Spironolactone improves left atrial function and atrioventricular coupling in patients with resistant hypertension.

To determine the blood pressure independent effects of spironolactone on left atrial (LA) size and function in patients with resistant hypertension (RHTN). Patients with RHTN (n = 36, mean age 55 ± 7) were prospectively recruited. Spironolactone was initiated at 25 mg/day and increased to 50 mg/day after 4 weeks. Other antihypertensives were withdrawn to maintain constant blood pressure. Cardiac magnetic resonance imaging was performed at baseline and after 6 months of spironolactone treatment and changes in LA functional metrics were assessed. LA size and function parameters were improved (p < 0.05) from baseline to month-6: LA volumes indexed to body surface area (LAVI) were reduced (LAVImaximum 41.4 ± 12 vs. 33.2±9.7 mL/m2; LAVIpre-A 32.6 ± 9.8 vs. 25.6 ± 8.1 mL/m2; median LAVIminimum 18.5 [13.9-24.8] vs. 14.1 [10.9-19.2] mL/m2); left atrioventricular coupling index was reduced (28.2 ± 11.5 vs. 22.7 ± 9.2%); LA emptying fractions (LAEF) were increased (median total LAEF 52.4 [48.7-60.3] vs. 55.9 [50.3-61.1] %; active LAEF 40.2 ± 8.6 vs. 43.1 ± 7.8%). LA global longitudinal strain in the active phase was increased (16.3 ± 4.1 vs. 17.8 ± 4.2%). The effect of spironolactone was similar in patients with high (N = 18) and normal (N = 18) aldosterone status (defined by plasma renin activity and 24-h urine aldosterone). Treatment of RHTN with spironolactone is associated with improvements in LA size and function, and atrioventricular coupling, regardless of whether aldosterone levels were normal or high at baseline. This study suggests the need for larger prospective studies examining effects of mineralocorticoid receptor antagonists on atrial function and atrioventricular coupling.

Adverse cardiac remodeling is absent in patients with true controlled resistant hypertension.

Resistant hypertension (RHTN), defined as blood pressure (BP) that is uncontrolled with ≥3 medications, including a long-acting thiazide diuretic, also includes a subset with BP that is controlled with ≥4 medications, so-called controlled RHTN. This resistance is attributed to intravascular volume excess. Patients with RHTN overall have a higher prevalence of left ventricular hypertrophy (LVH) and diastolic dysfunction compared to patients with non-RHTN. We tested the hypothesis that patients with controlled RHTN due to the intravascular volume excess have higher left ventricular mass index (LVMI), higher prevalence of LVH, larger intracardiac volumes, and more diastolic dysfunction compared to patients with controlled non-resistant hypertension (CHTN), defined as BP controlled with ≤3 anti-hypertensive medications. Patients with controlled RHTN (n = 69) or CHTN (n = 63) who were treated at the University of Alabama at Birmingham were offered enrollment and underwent cardiac magnetic resonance imaging. Diastolic function was assessed by peak filling rate, time needed in diastole to recover 80% of stroke volume, E:A ratios and left atrial volume. LVMI was higher in patients with controlled RHTN (64.4 ± 22.5 vs 56.9 ± 11.5; P = .017). Intracardiac volumes were similar in both groups. Diastolic function parameters were not significantly different between groups. There were no significant differences in age, gender, race, body mass index, dyslipidemia between the two groups. The findings show that patients with controlled RHTN have higher LVMI, but comparable diastolic function to those of patients with CHTN.

Racial Differences in XO (Xanthine Oxidase) and Mitochondrial DNA Damage-Associated Molecular Patterns in Resistant Hypertension.

