Abstract
Refractory hypertension is an extreme phenotype of antihypertensive treatment failure defined as lack of blood pressure (BP) control with ≥5 medications, including a long-acting thiazide and a mineralocorticoid receptor antagonist. Refractory hypertension is a subgroup of resistant hypertension, which is defined as BP > 135/85mmHg with three or more antihypertensive medications, including a diuretic. Resistant hypertension is generally attributed to persistent intravascular fluid retention. It is unknown whether alternative mechanisms are operative in refractory hypertension. Our objective was to determine whether refractory hypertension is characterized by persistent fluid retention, indexed by greater intracardiac volumes determined by cardiac magnetic resonance when compared to controlled resistant hypertension patients. Consecutive patients evaluated in our institution with refractory hypertension and controlled-resistant hypertension 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 refractory hypertension group (n=24) was younger (mean age 51.7±8.9 vs. 60.6±11.5yrs, p=0.003) and had a greater proportion of females (75.0% vs. 43%, p=0.02) compared with the controlled-resistant hypertension group (n=30). Refractory hypertension patients had a greater left ventricular mass index (88.3±35.0 vs. 54.6 ±12.5g/m2, p<0.001), posterior (10.1±3.1 vs. 7.7±1.5mm, p=0.001) and septal wall thickness (14.5±3.8 vs. 10.0±2.2mm, p<0.001). There was no difference in B-type natriuretic peptide levels and left atrial or ventricular volumes. Diastolic dysfunction was noted in refractory hypertension. Our findings demonstrate greater left ventricular hypertrophy without chamber enlargement in refractory hypertension, suggesting that antihypertensive treatment failure is not attributable to intravascular volume retention.
Keywords: Intravascular volume, resistant hypertension, cardiac MRI, target organ damage
Introduction
Refractory hypertension (RfHTN), an extreme phenotype of antihypertensive failure, is defined as failure to control blood pressure (BP) with 5 or more antihypertensive agents, including chlorthalidone and a mineralocorticoid receptor antagonist (MRA)1. This phenotype represents a subgroup of patients with resistant hypertension (RHTN) defined as lack of BP control in spite of the use of 3 or more antihypertensive agents, including a diuretic, or controlled BP with use of 4 or more antihypertensive agents, so called controlled RHTN2.
The prevalence of RfHTN among patients referred to hypertension specialty clinics has been reported to be between 5 to 10%3,4. RfHTN patients are more often female and of African ancestry as compared to patients with controlled RHTN1. Furthermore, patients with RfHTN have persistent BP elevation by ambulatory monitoring (ABPM) and a low rate of white coat effect5. Not surprisingly, large, community-based cohort studies have shown that RfHTN is associated with an increased risk of stroke and coronary heart disease as compared to hypertensive patients in general4.
Prior studies have indicated that RHTN is generally attributable to persistent intravascular fluid retention. Taler et al found that thoracic fluid content was increased in patients with uncontrolled RHTN and intensification of diuretic therapy was necessary to counteract this fluid retention in order to control BP6. In a study by Gaddam et al, patients with uncontrolled RHTN with higher levels of B-type natriuretic peptide (BNP) along with greater left atrial (LA) and left ventricular (LV) volumes, had significant improvement in BP and normalization of intracardiac volumes after diuresis was enhanced using spironolactone.7
In contrast, few recent studies have demonstrated that thoracic fluid content is similar in patients with RfHTN and controlled RHTN1. However, the RfHTN patients had elevated heart rate (HR) and urinary normetanephrine levels as compared to controlled RHTN1,8. These differences suggest a potential mechanistic distinction between RfHTN and RHTN in general in that RfHTN may be more neurogenic in etiology, i.e., secondary to excess sympathetic output, as opposed to being volume dependent, i.e. persistent intravascular fluid retention, as is typical of RHTN. If true, such a mechanistic distinction would have important therapeutic implications in that the treatment of RfHTN may require more effective sympatholytic therapies for BP control as opposed to further intensification of diuretic therapy.
