia, especialmente IL-6 e TNF-alfa, levando à inflamação sistêmica, hipercoagulabilidade e disfunção de múltiplos órgãos. A endotelite sistêmica e o tropismo viral direto às células tubulares proximais renais e podócitos são mecanismos fisiopatológicos importantes que levam à lesão renal em pacientes com infecção mais crítica, com uma apresentação clínica que varia de proteinúria e/ou hematúria glomerular a LRA fulminante, exigindo terapias renais substitutivas. Glomerulonefrite, rabdomiólise e drogas nefrotóxicas também estão associadas a danos renais em pacientes com COVID-19. Assim, a LRA e a proteinúria são fatores de risco independentes para mortalidade em pacientes com infecção por SARS-CoV-2. Fornecemos uma revisão abrangente da literatura, enfatizando o impacto do envolvimento renal agudo no prognóstico evolutivo e na mortalidade de pacientes com COVID-19.

COVID-19 and chronic kidney disease: a comprehensive review / COVID-19 e doença renal crônica: uma revisão abrangente

Abstract Kidney impairment in hospitalized patients with SARS-CoV-2 infection is associated with increased in-hospital mortality and worse clinical evolution, raising concerns towards patients with chronic kidney disease (CKD). From a pathophysiological perspective, COVID-19 is characterized by an overproduction of inflammatory cytokines (IL-6, TNF-alpha), causing systemic inflammation and hypercoagulability, and multiple organ dysfunction syndrome. Emerging data postulate that CKD under conservative treatment or renal replacement therapy (RRT) is an important risk factor for disease severity and higher in-hospital mortality amongst patients with COVID-19. Regarding RAAS blockers therapy during the pandemic, the initial assumption of a potential increase and deleterious impact in infectivity, disease severity, and mortality was not evidenced in medical literature. Moreover, the challenge of implementing social distancing in patients requiring dialysis during the pandemic prompted national and international societies to publish recommendations regarding the adoption of safety measures to reduce transmission risk and optimize dialysis treatment during the COVID-19 pandemic. Current data convey that kidney transplant recipients are more vulnerable to more severe infection. Thus, we provide a comprehensive review of the clinical outcomes and prognosis of patients with CKD under conservative treatment and dialysis, and kidney transplant recipients and COVID-19 infection.

Resumo O comprometimento renal em pacientes hospitalizados com infecção por SARS-CoV-2 está associado ao aumento da mortalidade hospitalar e pior evolução clínica, levantando preocupações em relação a pacientes com doença renal crônica (DRC). De uma perspectiva fisiopatológica, a COVID-19 é caracterizada por uma superprodução de citocinas inflamatórias (IL-6, TNF-alfa), causando inflamação sistêmica e hipercoagulabilidade, e síndrome de disfunção de múltiplos órgãos. Dados emergentes postulam que a DRC sob tratamento conservador ou terapia renal substitutiva (TRS) é um fator de risco importante para a gravidade da doença e maior mortalidade hospitalar entre pacientes com COVID-19. Em relação à terapia com bloqueadores RAAS durante a pandemia, havia uma suposição inicial de que a classe pudesse causar um aumento potencial na infectividade, e impacto deletério na gravidade da doença e mortalidade, mas que não foi confirmada na literatura médica. Além disso, o desafio de implementar o distanciamento social em pacientes que necessitam de diálise durante a pandemia incentivou sociedades nacionais e internacionais a publicar recomendações sobre a adoção de medidas de segurança para reduzir o risco de transmissão e otimizar o tratamento de diálise durante a pandemia COVID-19. Os dados atuais mostram que os receptores de transplante renal são mais vulneráveis a infecções mais graves. Assim, fizemos uma revisão abrangente dos desfechos clínicos e prognóstico de pacientes com DRC sob tratamento conservador e diálise, e receptores de transplante renal e infecção por COVID-19.

A review of Covid-19 and acute kidney injury: from pathophysiology to clinical results.

