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Research Article
Originally Published 18 May 2015
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Refractory Hypertension: Evidence of Heightened Sympathetic Activity as a Cause of Antihypertensive Treatment Failure

Tanja Dudenbostel, Maria C. Acelajado, Roberto Pisoni, Peng Li, Suzanne Oparil, and David A. CalhounAuthor Info & Affiliations
Hypertension
Volume 66, Number 1
https://doi.org/10.1161/HYPERTENSIONAHA.115.05449
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Abstract

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·cm5·m2; 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.

Introduction

Refractory hypertension has been proposed as a clinical phenotype of antihypertensive treatment failure.1 The initial description of this phenotype was based on a retrospective analysis of patients referred to a hypertension specialty clinic for resistant hypertension (RHTN).1 Of 304 consecutive patients with confirmed RHTN, 29 patients, or ≈10%, were identified as having refractory hypertension defined as failure to control systolic and diastolic blood pressure (BP) to <140/90 mm Hg after a minimum of 6 months of treatment by a clinical hypertension specialist. In that analysis, patients with refractory hypertension were receiving an average of 6 classes of antihypertensive agents, including the thiazide-like diuretic chlorthalidone and a mineralocorticoid receptor antagonist (MRA), most often spironolactone. Patients with refractory hypertension manifested a consistently higher resting clinic heart rate (HR) compared with patients with controlled RHTN. This elevation in HR was interpreted as evidence of heightened sympathetic tone, suggesting that increased sympathetic nervous system activity may play a potentially important role in the pathogenesis of antihypertensive treatment failure.
In a recent cross-sectional analysis of 14 809 hypertensive adults participating in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, refractory hypertension, defined as uncontrolled hypertension (>140/90 mm Hg) with use of ≥5 antihypertensive classes of agents, had a prevalence of 0.5% of all hypertensive participants and 3.6% of participants with RHTN.2 Black race, male sex, obesity, chronic kidney disease (CKD), diabetes mellitus, and history of stroke and coronary heart disease were associated with refractory hypertension in the REGARDS population. In this analysis, clinic HR was not higher in participants with refractory hypertension compared with all hypertensive participants or with participants with controlled RHTN.
This study was conducted to prospectively test for evidence of heightened sympathetic tone as indicated by 24-hour urinary normetanephrine levels, clinic and ambulatory HR, arterial stiffness, and peripheral vascular resistance in patients with refractory hypertension. In addition, brain natriuretic peptide (BNP) and thoracic fluid content (TFC) were measured as indices of intravascular fluid volume. Contemporary patients also referred for RHTN but whose BP was controlled with treatment, that is, controlled RHTN, served as a comparator group. The study design also allowed for prospective determination of the prevalence of refractory hypertension among patients referred to a hypertension specialty clinic for RHTN.

Methods

Patient Identification

Consecutive patients referred to the University of Alabama at Birmingham Hypertension Clinic for RHTN (BP >140/90 mm Hg with use of ≥3 antihypertensive medications, including a diuretic) and who were subsequently diagnosed with refractory hypertension or controlled RHTN were prospectively enrolled into the study protocol.
All referred patients underwent determination of aldosterone and cortisol status by measurement of plasma aldosterone concentration, plasma renin activity, and 24-hour urinary excretion of aldosterone, cortisol, sodium, potassium, and creatinine as part of their routine clinical care for RHTN.3–5 Other secondary causes of hypertension were excluded as clinically indicated.5

