David A. Calhoun

Resistant Hypertension: Diagnosis, Evaluation, and Treatment A Scientific Statement From the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research

Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.

Resistant Hypertension: Diagnosis, Evaluation, and Treatment. A Scientific Statement From the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research

Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.

Hyperaldosteronism Among Black and White Subjects With Resistant Hypertension

Abstract—Recent reports suggesting that the prevalence of primary hyperaldosteronism may be higher than historically thought have relied on an elevated plasma aldosterone concentration/plasma renin activity ratio to either diagnose or identify subjects at high risk of having primary hyperaldosteronism and have not included suppression testing of all evaluated subjects. In this prospective study of 88 consecutive patients referred to a university clinic for resistant hypertension, we determined the 24-hour urinary aldosterone excretion during high dietary salt ingestion, baseline plasma renin activity, and plasma aldosterone in all subjects. Primary hyperaldosteronism was confirmed if plasma renin activity was <1.0 ng/mL per hour and urinary aldosterone was >12 &mgr;g/24-hour during high urinary sodium excretion (>200 mEq/24-hour). Eighteen subjects (20%) were confirmed to have primary hyperaldosteronism. The prevalence of hyperaldosteronism was similar in black and white subjects. Of the 14 subjects with confirmed hyperaldosteronism who have been treated with spironolactone, all have manifested a significant reduction in blood pressure. In this population, an elevated plasma aldosterone/plasma renin activity ratio (>20) had a sensitivity of 89% and a specificity of 71% with a corresponding positive predictive value of 44% and a negative predictive value of 96%. These data provide strong evidence that hyperaldosteronism is a common cause of resistant hypertension in black and white subjects. The accuracy of these results is strengthened by having done suppression testing of all evaluated subjects.