The objective of our study was to determine if antihypertensive treatment failure in patients with RfHTN is characterized by persistent intravascular fluid retention as demonstrated by higher LA and LV end diastolic volumes and higher BNP levels. Patients with controlled RHTN served as the comparator group. We performed extensive laboratory testing and cardiac phenotyping of patients with RfHTN to assess ventricular dimensions, ventricular function, and the left ventricular mass/volume ratio as compared with controlled RHTN.
Methods
The authors declare that all supporting data are available within the article.
Study Population
We prospectively enrolled consecutive patients who were referred to the University of Alabama at Birmingham (UAB) Hypertension Clinic for uncontrolled RHTN (automated office blood pressure [AOBP] >135/85 mmHg with use of ≥3 antihypertensive medications, including a diuretic) between April 2014 and January 2018. RfHTN was defined as lack of BP control despite the use of five or more antihypertensive agents, including chlorthalidone and an MRA, typically spironolactone, after a minimum of 3 follow-up visits. Office BP readings were obtained using AOBP as described below. All patients were evaluated for hyperaldosteronism and pheochromocytoma. Renal artery stenosis was assessed if clinically indicated. Exclusion criteria were nonadherence based on self-report or low medication refill rates; chronic kidney disease stages 4 or 5 (estimated glomerular filtration rate <30 ml/min per 1.73 m2), or if pregnant or nursing. All patients underwent 24-hr ambulatory BP monitoring. RfHTN patients with white coat effect (defined as ambulatory awake BP <135/85 mmHg and clinic AOBP>135/85 mmHg) were excluded, as well as controlled RHTN with uncontrolled masked HTN, (defined as ambulatory awake BP >135/85 mmHg and clinic AOBP<135/85 mmHg). The UAB Institutional Review Board approved the study and written informed consent was obtained from all participants.
Automated office BP measurement
The clinic AOBP was measured using the BpTRU device (Coquitlam BC, Canada), after at least 5 minutes of quiet rest in a sitting position with the back supported and the arm supported at heart level9. An appropriate sized cuff was used with a cuff bladder encircling at least 80% of the arm10, 11. The BpTRU AOBP device automatically obtains 6 serial BP readings, one minute apart, before displaying the average of the last 5 readings with mean arterial pressure and BP variability. The assessments were unattended, i.e., unobserved in clinic10, 12-15. A BP cutoff of ≥ 135/85 mmHg for elevated BP was used based on recent literature validating automated BP devices16, 17.
24-hr ambulatory BP monitoring (ABPM)
Study patients also underwent ABPM using an automated, noninvasive, oscillometric device (Oscar 2; SunTech Medical Inc, Morrisville, NC)18, 19. ABPM measurements were obtained every 20 minutes during the daytime (awake) and every 30 minutes during the nighttime (asleep) phases of the 24-hr period. Awake and asleep times were self-reported by the patient. ABPM was determined to be valid if >80% of measurements were successful. Controlled BP by ABPM was defined as mean daytime (awake) BP <135/85 mmHg18, 19.
Cardiac MRI
All patients underwent (CMR) to evaluate cardiac and aortic structure and function. CMR was performed with a 1.5-T clinical scanner optimized for cardiac imaging (Signa, GE Healthcare) using a 4-element phased-array surface coil and prospective electrocardiographic triggering as described previously20. Imaging was performed using a rapid steady-state free precession cine sequence (10 k-space lines per segment). Standard short-axis and 2- and 4-chamber images were obtained from appropriate scout images and used for all the quantitative of right ventricular (RV), left ventricular (LV), and left atrial (LA) volumes. Cine images were reconstructed into 20 cardiac phases.