Routine Treatment Approach

Patients were identified as having refractory or controlled RHTN based on the BP in response to routine treatment provided by hypertension specialists. All patients referred for RHTN were seen by 2 clinical hypertension specialists at every clinic visit. The patient’s antihypertensive medication regimen was revised according to routine clinical care if the clinic BP remained above goal.5 All patients were counseled to ingest a low-salt/high-fiber diet according to guidelines.5 The standardized treatment approach included, as needed to achieve BP control, initiating and maximizing doses of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; a calcium channel blocker (most often amlodipine); preferential use of chlorthalidone as diuretic; addition of spironolactone (or eplerenone if spironolactone was not tolerated); preferential use of a combined α–β-antagonist (most often labetalol); addition of a centrally acting α2-adrenergic agonist (most often clonidine); and finally, addition of a vasodilator (minoxidil or hydralazine). Loop diuretics were reserved for use in patients with clinical evidence of fluid retention.
After routine clinical follow-up of ≥3 visits for ≥ 6 months, patients with refractory hypertension were identified. Refractory hypertension was defined as uncontrolled BP (>140/90 mm Hg) in spite of being adherent to a regimen that consisted of >5 classes of antihypertensive agents, including 25 mg of chlorthalidone daily and an MRA (25 mg of spironolactone daily or 50 mg of eplerenone twice daily) without evidence of underlying secondary causes of hypertension. Patients with controlled RHTN defined as controlled BP in the office with use of ≥4 antihypertensive agents per American Heart Association specifications were identified as control subjects.5
Controlled resistant and refractory patients were prospectively enrolled into the experimental protocol in a 2-to-1 fashion, that is, 2 control subjects were enrolled for each subject enrolled with refractory hypertension. The control subjects were recruited from patients seen consecutively in clinic after enrolling each refractory subject. Patients were excluded from the study if there were signs and symptoms of heart failure (HF) or if having been hospitalized within 30 days for an acute episode of HF,6,7 atrial fibrillation, if there were concerns that that patient was nonadherent with the prescribed antihypertensive regimen, or if the patient had stage 4 or 5 CKD.8
This study was approved by the University of Alabama at Birmingham Institutional Review Board, and written informed consent was obtained from all patients before study enrollment. The study was conducted according to institutional guidelines.

Patient Survey

All patients were surveyed, and medical records were reviewed for estimated duration of hypertension and history of diabetes mellitus, dyslipidemia, coronary artery disease (CAD), stroke, and HF. During clinic visits, patients were routinely asked whether they have taken their antihypertensive medications regularly. Medication adherence was routinely assessed by the Morisky 8-Item Medication Adherence Questionnaire.9 Adherence was considered inadequate if patients scored >2 points.

Biochemical Testing

Biochemical evaluation per study protocol included measurement of 24-hour urinary normetanephrine levels, serum creatinine, estimated glomerular filtration rate,10 serum potassium, BNP, and high-sensitivity C-reactive protein. Blood samples were obtained in the morning between 7 to 9 am at the study visit after overnight fasting and before taking the morning medication after being seated for 5 minutes.11 The 24-hour urine collections were done while patients were consuming their usual diet and without change in their level of physical activity. Adequacy of the 24-hour urine collection was assessed by measuring 24-hour creatinine excretion rates.

Clinic BP Measurements

Clinic BP was measured by a hypertension specialist after at least 5 minutes of quiet rest in the sitting position with the back supported using the auscultatory method while supporting the arm at the heart level during BP measurement. An appropriate sized cuff was used with a cuff bladder encircling at least 80% of the arm. Three BP readings were taken at intervals of 2 minutes by the physician, and the second and third readings were used to average BP. The BP was measured in both arms, and the arm with the higher BP was used for further BP measurements. All BP measurements were performed according to guidelines.5

Ambulatory BP, HR, and HR Variability

All patients underwent 24-hour ambulatory BP monitoring (ABPM) to confirm uncontrolled BP in patients with refractory hypertension and to confirm controlled BP in patients with clinically controlled RHTN. An automated, noninvasive, oscillometric device (Oscar 2; SunTech Medical, Inc, Morrisville, NC) was used to perform ABPM.12,13 An appropriate sized cuff was used with a cuff bladder encircling at least 80% of the arm, according to guidelines.6 The first measurement was obtained in the clinic to ensure a proper function. Recordings were made every 20 minutes for the daytime (awake) and every 30 minutes for the nighttime (asleep) for a 24-hour period. Awake and asleep periods were defined individually according to the patient’s self-reported data. All patients took prescribed medications normally during ABPM, which were performed on working days, whereas usual activities were maintained. Standard calculations for ABPM were recorded. Valid 24-hour ABPM had to have recorded >80% of successful measurements. Controlled ambulatory BP was defined as mean 24-hour BP <130/80 mm Hg with a daytime (awake) BP of <135/80 mm Hg and a nighttime (asleep) BP of <120/70 mm Hg by ambulatory monitoring according to guidelines.12,13
HR variability (HRV) was estimated by calculating the SD of daytime and nighttime HR values obtained with ABPM.14

Pulse Wave Analysis and Pulse Wave Velocity

All patients underwent applanation tonometry for measurement of carotid-femoral pulse wave velocity (PWV) and central pulse wave analysis computed from the radial artery waveform using a transfer function (SphygmoCor; AtCor Medical, Sydney, Australia) according to guidelines.15,16 Pulse wave assessments were done during the same early morning session (7:00–9:00 am) after overnight fasting and before morning medication under standardized conditions. Both tests were performed with the patient in a supine position after resting for at least 10 minutes. Three measurements were acquired, and the median was calculated.