Pathogenesis of Hypertension

Clinical Principles A clearer understanding of the pathogenesis of hypertension will probably lead to more highly targeted therapies and to greater reduction in hypertension-related cardiovascular disease morbidity than can be achieved with current empirical treatment. Physiologic Principles More than 90% of cases of hypertension do not have a clear cause. Hypertension clusters in families and results from a complex interaction of genetic and environmental factors. The hypertension-related genes identified to date regulate renal salt and water handling. Major pathophysiologic mechanisms of hypertension include activation of the sympathetic nervous system and reninangiotensinaldosterone system. Endothelial dysfunction, increased vascular reactivity, and vascular remodeling may be causes, rather than consequences, of blood pressure elevation; increased vascular stiffness contributes to isolated systolic hypertension in the elderly. Essential hypertension, or hypertension of unknown cause, accounts for more than 90% of cases of hypertension. It tends to cluster in families and represents a collection of genetically based diseases or syndromes with several resultant inherited biochemical abnormalities (1-4). The resulting phenotypes can be modulated by various environmental factors, thereby altering the severity of blood pressure elevation and the timing of hypertension onset. Many pathophysiologic factors have been implicated in the genesis of essential hypertension: increased sympathetic nervous system activity, perhaps related to heightened exposure or response to psychosocial stress; overproduction of sodium-retaining hormones and vasoconstrictors; long-term high sodium intake; inadequate dietary intake of potassium and calcium; increased or inappropriate renin secretion with resultant increased production of angiotensin II and aldosterone; deficiencies of vasodilators, such as prostacyclin, nitric oxide (NO), and the natriuretic peptides; alterations in expression of the kallikreinkinin system that affect vascular tone and renal salt handling; abnormalities of resistance vessels, including selective lesions in the renal microvasculature; diabetes mellitus; insulin resistance; obesity; increased activity of vascular growth factors; alterations in adrenergic receptors that influence heart rate, inotropic properties of the heart, and vascular tone; and altered cellular ion transport (Figure 1) (2). The novel concept that structural and functional abnormalities in the vasculature, including endothelial dysfunction, increased oxidative stress, vascular remodeling, and decreased compliance, may antedate hypertension and contribute to its pathogenesis has gained support in recent years. Figure 1. Pathophysiologic mechanisms of hypertension. Although several factors clearly contribute to the pathogenesis and maintenance of blood pressure elevation, renal mechanisms probably play a primary role, as hypothesized by Guyton (5) and reinforced by extensive experimental and clinical data. As discussed in this paper, other mechanisms amplify (for example, sympathetic nervous system activity and vascular remodeling) or buffer (for example, increased natriuretic peptide or kallikreinkinin expression) the pressor effects of renal salt and water retention. These interacting pathways play major roles in both increasing blood pressure and mediating related target organ damage. Understanding these complex mechanisms has important implications for the targeting of antihypertensive therapy to achieve benefits beyond lowering blood pressure. Genetics Evidence for genetic influence on blood pressure comes from various sources. Twin studies document greater concordance of blood pressures in monozygotic than dizygotic twins (6), and population studies show greater similarity in blood pressure within families than between families (7). The latter observation is not attributable to only a shared environment since adoption studies demonstrate greater concordance of blood pressure among biological siblings than adoptive siblings living in the same household (8). Furthermore, single genes can have major effects on blood pressure, accounting for the rare Mendelian forms of high and low blood pressure (3). Although identifiable single-gene mutations account for only a small percentage of hypertension cases, study of these rare disorders may elucidate pathophysiologic mechanisms that predispose to more common forms of hypertension and may suggest novel therapeutic approaches (3). Mutations in 10 genes that cause Mendelian forms of human hypertension and 9 genes that cause hypotension have been described to date, as reviewed by Lifton and colleagues (3, 9) (Figure 2). These mutations affect blood pressure by altering renal salt handling, reinforcing the hypothesis of Guyton (5) that the development of hypertension depends on genetically determined renal dysfunction with resultant salt and water retention (2). Figure 2. Mutations altering blood pressure in humans. NaCl TAL DCT CCT red blue In most cases, hypertension results from a complex interaction of genetic, environmental, and demographic factors. Improved techniques of genetic analysis, especially genome-wide linkage analysis, have enabled a search for genes that contribute to the development of primary hypertension in the population. Application of these techniques has found statistically significant linkage of blood pressure to several chromosomal regions, including regions linked to familial combined hyperlipidemia (10-13). These findings suggest that there are many genetic loci, each with small effects on blood pressure in the general population. Overall, however, identifiable single-gene causes of hypertension are uncommon, consistent with a multifactorial cause of primary hypertension (14). The candidate gene approach typically compares the prevalence of hypertension or the level of blood pressure among individuals of contrasting genotypes at candidate loci in pathways known to be involved in blood pressure regulation. The most promising findings of such studies relate to genes of the reninangiotensinaldosterone system, such as the M235T variant in the angiotensinogen gene, which has been associated with increased circulating angiotensinogen levels and blood pressure in many distinct populations (15-17), and a common variant in the angiotensin-converting enzyme (ACE) gene that has been associated in some studies with blood pressure variation in men (18, 19). However, these variants seem to only modestly affect blood pressure, and other candidate genes have not shown consistent and reproducible associations with blood pressure or hypertension in larger populations (3); thus, demonstration of common genetic causes of hypertension in the general population remains elusive (16, 20, 21). The best studied monogenic cause of hypertension is the Liddle syndrome, a rare but clinically important disorder in which constitutive activation of the epithelial sodium channel predisposes to severe, treatment-resistant hypertension (22). Epithelial sodium channel activation has been traced to mutations in the or subunits of the channel, resulting in inappropriate sodium retention at the renal collecting duct level. Patients with the Liddle syndrome typically present with volume-dependent, low-renin, and low-aldosterone hypertension. Screenings of general hypertensive populations indicate that the Liddle syndrome is rare and does not contribute substantially to the development of hypertension in the general population (23). In selected groups, however, evidence suggests that epithelial sodium channel activation might be a more common cause of hypertension. Epithelial sodium channel activation, as evidenced by increased sodium conductance in peripheral lymphocytes, has been noted in 11 of 44 (25%) patients with resistant hypertension (blood pressure uncontrolled while treated with 3 medications) presenting at our clinic (24). Three of the 11 patients were treated with amiloride, an epithelial sodium channel antagonist, and blood pressure was reduced in all patients. These preliminary results suggest that genetic causes of hypertension, although uncommon in general hypertensive populations, may be more frequent in selected hypertensive populations, particularly in those resistant to conventional pharmacologic therapies. Inherited Cardiovascular Risk Factors Cardiovascular risk factors, including hypertension, tend to cosegregate more commonly than would be expected by chance. Approximately 40% of persons with essential hypertension also have hypercholesterolemia. Genetic studies have established a clear association between hypertension and dyslipidemia (25). Hypertension and type 2 diabetes mellitus also tend to coexist. Hypertension is approximately twice as common in persons with diabetes as in persons without diabetes, and the association is even stronger in African Americans and Mexican Americans (26). The leading cause of death in patients with type 2 diabetes is coronary heart disease, and diabetes increases the risk for acute myocardial infarction as much as a previous myocardial infarction in a nondiabetic person (26). Since 35% to 75% of the cardiovascular complications of diabetes are attributable to hypertension, diabetic patients need aggressive antihypertensive treatment, as well as treatment of dyslipidemia and glucose control. Hypertension, insulin resistance, dyslipidemia, and obesity often occur concomitantly (27). Associated abnormalities include microalbuminuria, high uric acid levels, hypercoagulability, and accelerated atherosclerosis. This cosegregation of abnormalities, referred to as the insulin-resistance syndrome or the metabolic syndrome, increases cardiovascular disease (CVD) risk. Physicians must assess and treat these risk factors individually, recognizing that many hypertensive patients have insulin resistance, dyslipidemia, or both. Sympathetic Nervous System Increased sym