BACKGROUND: We previously reported increased plasma XO (xanthine oxidase) activity in patients with resistant hypertension. Increased XO can cause mitochondrial DNA damage and promote release of fragments called mitochondrial DNA damage-associated molecular patterns (mtDNA DAMPs). Here, we report racial differences in XO activity and mtDNA DAMPs in Black and White adults with resistant hypertension. METHODS: This retrospective study includes 91 resistant hypertension patients (44% Black, 47% female) with blood pressure >140/90 mm Hg on ≥4 medications and 37 normotensive controls (30% Black, 54% female) with plasma XO activity, mtDNA DAMPs, and magnetic resonance imaging of left ventricular morphology and function. RESULTS: Black-resistant hypertension patients were younger (mean age 52±10 versus 59±10 years; P=0.001), with higher XO activity and left ventricular wall thickness, and worse diastolic dysfunction than White resistant hypertension patients. Urinary sodium excretion (mg/24 hour per kg) was positively related to left ventricular end-diastolic volume (r=0.527, P=0.001) and left ventricular mass (r=0.394, P=0.02) among Black but not White resistant hypertension patients. Patients with resistant hypertension had increased mtDNA DAMPs versus controls (P<0.001), with Black mtDNA DAMPS greater than Whites (P<0.001). Transmission electron microscopy of skeletal muscle biopsies in resistant hypertension patients demonstrates mitochondria cristae lysis, myofibrillar loss, large lipid droplets, and glycogen accumulation. CONCLUSIONS: These data warrant a large study to examine the role of XO and mitochondrial mtDNA DAMPs in cardiac remodeling and heart failure in Black adults with resistant hypertension.

Diastolic function: modeling left ventricular untwisting as a damped harmonic oscillator.

Objective.We developed a method using cardiovascular magnetic resonance imaging to model the untwisting of the left ventricle (LV) as a damped torsional harmonic oscillator to estimate shear modulus (intrinsic myocardial stiffness) and frictional damping, then applied this method to evaluate the torsional stiffness of patients with resistant hypertension (RHTN) compared to a control group.Approach.The angular displacement of the LV during diastole was measured. Myocardial shear modulus and damping constant were determined by solving a system of equations modeling the diastolic untwisting as a damped, unforced harmonic oscillator, in 100 subjects with RHTN and 36 control subjects.Main Results.Though overall torsional stiffness was increased in RHTN (41.7 (27.1-60.7) versus 29.6 (17.3-35.7) kdyn*cm;p = 0.001), myocardial shear modulus was not different between RHTN and control subjects (0.34 (0.23-0.50) versus 0.33 (0.22-0.46) kPa;p= 0.758). RHTN demonstrated an increase in overall diastolic frictional damping (6.13 ± 3.77 versus 3.35 ± 1.70 kdyn*cm*s;p< 0.001), but no difference in damping when corrected for the overlap factor (74.3 ± 25.9 versus 68.0 ± 24.0 dyn*s/cm3;p = 0.201). There was an increase in the polar moment (geometric component of stiffness; 11.47 ± 6.95 versus 7.58 ± 3.28 cm4;p<0.001).Significance.We have developed a phenomenological method, estimating the intrinsic stiffness and relaxation properties of the LV based on restorative diastolic untwisting. This model finds increased overall stiffness in RHTN and points to hypertrophy, rather than tissue- level changes, as the major factor leading to increased stiffness.

Elucidation of obstructive sleep apnoea related blood pressure surge using a novel continuous beat-to-beat blood pressure monitoring system.

BACKGROUND: Obstructive sleep apnoea (OSA) episode related blood pressure (BP) surge may mediate the association of OSA with cardiovascular disease. However, BP is not measured during a clinical sleep study. METHOD: We tested the feasibility of incorporating the Caretaker physiological monitor, which utilizes a novel continuous beat-to-beat (b-b) BP monitoring technology, into polysomnography (PSG) and aimed to characterize BP surges related to obstructive respiratory events. B-b BP was concurrently collected and merged with PSG data on a posthoc basis. We compared BP surge between mean respiratory (apnoea, hypopnea and desaturation-alone events) and nonrespiratory events (spontaneous or leg movement-related arousals). We examined the association of the degree of oxygen desaturation with BP surge in a given respiratory event combining all events. A total of 17 consecutive patients (12 men, mean 52 years old, nine diagnostic and eight split-night PSGs) undergoing clinically indicated PSG were included after excluding one patient with poor signal quality due to excessive movement. RESULTS: Caretaker was well tolerated. Mean respiratory BP surge ranged from 5 to 19 mmHg [Median (IQR) = 13.9 (9.5--16.2)]. Mean BP surge between the respiratory and nonrespiratory events was similar [13.8 (4.5) vs. 14.9 (5.3) mmHg, P = 0.13]. Accounting for the count distribution of desaturation/BP surge data pair events, there was a linear correlation between the degree of oxygen desaturation and BP surge (R = 0.57, P < 0.001). In eight patients undergoing split-night sleep studies, the number of BP surge events (≥10 mmHg/h) decreased during continuous positive airway pressure in all but one patient. CONCLUSION: We demonstrated highly variable OSA-related BP surge patterns using the Caretaker's b-b BP monitoring technology that has the potential to be integrated into sleep studies.