Impedance Cardiography

Transthoracic impedance cardiography (Bio-Z ICG; Sonosite Inc, Bothell, WA, USA), was performed in the same session to assess TFC during systole (synchronized ECG monitoring) and systemic vascular resistance (SVR) by using bilateral neck and thoracic electrodes and a low-voltage high-amplitude alternating current to derive stroke volume.17–19

Statistical Analysis

Descriptive data are expressed as mean±SD. Categorical variables are expressed as percentages. Baseline variables for patients with refractory and RHTN were analyzed by 2-tailed Student t test. Statistical significant level was set at a P value of ≤0.05. All analyses were conducted using SAS 9.3 (SAS Institute, Cary, NC).

Results

Prevalence

During the study period (January 2010 to December 2012), 709 patients were referred to the University of Alabama at Birmingham Hypertension Clinic for RHTN. Of these, 150 patients were controlled on <3 antihypertensive medication classes and therefore identified as having controlled hypertension. The remaining 559 patients were confirmed to have RHTN based on elevated clinic BP measurements although prescribed ≥3 different classes of antihypertensive agents, that is, uncontrolled RHTN (Figure). During follow-up, 276 patients were excluded from the analysis because of suspected medication nonadherence, control of BP on <5 medications, not receiving spironolactone or eplerenone, control of ambulatory BP, that is, white coat RHTN, presence of CKD stage 4 or 5, or inadequate follow-up (≤ 2 visits). Thus, >90% of patients initially suspected of having refractory hypertension were controlled with medication changes, were pseudorefractory (nonadherent, white coat refractory), were lost to follow-up, or had uncontrolled hypertension in the setting of advanced CKD. Of the 559 patients confirmed to have RHTN, 15 never achieved BP control in the office or by 24-hour ABPM despite treatment with maximum tolerated doses of at least 5 antihypertensive agents, including chlorthalidone and an MRA. These 15 patients were identified as having refractory hypertension, resulting in an overall prevalence 2.7% among patients originally referred for RHTN.
Figure. Prevalence of refractory hypertension. CBP indicates clinic blood pressure; CHT, chlorthalidone; CKD, chronic kidney disease; HBP, home blood pressure; RHTN, resistant hypertension; and SPL, spironolactone.

Patient Characteristics and Comorbidities

Compared with patients with controlled RHTN (n=29), patients with refractory hypertension were younger, more often women, had higher clinic BP, higher clinic HR, and were treated with more antihypertensive medications (Tables 1 and 2; Table S1 in the online-only Data Supplement), including greater use of treated combined α–β-antagonists, calcium channel blockers, MRAs, α2-adrenergic agonists, vasodilators, and centrally acting agents. There was no difference in the use of angiotensin-converting enzyme inhibitor/angiotensin receptor blockers and thiazide or thiazide-like diuretics (Table 2; Table S1). Other characteristics, including race, body mass index (BMI), and duration of hypertension, were similar between the 2 groups. There was no statistically significant difference in comorbidities, including diabetes mellitus, CKD, CAD, or stroke. Patients with refractory hypertension did, however, have higher rates of before hospitalization for HF (P=0.002).
Table 1. Baseline Characteristics of Patients With Refractory and Controlled Resistant Hypertension
CharacteristicsRefractory Hypertension, n=15Controlled RHTN, n=29P Value
Age, y48.0±13.356.5±14.10.038
Women, %80.051.90.047
Black race, %60.055.20.765
BMI, kg/m232.4±7.132.6±7.00.942
No. of antihypertensive medication drug classes at maximum dose6±14.1±1.1<0.05
Clinic systolic BP, mm Hg178.0±27.9134.3±13.7<0.001
Clinic diastolic BP, mm Hg103.3±17.479.3±9.6<0.001
Clinic heart rate, bpm75.1±11.263.1±10.40.002
Duration of hypertension, y12.4±7.816.9±9.10.122
Current smoker, %13.310.30.784
Diabetes mellitus, %35.721.70.360
CKD stage 3, %35.728.60.652
CAD, %14.37.40.521
Stroke, %6.617.20.276
OSA, %41.663.60.180
HF/hospitalization, %40.00.00.002
Morisky score0.61.40.03
Values are expressed as mean±SD or n (%). BMI indicates body mass index; BP, blood pressure; CAD, coronary artery disease; CKD, chronic kidney disease; HF, heart failure; OSA, obstructive sleep apnea; and RHTN, resistant hypertension.
Table 2. Type of Antihypertensive Medications Among Adults With Refractory and Resistant Hypertension
Antihypertensive ClassRefractory Hypertension, n=15Controlled RHTN, n=29P Value
ACEi/ARBs100100NS
BBs10051.70.038
CCBs10075.90.038
Thiazides/loop100100NS
MRAs10058.60.004
α-2 agonists93.36.9<0.05
Vasodilators6013.80.001
Values are n (%). ACEi indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, β-blocker; CCB, calcium channel blocker; MRA, mineralocorticoid receptor antagonist; NS, not significant; and RHTN, resistant hypertension.