Efficacy of low-dose spironolactone in subjects with resistant hypertension

BACKGROUND Previous reports have demonstrated the antihypertensive efficacy of high doses of spironolactone in subjects with primary aldosteronism and, to a lesser degree, subjects with resistant hypertension. METHODS In current analysis, we examined the antihypertensive benefit of adding low-dose spironolactone to multidrug regimens that included a diuretic and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) in subjects with resistant hypertension with and without primary aldosteronism. Subjects referred for resistant hypertension were evaluated with an early morning plasma renin activity, 24-h urinary aldosterone and sodium during a high dietary salt ingestion. The diagnosis of primary aldosteronism was confirmed with a renin activity <1.0 ng/mL/h, urinary aldosterone >12 mug/24 h and urinary sodium >200 mEq/24 h. After biochemical evaluation, spironolactone (12.5 to 25 mg/d) was added to each subjects antihypertensive regimen. If blood pressure (BP) remained uncontrolled, the dose of spironolactone was titrated up to 50 mg/d. Follow-up BP was determined at 6 weeks, 3 months, and 6 months. RESULTS A total number of 76 subjects were included in the analysis, 34 of whom had biochemical primary aldosteronism. Low-dose spironolactone was associated with an additional mean decrease in BP of 21 +/- 21/10 +/- 14 mm Hg at 6 weeks and 25 +/- 20/12 +/- 12 mm Hg at 6-month follow-up. The BP reduction was similar in subjects with and without primary aldosteronism and was additive to the use of ACE inhibitors, ARBs, and diuretics. CONCLUSIONS We conclude that low-dose spironolactone provides significant additive BP reduction in African American and white subjects with resistant hypertension with and without primary aldosteronism.