Acute kidney injury (AKI) in hospitalized patients with COVID-19 is associated with higher mortality and a worse prognosis. Nevertheless, most patients with COVID-19 have mild symptoms, and about 5% can develop more severe symptoms and involve hypovolemia and multiple organ dysfunction syndrome. In a pathophysiological perspective, severe SARS-CoV-2 infection is characterized by numerous dependent pathways triggered by hypercytokinemia, especially IL-6 and TNF-alpha, leading to systemic inflammation, hypercoagulability, and multiple organ dysfunction. Systemic endotheliitis and direct viral tropism to proximal renal tubular cells and podocytes are important pathophysiological mechanisms leading to kidney injury in patients with more critical infection, with a clinical presentation ranging from proteinuria and/or glomerular hematuria to fulminant AKI requiring renal replacement therapies. Glomerulonephritis, rhabdomyolysis, and nephrotoxic drugs are also associated with kidney damage in patients with COVID-19. Thus, AKI and proteinuria are independent risk factors for mortality in patients with SARS-CoV-2 infection. We provide a comprehensive review of the literature emphasizing the impact of acute kidney involvement in the evolutive prognosis and mortality of patients with COVID-19.

COVID-19 and chronic kidney disease: a comprehensive review.

Kidney impairment in hospitalized patients with SARS-CoV-2 infection is associated with increased in-hospital mortality and worse clinical evolution, raising concerns towards patients with chronic kidney disease (CKD). From a pathophysiological perspective, COVID-19 is characterized by an overproduction of inflammatory cytokines (IL-6, TNF-alpha), causing systemic inflammation and hypercoagulability, and multiple organ dysfunction syndrome. Emerging data postulate that CKD under conservative treatment or renal replacement therapy (RRT) is an important risk factor for disease severity and higher in-hospital mortality amongst patients with COVID-19. Regarding RAAS blockers therapy during the pandemic, the initial assumption of a potential increase and deleterious impact in infectivity, disease severity, and mortality was not evidenced in medical literature. Moreover, the challenge of implementing social distancing in patients requiring dialysis during the pandemic prompted national and international societies to publish recommendations regarding the adoption of safety measures to reduce transmission risk and optimize dialysis treatment during the COVID-19 pandemic. Current data convey that kidney transplant recipients are more vulnerable to more severe infection. Thus, we provide a comprehensive review of the clinical outcomes and prognosis of patients with CKD under conservative treatment and dialysis, and kidney transplant recipients and COVID-19 infection.

Effects of continuous positive airway pressure treatment on aortic stiffness in patients with resistant hypertension and obstructive sleep apnea: A randomized controlled trial.

Resistant hypertension (RHT) is associated with obstructive sleep apnea (OSA) and increased aortic stiffness, measured by carotid-femoral pulse wave velocity (cf-PWV). We aimed to evaluate in a randomized controlled trial, the effect of Continuous positive airway pressure (CPAP) treatment on cf-PWV in comparison with a control group in patients with RHT and moderate-severe OSA. One-hundred and sixteen patients were randomized to 6-month CPAP treatment (56 patients) or no therapy (60 patients), while keeping their antihypertensive treatment unchanged. Carotid-femoral pulse wave velocity was performed at the beginning and end of the 6-month period. Intention-to-treat intergroup differences in cf-PWV changes were assessed by a generalized mixed-effects model with the allocation group as a fixed factor and adjusted for age, sex, changes in mean arterial pressure and the baseline cf-PWV values. Subgroup sensitivity analyses were performed, excluding patients with low CPAP adherence and low cf-PWV at baseline. CPAP and control groups had similar clinic-laboratorial characteristics. Patients had a mean cf-PWV of 9.4 ± 1.6 m/s and 33% presented cf-PWV > 10 m/s. During treatment, the control group had a mean increase in cf-PWV of +0.43 m/s (95% confidence interval [CI], +0.14 to +0.73 m/s; p = .005), whereas the CPAP group had a mean increase of +0.03 m/s (95% CI, -0.33 to +0.39 m/s; p = .87), resulting in a mean difference in changes between CPAP and control of -0.40 m/s (95% CI, -0.82 to +0.02 m/s; p = .059). Subgroup analyses did not change the results. In conclusion, a 6-month CPAP treatment did not reduce aortic stiffness, measured by cf-PWV, in patients with RHT and moderate/severe OSA, but treatment may prevent its progression, in contrast to no-CPAP therapy.