Biochemical Testing

The 24-hour urinary normetanephrine levels were significantly higher in patients with refractory hypertension compared with patients with controlled RHTN (Table 3). The 24-hour urinary excretion of sodium was significantly lower in patients with refractory hypertension. Other measured biochemical parameters, including plasma aldosterone concentration, plasma renin activity, estimated glomerular filtration rate, BNP, high-sensitivity C-reactive protein, and 24-hour urinary aldosterone and cortisol excretion, were not different between the 2 groups.
Table 3. Biochemical Characteristics of Patients With Refractory and Controlled Resistant Hypertension
Biochemical MeasuresRefractory Hypertension, n=15Controlled RHTN, n=29P Value
Potassium, mEq/L3.8±0.43.9±0.30.838
Creatinine, mg/dL1.0±0.51.1±0.30.560
eGFR, mL/min per 1.73 m284.0±29.670.0±23.60.139
BNP, pg/mL45.4±48.263.0±74.60.958
hsCRP, mg/L7.7±11.011.4±23.60.698
Aldosterone, ng/dL9.9±6.911.6±11.60.376
PRA, ng/mL per h2.8±4.31.14±1.170.230
U-aldosterone, µg per 24 h11.6±812.3±70.829
U-cortisol, µg per 24 h146.0±70155.0±630.768
U-sodium, mEq per 24 h122.7±54186.0±1000.024
U-normetanephrines, µg per 24 h464.4±250309.8±147.60.039
Values are mean±SD. BNP indicates brain natriuretic peptide; eGFR, estimated glomerular filtration rate; hsCRP, high-sensitivity C-reactive protein; PRA, plasma renin activity; RHTN, resistant hypertension; and U, urinary.

Ambulatory BP, HR, and HRV

Daytime and nighttime periods were defined according to participants’ self-report. The average nighttime period based on patient diary was from 10 pm to 6 am. Mean daytime and nighttime systolic and diastolic BP levels were all significantly greater in the refractory patients compared with the patients with controlled RHTN (Table 4). Likewise, mean daytime and nighttime HR was significantly higher in the refractory patients compared with controls. The largest difference in HR was during the daytime (82.1±11.5 versus 71.1±12.3 bpm, refractory versus controlled resistant, P=0.012). Patients with refractory hypertension had significantly reduced HRV compared with controlled resistant hypertensive patients (4.48 versus 6.11; P=0.036).
Table 4. Clinic and Ambulatory Blood Pressure Monitoring in Patients With Refractory and Controlled Resistant Hypertension
ParameterRefractory Hypertension, n=15Controlled RHTN, n=29P Value
24-h systolic BP, mm Hg174.0±20.2139.8±16.30.0017
 Daytime178.1±97.4141.0±15.70.0046
 Nighttime165.2±19.2133.5±19.80.0002
24-h diastolic BP, mm Hg94.7±19.875.7±11.80.006
 Daytime97.4±19.877.2±11.40.007
 Nighttime87.7±16.570.2±15.10.007
24-h PP, mm Hg74.7±29.464.0±12.70.022
 Daytime80.0±2164.0±12.60.022
 Nighttime77.5±18.563.6±14.70.03
24-h heart rate, bpm77.8±7.768.8±7.60.0018
 Daytime82.1±11.571.1±12.30.0118
 Nighttime72.7±965.6±90.038
Heart rate variability4.486.110.036
Values are mean±SD. BP indicates blood pressure; PP, pulse pressure; and RHTN, resistant hypertension.