Spironolactone Reduces Aortic Stiffness in Patients With Resistant Hypertension Independent of Blood Pressure Change.

Background Aortic stiffness is an independent predictor of cardiovascular events in patients with arterial hypertension. Resistant hypertension is often linked to hyperaldosteronism and associated with adverse outcomes. Spironolactone, a mineralocorticoid receptor antagonist, has been shown to reduce both the arterial blood pressure (BP) and aortic stiffness in resistant hypertension. However, the mechanism of aortic stiffness reduction by spironolactone is not well understood. We hypothesized that spironolactone reduces aortic stiffness in resistant hypertension independently of BP change. Methods and Results Patients with uncontrolled BP (≥140/90 mm Hg) despite use of ≥3 antihypertensive medications (including diuretics) were prospectively recruited. Participants were started on spironolactone at 25 mg/d, and increased to 50 mg/d at 4 weeks while other antihypertensive medications were withdrawn to maintain constant mean BP. Phase-contrast cardiac magnetic resonance imaging of the ascending aorta was performed in 30 participants at baseline and after 6 months of spironolactone treatment to measure aortic pulsatility, distensibility, and pulse wave velocity. Pulse wave velocity decreased (6.3±2.3 m/s to 4.5±1.8 m/s, P<0.001) and pulsatility and distensibility increased (15.9%±5.3% to 22.1%±7.9%, P<0.001; and 0.28%±0.10%/mm Hg to 0.40%±0.14%/mm Hg, P<0.001, respectively) following 6 months of spironolactone. Conclusions Our results suggest that spironolactone improves aortic properties in resistant hypertension independently of BP, which may support the hypothesis of an effect of aldosterone on the arterial wall. A larger prospective study is needed to confirm our findings.

Team Science: American Heart Association's Hypertension Strategically Focused Research Network Experience.

In 2015, the American Heart Association awarded 4-year funding for a Strategically Focused Research Network focused on hypertension composed of 4 Centers: Cincinnati Children's Hospital, Medical College of Wisconsin, University of Alabama at Birmingham, and University of Iowa. Each center proposed 3 integrated (basic, clinical, and population science) projects around a single area of focus relevant to hypertension. Along with scientific progress, the American Heart Association put a significant emphasis on training of next-generation hypertension researchers by sponsoring 3 postdoctoral fellows per center over 4 years. With the center projects being spread across the continuum of basic, clinical, and population sciences, postdoctoral fellows were expected to garner experience in various types of research methodologies. The American Heart Association also provided a number of leadership development opportunities for fellows and investigators in these centers. In addition, collaboration was highly encouraged among the centers (both within and outside the network) with the American Heart Association providing multiple opportunities for meeting and expanding associations. The area of focus for the Cincinnati Children's Hospital Center was hypertension and target organ damage in children utilizing ambulatory blood pressure measurements. The Medical College of Wisconsin Center focused on epigenetic modifications and their role in pathogenesis of hypertension using human and animal studies. The University of Alabama at Birmingham Center's areas of research were diurnal blood pressure patterns and clock genes. The University of Iowa Center evaluated copeptin as a possible early biomarker for preeclampsia and vascular endothelial function during pregnancy. In this review, challenges faced and successes achieved by the investigators of each of the centers are presented.

Effect of Serum Urate Lowering With Allopurinol on Blood Pressure in Young Adults: A Randomized, Controlled, Crossover Trial.