Effects of continuous positive airway pressure treatment on aldosterone excretion in patients with obstructive sleep apnoea and resistant hypertension: a randomized controlled trial.

OBJECTIVE: Aldosterone excess has been equally associated with resistant hypertension (RHT) and obstructive sleep apnoea (OSA). We conducted a randomized controlled study to assess the effect of continuous positive airway pressure (CPAP) treatment on 24-h urinary aldosterone excretion in patients with RHT and moderate/severe OSA. METHODS: A total of 117 patients were randomized (57 CPAP and 60 control groups). Aldosterone excretion was determined by 24 h urine (24h-UAldo) collected at randomization and after 6 months of follow-up. Twenty-four hour UAldo differences were assessed by general linear model with the allocation group (CPAP or control) as a fixed factor adjusted for their respective baseline values. Both intention-to-treat and per-protocol (45 patients with optimal adherence to CPAP) analyses were performed. RESULTS: Baseline 24h-UAldo was higher in severe OSA than in moderate OSA patients. After CPAP treatment, there was a borderline significant reduction in 24h-UAldo [mean difference: -2.5 µg/24 h; 95% confidence interval (95% CI): -5.3 to +0.3 µg/24 h; P = 0.07] in intention-to-treat analysis, whereas in the per-protocol analysis, the CPAP group had a greater reduction in 24h-UAldo than the control group (mean difference: -3.3 µg/24 h; 95% CI: -6.1 to -0.4 µg/24 h; P = 0.027). This effect occurred solely in patients with uncontrolled ambulatory BPs, and was more pronounced in those with the nondipping pattern, not using spironolactone, less obese, and with lowest sleep SaO2 levels. CONCLUSION: Only optimal CPAP treatment reduced aldosterone excretion in patients with uncontrolled RHT, while on intention-to-treat the effect was borderline. Although nondefinitive, our results suggest that CPAP treatment might improve cardiovascular outcomes by reducing aldosterone excess in resistant hypertensive individuals with OSA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01508754.

Nitroglycerin-mediated, but not flow-mediated vasodilation, is associated with blunted nocturnal blood pressure fall in patients with resistant hypertension.

BACKGROUND: Endothelial function by flow-mediated (FMD) and nitroglycerin-mediated vasodilations (NMD) was scarcely investigated in resistant hypertension. We aimed to assess the independent correlates of FMD and NMD in resistant hypertensive patients, particularly their associations with ambulatory blood pressures (BP) and nocturnal BP fall patterns. METHODS: In a cross-sectional study, 280 resistant hypertensive patients performed 24-h ambulatory BP monitoring, carotid-femoral pulse wave velocity, polysomnography, and brachial artery FMD and NMD by high-resolution ultrasonography. Independent correlates of FMD, NMD, and brachial artery diameter (BAD) were assessed by multiple linear and logistic regressions. RESULTS: Median (interquartile range) FMD was 0.75% (-0.6 to +4.4%) and NMD was 11.8% (7.1-18.4%). Baseline BAD and diabetes were independently associated with both FMD and NMD. Older age and prior cardiovascular diseases were associated with altered FMD, whereas higher night-time SBP and lower nocturnal SBP fall were associated with impaired NMD. Moreover, there was a significant gradient of impaired NMD according to blunted nocturnal BP decline patterns. BAD was independently associated with age, sex, BMI, albuminuria, and nocturnal SBP fall. Further adjustments to blood flow velocity, aortic stiffness, plasma aldosterone concentration, and sleep apnea did not change these relationships. CONCLUSION: NMD, but not FMD, is independently associated with unfavorable night-time BP levels and nondipping patterns, and may be a better cardiovascular risk marker in patients with resistant hypertension. BAD also may provide additional prognostic information.

Correlates of aortic stiffness progression in patients with resistant hypertension: importance of clinic and ambulatory blood pressure changes.

