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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

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

Resistant hypertension, defined as blood pressure levels above goal while taking ≥3 classes of antihypertensive medication or ≥4 classes regardless of blood pressure level, is associated with increased cardiovascular disease risk. The 2018 American Heart Association Scientific Statement on Resistant Hypertension recommends healthy lifestyle habits and thiazide-like diuretics and mineralocorticoid receptor antagonists for adults with resistant hypertension. The term apparent treatment-resistant hypertension (aTRH) is used when pseudoresistance cannot be excluded. We estimated the use of healthy lifestyle factors and recommended antihypertensive medication classes among US Black adults with aTRH. Data were pooled for Black participants in the JHS (Jackson Heart Study) in 2009 to 2013 (n=2496) and the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) in 2013 to 2016 (n=3786). Outcomes included lifestyle factors (not smoking, not consuming alcohol, ≥75 minutes of vigorous-intensity or ≥150 minutes of moderate or vigorous physical activity per week, and body mass index 2 ) and recommended antihypertensive medications (thiazide-like diuretics and mineralocorticoid receptor antagonists). Overall, 28.3% of participants who reported taking antihypertensive medication had aTRH. Among participants with aTRH, 14.5% and 1.2% had ideal levels of 3 and 4 of the lifestyle factors, respectively. Also, 5.9% of participants with aTRH reported taking a thiazide-like diuretic, and 9.8% reported taking a mineralocorticoid receptor antagonist. In conclusion, evidence-based lifestyle factors and recommended pharmacological treatment are underutilized in Black adults with aTRH. Increased use of lifestyle recommendations and antihypertensive medication classes specifically recommended for aTRH may improve blood pressure control and reduce cardiovascular disease–related morbidity and mortality among US Black adults. Graphic Abstract A graphic abstract is available for this article.

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.

BACKGROUND Obstructive sleep apnea (OSA), nocturnal hypertension, and nondipping systolic blood pressure (BP) are each highly prevalent among African Americans. However, few data are available on the association between OSA and nighttime BP in this population. METHODS We examined the association of OSA with nighttime BP among African Americans who completed 24-hour ambulatory BP monitoring (ABPM) at Exam 1 (2000–2004) of the Jackson Heart Study (JHS) and subsequently participated in the JHS Sleep Study (2012–2016). Type 3 home sleep apnea testing was used to assess OSA measures, including respiratory event index (REI4%) and percent sleep time RESULTS Among 206 participants who completed ABPM and participated in the Jackson Heart Sleep Study, 50.5% had nocturnal hypertension and 26.2% had moderate to severe OSA (REI4% ≥15 events/hour). After multivariable adjustment, each SD (13.3 events/hour) increase in REI4% was associated with 1.75 mm Hg higher nighttime DBP (95% confidence interval (CI): 0.38, 3.11) and a prevalence ratio of 1.11 (95% CI: 1.00, 1.24) for nocturnal hypertension. Each SD (10.4%) increase in nocturnal hypoxemia was associated with a 1.91 mm Hg higher nighttime SBP (95% CI: 0.15, 3.66). CONCLUSIONS Severity of OSA and nocturnal hypoxemia were associated with high nighttime BP in African American participants in the JHS.

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.

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

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 P P 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.

Resistant hypertension is defined as uncontrolled blood pressure despite the use of 3 or more antihypertensive agents of different classes, including a diuretic, usually thiazide-like, a long-acting calcium channel blocker, and a blocker of the renin- angiotensin system, either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, at maximal or maximally tolerated doses. Antihypertensive medication non-adherence and the white coat effect, defined as elevated blood pressure when measured in clinic but controlled when measured outside of clinic, must be excluded to make the diagnosis. Resistant hypertension is a high risk phenotype, leading to increased all-cause mortality and cardiovascular disease (CVD) outcomes. Healthy lifestyle habits are associated with reduced CV risk in patients with resistant hypertension. Aldosterone excess is common in patients with resistant hypertension, and addition of spironolactone or amiloride to the standard 3-drug antihypertensive regimen is effective at getting the blood pressure to goal in most of these patients. Refractory hypertension is defined as uncontrolled blood pressure despite use of 5 or more antihypertensive agents of different classes, including a long acting thiazide-like diuretic and a mineralocorticoid receptor antagonist, at maximal or maximally tolerated doses. Fluid retention, mediated largely by aldosterone excess, is the predominant mechanism underlying resistant hypertension, while patients with refractory hypertension typically exhibit increased sympathetic nervous system activity.

Background: Blacks have a high prevalence of hypertension and uncontrolled blood pressure (BP), each of which may be partially explained by untreated sleep apnea. We investigated the association of sleep apnea with uncontrolled BP and resistant hypertension in blacks. Methods: Between 2012 and 2016, Jackson Heart Sleep Study participants (N=913) underwent an in-home Type 3 sleep apnea study, clinic BP measurements, and anthropometry. Moderate or severe obstructive sleep apnea (OSA) was defined as a respiratory event index ≥15, and nocturnal hypoxemia was quantified as percent sleep time with > 80mm Hg, use of antihypertensive medication, or self-report of a diagnosis of hypertension. Controlled BP was defined as systolic BP Results: The analytic sample with hypertension (N=664) had a mean age of 64.0 (SD,10.6) years, and were predominately female (69.1%), obese (58.6%), and college educated (51.3%). Among the sample, 25.7% had OSA, which was untreated in 94% of participants. Overall, 48% of participants had uncontrolled hypertension and 14% had resistant hypertension. After adjustment for confounders, participants with moderate or severe OSA had a 2.0 times higher odds of resistant hypertension (95% confidence interval [CI], 1.14–3.67). Each standard deviation higher than Conclusion: Untreated moderate or severe OSA is associated with increased odds of resistant hypertension. These results suggest that untreated OSA may contribute to inadequate BP control in blacks.

OBJECTIVES Obstructive sleep apnea (OSA) is associated with treatment-resistant hypertension (RHTN) and may contribute to refractory hypertension (RfHTN). The objective of the current study was to test the hypothesis that patients with RfHTN have more severe OSA compared with patients with controlled RHTN. METHODS Patients (n = 187) referred to the University of Alabama at Birmingham Hypertension Clinic for evaluation and treatment of RHTN, defined as uncontrolled blood pressure (BP) (SBP ≥ 130 mmHg or DBP ≥ 80 mmHg) despite the use of at least three antihypertensive medications including a diuretic, were enrolled following completion of at least three follow-up clinic visits. RfHTN was defined as uncontrolled high BP despite treatment with five or more antihypertensive agents of different classes, including a long-acting thiazide-type diuretic and a mineralocorticoid receptor antagonist. Following enrollment, all patients (n = 130) completed 24-h ambulatory BP measurement and overnight diagnostic polysomnography during normal nightly use of continuous positive airway pressure. Analyses examined the severity of OSA and related sleep characteristics among patients with RfHTN versus controlled RHTN. RESULTS Of the 130 evaluated patients, 37 (28.5%) had RfHTN and 93 (71.5%) had controlled RHTN. In unadjusted analyses, there was not a significant difference in OSA severity, oxygen saturation, or hypoxemia time in patients with RfHTN versus controlled RHTN (P > 0.05). Men with RfHTN had more severe OSA compared with men with controlled RHTN (P = 0.044). In adjusted analyses, OSA severity was associated with sex (P

