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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.

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.

Masked uncontrolled hypertension (MUCH) is defined as controlled automated office blood pressure (BP; AOBP <135/85 mm Hg) in-clinic in patients receiving antihypertensive medication(s) but uncontrolled BP out-of-clinic by 24-hour ambulatory BP monitoring (ABPM; awake ≥135/85 mm Hg). We hypothesized that MUCH patients have greater out-of-clinic sympathetic activity compared with true controlled hypertensives. Patients being treated for hypertension were prospectively recruited after 3 or more consecutive clinic visits. All patients were evaluated by in-clinic automated office BP, plasma catecholamines, and spot-urine/plasma metanephrines. In addition, out-of-clinic 24-hour ABPM, 24-hour urinary for catecholamines and metanephrines was done. Out of 237 patients recruited, 169 patients had controlled in-clinic BP of which 156 patients had completed ABPM. Seventy-four were true controlled hypertensives, that is controlled by clinic automated office BP and by out-of-clinic ABPM. The remaining 82 were controlled by clinic automated office BP, but uncontrolled during out-of-clinic ABPM, indicative of MUCH. After exclusion of 4 patients because of inadequate or lack of 24-hour urinary collections, 72 true controlled hypertensive and 80 MUCH patients were analyzed. MUCH patients had significantly higher out-of-clinic BP variability and lower heart rate variability compared with true controlled hypertensives, as well as higher levels of out-of-clinic urinary catecholamines and metanephrines levels consistent with higher out-of-clinic sympathetic activity. In contrast, there was no difference in in-clinic plasma catecholamines and spot-urine/plasma levels of metanephrines between the 2 groups, consistent with similar levels of sympathetic activity while in clinic. MUCH patients have evidence of heightened out-of-clinic sympathetic activity compared with true controlled hypertensives, which may contribute to the development of MUCH.

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 <0.001), posterior wall thickness (10.1±3.1 versus 7.7±1.5 mm; P =0.001), and septal wall thickness (14.5±3.8 versus 10.0±2.2 mm; P <0.001). There was no difference in B-type natriuretic peptide levels and left atrial or ventricular volumes. Diastolic dysfunction was noted in RfHTN. Our findings demonstrate greater left ventricular hypertrophy without chamber enlargement in RfHTN, suggesting that antihypertensive treatment failure is not attributable to intravascular volume retention., (© 2018 American Heart Association, Inc.)

Resistant hypertension, defined as blood pressure >140/90 mm Hg despite using ≥3 antihypertensive medications, is a well-recognized clinical entity. Patients with resistant hypertension are at an increased risk of cardiovascular disease compared with those with more easily controlled hypertension. Coronary heart disease mortality rates of younger adults are stagnating or on the rise. The purpose of our study was to characterize the phenotype and risk factors of younger patients with resistant hypertension, given the dearth of data on cardiovascular risk profile in this cohort. We conducted a cross-sectional analysis with predefined age groups of a large, ethnically diverse cohort of 2170 patients referred to the Hypertension Clinic at the University of Alabama at Birmingham. Patients (n=2068) met the inclusion criteria and were classified by age groups, that is, ≤40 years (12.7% of total cohort), 41 to 55 years (32.1%), 56 to 70 years (36.1%), and ≥71 years (19.1%). Patients aged ≤40 years compared with those aged ≥71 years had significantly earlier onset of hypertension (24.7±7.4 versus 55.0±14.1 years; P <0.0001), higher rates of obesity (53.4% versus 26.9%; P <0.0001), and significantly higher levels of plasma aldosterone (11.3±9.8 versus 8.9±7.4 ng/dL; P =0.005), plasma renin activity (4.9±10.2 versus 2.5±5.0 ng/mL per hour; P =0.001), 24-hour urinary aldosterone (13.4±10.0 versus 8.2±6.2 µg/24 h; P <0.0001), and sodium excretion (195.9±92.0 versus 146.8±67.1 mEq/24 h; P <0.0001). Among patients with resistant hypertension, younger individuals have a distinct phenotype characterized by overlapping risk factors and comorbidities, including obesity, high aldosterone, and high dietary sodium intake compared with elderly., (© 2017 American Heart Association, Inc.)

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., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: Resistant hypertension (RHTN), blood pressure (BP) at least 140/90 mmHg despite using at least three different medications, including a diuretic, is associated with high dietary sodium and hyperaldosteronism. Mineralocorticoid receptor antagonists are recommended for treatment of RHTN, however, BP response to these agents varies widely. In the current analysis, we assessed predictors of BP response to spironolactone in patients with RHTN., Methods: We retrospectively evaluated the BP response to adding spironolactone 12.5-25 mg to existing medications. A favorable BP response was defined as a reduction in SBP of at least 10 mmHg. Tested variables included baseline characteristics and biochemical parameters., Results: A total of 79 patients with RHTN were included in the analysis. Evaluated patients were more likely women (53.2%) and African-American (55.8%); were generally obese (76%) and were prescribed an average of four antihypertensive medications. Baseline SBP was 153.6 ± 22.3 mmHg; addition of spironolactone resulted in a mean reduction of 15.5 ± 20.7 mmHg. Patients with high urinary sodium excretion (≥200 mEq/24 h) had a significantly greater BP reduction compared with patients with normal excretion (<200 mEq/24 h) (P = 0.008). Multivariable analysis identified 24 h urinary sodium excretion as a significant predictor of BP response (P = 0.021) after controlling for potential confounders, including primary aldosteronism., Conclusion: The antihypertensive effect of spironolactone is positively related to urinary sodium excretion regardless of aldosterone status. These findings suggest that mineralocorticoid receptor antagonists may be of preferential benefit in counteracting the BP effects of high dietary sodium.