OBJECTIVE: To determine whether serum urate reduction with allopurinol lowers blood pressure (BP) in young adults and the mechanisms mediating this hypothesized effect. METHODS: We conducted a single-center, randomized, double-blind, crossover clinical trial. Adults ages 18-40 years with baseline systolic BP ≥120 and <160 mm Hg or diastolic BP ≥80 and <100 mm Hg, and serum urate ≥5.0 mg/dl for men or ≥4.0 mg/dl for women were enrolled. Main exclusion criteria included chronic kidney disease, gout, or past use of urate-lowering therapies. Participants received oral allopurinol (300 mg daily) or placebo for 1 month followed by a 2-4 week washout and then were crossed over. Study outcome measures were change in systolic BP from baseline, endothelial function estimated as flow-mediated dilation (FMD), and high-sensitivity C-reactive protein (hsCRP) levels. Adverse events were assessed. RESULTS: Ninety-nine participants were randomized, and 82 completed all visits. The mean ± SD age was 28.0 ± 7.0 years, 62.6% were men, and 40.4% were African American. In the primary intent-to-treat analysis, systolic BP did not change during the allopurinol treatment phase (mean ± SEM -1.39 ± 1.16 mm Hg) or placebo treatment phase (-1.06 ± 1.08 mm Hg). FMD increased during allopurinol treatment periods compared to placebo treatment periods (mean ± SEM 2.5 ± 0.55% versus -0.1 ± 0.42%; P < 0.001). There were no changes in hsCRP level and no serious adverse events. CONCLUSION: Our findings indicate that urate-lowering therapy with allopurinol does not lower systolic BP or hsCRP level in young adults when compared with placebo, despite improvements in FMD. These findings do not support urate lowering as a treatment for hypertension in young adults.

Paradoxical Increase of 24-Hour Urinary Aldosterone Levels in Obese Patients With Resistant Hypertension on a High Salt Diet.

BACKGROUND: Having previously reported that aldosterone levels increase progressively with body mass index (BMI), the current analysis was done to determine to what extent this association is related to dietary high salt intake. We anticipated that aldosterone levels would decrease with higher sodium status consistent with classical suppression of aldosterone release secondary to progressive fluid retention induced by high dietary sodium intake. METHODS: Cross-sectional analysis of a large diverse cohort of 2,705 patients with resistant hypertension (HTN) seen in a referral HTN Clinic. Dietary sodium intake was indexed by 24-hour (h) urinary sodium (UNa), aldosterone status was determined by plasma aldosterone concentration, plasma renin activity, and 24 h urinary aldosterone (UAldo). Patients with normal weight served as control. RESULTS: In this study, 1,572 individuals with complete 24 h urine collections were analyzed. Mean BMI was 32.5 ± 7.1 kg/m2 and ranged from 24.6 ± 2.4 kg/m2 (first quartile) to 41.0 ± 4.2 kg/m2 (fourth quartile). BMI was positively associated with 24 h UNa and UAldo levels (P < 0.0001), 24 h UNa and UAldo. There was a positively stronger correlation in obese (r = 0.273, P < 0.0001) compared with normal weight individuals (r = 0.108, P = 0.0342) independent of number and classes of antihypertensive medications. CONCLUSIONS: Our analysis shows that there is an altered regulation of aldosterone in obese patients in the setting of high dietary salt intake.

Masked Uncontrolled Hypertension Is Accompanied by Increased Out-of-Clinic Aldosterone Secretion.

