Elizabeth S. Muxfeldt

Prognostic Influence of Office and Ambulatory Blood Pressures in Resistant Hypertension

BACKGROUND The prognostic value of office and ambulatory blood pressures (BPs) in patients with resistant hypertension is uncertain. METHODS This prospective study investigates the importance of office and ambulatory BPs as predictors of cardiovascular morbidity and mortality. At baseline, 556 resistant hypertensive patients underwent clinical-laboratory and 24-hour ambulatory BP monitoring examinations. Primary end points were a composite of fatal and nonfatal cardiovascular events and all-cause and cardiovascular mortalities. Multiple Cox regression was used to assess associations between BP and subsequent end points. RESULTS After median follow-up of 4.8 years, 109 patients (19.6%) reached the primary end point, and 70 all-cause deaths (12.6%) occurred (46 had cardiovascular causes). After adjustment for age, sex, body mass index, diabetes mellitus, smoking, physical inactivity, dyslipidemia, previous cardiovascular diseases, serum creatinine level, and number of antihypertensive drugs in use, no office BP showed any prognostic value. After further adjustment for office BP, higher mean ambulatory BPs were independent predictors of the composite end point. The hazard ratios associated with a 1-SD increment in daytime and nighttime systolic BP were 1.26 (95% confidence interval, 1.04-1.53) and 1.38 (1.13-1.68), respectively; the corresponding values for diastolic BP were 1.31 (1.05-1.63) and 1.36 (1.10-1.69). Ambulatory systolic and diastolic BP were equivalent predictors, and both were better than pulse pressure; nighttime BP was superior to daytime BP. For all-cause mortality, only the ambulatory BP monitoring diagnosis of true resistant hypertension was an independent predictor. CONCLUSION Higher ambulatory BP predicts cardiovascular morbidity and mortality in resistant hypertensive patients, whereas office BP has no prognostic value.

Efficacy of Spironolactone Therapy in Patients With True Resistant Hypertension

The role of spironolactone in resistant hypertension management is unclear. The aim of this prospective trial was to evaluate the antihypertensive effect of spironolactone in patients with true resistant hypertension diagnosed by ambulatory blood pressure monitoring. A total of 175 patients had clinical and complementary exams obtained at baseline and received spironolactone in doses of 25 to 100 mg/d. A second ambulatory blood pressure monitoring was performed after a median interval of 7 months. Paired Student t test was used to assess differences in blood pressure before and during spironolactone administration, and multivariate analysis adjusted for age, sex, and number of antihypertensive drugs to assess the predictors of blood pressure fall. There were mean reductions of 16 and 9 mm Hg, respectively, in 24-hour systolic and diastolic blood pressures (95% CIs: 13 to 18 and 7 to 10 mm Hg; P<0.001). Office systolic blood pressure and diastolic blood pressure also decreased (14 and 7 mm Hg). Controlled ambulatory blood pressure was reached in 48% of patients. Factors associated with better response were higher waist circumference, lower aortic pulse wave velocity, and lower serum potassium. No association with plasma aldosterone or aldosterone:renin ratio was found. Adverse effects were observed in 13 patients (7.4%). A third ambulatory blood pressure monitoring performed in 78 patients after a median of 15 months confirmed the persistence of the spironolactone effect. In conclusion, spironolactone administration to true resistant hypertensive patients is safe and effective in decreasing blood pressure, especially in those with abdominal obesity and lower arterial stiffness. Its addition to an antihypertensive regimen as the fourth or fifth drug is recommended.

Prognostic Value of Nocturnal Blood Pressure Reduction in Resistant Hypertension

BACKGROUND The prognostic value of nocturnal blood pressure (BP) reduction in resistant hypertension (RH) is unknown. The objective of this prospective study was to evaluate its importance as a predictor of cardiovascular morbidity and mortality. METHODS At baseline, 556 patients with RH underwent clinical and laboratory examinations and 24-hour ambulatory BP monitoring. The primary end points were a composite of fatal or nonfatal cardiovascular events, all-cause mortality, and cardiovascular mortality. Multiple Cox regression was used to assess associations between the nocturnal BP reduction and the subsequent end points. RESULTS After a mean follow-up of 4.8 years (range, 1-103 months), 109 patients (19.6%) reached the composite end point, with 70 all-cause and 46 cardiovascular deaths. A nondipping pattern was present in 360 patients (65.0%). After adjustment for age, sex, body mass index, diabetes, smoking status, physical inactivity, dyslipidemia, previous cardiovascular disease, number of antihypertensive drugs in use, and office and 24-hour ambulatory BP readings, the nondipping pattern was an independent predictor of the composite end point (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.12-2.71) and of cardiovascular mortality (HR, 2.31; 95% CI, 1.09-4.92). In subgroup analysis, the reduced (HR, 1.71; 95% CI, 1.03-2.83) and reverted (HR, 1.89; 95% CI, 1.04-3.43) dipping patterns were predictive of total cardiovascular events. The effect of the nondipping pattern on cardiovascular prognosis was stronger in younger patients and in those with true RH. CONCLUSIONS The nocturnal BP variability patterns provide valuable prognostic information for stratification of cardiovascular morbidity and mortality risk in patients with RH, above and beyond other traditional cardiovascular risk factors and mean ambulatory BP levels.