Pulsatile Hemodynamic Parameters

PWV was significantly greater in the patients with refractory hypertension compared with those with controlled RHTN (Table 5) indicative of greater arterial stiffness.15,16 Central systolic and diastolic pressures were significantly greater in refractory patients, as was the augmentation index (Table 5).
Table 5. Results of Pulsatile and Impedance Hemodynamics in Patients With Refractory and Controlled Resistant Hypertension
ParametersRefractory Hypertension, n=15Controlled RHTN, n=29P Value
Brachial artery measures
 Heart rate, bpm75.0±11.763.0±10.40.002
 Systolic BP, mm Hg177.2±28.9133.6±13.1<0.001
 Diastolic BP, mm Hg101.4±16.579.3±9.6<0.001
 MAP, mm Hg130.3±16.897.6±10.4<0.001
 PP, mm Hg75.8±28.154.4±14.90.009
Central aortic measures
 Systolic BP, mm Hg163.7±26.1121.9±14.1<0.001
 Diastolic BP, mm Hg103.3±16.780.1±9.8<0.001
 PP, mm Hg60.4±26.941.8±14.00.034
 AP, mm Hg18.9±12.710.7±10.10.07
 AIx, %29.6±10.722.4±14.90.03
 AIx75, %30.9±6.716.8±12.00.004
 PWV, m/s11.8±2.29.4±1.50.009
Impedance measures
 SVRI, dyne·s·cm5·m23795±17532382±3490.008
 TFC, k ohm/m232.3±5.431.8±7.1NS
Values are mean±SD. AIx indicates augmentation index; AIx75, augmentation index standardized to a heart rate of 75 bpm; AP, aortic pressure; BP, blood pressure; MAP, mean arterial pressure; NS, not significant; PP, pulse pressure; PWV, pulse wave velocity; RHTN, resistant hypertension; SVRI, systemic vascular resistance normalized for body surface area; and TFC, thoracic fluid content.

Impedance Cardiography

TFC was similar in both groups. SVR index normalized for body surface area was 1.6-fold greater in patients with refractory hypertension compared with control patients (3795±1753 versus 2382±349 dyne·s cm5 m2; P=0.008; Table 5) in spite of greater use of vasodilators (Table 2 and Table S1).