Background Sleep characteristics and disorders are associated with higher blood pressure ( BP ) when measured in the clinic setting. Methods and Results We tested whether self‐reported sleep characteristics and likelihood of obstructive sleep apnea ( OSA ) were associated with nocturnal hypertension and nondipping systolic BP ( SBP ) among participants in the CARDIA (Coronary Artery Risk Development in Young Adults) study who completed 24‐hour ambulatory BP monitoring during the year 30 examination. Likelihood of OSA was determined using the STOP ‐Bang questionnaire. Global sleep quality, habitual sleep duration, sleep efficiency, and midsleep time were obtained from the Pittsburgh Sleep Quality Index. Nocturnal hypertension was defined as mean asleep SBP ≥120 mm Hg or diastolic BP ≥70 mm Hg. Nondipping SBP was defined as a decline in awake‐to‐asleep SBP SBP was 41.3% and 32.5%, respectively. After multivariable adjustment including cardiovascular risk factors, the prevalence ratios (PRs) for nocturnal hypertension and nondipping SBP associated with high versus low likelihood of OSA were 1.32 (95% CI, 1.00–1.75) and 1.31 (95% CI, 1.02–1.68), respectively. The association between likelihood of OSA and nocturnal hypertension was stronger for white participants (PR: 2.09; 95% CI, 1.23–3.48) compared with black participants (PR: 1.11; 95% CI, 0.79–1.56). The PR for nondipping SBP associated with a 1‐hour later midsleep time was 0.92 (95% CI, 0.85–0.99). Global sleep quality, habitual sleep duration, and sleep efficiency were not associated with either nocturnal hypertension or nondipping SBP . Conclusions These findings suggest that addressing OSA risk and sleep timing in a clinical trial may improve BP during sleep.

Refractory hypertension (RfHTN) is an extreme phenotype of antihypertensive treatment failure defined as lack of blood pressure control with ≥5 medications, including a long-acting thiazide and a mineralocorticoid receptor antagonist. RfHTN is a subgroup of resistant hypertension (RHTN), which is defined as blood pressure >135/85 mm Hg with ≥3 antihypertensive medications, including a diuretic. RHTN is generally attributed to persistent intravascular fluid retention. It is unknown whether alternative mechanisms are operative in RfHTN. Our objective was to determine whether RfHTN is characterized by persistent fluid retention, indexed by greater intracardiac volumes determined by cardiac magnetic resonance when compared with controlled RHTN patients. Consecutive patients evaluated in our institution with RfHTN and controlled RHTN were prospectively enrolled. Exclusion criteria included advanced chronic kidney disease and masked or white coat hypertension. All enrolled patients underwent biochemical testing and cardiac magnetic resonance. The RfHTN group (n=24) was younger (mean age, 51.7±8.9 versus 60.6±11.5 years; P =0.003) and had a greater proportion of women (75.0% versus 43%; P =0.02) compared with the controlled RHTN group (n=30). RfHTN patients had a greater left ventricular mass index (88.3±35.0 versus 54.6±12.5 g/m 2 ; P P =0.001), and septal wall thickness (14.5±3.8 versus 10.0±2.2 mm; P

A 78-year-old black man presented to the Hypertension Clinic at the University of Alabama at Birmingham for uncontrolled blood pressure (BP). His BP remained uncontrolled (automated office, ≥135/85 mm Hg) from August 2011 to August 2016 in spite of use of 6 antihypertensive agents in adequate doses (Figure 1). During this time period, his average systolic BP was 167.1 mm Hg and average diastolic BP was 68.7 mm Hg. Figure 1. Blood pressure (BP) and antihypertensive medications before and after surgery. CABG indicates coronary artery bypass grafting. The patient was on 3 antihypertensive medications on initial presentation to University of Alabama at Birmingham in 2011, including an angiotensin receptor blocker (irbesartan), a calcium channel blocker (amlodipine), and a long-acting thiazide-like diuretic (chlorthalidone). Spironolactone was added as a fourth antihypertensive agent. Eventually, hydralazine—a vasodilator—and clonidine—a centrally acting sympatholytic—were added as the fifth and sixth antihypertensive agents. The patient’s BP remained uncontrolled on 6 different classes of antihypertensive medications (Figure 1). Comorbidities and secondary causes of hypertension were evaluated by biochemical analysis and imaging. ### Biochemical Analysis The patient was diagnosed with mild chronic kidney disease. Mean serum creatinine was 1.35 mg/dL with an estimated glomerular filtration rate of 58 mL/min per 1.73 m2. Diabetes mellitus was excluded (HbA1c was 5.5%), primary aldosteronism was excluded as the plasma aldosterone–renin ratio was

See related article, pp 585–591 A growing body of literature associates primary aldosteronism (PA) with increased risk of cardiovascular complications, including cardiovascular attributable death, left ventricular hypertrophy, stroke, proteinuria, and atrial fibrillation. This increased cardiovascular risk is in no doubt related in large part to aldosterone-induced increases in blood pressure (BP), which are often resistant and severe. Additional mechanisms that are seemingly independent of increases in BP that likely contribute to the development and progression of cardiovascular disease in PA patients include aldosterone-induced inflammation, fibrosis, cellular hypertrophy, and oxidative stress.1 Further, in line with classical physiological effects, aldosterone and high dietary sodium exposure promotes intravascular fluid retention with associated increases in intracardiac heart volumes, including the left atrium, which would be anticipated to contribute to increased risk of incident atrial fibrillation.2 Demonstration of the increased risk of PA in relation to cardiovascular outcomes, including atrial fibrillation, has been largely based on retrospective or cross-sectional analyses. For example, in one of the earliest reports, Milliez et al3 retrospectively compared the history of specific cardiovascular events in 124 patients with confirmed PA and 465 control patients with primary hypertension. In spite of seemingly similar levels of BP control, the PA patients were significantly more likely to have had a history of stroke and myocardial infarction and were >12 times as likely to have been previously diagnosed with an episode of atrial fibrillation. Reincke et al4 conducted a longitudinal assessment of patients included in a German registry of PA who had been treated with adrenalectomy and a mineralocorticoid receptor antagonist (MRA). Although the 10-year all-cause mortality was similar to PA patients to that of matched hypertensive controls, the PA patients were significantly more likely to have died from cardiovascular complications than the control patients without PA. Combined, these 2 …

Hyponatremia is a common adverse effect of diuretic use. The purpose of this study was to determine the incidence of Diuretic-induced hyponatremia (DIH) (serum sodium

Chlorthalidone and spironolactone are commonly used diuretics for patients with difficult-to-manage hypertension. Hyponatremia is a common adverse effect that results in discontinuing these medications in many subjects. We designed this study to determine the incidence of hyponatremia on spironolactone after developing a hyponatremic episode on chlorthalidone. Electronic health records were searched for patients seen at UAB’s outpatient clinics. Inclusion criteria included: patients who developed hyponatremia (serum sodium

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. Summary: Aside for small exceptions, European and American guidelines agree in terms of recommendations for diagnosing, evaluating, and treating resistant hypertension.

Background The association between serum urate and hypertension continues to be controversial. Animal models and studies in adolescents provided strong support of urate- lowering therapy (ULT) efficacy to improve early hypertension (1), while one recent randomized-controlled study in adults failed to find benefit (2). Objectives To test the hypothesis that serum urate reduction with allopurinol would lead to blood pressure reductions in young adults with pre-hypertension. Methods Single center, double-blinded, crossover trial in which participants were randomly assigned to allopurinol (300 daily mg) or placebo for a period of one month each. Adults ages 18-40, with baseline systolic blood pressure (SBP) ≥ 120 and 297.4 µmol/L) or ≥ 4.0 mg/dL (237.9 µmol/L) (men or women, respectively) were enrolled. Main exclusion criteria included chronic kidney disease, gout, or use of ULTs. The primary outcome was change from baseline in SBP assessed by 24 hour ambulatory blood pressure monitoring. Safety assessments were also conducted. Results 99 participants were randomized, and 82 completed study participation (Table 1). Serum urate decreased by -1.33 ± 1.21 mg/dL (-79.1 ± 72.0 µmol/L) during the allopurinol period (p 6.5 mg/dL (> 386.7 µmol/L) at baseline visit. No allopurinol hypersensitivity events or other serious adverse events were observed. Conclusion In the intention-to-treat analysis, urate -lowering therapy with allopurinol in young adults did not lead to reductions in blood pressure when compared with placebo. Blood pressure reductions with allopurinol may be limited only to participants with higher baseline serum urate levels. References [1] Feig DI, Soletsky B, Johnson RJ. JAMA. 2008;300:924-32. [2] McMullan CJ, Borgi L, Fisher N, et al. Clin J Am Soc Nephrol. 2017;12:807-16. Disclosure of Interests Angelo Gaffo: None declared, David Calhoun: None declared, Elizabeth Rahn: None declared, Suzanne Oparil: None declared, Paul Muntner Grant/research support from: Dr. Muntner declares research grant from Amgen, Peng Li: None declared, David Redden: None declared, Tanja Dudenbostel: None declared, Jeff Foster: None declared, Stephanie Biggers: None declared, Daniel Feig: None declared, Kenneth Saag Grant/research support from: Amgen, Ironwood/AstraZeneca, Horizon, SOBI, Takeda, Consultant for: Abbvie, Amgen, Ironwood/AstraZeneca, Bayer, Gilead, Horizon, Kowa, Radius, Roche/Genentech, SOBI, Takeda, Teijin