Relation of Left Ventricular Hypertrophy With Systemic Inflammation and Endothelial Damage in Resistant Hypertension

The relation between left ventricular hypertrophy (LVH) and unfavorable cardiovascular prognosis may involve systemic inflammation and endothelial dysfunction/damage. The aim of this study was to investigate in a cross-sectional design the relationships of LVH with C-reactive protein (CRP) levels (a marker of systemic low-grade inflammation) and with microalbuminuria (a marker of glomerular endothelial damage) in 705 patients with resistant hypertension. At baseline, all were submitted to a laboratory evaluation including 24-hour urinary albumin excretion, 2D echocardiogram, and 24-hour ambulatory blood pressure monitoring. A total of 463 patients also had high-sensitivity CRP levels determined. LVH was defined as an indexed left ventricular mass >110 g/m2 in women and >125 g/m2 in men. Microalbuminuria was evaluated in 3 categories: low normal (<15 mg/24 hours), high normal (between 15 and 29 mg/24 hours), and abnormal (between 30 and 299 mg/24 hours). CRP was dichotomized at the median value (3.7 mg/L). Associations with LVH were examined after adjustment for all of the potential confounders by multivariate logistic regression. A total of 534 patients (75.7%) had LVH. After full adjustment, both abnormal microalbuminuria (odds ratio: 1.97; 95% CI: 1.04 to 3.73) and high CRP (OR: 1.76; 95% CI: 1.06 to 2.93) were independently associated with LVH occurrence. The high-normal albuminuria was associated with a borderline significant 46% increased chance of having LVH. Furthermore, the association between high CRP and LVH was observed exclusively in the subgroup with normal albuminuria. In conclusion, both systemic inflammation and endothelial damage were associated with LVH occurrence. These relationships offer insight into the pathophysiological mechanisms linking LVH to atherosclerosis and to increased cardiovascular morbidity and mortality.

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.

A blunted decrease in nocturnal blood pressure is independently associated with increased aortic stiffness in patients with resistant hypertension

Increased arterial stiffness may be causally related to resistant hypertension. Our objective was to investigate the variables, particularly those derived from ambulatory blood pressure (BP) monitoring (ABPM), associated with increased aortic stiffness in resistant hypertensives. In a cross-sectional study, 600 resistant hypertensive patients without peripheral arterial disease were evaluated. Arterial stiffness was assessed by aortic pulse wave velocity (PWV), and was considered increased if >12 m s−1. Statistical analyses included multiple linear and logistic regressions to assess the independent correlates of increased aortic stiffness. One hundred and sixty-eight patients (28%) had aortic PWV >12 m s−1. Patients with increased PWV were older and had a higher prevalence of cardiovascular risk factors than did those patients with low PWV. On ABPM, patients with elevated PWV had higher daytime and night time systolic BP (SBP) and pulse pressures (PP), less nocturnal decrease in SBP and a higher prevalence of non-dipping pattern. On multiple linear regression, the independently associated variables with aortic PWV were age (P<0.001), 24-h PP (P<0.001), high-density lipoprotein (HDL)-cholesterol (P<0.001), microalbuminuria (P<0.001), fasting glycemia (P=0.001) and a decrease in nocturnal SBP (P=0.002). Multivariate logistic regression confirmed these results, with the non-dipping patients having a 72% higher likelihood of presenting with increased aortic stiffness (95% confidence interval: 1.12–2.65, P=0.013). This association was observed in both the reduced and reverted dipping patterns, but not in the extreme dipping pattern. In conclusion, a blunted nocturnal decrease in BP is independently associated with increased aortic stiffness in resistant hypertensive patients. Other independent correlates are older age, diabetes, microalbuminuria, low HDL-cholesterol and a widened 24-h PP.

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.