OBJECTIVES: Correlates of serial aortic stiffness changes were scarcely evaluated. We aimed to evaluate them in patients with resistant hypertension, with particular attention to the importance of changes in clinic and ambulatory blood pressures (BP). METHODS: In a prospective study, two carotid-femoral pulse wave velocity (cf-PWV) measurements (three measures in each occasion) were performed with the Complior equipment in 442 resistant hypertensive patients over a mean follow-up of 4.6 years. Multivariable regressions assessed the independent correlates of changes in cf-PWV. All analyses were further adjusted for baseline cf-PWV and BP values, and for the time interval between measurements. RESULTS: Carotid-femoral PWV had a median increase of 0.11 m/s per year (1.1% per year). Overall, 224 patients (51%) had an increase or persisted with high cf-PWV, whereas 218 (49%) reduced or persisted with low values. On multivariable regressions, both changes in clinic SBP (partial correlation 0.34, P < 0.001) and in 24-h SBP (partial correlation 0.40, P < 0.001) were correlates of changes in cf-PWV. This means that the white-coat effect, defined as the difference between clinic and daytime BPs, affected cf-PWV changes (partial correlation 0.19, P < 0.001). The other independent correlates of aortic stiffness progression were older age, presence of diabetes, higher waist circumference and worse renal function. CONCLUSION: The exaggerated white-coat effect, by acutely increasing clinic BPs during cf-PWV examination, may partially obscure the beneficial effects of reducing ambulatory BP levels on aortic stiffness attenuation. Arterial stiffness measurements under ambulatory conditions may be needed to correctly assess aortic stiffness changes in resistant hypertensive patients.

Effects of continuous positive airway pressure treatment on clinic and ambulatory blood pressures in patients with obstructive sleep apnea and resistant hypertension: a randomized controlled trial.

The effect of continuous positive airway pressure (CPAP) on blood pressures (BPs) in patients with resistant hypertension and obstructive sleep apnea is not established. We aimed to evaluate it in a randomized controlled clinical trial, with blinded assessment of outcomes. Four hundred thirty-four resistant hypertensive patients were screened and 117 patients with moderate/severe obstructive sleep apnea, defined by an apnea-hypopnea index ≥15 per hour, were randomized to 6-month CPAP treatment (57 patients) or no therapy (60 patients), while maintaining antihypertensive treatment. Clinic and 24-hour ambulatory BPs were obtained before and after 6-month treatment. Primary outcomes were changes in clinic and ambulatory BPs and in nocturnal BP fall patterns. Intention-to-treat and per-protocol (limited to those with uncontrolled ambulatory BPs) analyses were performed. Patients had mean (SD) 24-hour BP of 129(16)/75(12) mm Hg, and 59% had uncontrolled ambulatory BPs. Mean apnea-hypopnea index was 41 per hour and 58.5% had severe obstructive sleep apnea. On intention-to-treat analysis, there was no significant difference in any BP change, neither in nocturnal BP fall, between CPAP and control groups. The best effect of CPAP was on night-time systolic blood pressure in per-protocol analysis, with greater reduction of 4.7 mm Hg (95% confidence interval, -11.3 to +3.1 mm Hg; P=0.24) and an increase in nocturnal BP fall of 2.2% (95% confidence interval, -1.6% to +5.8%; P=0.25), in comparison with control group. In conclusion, CPAP treatment had no significant effect on clinic and ambulatory BPs in patients with resistant hypertension and moderate/severe obstructive sleep apnea, although a beneficial effect on night-time systolic blood pressure and on nocturnal BP fall might exist in patients with uncontrolled ambulatory BP levels.

Is home blood pressure monitoring useful in the management of patients with resistant hypertension?