Objectives Refractory hypertension has been defined as uncontrolled blood pressure (at or above 140/90 mmHg) when on five or more classes of antihypertensive medication, inclusive of a diuretic. Because unbiased estimates of the prevalence of refractory hypertension in the United States are lacking, we aim to provide such estimates using data from the National Health and Nutrition Examination Surveys (NHANES). Methods Refractory hypertension was assessed across multiple NHANES cycles using the aforementioned definition. Eight cycles of NHANES surveys (1999-2014) representing 41 552 patients are the subject of this study. Prevalence of refractory hypertension across these surveys was estimated in the drug-treated hypertensive population after adjusting for the complex survey design and standardizing for age. Results Across all surveys, refractory hypertension prevalence was 0.6% [95% confidence interval (CI) (0.5, 0.7)] amongst drug-treated hypertensive adults; 6.2% [95% CI (5.1, 7.6)] of individuals with treatment-resistant hypertension actually had refractory hypertension. Although the prevalence of refractory hypertension ranged from 0.3% [95% CI (0.1, 1.0)] to 0.9% [95% CI (0.6, 1.2)] over the eight cycles considered, there was no significant trend in prevalence over time. Refractory hypertension prevalence amongst those prescribed five or more drugs was 34.5% [95% CI (27.9, 41.9)]. Refractory hypertension was associated with advancing age, lower household income, black race, and also chronic kidney disease, albuminuria, diabetes, prior stroke, and coronary heart disease. Conclusions We provided the first nationally representative estimate of refractory hypertension prevalence in US adults.

Background The extra-renal effects of aldosterone on left ventricular (LV) structure and function are exacerbated by increased dietary sodium in persons with hypertension. Previous studies demonstrated endothelial dysfunction and increased oxidative stress with high salt diet in normotensive salt-resistant subjects. We hypothesized that increased xanthine oxidase (XO), a product of endothelial cells, is related to 24-h urinary sodium and to LV hypertrophy and function in patients with resistant hypertension (RHTN). Methods The study group included persons with RHTN (n = 91), defined as a blood pressure > 140/90 mmHg on ≥ 3 medications at pharmacologically effective doses. Plasma XO activity and 24-h urine were collected, and cardiac magnetic resonance imaging (MRI) was performed to assess LV function and morphology. Sixty-seven normotensive persons on no cardiovascular medications served as controls. A subset of RHTN (n = 19) received spironolactone without salt restriction for six months with follow-up XO activity measurements and MRI analyses. Results XO activity was increased two-fold in RHTN vs. normal and was positively correlated with LV mass, LV diastolic function, and 24-h urinary sodium. In RHTN patients receiving spironolactone without salt restriction, LV mass decreased, but LV diastolic function and XO activity did not improve. Baseline urinary sodium was positively associated with rate of change of LV mass to volume ratio and the LV E/A ratio. Conclusions These results demonstrate a potential role of endothelium-derived oxidative stress and excess dietary salt in the pathophysiology of LV hypertrophy and diastolic dysfunction in persons with RHTN unaffected by the addition of spironolactone.

Spanish Sleep Network., [Rationale] Continuous positive airway pressure (CPAP) can significantly reduce blood pressure (BP) levels in patients with resistant hypertension and sleep apnea (OSA); however, the effect on patients with refractory hypertension (RfH) is not known. This study seeks to evaluate the effect of CPAP treatment on BP levels in patients with OSA and RfH, compared with those with OSA and resistant hypertension., [Methods] Post-hoc analysis of the HIPARCO randomized clinical trial on the effect of CPAP treatment on BP levels in patients with resistant hypertension. Those patients with uncontrolled 24-h ambulatory BP monitoring readings (>130 and/or >80 mmHg) in SBP or DBP were considered to have resistant hypertension (if they were taking three or four antihypertensive drugs) or RfH (if they were taking at least five drugs). OSA patients were randomized to receive CPAP or usual care for 3 months. They underwent a second 24-h ambulatory BP monitoring study to establish the effect of CPAP treatment on BP levels in both groups., [Results] A total of 98 patients were randomized to CPAP (19 RfH/79 resistant hypertension) and 96 to usual care (21 RfH/75 resistant hypertension). BP readings dropped more marked in patients with RfH than resistant hypertension, in both 24-h SBP (−9 vs. −1.6 mmHg, P = 0.021) and 24-h DBP (−7.3 vs. −2.3 mmHg, P = 0.074), especially at night (−11.3 vs. −3.8, P = 0.121 and −8.8 vs. −2.2, P = 0.054) respectively. Adjusted difference between groups was statistically significant in 24-h SBP levels (−7.4 mmHg, P = 0.021)., [Conclusion] CPAP lowers BP levels in both resistant hypertension and RfH patients although the degree of this reduction is higher in those with RfH especially during the night.

Refractory hypertension (RfH) is defined as a lack of blood pressure control despite the administration of at least 5 anti-hypertensive drugs. The factors associated with its natural history are unknown. This study aimed to evaluate both the incidence of RfH in an cohort of patients with resistant hypertension (RH) and the factors involved in that progression. This was an observational prospective multicenter study (24 centers) with 172 patients with confirmed RH (24-h ABPM) who underwent a further 24 h ABPM study at the end of the follow-up. Prospective information was obtained from all patients in their corresponding Hypertension Units via a standard clinical protocol, and they all underwent a sleep study. Thirty patients were diagnosed with RfH (17.4%) after a mean follow-up of 57 months, despite the prescription of a greater number of long-acting thiazide-like diuretics and mineralocorticoid receptor antagonists. The factors associated with progression to RfH were: a longer period since the diagnosis of RH (OR: 1.06, 95% CI: 1.01–1.1, p = 0.007); the HbA1c concentration (OR: 1.42, 95% CI: 1.42–1.8; p = 0.005); the initial heart rate (OR: 1.05, 95% CI: 1.01–1.09, p = 0.004); and poor adherence to continuous positive airway pressure (CPAP) in cases of obstructive sleep apnea (OR: 3.36, 95% CI: 1.47–7.7, p = 0.004). In conclusion, a considerable percentage of patients evolved from the RH to the RfH phenotype despite changes in their treatment. Some easily measurable variables, such as heart rate, the time since the diagnosis, the HbA1c level, and the presence of untreated obstructive sleep apnea (or poor adherence to CPAP) have been demonstrated to be prognostic factors in the progression to RfH.