Masked uncontrolled hypertension (MUCH) in treated patients is defined as controlled office blood pressure (BP) but uncontrolled out-of-clinic ambulatory BP. Previously, we have shown that patients with MUCH have evidence of heightened out-of-clinic sympathetic nervous system activity. The aim is to test the hypothesis that MUCH patients have higher aldosterone secretion compared with patients with true controlled hypertension. Two hundred twenty-two patients were recruited after having controlled office BP readings at ≥3 clinic visits. Patients taking MR (mineralocorticoid receptor) antagonists and epithelial sodium channel blockers were excluded. All patients were evaluated by clinic automated office BP and morning serum aldosterone and plasma renin activity. Out-of-clinic ambulatory BP monitoring and 24-hour urinary aldosterone, catecholamines, and metanephrines were also measured. Sixty-four patients had MUCH, and the remaining 48 patients had true controlled hypertension. MUCH patients had significantly higher out-of-clinic levels of 24-hour urinary aldosterone, catecholamines, and metanephrines compared with true controlled hypertension. The 2 groups did not differ in serum aldosterone, plasma renin activity, or aldosterone-renin ratio collected in clinic. In addition, 32.8% of MUCH patients had high out-of-clinic 24-hour urinary aldosterone (≥12 µg) but normal clinic serum aldosterone (<15 ng/dL) and aldosterone-renin ratio (<20). Further, in correlation matrix analysis, higher 24-hour urinary catecholamines and metanephrines were associated with higher 24-hour urinary aldosterone and plasma renin activity levels in MUCH patients. Patients with MUCH have higher out-of-clinic urinary aldosterone levels compared with patients with true controlled hypertension. This study suggests that patients with MUCH likely have higher out-of-clinic sympathetic nervous system tone increases aldosterone secretion mediated by increased renin release that may contribute to their higher out-of-clinic BP.

Uric Acid Is Not Associated With Blood Pressure Phenotypes and Target Organ Damage According to Blood Pressure Phenotypes.

BACKGROUND: Hypertensive patients with increased serum uric acid (SUA) are at increased cardiovascular (CV) risks. Both the European and American hypertension guidelines endorse the utilization of 24 h-ambulatory blood pressure monitoring (24 h-ABPM) for hypertensive patients with increased CV risk. While there is difference in identifying uric acid as a CV risk factor between the European and American guidelines. Therefore, it is unknown whether 24 h-ABPM should be used routinely in hypertensive patients with increased SUA. METHODS: To address this knowledge gap, we investigated (i) the correlation between SUA and 24 h-ABP; (ii) the association between SUA and blood pressure (BP) phenotypes (controlled hypertension [CH], white-coat uncontrolled hypertension [WCUH], masked uncontrolled hypertension [MUCH], and sustained uncontrolled hypertension [SUCH]); (iii) the association between SUA and target organ damage (TOD: microalbuminuria, left ventricular hypertrophy [LVH], and arterial stiffness) according to BP phenotypes. RESULTS: In 1,336 treated hypertensive patients (mean age 61.2 and female 55.4%), we found (i) there was no correlation between SUA and 24 h, daytime, and nighttime systolic blood pressure/diastolic blood pressure, respectively; (ii) in reference to CH, SUA increase was not associated WCUH (odds ratio [OR] 0.968, P = 0.609), MUCH (OR 1.026, P = 0.545), and SUCH (OR 1.003, P = 0.943); (iii) the overall prevalence of microalbuminuria, LVH, and arterial stiffness was 2.3%, 16.7%, and 23.2%, respectively. After adjustment for covariates, including age, sex, smoking, body mass index, diabetes mellitus, and estimated glomerular filtration rate, there was no association between SUA and TOD in all BP phenotypes. CONCLUSIONS: These preliminary findings did not support routine use of 24 h-ABPM in treated hypertensive patients with increased SUA.

The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study.