Discussion

This study is the first prospective assessment of patients diagnosed with refractory hypertension, an extreme phenotype of antihypertensive treatment failure. Novel findings demonstrate that patients with refractory hypertension compared with patients with controlled RHTN have (1) greater 24-hour urinary normetanephrine levels, (2) increased arterial stiffness, (3) higher HR, (4) lower HRV, and (5) higher SVR. Collectively, these findings implicate heightened sympathetic tone as an important cause of antihypertensive treatment failure.20–24 The prevalence of true refractory hypertension was only 2.7% of patients referred to a hypertension specialty clinic for RHTN, considerably less than observed in a previous retrospective analysis.1 Combined, these findings indicate that true antihypertensive treatment failure is uncommon but is characterized by biochemical and hemodynamic parameters consistent with excessive sympathetic output.
Previous studies clearly establish that increased sympathetic nerve activity (SNA) is associated with development and maintenance of arterial hypertension.25 Activity of the sympathetic nervous system increases progressively and in parallel with hypertension severity.26–30 In patients with RHTN, catheter-based radiofrequency ablation of the renal nerves lowers BP concomitant with reductions in muscle SNA as measured by microneurography.31–33 The current findings add to this body of literature in suggesting that persistent sympathetic hyperactivity also contributes importantly to antihypertensive failure.
There is growing evidence that SNA may be associated with arterial stiffness and that the degree of sympathetic activation may influence arterial compliance.24–26 In an Italian study carried out in people with unilateral lesions of the upper or lower extremity that required surgical intervention, reduction of adrenergic tone by ipsilateral brachial plexus anesthesia or ipsilateral removal of the lumbar sympathetic ganglia resulted in markedly increased distensibility of the radial and femoral arteries, respectively.25
Furthermore, recent studies in normotensive and hypertensive humans have shown that SNA is an independent determinant of PWV.24,26 Finally, there is growing evidence that increased HR, a reliable marker of SNA and cardiovascular risk, is also an important determinant of arterial distensibility and PWV.26 Collectively, the current findings of higher HR levels, greater excretion of urinary normetanephrines, reduced HRV, greater arterial stiffness, and increased vascular resistance support heightened sympathetic output as an important cause of refractory hypertension.
Certain clinical conditions and medications may alter measured levels of catecholamines and metabolites in plasma and urine.33 Drugs that inhibit central sympathetic outflow (eg, clonidine, a drug that was used in the majority of refractory patients) decrease plasma catecholamine levels in normotensive and hypertensive subjects but have little effect on the excessive catecholamine secretion seen, for example, in patients with pheochromocytoma.33,34 Drugs that tend to increase plasma catecholamines (eg, prazosin, β-blockers, and diuretics) do so only slightly.35
It is possible, however, that the higher 24-hour urinary normetanephrine levels observed in patients with refractory hypertension were because of greater use of vasodilators, which are known to increase sympathetic output. To evaluate this possibility, we compared 24-hour urinary normetanephrine levels in the 2 study groups after excluding patients who were receiving hydralazine or minoxidil. Urinary levels of 24-hour normetaphrines remained significantly higher in the refractory patients compared with the controlled resistant patients, suggesting that the higher normetanephrine levels in the refractory patients was not related to use of vasodilators.
We also compared 24-hour urinary normetanephrine excretion in all of the patients with refractory and controlled RHTN who were receiving β-blockers. Higher 24-hour urinary normetanephrine levels were still observed in the refractory group in spite of use of β-blockers by both groups of patients suggesting a β-blocker independent increase.
Patients in this study with refractory hypertension were characterized by increased vascular stiffness, as indexed by PWV, and central aortic BP, compared with patients with controlled RHTN. Although this is being described for the first time in association with refractory hypertension, the finding is consistent with previous evaluations of patients with uncontrolled RHTN. For example, in the prospective community-based Maine Syracuse Longitudinal Study, a subgroup of 46 patients met the criteria for uncontrolled RHTN that is, elevated BP with use of ≥3 antihypertensive drug classes, including a diuretic.36,37 PWV was significantly higher in this group compared with a control group of 48 patients without RHTN, that is, BP controlled with ≤2 antihypertensive drug classes. Similarly, in a prospective evaluation of 90 Brazilian patients with RHTN by Martins et al,38 47 patients were classified as having uncontrolled RHTN. PWV was significantly higher in this uncontrolled group compared with patients whose BP was treatment resistant but controlled.
In a previous retrospective analysis, we reported that patients with refractory hypertension had a consistently higher resting clinic HR compared with patients with controlled RHTN.1 This elevation in HR was interpreted as evidence of heightened sympathetic tone, suggesting that increased sympathetic nervous system activity may play a potentially important role in the pathogenesis of antihypertensive treatment failure. This prospective study confirms those previous findings in demonstrating that clinic HR was again significantly higher in patients with refractory versus controlled RHTN. We further show that HR as measured during ambulatory monitoring is also significantly higher in refractory patients, particularly at night.
The current evaluation includes an estimate of SVR as measured by transthoracic impedance cardiography. Despite being on more vasodilators, a 1.6-fold higher SVR was observed in patients with refractory hypertension (Table 5). However, greater use of centrally acting agents in refractory hypertensive patients may have affected these results by increasing SVR.18