The Lancet Commission on Hypertension identified that a key action to address the worldwide burden of high blood pressure (BP) was to improve the quality of BP measurements by using BP devices that have been validated for accuracy. Currently, there are over 3 000 commercially available BP devices, but many do not have published data on accuracy testing according to established scientific standards. This problem is enabled through weak or absent regulations that allow clearance of devices for commercial use without formal validation. In addition, new BP technologies have emerged (e.g. cuffless sensors) for which there is no scientific consensus regarding BP measurement accuracy standards. Altogether, these issues contribute to the widespread availability of clinic and home BP devices with limited or uncertain accuracy, leading to inappropriate hypertension diagnosis, management and drug treatment on a global scale. The most significant problems relating to the accuracy of BP devices can be resolved by the regulatory requirement for mandatory independent validation of BP devices according to the universally-accepted International Organization for Standardization Standard. This is a primary recommendation for which there is an urgent international need. Other key recommendations are development of validation standards specifically for new BP technologies and online lists of accurate devices that are accessible to consumers and health professionals. Recommendations are aligned with WHO policies on medical devices and universal healthcare. Adherence to recommendations would increase the global availability of accurate BP devices and result in better diagnosis and treatment of hypertension, thus decreasing the worldwide burden from high BP.

Background Multiple studies indicate that primary aldosteronism (PA) is common in patients with resistant hypertension, with an estimated prevalence of approximately 20%. Additional studies suggest that beyond this 20% of patients with classical PA, there is a larger proportion of patients with lesser degrees of hyperaldosteronism which contributes even more broadly to antihypertensive treatment resistance. Given these observations, it is intuitive that use of aldosterone antagonists will provide antihypertensive benefit in patients with resistant hypertension and evidence of aldosterone excess. Intriguingly, however, are clinical findings demonstrating substantive benefit of aldosterone antagonists in patients with resistant hypertension, but without demonstrative evidence of hyperaldosteronism, that is, with seemingly normal or even low aldosterone levels. Conclusion Spironolactone is clearly established as the most effective fourth agent for treatment of uncontrolled resistant hypertension. Emerging observations suggest a further role of spironolactone for counteracting the effects of diet high in sodium, particularly in obese, hypertensive patients.

The association between hyperuricemia and hypertension is controversial. Animal models, epidemiological data, and small clinical trials have favored a causative role for hyperuricemia in hypertension but more studies are necessary to elucidate putative mechanisms, population susceptibility, and potential for urate-lowering therapies (ULT) to decrease blood pressure (BP).To describe the background and design of the Serum Urate Reduction to Prevent Hypertension (SURPHER) study.SURPHER is a single center, double-blinded, crossover trial in which participants are randomly assigned to allopurinol (300mg) or placebo. Enrollment focused on adults 18-40years old with baseline systolic blood pressure≥120 and160mmHg or diastolic blood pressure≥80 and100mmHg, and serum urate ≥5.0mg/dL or ≥4.0mg/dL for men or women, respectively. SURPHER recruitment targets participants without chronic kidney disease (estimated glomerular filtration rate60mL/min/1.73m2), and without prior diagnosis of gout or use of ULT to treat gout. The primary outcome is change from baseline in blood pressure assessed by 24hour ambulatory blood pressure monitoring and mechanistic outcomes include changes in endothelial function as measured by flow-mediated dilation, as well as C-reactive protein levels.Since June 16, 2014 until present, SURPHER is recruiting participants in the city of Birmingham, Alabama.The study aims to enroll otherwise healthy young adults for a pharmacological intervention study with multiple study-related procedures. Challenges related to recruitment are anticipated and multiple strategies for increasing recruitment and retention are planned if necessary.

Background and objective We directly compared sleep apnoea (SA) rates and risk of cardiovascular and mortality outcomes among SA patients with resistant hypertension (RH) and non-RH within a large diverse hypertension population. Methods A retrospective cohort study between 1 January 2006 and 31 December 2010 among hypertensive adults (age ≥ 18 years) was performed within an integrated health system. Rates of SA in RH and non-RH were determined. Multivariable logistic regression analyses were used to calculate OR for SA. Cox proportional hazard modelling was used to estimate hazard ratios (HRs) for cardiovascular and mortality outcomes between SA in RH versus SA in non-RH adjusting for age, gender, race, BMI, chronic kidney disease and other comorbidities. Results SA was identified in 33 682 (7.2%) from 470 386 hypertensive individuals. SA in RH accounted for 5806 (9.6%) compared to SA in non-RH 27 876 individuals (6.8%). Multivariable OR (95% CI) for SA was 1.16 (1.12, 1.19), 3.57 (3.47, 3.66) and 2.20 (2.15, 2.25) for RH versus non-RH, BMI ≥ 30, and males, respectively. Compared to SA in non-RH individuals, SA in RH had a multivariable adjusted HR (95% CI) of 1.24 (1.13, 1.36), 1.43 (1.28, 1.61), 0.98 (0.85, 1.12) and 1.04 (0.95, 1.14) for ischaemic heart event (IHE), congestive heart failure (CHF), stroke and mortality, respectively. Conclusion We observed a modest increase in likelihood for SA among RH compared to non-RH patients. Risks for IHE and CHF were higher for SA in RH compared to SA in non-RH patients; however, there were no differences in risk for stroke and mortality.

Resistant or difficult to treat hypertension is defined as high blood pressure that remains uncontrolled with 3 or more different antihypertensive medications, including a diuretic. Recent definitions also include controlled blood pressure with use of 4 or more medications as also being resistant to treatment. Recently, refractory hypertension, an extreme phenotype of antihypertensive treatment failure has been defined as hypertension uncontrolled with use of 5 or more antihypertensive agents, including a long-acting thiazide diuretic and a mineralocorticoid receptor antagonist. Patients with resistant vs refractory hypertension share similar characteristics and comorbidities, including obesity, African American race, female sex, diabetes, coronary heart disease, chronic kidney disease, and obstructive sleep apnea. Patients with refractory vs resistant hypertension tend to be younger and are more likely to have been diagnosed with congestive heart failure. Refractory hypertension might also differ from resistant hypertension in terms of underlying cause. Preliminary evidence suggests that refractory hypertension is more likely to be neurogenic in etiology (ie, heightened sympathetic tone), vs a volume-dependent hypertension that is more characteristic of resistant hypertension in general.

In 2014, the American Heart Association (AHA) announced the funding of a Strategically Focused Research Network (SFRN) focused on hypertension. Hypertension was chosen for a SFRN because interdisciplinary hypertension research has great potential to impact the AHA’s mission and 2020 goals of improving the cardiovascular health of all Americans by 20% while reducing deaths from cardiovascular disease (CVD) and stroke by 20% by 2020. Four centers with highly integrated basic, clinical, and population science projects were selected for the AHA SFRN: Cincinnati Children’s Hospital, Medical College of Wisconsin (MCW), University of Alabama at Birmingham (UAB), and University of Iowa (UI). The Cincinnati center is studying ambulatory blood pressure (BP) and hypertensive target organ damage in adolescents. The MCW center is studying epigenetics of hypertension by conducting studies of genome-wide DNA methylation patterns. The UAB center is studying racial differences in the prevalence and determinants of abnormal diurnal BP patterns. The UI center is studying copeptin, a possible early biomarker for preeclampsia and vascular endothelial function, and arterial stiffness changes occurring before and during preeclampsia. In this article, we provide an overview of the science being conducted at each center and describe the innovative training program incorporated into the SFRN. A goal of the Hypertension SFRN is to facilitate collaborative research. Therefore, we describe opportunities and resources available to researchers interested in collaborating with SFRN investigators. The AHA Hypertension SFRN has the potential to identify new approaches for the prevention and treatment of hypertension and, ultimately, improve the cardiovascular health of Americans. The SFRN is a mechanism initiated by the AHA to address key strategic issues as determined by the AHA Board of Directors. In 2014, hypertension was selected for a SFRN because improvement in its prevention and treatment has the potential to impact the AHA’s mission and 2020 goals: to …