BACKGROUND: Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease. OBJECTIVE: To characterize the prevalence of nonsuppressible renin-independent aldosterone production, as well as biochemically overt primary aldosteronism, in relation to blood pressure. DESIGN: Cross-sectional study. SETTING: 4 U.S. academic medical centers. PARTICIPANTS: Participants with normotension (n = 289), stage 1 hypertension (n = 115), stage 2 hypertension (n = 203), and resistant hypertension (n = 408). MEASUREMENTS: Participants completed an oral sodium suppression test, regardless of aldosterone or renin levels, as a confirmatory diagnostic for primary aldosteronism and to quantify the magnitude of renin-independent aldosterone production. Urinary aldosterone was measured in participants in high sodium balance with suppressed renin activity. Biochemically overt primary aldosteronism was diagnosed when urinary aldosterone levels were higher than 12 µg/24 h. RESULTS: Every blood pressure category had a continuum of renin-independent aldosterone production, where greater severity of production was associated with higher blood pressure, kaliuresis, and lower serum potassium levels. Mean adjusted levels of urinary aldosterone were 6.5 µg/24 h (95% CI, 5.2 to 7.7 µg/24 h) in normotension, 7.3 µg/24 h (CI, 5.6 to 8.9 µg/24 h) in stage 1 hypertension, 9.5 µg/24 h (CI, 8.2 to 10.8 µg/24 h) in stage 2 hypertension, and 14.6 µg/24 h (CI, 12.9 to 16.2 µg/24 h) in resistant hypertension; corresponding adjusted prevalence estimates for biochemically overt primary aldosteronism were 11.3% (CI, 5.9% to 16.8%), 15.7% (CI, 8.6% to 22.9%), 21.6% (CI, 16.1% to 27.0%), and 22.0% (CI, 17.2% to 26.8%). The aldosterone-renin ratio had poor sensitivity and negative predictive value for detecting biochemically overt primary aldosteronism. LIMITATION: Prevalence estimates rely on arbitrary and conventional thresholds, and the study population may not represent nationwide demographics. CONCLUSION: The prevalence of primary aldosteronism is high and largely unrecognized. Beyond this categorical definition of primary aldosteronism, there is a prevalent continuum of renin-independent aldosterone production that parallels the severity of hypertension. These findings redefine the primary aldosteronism syndrome and implicate it in the pathogenesis of "essential" hypertension. PRIMARY FUNDING SOURCE: National Institutes of Health.

Apparent treatment-resistant hypertension: characteristics and prevalence in a real-world environment of an integrated health system.

OBJECTIVES: We compared the prevalence of apparent treatment-resistant hypertension (aTRH) according to the seventh report of the Joint National Committee (JNC 7) and the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline in an integrated healthcare delivery system. METHODS: We identified individuals aged at least 18 years with hypertension from Kaiser Permanente Southern California between 1 July 2014 and 30 June 2015. aTRH was defined as either blood pressure (BP) above goal (≥140/90 mmHg per JNC7, and ≥130/80 mmHg per 2017 ACC/AHA for most adults with hypertension) while taking at least 3 classes of antihypertensive medication or taking at least four classes regardless of BP level. A secondary analysis was conducted requiring use of a diuretic for the definition of aTRH. Patient clinical characteristics and antihypertensive medication use were described using electronic health records. RESULTS: We included 469 509 patients with treated hypertension [mean (SD) age 65 years (12), 46% white, 26% Hispanic, 13% black, and 12% Asian]. The prevalence of aTRH was 16.9 and 21.8% according to the JNC 7 and the 2017 ACC/AHA guidelines, respectively [Δ = 4.9% (95% CI: 4.7--5.1%)]. By requiring a diuretic to be considered as aTRH, the prevalence of aTRH decreased to 13.4 and 17.2% according to the JNC 7 and the 2017 ACC/AHA guidelines, respectively. Among patients with aTRH, 1.9% received a long-acting thiazide-like diuretic, and 5.6% received a mineralocorticoid receptor blocker. CONCLUSION: The prevalence of aTRH increased using the more stringent BP goals of the 2017 ACC/AHA guideline. The use of recommended therapy for aTRH was suboptimal suggesting a potential area for improvement.

Reserpine Substantially Lowers Blood Pressure in Patients With Refractory Hypertension: A Proof-of-Concept Study.

BACKGROUND: Refractory hypertension (RfHTN), a phenotype of antihypertensive treatment failure, is defined as uncontrolled automated office blood pressure (AOBP) ≥130/80 mm Hg and awake ambulatory blood pressure (ABP) ≥130/80 mm Hg on ≥5 antihypertensive medications, including chlorthalidone and a mineralocorticoid receptor antagonist. Previous studies suggest that RfHTN is attributable to heightened sympathetic tone. The current study tested whether reserpine, a potent sympatholytic agent, lowers blood pressure (BP) in patients with RfHTN. METHODS: Twenty-one out of 45 consecutive patients with suspected RfHTN were determined to be fully adherent with their antihypertensive regimen. Seven patients agreed to participate in the current clinical trial with reserpine and 6 patients completed the study. Other sympatholytic medications, such as clonidine or guanfacine, were tapered and discontinued before starting reserpine. Reserpine 0.1 mg daily was administered in an open-label fashion for 4 weeks. All patients were evaluated by AOBP and 24-hour ABP at baseline and after 4 weeks of treatment. RESULTS: Reserpine lowered mean systolic and diastolic AOBP by 29.3 ± 22.2 and 22.0 ± 15.8 mm Hg, respectively. Mean 24-hour systolic and diastolic ABPs were reduced by 21.8 ± 13.4 and 15.3 ± 9.6 mm Hg, mean awake systolic and diastolic ABPs by 23.8 ± 11.8 and 17.8 ± 9.2 mm Hg, and mean asleep systolic and diastolic ABPs by 21.5 ± 11.4 and 13.7 ± 6.4 mm Hg, respectively. CONCLUSIONS: Reserpine, a potent sympatholytic agent, lowers BP in patients whose BP remained uncontrolled on maximal antihypertensive therapy, lending support to the hypothesis that excess sympathetic output contributes importantly to the development of RfHTN.