BACKGROUND: Ambulatory blood pressure (BP) monitoring (ABPM) is a cornerstone in resistant hypertension (RHT) management. However, it has higher cost and lower patients' acceptance than home BP monitoring (HBPM). Our objective was to evaluate HBPM usefulness in the management of patients with RHT. METHODS: A total of 240 patients were submitted to 24-hour ABPM and 5-day HBPM (triplicate morning and evening measurements). Patients with uncontrolled office BP (≥140/90mm Hg) were classified as true RHT (daytime or home BP ≥135/85mm Hg) or white-coat RHT (daytime or home BP <135/85mm Hg), and patients with controlled office BP were classified as masked RHT (daytime or home BP ≥135/85mm Hg) or controlled RHT (daytime or home BP <135/85mm Hg). Sensitivity, specificity, predictive values, and likelihood ratios for HBPM were calculated. Agreement between the procedures was evaluated using kappa coefficients and the Bland-Altman method. RESULTS: Mean office BP was 157±26/84±16mm Hg, mean daytime BP was 134±18/77±13mm Hg, and mean home BP was 143±20/76±14mm Hg. The ABPM and HBPM diagnoses were 35% and 48%, respectively, for true RHT; 36% and 23%, respectively, for white-coat RHT; 7% and 17%, respectively, for masked RHT; and 22% and 13%, respectively, for controlled RHT. HBPM overestimated systolic BP by 8.8 (95% confidence interval (CI) = 6.8-10.7) mm Hg and diastolic BP by 0.2 (95% CI = -1.0 to 1.4) mm Hg. The specificity, sensitivity, and positive and negative predictive values of HBPM in detecting controlled ambulatory BP were 91%, 55%, 89%, and 59%. CONCLUSIONS: HBPM presented good agreement with ABPM and can be used as a complementary method in the follow-up of resistant hypertensive patients, particularly in those with controlled ambulatory BPs.

Cardiovascular and renal complications in patients with resistant hypertension.

With an increased prevalence, resistant hypertension is recognized as an entity with a high cardiovascular morbidity and mortality. In a large cohort of patients with resistant hypertension, the crude incidence rate of total cardiovascular events reached 4.32 per 100 patient-years of follow-up (19.6 %), with a cardiovascular mortality of 8.3 % (incidence rate of 1.72 per 100 patient-years). Cardiovascular event rates are significantly higher in resistant hypertensives compared with non-resistant (18.0 % versus 13.5 %). In the same way, the prevalence of established cardiovascular and renal disease, as the asymptomatic organ damage (represented by left ventricular hypertrophy, carotid wall thickening, arterial stiffness, and microalbuminuria) is higher in these patients. Many studies have demonstrated a strong association between damage to these organs with higher blood pressure levels, the diagnosis of true resistant hypertension, and refractory hypertension. All efforts should be employed in order to control blood pressure and also to regress and/or prevent subclinical cardiovascular and renal damage. The focus should be on prevention of cardiovascular and renal complications, improving the prognosis of resistant hypertension.

Diagnostic accuracy of the Berlin questionnaire in detecting obstructive sleep apnea in patients with resistant hypertension.

OBJECTIVES: Obstructive sleep apnea (OSA) is strongly associated with resistant hypertension. The Berlin questionnaire is the most widely used screening tool to identify patients at high risk of having OSA. The objective was to test the diagnostic accuracy of the Berlin questionnaire in detecting OSA in resistant hypertensive patients. METHODS: A cross-sectional analysis of 422 resistant hypertensive patients [31% men; mean (SD) age 62.4 (9.9) years] submitted to polysomnography (PSG), in whom the Berlin questionnaire was previously applied. OSA was defined by an apnea-hypopnea index of at least 5 per hour and moderate-to-severe OSA by an apnea-hypopnea index of at least 15. Statistical analysis included bivariate comparisons between patients at high and low risk by the Berlin questionnaire, and logistic regression to assess the predictors of agreement between the Berlin questionnaire and PSG. Sensitivity, specificity, positive and negative predictive values and likelihood ratios for the Berlin questionnaire in detecting OSA were calculated. RESULTS: OSA was diagnosed in 347 patients (82.2%) and moderate-to-severe OSA in 234 patients (55.5%). In patients at high risk, moderate-to-severe OSA was confirmed in 58.3%, whereas in those at low risk, it was excluded in 50.4%. The accuracy of the Berlin questionnaire in detecting OSA was 55.6%. The specificity, sensitivity, positive and negative predictive value of the Berlin questionnaire in detecting moderate-to-severe OSA was 40, 69, 58 and 50%, respectively. The positive and negative likelihood ratios were 1.15 and 0.78, with a very low agreement (kappa = 0.081). CONCLUSION: In a large cohort of resistant hypertensive patients, the Berlin questionnaire had a low accuracy of identifying patients with OSA and should not be used as a screening method for selecting patients to PSG.

Prevalence and associated factors of obstructive sleep apnea in patients with resistant hypertension.

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 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.