Combined QT Interval and Voltage Criteria Improve Left Ventricular Hypertrophy Detection in Resistant Hypertension

QT interval parameters have been associated with left ventricular hypertrophy (LVH) in hypertensive patients. The aim of this study is to assess this relationship in resistant hypertension and, in particular, to evaluate whether any QT interval parameter could provide additive information for LVH beyond that obtained from the best electrocardiographic voltage criterion. In a cross-sectional study, 471 resistant hypertensives were submitted to standard 12-lead ECGs, 24-hour ambulatory blood pressure monitoring, and 2D echocardiographic examinations. QT interval durations and QRS voltages were measured, and maximum rate–corrected QT interval duration (QTcmax) and dispersion (QTd), and Sokolow’s and Cornell’s voltage product were calculated. Statistical analyses involved bivariate tests and multivariate logistic regression, with LVH as the dependent variable. A total of 383 patients (81%) had echocardiographic LVH. In bivariate comparisons, both QT interval parameters showed a predictive performance for LVH similar to Cornell’s product, the best ECG voltage criterion. In multivariate analysis, QT parameters and Cornell’s product were independently associated with LVH, after adjustment for other LVH determinants. QTc interval >440 ms1/2 and dispersion >60 ms were associated with a 2-fold (95% confidence interval [CI], 1.1 to 3.8) greater chance of having LVH, whereas Cornell’s product >240 mV·ms implied a 2.6-fold (95% CI, 1.2 to 6.1) increased chance of LVH. The combination of prolonged QT interval and increased Cornell’s product was associated with a 5.3- to 9.3-fold higher chance of having LVH. Hence, although in isolation, no QT interval parameter performs better for LVH detection than simpler Cornell’s product, it provides additive information and can be used in combination with voltage criteria to refine LVH risk stratification in resistant hypertension.

Pulse pressure or dipping pattern: which one is a better cardiovascular risk marker in resistant hypertension?

Objective Nocturnal blood pressure (BP) reduction and ambulatory pulse pressure (PP) are well known prognostic markers obtained from ambulatory BP monitoring (ABPM). The aim of this study is to investigate which one of these ABPM parameters is related to high cardiovascular risk profile in resistant hypertension, based on their associations with target organ damage (TOD). Methods Clinical-demographic, laboratory and ABPM variables were recorded in a cross-sectional study involving 907 resistant hypertensive patients. Nocturnal systolic BP reduction and 24-h PP were assessed both as continuous and dichotomized variables (PP at the upper tertile value: 63 mmHg). Statistical analyses included bivariate tests and multivariate logistic regression with each TOD as the dependent variable. Results Patients with the nondipping pattern and high 24-h PP shared some characteristics: they were older, had higher prevalence of cerebrovascular disease and nephropathy, higher office and 24-h BP levels, increased serum creatinine and microalbuminuria, and higher left ventricular mass index than their counterparts. Additionally, patients with high PP had a greater prevalence of diabetes and other TOD. In multivariate logistic regression, high PP was independently associated with all TODs even after adjustment for sex, age, BMI, cardiovascular risk factors, 24-h mean arterial pressure and antihypertensive treatment, whereas nondipping pattern was only associated with hypertensive nephropathy. Furthermore, PP was more strongly associated with the number of TOD than the nocturnal systolic blood pressure (SBP) fall. Conclusions In a large group of resistant hypertensive patients, an increased 24-h PP shows a closer correlation with high cardiovascular risk profile than the nocturnal BP reduction.

Prognostic impact of the ambulatory arterial stiffness index in resistant hypertension

Objective The ambulatory arterial stiffness index (AASI), derived from ambulatory blood pressure (BP) monitoring recordings, is an indirect marker of arterial stiffness and a potential predictor of cardiovascular risk. Resistant hypertension is defined as uncontrolled office BP despite the use of at least three antihypertensive drugs. The aim of this prospective study was to investigate the AASI prognostic value in patients with resistant hypertension. Methods At baseline, 547 patients underwent clinical–laboratory, and 24-h ambulatory BP monitoring examinations. AASI was defined as 1 minus the regression slope of DBP on SBP, and was calculated by standard and symmetric regression. Primary endpoints were a composite of fatal and nonfatal cardiovascular events and all-cause and cardiovascular mortalities. Multiple Cox regression was used to assess associations between AASI and subsequent endpoints. Results After median follow-up of 4.8 years, 101 patients (18.4%) reached the primary endpoint, and 65 all-cause deaths (11.9%) occurred (45 from cardiovascular causes). 24-h AASI was the best independent predictor of composite endpoint (hazard ratio 1.46, 95% confidence interval 1.12–1.92, for increments of 1-SD = 0.14), whereas cardiovascular mortality was best predicted by night-time AASI (hazard ratio 1.73, 95% confidence interval 1.13–2.65), after adjustments for cardiovascular risk factors, including mean ambulatory BPs and nocturnal BP reduction. Symmetric AASI was not superior to standard AASI. In sensitivity analysis, 24-h AASI was a better predictor of cardiovascular outcomes in women, in younger individuals, and in nondiabetic individuals. Conclusion AASI is a predictor of cardiovascular morbidity and mortality in resistant hypertension, over and beyond traditional risk factors and other ambulatory BP monitoring parameters.