Aortic blood pressure and arterial stiffness in patients with controlled resistant and non-resistant hypertension.

The purpose of the current study was to determine whether aortic blood pressure (BP) and arterial stiffness are greater in patients with controlled resistant hypertension (RHTN) than controlled non-resistant hypertension (non-RHTN) despite similar clinic BP level. Participants were recruited from University of Alabama at Birmingham (UAB) Hypertension Clinic. Controlled hypertension was defined as automated office BP measurement with BP < 135/85 mm Hg. A total of 141 participants were evaluated by pulse wave analysis (PWA) and carotid-femoral pulse wave velocity (cf-PWV). Among them, 75 patients had controlled RHTN with use of 4 or more antihypertensive medications and 56 patients had controlled non-RHTN with use of 3 or less antihypertensive medications. Compared to patients with controlled non-RHTN, those with controlled RHTN were more likely to be African American and had a higher prevalence of diabetes mellitus and congestive heart failure. The mean number of antihypertensive medications was greater in patients with controlled RHTN (4.4 ± 0.8 vs 2.3 ± 0.7, P < .001). Clinic brachial BP, aortic BP, augmentation pressure (AP), augmentation index normalized for heart rate of 75 beats per minute (AIx@75) and cf-PWV were similar in both groups. In summary, there was no significant difference in central BP or arterial stiffness between patients with controlled RHTN and controlled non-RHTN. These findings suggest that the higher residual cardiovascular risk observed in patients with RHTN after achieving BP control compared to patients with more easily controlled hypertension is not likely attributable to persistent differences in central BP and arterial stiffness.

Antihypertensive Medication Adherence and Confirmation of True Refractory Hypertension.

Refractory hypertension (RfHTN) is a phenotype of antihypertensive treatment failure defined as uncontrolled BP despite the use of effective doses of ≥5 antihypertensive medications including a long-acting thiazide-like diuretic (chlorthalidone) and a mineralocorticoid receptor antagonist. The degree of medication nonadherence is unknown among patients with RfHTN. In this prospective evaluation, 54 patients with apparent RfHTN were recruited from the University of Alabama at Birmingham Hypertension Clinic after having uncontrolled BP at 3 or more clinic visits. All patients' BP was evaluated by automated office BP and 24-hour ambulatory BP monitoring (n=49). Antihypertensive medication adherence was determined by measuring 24-hour urine specimens for antihypertensive medications and their metabolites by high-performance liquid chromatography-tandem mass spectrometry (n=45). Of the 45 patients who completed 24-hour ambulatory BP monitoring, 40 (88.9%) had confirmed RfHTN based on an elevated automated office BP (≥130/80 mm Hg), mean 24-hour ABP (≥125/75 mm Hg), and mean awake (day-time) ABP (≥130/80 mm Hg). Out of the 40 fully evaluated patients with RfHTN, 16 (40.0%) were fully adherent with all prescribed medications. Eighteen (45.0%) patients were partially adherent and 6 (15.0%) had none of the prescribed agents detected in their urine. Of 18 patients who were partially adherent, 5 (12.5%) were adherent with at least 5 medications, including chlorthalidone and the mineralocorticoid receptor antagonist, consistent with true RfHTN. Of patients identified as having apparent RfHTN, 52.5% were adherent with at least 5 antihypertensive medications, including chlorthalidone and a mineralocorticoid receptor antagonist, confirming true RfTHN. These findings validate RfHTN as a rare, but true phenotype of antihypertensive treatment failure.