Fabry disease is an X-linked lysosomal storage disorder caused by the deficiency of the enzyme, α-galactosidase A that induces the accumulation of the substrate globotriaosylceramide. Currently approved enzyme replacement therapy using recombinant human α-galactosidase A improves patient symptoms but a majority of patients experience adverse events due to the multiple infusions required for full therapeutic efficacy. Our approach is to use medicinal chemistry and phylogenic comparisons to introduce mutations into the human enzyme to increase catalytic activity and/or stability to generate an improved therapeutic enzyme that may require fewer infusions. We designed mutations at three regions of the human α-galactosidase A: the active site, the dimer interface, and a site for glycosylation. The M208E mutation, adjacent to the Y207 active site residue, increased enzyme activity 3.01-fold. This mutation introduced a charged Glu residue that is adjacent to the Y207 active site residue and close to a site of N-glycosylation. The W277C mutation, designed to promote dimer stability, introduced a strong thiol-aromatic interaction (Cys-Phe) at the dimer interface and increased activity 2.31-fold. The W277C and M208E mutations modify the structure of the enzyme into forms with enhanced thermal stability 3.7- and 3.9-fold, respectively and positive cooperativity resulting in increased Hill coefficient from 1.0 to 4.60 and 3.47, respectively. Enhanced thermal stability and positive cooperativity predict improved in vivo activity and superior therapeutic properties. Our results demonstrate the value of in vitro mutagenesis for α-galactosidase A and support future perspectives to validate these results in Fabry disease patients.

Introduction: Masked uncontrolled hypertension (MUCH) is defined as controlled automated office blood pressure (AOBP) in clinic, but uncontrolled out-of-clinic BP by 24-hr ambulatory blood pressure monitoring (ABPM). Prior studies indicate that the prevalence of masked hypertension in patients with newly diagnosed obstructive sleep apnea (OSA) is nearly 30%. In addition, patients with OSA have a higher prevalence of masked hypertension than patients without OSA. Aim: Prospective determination of the prevalence and severity of OSA in patients with MUCH. Methods: In this prospective evaluation, 167 treated hypertensive patients were recruited from the University of Alabama at Birmingham Hypertension Clinic after having controlled BP at three or more clinic visits. All patients were evaluated by AOBP with the BpTRU device, ABPM, and diagnostic polysomnography (PSG) to determine the presence and severity of OSA based on the apnea-hypopnea index (AHI). Out of 153 who completed ABPM, 58 patients were controlled by AOBP and by ABPM, indicating true controlled hypertension and the remaining 95 patients were controlled by AOBP, but uncontrolled by ABPM, indicative of MUCH. 49 true controlled hypertensive and 69 MUCH patients completed PSG. Results: MUCH patients had a mean AHI of 10.3±13.3 compared to 4.5±10.2 events/hr in true controlled hypertension (p =0.045). Overall, the prevalence of OSA was 48.5% in patients with MUCH compared to 26.5% in true controlled hypertension (p = 0.01). Conclusion: MUCH has significant higher prevalence and severity of OSA compared to true controlled hypertension. These findings suggest that untreated OSA may contribute to the development of MUCH.

Prior studies suggest benefits of blood pressure lowering on cardiovascular risk may be attenuated in patients with resistant hypertension compared with the general hypertensive population, but prospective data are lacking.We assessed intensive (120 mm Hg) versus standard (140 mm Hg) systolic blood pressure targets on adverse outcome risk according to baseline resistant hypertension status, using Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Systolic Blood Pressure Intervention Trial (SPRINT) patient-level data. Patients were categorized as having baseline apparent resistant hypertension (blood pressure ≥130/80 mm Hg while using 3 antihypertensive drugs or use of ≥4 drugs regardless of blood pressure) or non-resistant hypertension (all others). Cox regression was used to assess effects of treatment assignment, resistant hypertension status, their interaction, and other covariates, on first occurrence of 2 outcomes: myocardial infarction, stroke, cardiovascular death ± heart failure, and the same outcomes plus all-cause death, individually.Among 14,094 patients, 2710 (19.2%) had baseline apparent resistant hypertension. In adjusted models, an intensive target reduced risk of both outcomes (myocardial infarction/stroke/cardiovascular death: hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.71-0.93; myocardial infarction/stroke/heart failure/cardiovascular death: HR 0.78; 95% CI, 0.69-0.88) as well as stroke (HR 0.72; 95% CI, 0.55-0.94) and heart failure (HR 0.73; 95% CI, 0.59-0.91). An intensive target also appeared to reduce myocardial infarction, cardiovascular death, and all-cause death risk. Benefits were observed irrespective of baseline resistant hypertension status.Our findings provide the first evidence to support guidance to treat resistant hypertension to the same blood pressure goal as non-resistant hypertension.

This review will summarize recent developments in the research on the mineralocorticoid receptor and its impact on obstructive sleep apnea and metabolic syndrome. Aldosterone excess plays an important role in the association between resistant hypertension and obstructive sleep apnea. The prevalence of obesity is increasing rapidly worldwide and is especially common among patients with obstructive sleep apnea, resistant hypertension, and metabolic syndrome, suggesting probable mechanistic links between these three conditions. Mineralocorticoid receptor expression is increased in obese individuals, which may contribute to the common association between obesity and hyperaldosteronism. Mineralocorticoid receptor blockers reduce the severity of obstructive sleep apnea among resistant hypertension patients. A large body of literature demonstrates a strong association between obesity, hyperaldosteronism, resistant hypertension, and sleep apnea, including specific benefit of treatment with mineralocorticoid receptor blockers for these separate disorders.

Background: African-Americans have the highest prevalence of elevated blood pressure (BP) and poorer BP control than other racial/ethnic groups in the US. Untreated sleep apnea, common among minority populations, may explain the high prevalence of uncontrolled BP. We studied the association of objective measurements of sleep apnea severity with resistant hypertension and uncontrolled BP among African-Americans in the Jackson Heart Study (JHS) Sleep Ancillary study. Methods: Between 2012 and 2016, JHS participants (N=913) underwent an in-home sleep apnea study (measuring nasal pressure, abdominal and thoracic inductance plethysmography, oximetry, position, ECG); resting blood pressure; anthropometry; and completed questionnaires. Sleep apnea was defined as an apnea-hypopnea index > 15 and nocturnal hypoxemia was quantified as % sleep time > 90mmHg. Controlled BP was defined as systolic BP < 2 antihypertensive medications. Resistant hypertension was defined as having elevated BP while on 3-4 antihypertensive medications with one being a diuretic; or use of > 4 antihypertensive medications. The study sample was limited to individuals with prevalent hypertension (N=613). Multinomial models were fit to determine the association between sleep apnea severity and resistant hypertension or uncontrolled BP (vs. controlled BP) adjusted for age, sex, education, smoking status, obesity (body mass index>30) and diabetes. Results: The study sample had a mean age of 54.8 years, were predominately female (69.8%), obese (57.8%), and college educated (52.7%). Approximately 40.5% had sleep apnea, which was untreated in 95% of individuals. Among the sample, 25.4% had uncontrolled BP and 4.9% were classified as resistant hypertension. After adjustment for confounders, individuals with sleep apnea had a 2.6-fold higher odds of resistant hypertension (95% confidence interval: 1.1, 5.9). A standard deviation higher %Sat Conclusion: Among our sample of African-Americans in the JHS, sleep apnea was related to resistant hypertension but not uncontrolled BP. The study identifies the high burden of untreated sleep apnea in African-Americans and its association with resistant hypertension, a significant risk factor for stroke and heart disease. Research is needed on the impact of treating sleep apnea as a strategy for decreasing resistant hypertension, and thus, narrowing cardiovascular health disparities.