Effects of Dietary Sodium Reduction on Blood Pressure in Subjects With Resistant Hypertension Results From a Randomized Trial

Observational studies indicate a significant relation between dietary sodium and level of blood pressure. However, the role of salt sensitivity in the development of resistant hypertension is unknown. The present study examined the effects of dietary salt restriction on office and 24-hour ambulatory blood pressure in subjects with resistant hypertension. Twelve subjects with resistant hypertension entered into a randomized crossover evaluation of low (50 mmol/24 hours×7 days) and high sodium diets (250 mmol/24 hours×7 days) separated by a 2-week washout period. Brain natriuretic peptide; plasma renin activity; 24-hour urinary aldosterone, sodium, and potassium; 24-hour ambulatory blood pressure monitoring; aortic pulse wave velocity; and augmentation index were compared between dietary treatment periods. At baseline, subjects were on an average of 3.4±0.5 antihypertensive medications with a mean office BP of 145.8±10.8/83.9±11.2 mm Hg. Mean urinary sodium excretion was 46.1±26.8 versus 252.2±64.6 mmol/24 hours during low- versus high-salt intake. Low- compared to high-salt diet decreased office systolic and diastolic blood pressure by 22.7 and 9.1 mm Hg, respectively. Plasma renin activity increased whereas brain natriuretic peptide and creatinine clearance decreased during low-salt intake, indicative of intravascular volume reduction. These results indicate that excessive dietary sodium ingestion contributes importantly to resistance to antihypertensive treatment. Strategies to substantially reduce dietary salt intake should be part of the overall treatment of resistant hypertension.

Drugs targeting the renin–angiotensin–aldosterone system

Effective antihypertensive therapy has made a major contribution to the reductions in the morbidity and mortality of cardiovascular disease that have been achieved since the 1960s. However, blood-pressure control with conventional drugs has not succeeded in reducing cardiovascular disease risks to levels seen in normotensive persons. Drugs that inhibit or antagonize components of the renin–angiotensin–aldosterone system are addressing this deficiency by targeting both blood pressure and related structural and functional abnormalities of the heart and blood vessels, thus preventing target-organ damage and related cardiovascular events.

Mechanisms responsible for sympathetic activation by cigarette smoking in humans.

The pressor and tachycardic effects of cigarette smoking are associated with an increase in plasma catecholamines, suggesting the dependence of these effects on adrenergic stimulation. Whether the stimulation occurs at a central or a peripheral level and whether reflex mechanisms are involved is unknown. Methods and ResultsIn nine normotensive healthy subjects (age, 33.0±3.5 years, mean±SEM), we measured blood pressure (Finapres device), heart rate (ECG), calf blood flow and vascular resistance (venous occlusion plethysmography), plasma norepinephrine and epinephrine (high-performance liquid chromatography assay), and postganglionic muscle sympathetic nerve activity (microneurography from the peroneal nerve) while subjects were smoking a filter cigarette (nicotine content, 1.1 mg) or were in control condition. Cigarette smoking (which raised plasma nicotine measured by highperformance liquid chromatography from 1.0±0.9 to 44.2±7.1 ng/mL) markedly and significantly increased mean arterial pressure (+13.2±2.3%), heart rate (+30.3±4.7%), calf vascular resistance (+ 12.1±4.9%), plasma norepinephrine (+34.8±7.0%), and plasma epinephrine (+90.5±39.0%). In contrast, muscle sympathetic nerve activity showed a marked reduction (integrated activity −31.8±5.1%, P < .01). The reduction was inversely related to the increase in mean arterial pressure (r= −.67, P < .05), but the slope of the relation was markedly less (−54.1±7.5%, P < .05) than that obtained by intravenous infusion of phenylephrine in absence of smoking. The hemodynamic and neurohumoral changes were still visible 30 minutes after smoking and occurred again on smoking a second cigarette. Sham smoking was devoid of any hemodynamic and neurohumoral effect. ConclusionsThese data support the hypothesis that in humans the sympathetic activation induced by smoking depends on an increased release and/or a reduced clearance of catecholamines at the neuroeffector junctions. Central sympathetic activity is inhibited by smoking, presumably via a baroreceptor stimulation triggered by the smoking-related pressor response. The baroreflex is impaired by smoking, however, indicating that partial inability to reflexly counteract the effect of sympathetic activation is also responsible for the pressor response.

Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide

Objectives Aliskiren is a novel, orally active renin inhibitor. Its antihypertensive efficacy and safety, alone and in combination with hydrochlorothiazide (HCTZ), were investigated in an 8-week, double-blind, placebo-controlled trial in hypertensive patients. The effects of these treatments on plasma renin activity (PRA) were also assessed. Methods A total of 2776 patients aged ≥ 18 years with mean sitting diastolic blood pressure (MSDBP) 95–109 mmHg were randomized to receive once-daily treatment with aliskiren (75, 150 or 300 mg), HCTZ (6.25, 12.5 or 25 mg), the combination of aliskiren and HCTZ, or placebo, in a factorial design. The primary endpoint was the change in MSDBP from baseline to week 8. PRA was assessed at these timepoints at selected study centers. Results Aliskiren monotherapy was superior to placebo (P < 0.001; overall Dunnetts test) in reducing MSDBP and mean sitting systolic blood pressure (MSSBP). Combination treatment was superior to both component monotherapies in reducing BP (maximum MSSBP/MSDBP reduction of 21.2/14.3 mmHg from baseline with aliskiren/HCTZ 300/25 mg), and resulted in more responders (patients with MSDBP < 90 mmHg and/or ≥ 10 mmHg reduction) and better control rates (patients achieving MSSBP/MSDBP < 140/90 mmHg) than either monotherapy. Aliskiren monotherapy reduced PRA by up to 65% from baseline. Although HCTZ monotherapy increased PRA by up to 72%, PRA decreased in all of the combination therapy groups. All active treatments were well tolerated. Conclusions Aliskiren monotherapy demonstrated significant BP lowering, and its effect was considerably greater when combined with HCTZ. Renin inhibition with aliskiren neutralized the compensatory rise in PRA induced by HCTZ.

Characterization of Resistant Hypertension: Association Between Resistant Hypertension, Aldosterone, and Persistent Intravascular Volume Expansion

BACKGROUND Resistant hypertension is a common clinical problem and greatly increases the risk of target organ damage. METHODS We evaluated the characteristics of 279 consecutive patients with resistant hypertension (uncontrolled despite the use of 3 antihypertensive agents) and 53 control subjects (with normotension or hypertension controlled by using <or=2 antihypertensive medications). Participants were prospectively examined for plasma aldosterone concentration, plasma renin activity, aldosterone to renin ratio, brain-type natriuretic peptide, atrial natriuretic peptide, and 24-hour urinary aldosterone (UAldo), cortisol, sodium, and potassium values while adhering to a routine diet. RESULTS Plasma aldosterone (P < .001), aldosterone to renin ratio (P < .001), 24-hour UAldo (P = .02), brain-type natriuretic peptide (P = .007), and atrial natriuretic peptide (P = .001) values were higher and plasma renin activity (P = .02) and serum potassium (P < .001) values were lower in patients with resistant hypertension vs controls. Of patients with resistant hypertension, men had significantly higher plasma aldosterone (P = .003), aldosterone to renin ratio (P = .02), 24-hour UAldo (P < .001), and urinary cortisol (P < .001) values than women. In univariate linear regression analysis, body mass index (P = .01), serum potassium (P < .001), urinary cortisol (P < .001), urinary sodium (P = .02), and urinary potassium (P < .001) values were correlated with 24-hour UAldo levels. Serum potassium (P = .001), urinary potassium (P < .001), and urinary sodium (P = .03) levels were predictors of 24-hour UAldo levels in multivariate modeling. CONCLUSIONS Aldosterone levels are higher and there is evidence of intravascular volume expansion (higher brain-type and atrial natriuretic peptide levels) in patients with resistant hypertension vs controls. These differences are most pronounced in men. A significant correlation between 24-hour urinary aldosterone levels and cortisol excretion suggests that a common stimulus, such as corticotropin, may underlie the aldosterone excess in patients with resistant hypertension.