A reduced heart rate variability is independently associated with a blunted nocturnal blood pressure fall in patients with resistant hypertension.

BACKGROUND: A blunted nocturnal blood pressure (BP) fall is a marker of worse cardiovascular outcomes, and autonomic imbalance may be involved. The objective was to evaluate the associations between the nocturnal BP fall and heart rate variability (HRV) parameters in resistant hypertension. DESIGN AND METHODS: In a cross-sectional analysis, 424 resistant hypertensive patients performed 24-h ambulatory BP and Holter monitoring, and 221 patients also performed polysomnography. Time-domain HRV parameters evaluated were the standard deviation of all normal RR intervals (SDNN), the standard deviation of the averaged normal RR intervals for all 5-min segments (SDANN), the root mean square of differences between adjacent R-R intervals (rMSSD) and the percentage of adjacent R-R intervals that varied by more than 50 ms (pNN50). Multivariate linear and logistic regressions assessed associations between the nocturnal BP fall and HRV parameters. RESULTS: Two hundred and sixty-six patients (63%) presented a nondipping pattern. These patients had lower SDNN and SDANN than normal dipping patients, but equal rMSSD and pNN50. On multivariate analysis, after adjustments for several confounders, a reduced SDNN (<70 ms) implied a 2.9 to 3.4-fold [95% confidence interval (CI) 1.2-8.5] and a reduced SDANN (<50 ms) a 3.7 to 4.2-fold (95% CI 1.5-11.4) higher odds of having a nondipping pattern. Further adjustment for the presence and severity of obstructive sleep apnoea did not change the results. CONCLUSION: Reduced SDNN and SDANN, two HRV parameters that mainly reflect sympathetic overactivity, were independently associated with a blunted nocturnal BP fall in resistant hypertension. These relationships offer insight into physiopathological mechanisms linking the circadian BP variability to cardiovascular outcomes.

How to use ambulatory blood pressure monitoring in resistant hypertension.

Resistant hypertension is defined as an uncontrolled office blood pressure (BP) despite the use of at least three antihypertensive drugs, in adequate doses and combinations, preferentially including one diuretic. It is a clinical diagnosis based on office BP measurements. Ambulatory BP monitoring (ABPM) is the cornerstone in the management of patients with resistant hypertension, as it is mandatory for diagnosis, treatment, follow-up and prognosis. In relation to diagnosis, ABPM measurements have classified patients with resistant hypertension into four subgroups: true, white-coat, controlled and masked resistant hypertension. This classification largely defines the therapeutic approach and the follow-up for each group. In this way, the target of antihypertensive treatment is ambulatory BP control and not office BP control. Chronotherapy based on ABPM values might frequently lead to a more rational treatment regimen. In relation to prognosis, uncontrolled ambulatory BP levels at baseline identify a subgroup of patients with a very high cardiovascular risk profile and a significantly worse prognosis. ABPM parameters can provide a better cardiovascular risk stratification than other traditional risk factors and office BPs.

Prognostic significance of baseline heart rate and its interaction with beta-blocker use in resistant hypertension: a cohort study.

BACKGROUND: The prognostic significance of heart rate (HR) and its relationship with beta-blocker use are controversial and have never been evaluated in resistant hypertension. METHODS: In a prospective study, 528 patients with resistant hypertension had HR measured on clinical examination, electrocardiography (ECG), and during ambulatory blood pressure monitoring. Primary endpoints were a composite of fatal and nonfatal cardiovascular events, all-cause and cardiovascular mortality. Multivariable Cox regression was used to assess the associations between slow HR (< 60 bpm or < 55 bpm for nighttime HR) and fast HR (> 75 bpm or > 70 bpm for nighttime HR) and the occurrence of endpoints in relation to the reference middle HR (60-75 bpm) subgroup. RESULTS: After a median follow-up of 4.8 years, 62 patients died, 44 from cardiovascular causes; and 94 cardiovascular events occurred. Fast and slow HRs were mainly predictors of mortality, and ambulatory HRs were more significant risk markers than clinic or ECG HR. A slow 24-hour HR was a predictor of the composite endpoint (hazard ratio, 2.0; 95% confidence interval [CI], 1.2-3.4), whereas both slow and fast ambulatory HRs were predictors of cardiovascular mortality (hazard ratio, 2.3; 95% CI, 1.1-5.1). Four hundred and seventeen patients (79%) were using beta-blockers and this affected the HR prognostic value. A fast HR was a more significant risk marker in patients using beta-blockers, whereas a slow HR was a predictor mainly in those not using beta-blockers. CONCLUSIONS: There is an overall U-shaped relationship between HRs, particularly when measured during ambulatory monitoring, and prognosis in resistant hypertension. A fast HR is a significant predictor in patients using beta-blockers, while a slow heart rate is a more important predictor in those not using beta-blockers.