Refractory hypertension is an extreme phenotype of treatment failure defined as uncontrolled blood pressure in spite of ≥5 classes of antihypertensive agents, including chlorthalidone and a mineralocorticoid receptor antagonist. A prospective evaluation of possible mechanisms of refractory hypertension has not been done. The goal of this study was to test for evidence of heightened sympathetic tone as indicated by 24-hour urinary normetanephrine levels, clinic and ambulatory heart rate (HR), HR variability, arterial stiffness as indexed by pulse wave velocity, and systemic vascular resistance compared with patients with controlled resistant hypertension. Forty-four consecutive patients, 15 with refractory and 29 with controlled resistant hypertension, were evaluated prospectively. Refractory hypertensive patients were younger (48±13.3 versus 56.5±14.1 years; P =0.038) and more likely women (80.0 versus 51.9%; P =0.047) compared with patients with controlled resistant hypertension. They also had higher urinary normetanephrine levels (464.4±250.2 versus 309.8±147.6 µg per 24 hours; P =0.03), higher clinic HR (77.8±7.7 versus 68.8±7.6 bpm; P =0.001) and 24-hour ambulatory HR (77.8±7.7 versus 68.8±7.6; P =0.0018), higher pulse wave velocity (11.8±2.2 versus 9.4±1.5 m/s; P =0.009), reduced HR variability (4.48 versus 6.11; P =0.03), and higher systemic vascular resistance (3795±1753 versus 2382±349 dyne·s·cm 5 ·m 2 ; P =0.008). These findings are consistent with heightened sympathetic tone being a major contributor to antihypertensive treatment failure and highlight the need for effective sympatholytic therapies in patients with refractory hypertension.

Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial (hypopnea) or complete interruption (apnea) in breathing during sleep due to airway collapse in the pharyngeal region. OSA and its cardiovascular consequences have been widely explored in observational and prospective studies. Most evidence verifies the positive relationship between OSA and hypertension, coronary artery disease, atrial fibrillation, stroke and heart failure. However, more studies are needed to better assess the impact of OSA, and possible benefit of treatment with continuous positive airway pressure (CPAP) on dyslipidemia, type 2 diabetes, insulin resistance and cardiovascular mortality. The leading pathophysiological mechanisms involved in the changes triggered by OSA, include intermittent hypoxemia and re-oxygenation, arousals and changes in intrathoracic pressure. Hypertension is strongly related with activation of the sympathetic nervous system, stimulation of the renin-angiotensin-aldosterone system and impairment of endothelial function. The high prevalence of OSA in the general population, hypertensive patients and especially obese individuals and patients resistant to antihypertensive therapy, highlights the need for effective screening, diagnosis and treatment of OSA to decrease cardiovascular risk.

Hypertension (HTN) and CKD are closely associated with an intermingled cause and effect relationship. Blood pressure (BP) typically rises with declines in kidney function, and sustained elevations in BP hasten progression of kidney disease. This review addresses current management issues in HTN in patients with CKD including altered circadian rhythm of BP, timing of antihypertensive medication dosing, BP targets, diagnostic challenges in evaluating secondary forms of HTN, and the role of salt restriction in CKD. HTN in patients with CKD is often accompanied by a decrease in the kidney’s ability to remove salt. Addressing this salt sensitivity is critical for the management of HTN in CKD. In addition to the well-established use of an ACEI or angiotensin receptor blocker, dietary salt restriction and appropriate diuretic therapy make up the mainstay of HTN treatment in patients with CKD. Bedtime dosing of antihypertensive medications can restore nocturnal dips in BP, and future clinical practice guidelines may recommend bedtime dosing of 1 or more antihypertensive medications in patients with CKD.

Background Implantable hypoglossal nerve upper airway stimulation (HNS) is a novel strategy approved by the US Food and Drug Administration for the management of moderate-to-severe obstructive sleep apnea (OSA) in patients with continuous positive airway pressure therapy intolerance or failure. Because of the proximity of a cardiac implantable electronic device (CIED) to this stimulator, interaction between these devices is theoretically possible. Objective The purpose of this study was to assess interactions between an implantable HNS device and a CIED. Methods We retrospectively analyzed 14 ad hoc patients with continuous positive airway pressure-intolerant, moderate-to-severe OSA and pre-existing transvenous CIEDs undergoing HNS implantation (Inspire II, Inspire Medical Systems). We assessed these devices for their pre and postimplant OSA outcomes and for possible device–device interaction. All patients were followed up for 1 year. Results Of the 14 patients, 9 had a pacemaker (8 dual-chamber, 1 single-chamber), 4 had an implantable cardioverter-defibrillator (2 dual-chamber, 1 single-chamber), and 1 had a cardiac resynchronization therapy device. All the HNS devices were implanted on the opposite side of the CIED. All CIEDs were programmed bipolar. HNS were programmed either unipolar or bipolar. During implant, intraoperative testing was performed to confirm that bipolar and unipolar HNS stimulation did not impact CIED sensing. During the follow-up period, no oversensing episodes were noted on the CIEDs. Conclusion In this early experience, simultaneous use of a novel hypoglossal nerve upper airway stimulation device with transvenous CIEDs seems to be safe, effective, and without any device–device interactions.

Background Both serum urate (sUA) and endothelial dysfunction have been associated with hypertension and cardiovascular disease. Increasing sUA level has been associated with endothelial dysfunction and higher inflammatory markers. To date, however, few studies have examined the relationship between sUA, endothelial dysfunction, and blood pressure (BP) including young and largely healthy individuals. Objectives To determine whether there is an association between higher sUA, endothelial dysfunction as measured by flow-mediated dilation (FMD), and BP in young adults. Methods We conducted a cross-sectional analysis of baseline data for consecutively enrolled individuals (age 18 – 40 years). Enrollment criteria included baseline systolic BP (SBP) ≥120 and Results 86 participants included in the analysis. Participants recruited had a mean age (±standard deviation) of 28.5±6.9 years, 36% were female, 41% African-Americans, mean BMI was 29.2±6.8 kg/m2, and mean sUA was 5.9±1.2 mg/dL (n=77, range from 3.9 to 8.5 mg/dL). We found no significant cross-sectional associations between sUA, FMD, and BP variables assessed by ABPM (Table). Participants in the upper tertile of sUA had significantly worse FMD than those in the lower tertiles (Figure). However, this difference was no longer significant after multivariable adjustment age, gender, race, and BMI. Conclusions In this cross-sectional analysis of young adults, there was no evidence to support an association between sUA levels and endothelial dysfunction or BP. Endothelial dysfunction or BP might be associated with changes in sUA when measured longitudinally in individuals, but not when measured cross-sectionally in populations. Larger studies will be needed to confirm these results. References Ruggiero, C. Am J Cardiol, 2007. 100(1): p. 115–21. Rossi, R. J Am Coll Cardiol, 2004. 44(8): p. 1636–40. Feig, D. JAMA, 2008. 300(8): p. 924–32. Acknowledgements National Institute of Arthritis and Musculoskeletal and Skin Diseases P50AR060772, K24AR052361 (to KGS). Disclosure of Interest M. Saddekni: None declared, K. Saag Grant/research support from: AstraZeneca, Crealta, Takeda, Consultant for: Ardea/AstraZeneca, Crealta, Takeda, T. Dudenbostel: None declared, D. Calhoun: None declared, S. Oparil Grant/research support from: NHLBI Brigham and Women9s Hospital, Center CVD Prev, Novartis Pharmaceutical Corporation, AstraZeneca AB (Duke University), Actelion Pharmaceuticals US,NIH/NHLBI, Merck and Co., Consultant for: Amgen, Bayer, Boehringer Ingelheim, AstraZeneca, Medtronic, GlaxoSmithKline, Forest Labs Inc., D. Feig: None declared, P. Muntner: None declared, P. Foster: None declared, S. Biggers: None declared, E. Rahn: None declared, P. Li: None declared, D. Redden: None declared, A. Gaffo Grant/research support from: Amgen, AstraZeneca, Consultant for: Cymabay, Ardea, Employee of: US Government