The validity of the calculation of cardiac output by impedance cardiography has limitations, including (1) the difficulty of acquiring the signal because of spontaneous movements of the patient, disorders of heart rhythm, and interference from electric devices in the environment and (2) invalidation of the physical modeling of the system because of the presence of conditions, such as pregnancy, obesity, pleural effusion, chronic congestive HF with pulmonary edema, or severe aortic valve disease that can change baseline thoracic impedance.18 In our study, participants were evaluated when clinically stable in normal sinus rhythm and without HF or clinical signs of volume overload at the time of the study.18
An alternative hypothesis to refractory hypertension being neurogenic in pathogenesis is it being secondary to inappropriate fluid retention. Such an effect is consistent with what has been described of RHTN in general, that is, being volume dependent. For example, Taler et al39 used impedance cardiography to demonstrate that intensification of diuretic therapy based on high TFC values improved BP control rates in patients with RHTN. To test this possibility, we measured BNP levels and TFC in patients with refractory and controlled RHTN as indices of intravascular volume. We have previously reported that BNP levels do correlate with intravascular volume expansion in patients with RHTN.40 BNP levels and TFC values were the same in the refractory patients and patients with resistant but well-controlled hypertension. This argues against persistent fluid retention as being a major cause of refractory hypertension. The absence of a critical role of fluid retention in causing refractory hypertension has important clinical implications as it suggests that continued intensification of diuretic therapy, as is often suggested for lack of BP control, may not be appropriate or effective.
This study confirms important negatives in terms of potential mechanisms of antihypertensive treatment failure, foremost being hyperaldosteronism. Aldosterone excess has been demonstrated in multiple studies to be an important contributor to RHTN.5,41 However, aldosterone levels, both serum and 24-hour urinary levels, as well as the aldosterone:renin ratio were not different in patients with refractory versus controlled RHTN. Furthermore, as previously shown, patients with refractory hypertension were unresponsive to use of an MRA,1 along with all other classes of antihypertensive agents. Although aldosterone and renin activities are ideally assessed after the withdrawal of antihypertensive agents, this was not possible for safety reasons in these high-risk patients. Although β-blockers predictably suppress and diuretics, angiotensin-converting enzyme inhibitor, angiotensin receptor blockers increase plasma renin activity, effects on aldosterone release are minimal or absent.42 These observations suggest that although hyperaldosteronism may commonly contribute to antihypertensive treatment resistance, aldosterone excess is not likely a mediator of antihypertensive treatment failure in patients with refractory hypertension.
Likewise, lower levels of 24-hour urinary sodium excretion in patients with refractory hypertension argue against extreme dietary sodium excess as being the primary cause of refractory hypertension.
Indicators of mineralocorticoid excess other than aldosterone excess were not observed in patients with refractory hypertension. For example, biochemical abnormalities suggestive of apparent mineralocorticoid excess (ie, low plasma aldosterone concentration and low plasma renin activity) were absent. Similarly, comparable 24-hour urinary cortisol levels did not suggest glucocorticoid excess (Table 3).
In the current prospective analysis, the overall prevalence of refractory hypertension was 2.7% of patients referred to a hypertension specialty clinic for RHTN. Patients remained refractory to treatment despite being adherent to treatment regimens that included on average, 6 different classes of agents, including in all patients, use of a diuretic, and a MRA. In our previous retrospective analysis, the prevalence of refractory hypertension was estimated at ≈10% of patients referred to our hypertension specialty clinic with RHTN.1 The lower prevalence observed in the current prospective analysis is likely attributable to a more systematic use of the combination of chlorthalidone and spironolactone. We and others have found this combination to be particularly effective for treatment of RHTN.15 In the current analysis, all participants diagnosed with refractory hypertension were receiving diuretic and an MRA, whereas, during the time period of the retrospective analysis, the combination was used in only 1 of 3 of the patients designated as being refractory to treatment.
In this study, patients with refractory hypertension were more likely black and women compared with subjects with controlled RHTN, the latter difference being statistically significant. Similar observations were reported in the previous retrospective study of refractory hypertension.1 In the cross-sectional analysis of the REGARDS cohort, black race and male sex were associated with higher risk of having refractory hypertension.2 Together, the findings of the 3 studies suggest that blacks are more likely to have refractory hypertension, as is true of RHTN,6 whereas the association with sex, if any, needs clarification with additional studies.
This study has some limitations, including (1) the reliance on patient report and an 8-item questionnaire for assessing medication adherence, both known to be of inconsistent reliability, (2) use of greater number of classes and, in some cases, higher doses of antihypertensive agents in patients with refractory hypertension, which may have contributed to the higher urinary normetanephrine levels, and (3) the lack of a direct measure of sympathetic activity as with microneurography or norepinephrine secretion from sympathetic nerve terminals, such as plasma norepinephrine with or without the spillover approach.
This study is strengthened by its prospective design, rigorous comparison with patients with controlled RHTN, and exclusion of common causes of pseudoresistance, including white coat effect, inadequate treatment, and poor medication adherence.