Prevalence and associated factors of subclinical hypercortisolism in patients with resistant hypertension.

BACKGROUND: Subclinical hypercortisolism is a secondary cause of hypertension that had never been evaluated in resistant hypertensive patients, a subgroup of general hypertensive individuals with an expected high prevalence of secondary hypertension. METHODS: Four hundred and twenty-three patients with resistant hypertension and ages up to 80 years were screened for the presence of subclinical hypercortisolism by morning serum cortisol after a midnight 1 mg dexamethasone suppression test (DST). Those with morning cortisol of at least 50  nmol/l had hypercortisolism confirmed by two salivary cortisol of at least 3.6  nmol/l collected at 2300  h. Statistical analysis included bivariate tests between those with positive and negative screening test and with and without confirmed hypercortisolism, and logistic regressions to assess their independent correlates. RESULTS: One hundred and twelve patients (prevalence 26.5%, 95% confidence interval 22.0-31.9%) had the screening test positive for suspected hypercortisolism. None had overt Cushing syndrome. Patients with positive screening were older, more frequently males, had higher prevalences of diabetes and target-organ damage and higher nighttime SBPs than patients with normal screening test results. Thirty-four patients (total prevalence 8.0%, 95% confidence interval: 5.7-11.2%) had confirmed hypercortisolism. Independent correlates of a positive DST were older age (P = 0.007), male sex (P = 0.012) and presence of cardiovascular diseases (P = 0.002) and chronic kidney disease (P = 0.016). Correlates of confirmed subclinical hypercortisolism were older age (P = 0.020), diabetes (P = 0.06) and a nondipping pattern on ambulatory blood pressure monitoring (P = 0.04). CONCLUSION: Patients with resistant hypertension had a relatively high prevalence of subclinical hypercortisolism, and its presence is associated with several markers of worse cardiovascular prognosis.

Appropriate time interval to repeat ambulatory blood pressure monitoring in patients with white-coat resistant hypertension.

Resistant hypertension is defined as uncontrolled office blood pressure, despite the use of ≥3 antihypertensive drugs. Ambulatory blood pressure monitoring (ABPM) is mandatory to diagnose 2 different groups, those with true and white-coat resistant hypertension. Patients are found to change categories between controlled/uncontrolled ambulatory pressures without changing their office blood pressures. In this way, ABPM should be periodically repeated. The aim of this study was to evaluate the most appropriate time interval to repeat ABPM to assure sustained blood pressure control in patients with white-coat resistant hypertension. This prospective study enrolled 198 patients (69% women; mean age: 68.9±9.9 years) diagnosed as white-coat resistant hypertension on ABPM. Patients were submitted to a second confirmatory examination 3 months later and repeated twice at 6-month intervals. Statistical analyses included Bland-Altman repeatability coefficients and multivariate logistic regression. Mean office blood pressure was 163±20/84±17 mm Hg, and mean 24-hour blood pressure was 118±8/66±7 mm Hg. White-coat resistant hypertension diagnosis presented a moderate reproducibility and was confirmed in 144 patients after 3 months. In the third and fourth ABPMs, 74% and 79% of patients sustained the diagnosis. In multivariate regression, a daytime systolic blood pressure ≤115 mm Hg in the confirmatory ABPM triplicated the chance of white-coat resistant hypertension status persistence after 1 year. In conclusion, a confirmatory ABPM is necessary after 3 months of the first white-coat-resistant hypertension diagnosis, and the procedure should be repeated at 6-month intervals, except in patients with daytime systolic blood pressure ≤115 mm Hg, in whom it may be repeated annually.