An estimated 10% to 30% of hypertensive patients can be considered to be resistant to treatment defined as controlled or uncontrolled blood pressure (BP) with use of ≥4 medications, including a diuretic.1–4 A large number of cross-sectional and longitudinal studies have demonstrated that patients with treatment-resistant hypertension compared with patients with more easily controlled hypertension have increased cardiovascular risk, including coronary artery disease, congestive heart failure, stroke, and chronic kidney disease (CKD). Since publication of the first Scientific Statement on the Diagnosis, Evaluation, and Treatment of Resistant Hypertension by the American Heart Association in 2008, which coincided with development of device-based strategies for treating resistant hypertension, resistant hypertension has become a major focus of intensive experimental and clinical investigation.1 In that context, this review highlights scientific advances specific for resistant hypertension that have occurred in the last 2 years, including important findings related to prognosis, medication adherence, clinical use of aldosterone antagonists, and application of device-based therapies. Multiple cross-sectional studies have related resistant hypertension to prevalent cardiovascular and renal diseases.2–8 Recent analyses have strengthened those associations with use of longitudinal or prospective assessments. From a secondary analysis of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) results, which included 1870 participants with resistant hypertension, Muntner et al9 reported that compared with study participants without resistant hypertension, participants with resistant hypertension had a 44%, 57%, 23%, 88%, 95%, and 30% higher risk of incident coronary heart disease, stroke, peripheral artery disease, heart failure, end-stage renal disease, and all-cause mortality, respectively, during the almost 5-year duration of the study after adjustment for multiple traditional risk factors, such as age, smoking, diabetes mellitus, and low-density lipoprotein cholesterol. Because of the ALLHAT study design, diuretic use in this analysis was not required to …

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in 33,357 high-risk hypertensive participants. ALLHAT compared cardiovascular disease outcomes in participants initially treated with an angiotensin-converting enzyme inhibitor (lisinopril), a calcium channel blocker (amlodipine), or a thiazide-type diuretic (chlorthalidone). We report stroke outcomes in 1517 participants in-trial and 1596 additional participants during post-trial passive surveillance, for a total follow-up of 8-13 years. Stroke rates were higher with lisinopril (6-year rate/100 = 6.4) than with chlorthalidone (5.8) or amlodipine (5.5) in-trial but not including post-trial (10-year rates/100 = 13.2 [chlorthalidone], 13.1[amlodipine], and 13.7 [lisinopril]). In-trial differences were driven by race (race-by-lisinopril/chlorthalidone interaction P = .005, race-by-amlodipine/lisinopril interaction P = .012) and gender (gender-by-lisinopril/amlodipine interaction P = .041), separately. No treatment differences overall, or by race or gender, were detected over the 10-year period. No differences appeared among treatment groups in adjusted risk of all-cause mortality including post-trial for participants with nonfatal in-trial strokes. Among Blacks and women, lisinopril was less effective in preventing stroke in-trial than either chlorthalidone or amlodipine, even after adjusting for differences in systolic blood pressure. These differences abated by the end of the post-trial period.

Glucagon-like peptide-1 receptor agonists, used to treat type 2 diabetes mellitus, are associated with small reductions in systolic blood pressure (SBP) and increases in heart rate. However, findings based on clinic measurements do not adequately assess a drug’s 24-hour pharmacodynamic profile. The effects of dulaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, on BP and heart rate were investigated using ambulatory BP monitoring. Patients (n=755; 56±10 years; 81% white; 48% women), with type 2 diabetes mellitus, taking ≥1 oral antihyperglycemic medication, with a clinic BP between 90/60 and 140/90 mm Hg were randomized to dulaglutide (1.5 or 0.75 mg) or placebo subcutaneously for 26 weeks. Ambulatory BP monitoring was performed at baseline and at 4, 16, and 26 weeks. The primary end point was change from baseline to week 16 in mean 24-hour SBP, a tree gatekeeping strategy compared the effects of dulaglutide to placebo. Both doses of dulaglutide were noninferior to placebo for changes in 24-hour SBP and diastolic blood pressure, and dulaglutide 1.5 mg significantly reduced SBP (least squares mean difference [95% confidence interval]), −2.8 mm Hg [−4.6, −1.0]; P ≤0.001). Dulaglutide 0.75 mg was noninferior to placebo (1.6 bpm; [0.3, 2.9]; P ≤0.02) for 24-hour heart rate (least squares mean difference [95% confidence interval]), but dulaglutide 1.5 mg was not (2.8 bpm [1.5, 4.2]). Dulaglutide 1.5 mg was associated with a reduction in 24-hour SBP and an increase in 24-hour heart rate. The mechanisms responsible for the observed effects remain to be clarified.

Resistant hypertension is a clinically distinct subgroup of hypertension defined by the failure to achieve blood pressure control on optimal dosing of at least 3 antihypertensive medications of different classes, including a diuretic. The pathophysiology of hypertension can be attributed to aldosterone excess in more than 20% of patients with resistant hypertension. Existing dogma attributes the increase in blood pressure seen with increases in aldosterone to its antinatriuretic effects in the distal nephron. However, emerging research, which has identified and has begun to define the function of amiloride-sensitive sodium channels and mineralocorticoid receptors in the systemic vasculature, challenges impaired natriuresis as the sole cause of aldosterone-mediated resistant hypertension. This review integrates these findings to better define the role of the vasculature and aldosterone in the pathophysiology of resistant hypertension. In addition, a brief guide to the treatment of resistant hypertension is presented.

Few data exist on whether healthy lifestyle factors are associated with better prognosis among individuals with apparent treatment-resistant hypertension, a high-risk phenotype of hypertension. The purpose of this study was to assess the association of healthy lifestyle factors with cardiovascular events, all-cause mortality, and cardiovascular mortality among individuals with apparent treatment-resistant hypertension. We studied participants (n=2043) from the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) study with apparent treatment-resistant hypertension (blood pressure ≥140/90 mm Hg despite the use of 3 antihypertensive medication classes or the use of ≥4 classes of antihypertensive medication regardless of blood pressure control). Six healthy lifestyle factors adapted from guidelines for the management of hypertension (normal waist circumference, physical activity ≥4 times/week, nonsmoking, moderate alcohol consumption, high Dietary Approaches to Stop Hypertension diet score, and low sodium-to-potassium intake ratio) were examined. A greater number of healthy lifestyle factors were associated with lower risk for cardiovascular events (n=360) during a mean follow-up of 4.5 years. Multivariable-adjusted hazard ratios [HR (95% confidence interval)] for cardiovascular events comparing individuals with 2, 3, and 4 to 6 versus 0 to 1 healthy lifestyle factors were 0.91 (0.68–1.21), 0.80 (0.57–1.14), and 0.63 (0.41–0.95), respectively ( P -trend=0.020). Physical activity and nonsmoking were individual healthy lifestyle factors significantly associated with lower risk for cardiovascular events. Similar associations were observed between healthy lifestyle factors and risk for all-cause and cardiovascular mortality. In conclusion, healthy lifestyle factors, particularly physical activity and nonsmoking, are associated with a lower risk for cardiovascular events and mortality among individuals with apparent treatment-resistant hypertension.

Apparent treatment-resistant hypertension (aTRH) is defined as uncontrolled hypertension despite the use of three or more antihypertensive medication classes or controlled hypertension while treated with four or more antihypertensive medication classes. We evaluated the association of aTRH with incident stroke, coronary heart disease (CHD), and all-cause mortality. Participants from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) Study treated for hypertension with aTRH (n = 2043) and without aTRH (n = 12,479) were included. aTRH was further categorized as controlled aTRH (≥4 medication classes and controlled hypertension) and uncontrolled aTRH (≥3 medication classes and uncontrolled hypertension). Over a median of 5.9, 4.4, and 6.0 years of follow-up, the multivariable adjusted hazard ratio for stroke, CHD, and all-cause mortality associated with aTRH versus no aTRH was 1.25 (0.94–1.65), 1.69 (1.27–2.24), and 1.29 (1.14–1.46), respectively. Compared with controlled aTRH, uncontrolled aTRH was associated with CHD (hazard ratio, 2.33; 95% confidence interval, 1.21–4.48), but not stroke or mortality. Comparing controlled aTRH with no aTRH, risk of stroke, CHD, and all-cause mortality was not elevated. aTRH was associated with an increased risk for coronary heart disease and all-cause mortality.