Perspectives

In summary, refractory hypertension is being used to identify an extreme clinical phenotype of antihypertensive treatment failure, which in this study was defined as BP that remains elevated in spite of use of at least 5 different classes of antihypertensive agents, including chlorthalidone and an MRA. The current findings demonstrate that true refractory hypertension is uncommon among patients originally referred to hypertension specialists for RHTN. Refractory hypertension seems unique in terms of mechanism from the more common phenotype of RHTN, with the latter being broadly attributed to inappropriate fluid retention, whereas the current results suggest that the former is more likely neurogenic in pathogenesis. If true, such patients may preferentially benefit from treatment strategies that effectively reduce sympathetic output, if and when such strategies are available.

Novelty and Significance

What Is New?

•
This is the first prospective study that characterizes patients with refractory hypertension, a proposed novel phenotype of antihypertensive treatment failure.

What Is Relevant?

•
This study demonstrates that heightened sympathetic tone as indicated by clinic and ambulatory heart rate, arterial stiffness, and 24-hour urinary metanephrine and normetanephrine levels may contribute importantly to antihypertensive treatment failure.

Summary

Refractory hypertension refers to an extreme clinical phenotype of antihypertensive treatment failure defined as elevated blood pressure in spite of use of at least 5 different classes of antihypertensive agents, including chlorthalidone and a mineralocorticoid receptor antagonist. The phenotype seems distinct from resistant hypertension in general, which has been broadly attributed to inappropriate fluid retention, in that, the current study findings suggest that refractory hypertension is more likely caused by excess sympathetic output. Additional prospective studies are needed to further elucidate mechanisms of antihypertensive treatment failure. Patients with refractory hypertension may preferentially benefit from treatment strategies that effectively reduce sympathetic output, rather than intensified diuretic treatment. Clinically, successful pharmacological treatments that reduce sympathetic output, at least at doses that are well tolerated, are currently not available. Device-based procedures, such as renal denervation, although promising, have failed to date to show convincing blood pressure–lowering effects in large, sham-controlled clinical trials. The current findings highlight the potential clinical need for effective sympatholytic therapies for patients with refractory hypertension.

Supplemental Material

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Go to Hypertension
Hypertension
Volume 66 • Number 1 • July 2015
Pages: 126 - 133
PubMed: 25987662

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© 2015 American Heart Association, Inc.

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History

Received: 8 April 2015
Revision received: 19 April 2015
Accepted: 21 April 2015
Published online: 18 May 2015
Published in print: July 2015

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Keywords

  1. aldosterone
  2. arterial stiffness
  3. blood pressure monitoring, ambulatory
  4. catecholamines
  5. sympathetic activity

Subjects

  1. Diagnostic Testing
  2. Hypertension

Authors

Affiliations

Tanja Dudenbostel
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (T.D., S.O., D.A.C.), Department of Biostatistics (P.L.), University of Alabama, Birmingham; Department of Medicine, University of South Alabama, Mobile (M.C.A.); and Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston (R.P.).
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Maria C. Acelajado
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (T.D., S.O., D.A.C.), Department of Biostatistics (P.L.), University of Alabama, Birmingham; Department of Medicine, University of South Alabama, Mobile (M.C.A.); and Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston (R.P.).
View all articles by this author
Roberto Pisoni
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (T.D., S.O., D.A.C.), Department of Biostatistics (P.L.), University of Alabama, Birmingham; Department of Medicine, University of South Alabama, Mobile (M.C.A.); and Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston (R.P.).
View all articles by this author
Peng Li
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (T.D., S.O., D.A.C.), Department of Biostatistics (P.L.), University of Alabama, Birmingham; Department of Medicine, University of South Alabama, Mobile (M.C.A.); and Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston (R.P.).
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Suzanne Oparil
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (T.D., S.O., D.A.C.), Department of Biostatistics (P.L.), University of Alabama, Birmingham; Department of Medicine, University of South Alabama, Mobile (M.C.A.); and Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston (R.P.).
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David A. Calhoun
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (T.D., S.O., D.A.C.), Department of Biostatistics (P.L.), University of Alabama, Birmingham; Department of Medicine, University of South Alabama, Mobile (M.C.A.); and Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston (R.P.).
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Notes

The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.115.05449/-/DC1.
Correspondence to Tanja Dudenbostel, University of Alabama at Birmingham, 933 19th St S, CHSB Suite 115, Birmingham, AL, 35294. E-mail [email protected]

Disclosures

None.

Sources of Funding

Research reported was supported by the National Institutes of Health (NIH 1R01 HL113004), National Center for Advancing Translational Sciences of the National Institutes of Health (NIH UL1TR00165), NIH T32 HL007457, and NIH T32HL079888.

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