Blood pressure monitoring in sleep: time to wake up.

Hypertension is a highly common condition with well-established adverse consequences. Ambulatory blood pressure monitoring has repeatedly been shown to better predict cardiovascular outcomes and mortality, compared to single office visit blood pressure. Non-dipping of sleep-time blood pressure is an independent marker for increased cardiovascular risk. We review blood pressure variability and the challenges of blood pressure monitoring during sleep. Although pathological sleep such as obstructive sleep apnea has been associated with non-dipping of sleep-time blood pressure, blood pressure is not routinely measured during sleep due to lack of unobtrusive blood pressure monitoring technology. Second, we review existing noninvasive continuous blood pressure monitoring technologies. Lastly, we propose including sleep-time blood pressure monitoring during sleep studies and including sleep studies in patients undergoing ambulatory blood pressure monitoring.

Masked Uncontrolled Hypertension Is Not Attributable to Medication Nonadherence.

Masked uncontrolled hypertension (MUCH) in treated hypertensive patients is defined as controlled automated office blood pressure (BP; <135/85 mm Hg) in-clinic but uncontrolled out-of-clinic BP by ambulatory BP monitoring (awake [daytime] readings ≥135/85 mm Hg or 24-hour readings ≥130/80 mm Hg). To determine whether MUCH is attributable to antihypertensive medication nonadherence. One hundred eighty-four enrolled patients were confirmed to have controlled office BP; of these, 167 patients were with adequate 24-hour ambulatory BP recordings. Of 167 patients, 86 were controlled by in-clinic BP assessment but had uncontrolled ambulatory awake BP, indicative of MUCH. The remaining 81 had controlled in-clinic and ambulatory awake BP, consistent with true controlled hypertension. After exclusion of 9 patients with missing 24-hour urine collections, antihypertensive medication adherence was determined based on the detection of urinary drugs or drug metabolites by high-performance liquid chromatography-tandem mass spectrometry. Of the 81 patients with MUCH, 69 (85.2%) were fully adherent and 12 (14.8%) were partially adherent (fewer medications detected than prescribed). Of the 77 patients with true controlled hypertension, 69 (89.6%) were fully adherent with prescribed antihypertensive medications and 8 (10.4%) were partially adherent. None of the patients in either group were fully nonadherent. There was no statistically significant difference in complete or partial adherence between the MUCH and true controlled groups (P=0.403). Measurement of urinary drug and drug metabolite levels demonstrates a similarly high level of antihypertensive medication adherence in both MUCH and truly controlled hypertensive patients. These findings indicate that MUCH is not attributable to antihypertensive medication nonadherence.

Resistant Hypertension Management: Comparison of the 2017 American and 2018 European High Blood Pressure Guidelines.

PURPOSE OF REVIEW: To compare European and American guidelines for the diagnosis, evaluation, and management of resistant hypertension. RECENT FINDINGS: Resistant hypertension is defined as high blood pressure that remains above goal with the use of 3 or more antihypertensive agents, commonly a renin-angiotensin blocker (either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker), a long-acting calcium channel blocker, and thiazide or thiazide-like diuretic. Resistant hypertension is common, with a recent analysis indicating that it affects approximately 17-19% of adult Americans with hypertension. Pseudocauses of apparent resistant hypertension, including inaccurate blood pressure measurement, white coat effect, undertreatment, and poor medication adherence, must be excluded in order to confirm true resistant hypertension. Evaluation of resistant hypertension requires identifying and treating secondary causes of hypertension, including obstructive sleep apnea, primary aldosteronism, and renal artery stenosis. Treatment of resistant hypertension includes a combined use of lifestyle modification and prescription of effective multiple-drug combinations. Preferential use of a long-acting thiazide-like diuretic, either chlorthalidone or indapamide, and a mineralocorticoid receptor blocker, most commonly spironolactone, is recommended if needed to achieve blood pressure control. Aside for small exceptions, European and American guidelines agree in terms of recommendations for diagnosing, evaluating, and treating resistant hypertension.