Background Studies suggest that treatment-resistant hypertension is common and increasing in prevalence among US adults. Although hypertension is a risk factor for end-stage renal disease (ESRD), few data are available for the association between treatment-resistant hypertension and ESRD risk. Study Design Prospective cohort study. Setting & Participants We analyzed data from 9,974 REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study participants treated for hypertension without ESRD at baseline. Predictor Treatment-resistant hypertension was defined as uncontrolled blood pressure (BP) with concurrent use of 3 antihypertensive medication classes including a diuretic or use of 4 or more antihypertensive medication classes including a diuretic regardless of BP. Outcome Incident ESRD was identified by linkage of REGARDS Study participants with the US Renal Data System. Measurements During a baseline in-home study visit, BP was measured twice and classes of antihypertensive medication being taken were determined by pill bottle inspection. Results During a median follow-up of 6.4 years, there were 152 incident cases of ESRD (110 ESRD cases among 2,147 with treatment-resistant hypertension and 42 ESRD cases among 7,827 without treatment-resistant hypertension). The incidence of ESRD per 1,000 person-years for hypertensive participants with and without treatment-resistant hypertension was 8.86 (95% CI, 7.35-10.68) and 0.88 (95% CI, 0.65-1.19), respectively. After multivariable adjustment, the HR for ESRD comparing hypertensive participants with versus without treatment-resistant hypertension was 6.32 (95% CI, 4.30-9.30). Of participants who developed incident ESRD during follow-up, 72% had treatment-resistant hypertension at baseline. Limitations BP, estimated glomerular filtration rate, and albuminuria assessed at a single time. Conclusions Individuals with treatment-resistant hypertension are at increased risk for ESRD. Appropriate clinical management strategies are needed to treat treatment-resistant hypertension in order to preserve kidney function in this high-risk group.

Objective:Patients with resistant hypertension (RHTN) have a higher prevalence of diastolic dysfunction, left ventricular hypertrophy (LVH) and increased of risk of cardiovascular complications compared to patients with more easily controlled hypertension (i.e. controlled non-RHTN)), which is blood

SPRINT was a well designed and executed randomized clinical trial funded by the National Institutes of Health (NIH) in which 9,361 hypertensive patients at high risk of cardiovascular disease with blood pressure (BP) above 130 mm H g and below 180 mm H g, were randomly assigned to be treated to a goal systolic BP (SBP) of less than 140 vs. less than 120 mm Hg. The trial recruited hypertensive individuals in the United States who were older than 50 years of age and had never had a stroke and were not diabetic, but were either older than 75 years of age (28% of subjects), had chronic kidney disease with estimated glomerular filtration rate (eGFR) 20 m l/min/1.73 m 2 of body surface (28% of subjects), or had clinical or subclinical cardiovascular disease or a Framingham score indicating 10-year risk of >15% of cardiovascular disease. By 1-year post-randomization, the trial achieved SBPs of 121.4 mm H g in the intensive treatment group and 136.2 mm H g in the standard treatment group, a difference that was maintained throughout the trial. SPRINT was stopped early after a median follow-up of 3.26 years because of a 25% relative risk reduction in the intensive treatment group of the primary endpoint (myocardial infarction or other coronary syndromes, stroke, heart failure, or death from cardiovascular causes) and 27% in all-cause mortality. In order to achieve these results, patients in the intensive therapy group took a mean of approximately 3 vs. 2 antihypertensive drugs in the standard therapy group. About 3,000 patients in each group completed 3 years of the trial, a little more than 1,000 completed 4 and slightly less than 300 in each group completed 5 years of the trial. The beneficial results were found across all prespecified groups. However, it is noteworthy that individuals older than 75 years of age appeared to benefit more than younger subjects. Is it possible that these older individuals were “survivors,” who although at high cardiovascular risk, were able to benefit more than the more “mixed” younger group? As well, those subjects who entered the trial with SBP of

Left ventricular hypertrophy and diastolic dysfunction (LVDD) remain highly frequent markers of cardiac damage and risk of progression to symptomatic heart failure, especially in resistant hypertension (RHTN). We have previously demonstrated that administration of sildenafil in hypertensive rats improves LVDD, restoring phosphodiesterase type 5 (PDE-5) inhibition in cardiac myocytes.We hypothesized that the long-acting PDE-5 inhibitor tadalafil may be clinically useful in improving LVDD in RHTN independently of blood pressure (BP) reduction. A single blinded, placebo-controlled, crossover study enrolled 19 patients with both RHTN and LVDD. Firstly, subjects received tadalafil (20 mg) for 14 days and after a 2-week washout period, they received placebo orally for 14 days. Patients were evaluated by office BP and ambulatory BP monitoring (ABPM), endothelial function (FMD), echocardiography, plasma brain natriuretic peptide (BNP-32), cyclic guanosine monophosphate (cGMP) and nitrite levels.No significant differences were detected in BP measurements. Remarkably, at least four echocardiographic parameters related with diastolic function improved accompanied by decrease in BNP-32 in tadalafil use. Although increasing cGMP, tadalafil did not change endothelial function or nitrites. There were no changes in those parameters after placebo.The current findings suggest that tadalafil improves LV relaxation through direct effects PDE-5-mediated in the cardiomyocytes with potential benefit as an adjunct to treat symptomatic subjects with LVDD such as RHTN patients.

Apparent treatment-resistant hypertension is defined as systolic/diastolic BP ≥ 140/90 mmHg with concurrent use of three or more antihypertensive medication classes or use of four or more antihypertensive medication classes regardless of BP level.The prevalence of apparent treatment-resistant hypertension among Reasons for Geographic and Racial Differences in Stroke study participants treated for hypertension (n=10,700) was determined by level of estimated GFR and albumin-to-creatinine ratio, and correlates of apparent treatment-resistant hypertension among those participants with CKD were evaluated. CKD was defined as an albumin-to-creatinine ratio ≥ 30 mg/g or estimated GFR60 ml/min per 1.73 m(2).The prevalence of apparent treatment-resistant hypertension was 15.8%, 24.9%, and 33.4% for those participants with estimated GFR ≥ 60, 45-59, and45 ml/min per 1.73 m(2), respectively, and 12.1%, 20.8%, 27.7%, and 48.3% for albumin-to-creatinine ratio10, 10-29, 30-299, and ≥ 300 mg/g, respectively. The multivariable-adjusted prevalence ratios (95% confidence intervals) for apparent treatment-resistant hypertension were 1.25 (1.11 to 1.41) and 1.20 (1.04 to 1.37) for estimated GFR levels of 45-59 and45 ml/min per 1.73 m(2), respectively, versus ≥ 60 ml/min per 1.73 m(2) and 1.54 (1.39 to 1.71), 1.76 (1.57 to 1.97), and 2.44 (2.12 to 2.81) for albumin-to-creatinine ratio levels of 10-29, 30-299, and ≥ 300 mg/g, respectively, versus albumin-to-creatinine ratio10 mg/g. After multivariable adjustment, men, black race, larger waist circumference, diabetes, history of myocardial infarction or stroke, statin use, and lower estimated GFR and higher albumin-to-creatinine ratio levels were associated with apparent treatment-resistant hypertension among individuals with CKD.This study highlights the high prevalence of apparent treatment-resistant hypertension among individuals with CKD.