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., (© 2015 American Heart Association, Inc.)

In this review, we discuss the possible pathophysiological mechanisms and the role of arterial stiffness as a biomarker, a blood pressure-independent predictor of cardiovascular morbidity and mortality. The effects of different antihypertensive drug classes on noninvasively assessed markers of arterial stiffness are also discussed. Current evidence will be reviewed regarding the effect of drugs on arterial stiffness, including the peripheral and central effects of angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, dihydropyridine calcium channel blockers, beta blockers (including vasodilating beta blockers), diuretics, and mineralocorticoid antagonists.

Among patients with resistant hypertension (RHTN), there are those whose blood pressure (BP) remains uncontrolled in spite of maximal medical therapy. This retrospective analysis aims to characterize these patients with refractory hypertension. Refractory hypertension was defined as BP that remained uncontrolled after ≥3 visits to a hypertension clinic within a minimum 6-month follow-up period. Of the 304 patients referred for RHTN, 29 (9.5%) remained refractory to treatment. Patients with refractory hypertension and those with controlled RHTN had similar aldosterone levels and plasma renin activity (PRA). Patients with refractory hypertension had higher baseline BP (175±23/97±15 mm Hg vs 158±25/89±15 mm Hg; P=.001/.005) and heart rate, and higher rates of prior stroke and congestive heart failure. During follow-up, the BP of patients with refractory hypertension remained uncontrolled (168.4±14.8/93.8±17.7 mm Hg) in spite of use of an average of 6 antihypertensive medications, while those of patients with controlled RHTN decreased to 129.3±11.2/77.6±10.8 mm Hg. Spironolactone reduced the BP by 12.9±17.8/6.6±13.7 mm Hg in patients with refractory hypertension and by 24.1±16.7/9.2±12.0 mm Hg in patients with controlled RHTN. In patients with RHTN, approximately 10% remain refractory to treatment. Similar aldosterone and PRA levels and a diminished response to spironolactone suggest that aldosterone excess does not explain the treatment failure., (© 2011 Wiley Periodicals, Inc.)

The morning blood pressure surge (MBPS) has been shown to be an independent predictor of cardiovascular events. There is insufficient evidence on the effect of nebivolol, a vasodilating β1-receptor blocker, on the MBPS when given in the morning or the evening. This is a prospective, randomized, double-blind, crossover study designed to test morning vs. evening dosing of nebivolol in nondiabetic, hypertensive patients. Patients received nebivolol 5 mg/day (force-titrated to 10 mg/day after 1 week) in the morning or evening and corresponding placebos. Patients underwent ambulatory BP monitoring at baseline and after each treatment phase. Forty-two patients were randomized, of whom 38 completed both study periods. Both morning and evening dosed nebivolol significantly lowered daytime, nighttime, and 24-hour BP after 3 weeks of treatment. Evening (but not morning) dosing significantly reduced prewaking systolic BP from baseline (8.64 ± 26.46 mm Hg, P = .048). Nebivolol given in the morning or the evening significantly reduces 24-hour BP parameters. Evening dosed nebivolol may confer some advantage over morning dosing in reducing prewaking systolic BP., (© 2012 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

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. [ABSTRACT FROM AUTHOR]

Resistant hypertension (RHTN) is an increasingly common clinical problem that is often heterogeneous in etiology, risk factors, and comorbidities. It is defined as uncontrolled blood pressure on optimal doses of three antihypertensive agents, ideally one being a diuretic. The definition also includes controlled hypertension with use of four or more antihypertensive agents. Recent observational studies have advanced the characterization of patients with RHTN. Patients with RHTN have higher rates of cardiovascular events and mortality compared with patients with more easily controlled hypertension. Secondary causes of hypertension, including obstructive sleep apnea, primary aldosteronism, renovascular disease, are common in patients with RHTN and often coexist in the same patient. In addition, RHTN is often complicated by metabolic abnormalities. Patients with RHTN require a thorough evaluation to confirm the diagnosis and optimize treatment, which typically includes a combination of lifestyle adjustments, and pharmacologic and interventional treatment. Combination therapy including a diuretic, a long-acting calcium channel blocker, an angiotensin-converting enzyme inhibitor, a beta blocker, and a mineralocorticoid receptor antagonist where warranted is the classic regimen for patients with treatment-resistant hypertension. Mineralocorticoid receptor antagonists like spironolactone or eplerenone have been shown to be efficacious in patients with RHTN, heart failure, chronic kidney disease, and primary aldosteronism. Novel interventional therapies, including baroreflex activation and renal denervation, have shown that both of these methods may be used to lower blood pressure safely, thereby providing exciting and promising new options to treat RHTN. [ABSTRACT FROM AUTHOR]