Slice thickness for the short axis, 2-chamber, and 4-chamber images was 8 mm without any slice gap. The following parameters were used: matrix size, 256 × 128; field of view, 40 × 40 cm; typical repetition time, 3.9 msec; typical echo time, 1.6 msec; flip angle, 45°; bandwidth, 125 Hz per pixel; and typical acquired temporal resolution, 39 msec. CAAS Flow and CAAS MRV software (Pie Medical Imaging, Maastricht, Netherlands) was used to evaluate ventricular and atrial volume and function. LA contours were manually drawn on 2- and 4-chamber long-axis views at ventricular end systole; this phase corresponds with the largest LA area. The inferior LA border was defined as the plane of the mitral annulus. We excluded the pulmonary veins and the LA appendage as recommended by echocardiographic guidelines21. The LA base-to-mitral-valve length was obtained from the middle of the plane of the mitral annulus to the posterior wall. LA volume was calculated by the area-length method V=8/3π (A2ch A4ch/L), where A2CH and A4CH represent the LA area acquired from the long-axis 2- and 4-chamber views by planimeter, respectively, and L is the shortest length from basal wall to the mitral valve annulus. Short-axis cine MRI was performed, and the epicardial and endocardial contours of the ventricles at end systole and end diastole were manually drawn for each slice22. Chamber volumes and LV mass were indexed to the body surface area. Ventricular ejection fraction was calculated as EF = [EDV-ESV]/EDVx100.
For assessment of diastolic function, segmentation for each short-axis slice was performed across all temporal phases. Volumetric data was used to analyze the LV volume-filling time course23,24. The following CMR diastolic parameters were evaluated:
Peak filling rate (PFR): Maximal LV filling rate defined by maximal change in LV volume between sequential temporal phases (Δ volume/Δ phase). This index was also adjusted for stroke volume to generate normalized peak filling rate24.
Diastolic volume recovery (DVR): Proportion of diastole required for recovery of 80% of stroke volume24.
The LV inflow contour was manually traced throughout the cardiac cycle, and velocity encoded, phase contrast MRI was performed to obtain early and late LV filling velocities25.
Statistical Analysis
Descriptive statistics are presented as mean ± standard deviation, median with range, or frequency number and percentage within the group, as appropriate. Between-group differences were compared by independent student-t test or non-parametric Wilcoxon rank sum test for continuous variables, as appropriate, and by chi-squared test for categorical variables. The p-values are provided for descriptive purposes. Reported p values are two sided with p < 0.002 considered significant after applying a Bonferroni correction for multiple testing of cardiac parameters. Differences in baseline characteristics (Tables 1 & 2) are considered statistically significant for p < 0.05. Data analyses were carried out using SAS version 9.3 (SAS Institute Inc; Cary, NC).
Table 1.
Baseline characteristics in refractory and controlled resistant hypertension
| Patient Characteristics | Refractory hypertension (n=24) | Controlled resistant hypertension (n=30) | p-value |
|---|---|---|---|
| Demographics | |||
| Age (Years) | 51.7 ± 8.9 | 60.6 ± 11.5 | 0.003 |
| Female (%) | 18 (75.0%) | 13 (43.3%) | 0.02 |
| African Americans (%) | 19 (79.2%) | 16 (53.3%) | 0.05 |
| Body mass index (kg/m2) | 34.6 ± 4.8 | 31.7 ± 5.7 | 0.05 |
| Body surface area (m2) | 2.00 ± 0.26 | 2.06 ± 0.26 | 0.428 |
| Co-Morbidities | |||
| Lifelong non-smoker (%) | 14 (58.3%) | 20 (66.7%) | 0.4 |
| Dyslipidemia (%) | 11 (45.8%) | 17 (56.7%) | 0.43 |
| Congestive heart failure (%) | 5 (20.8%) | 1 (3.3%) | 0.04 |
| Arrhythmia (%) | 2 (8.3%) | 4 (13.3%) | 0.56 |
| Coronary artery disease (%) | 3 (12.5%) | 2 (6.7%) | 0.46 |
| Peripheral vascular disease (%) | 4 (16.7%) | 1 (3.3%) | 0.09 |
| Diabetes mellitus (%) | 12 (50%) | 7 (23.3%) | 0.04 |
| Prior stroke/Transient ischemic attack (%) | 5 (20.8%) | 2 (6.7%) | 0.12 |
| Obstructive sleep apnea (%) | 12 (50%) | 11 (36.7%) | 0.32 |
| Automated office BP (AOBP) | |||
| Systolic BP (mmHg) | 164.8 ± 21.5 | 115.6 ± 12.1 | <0.0001 |
| Diastolic BP (mmHg) | 95.8 ± 13.0 | 69.9± 8.1 | <0.0001 |
| Heart rate (beats/min) | 75.3 ± 13.3 | 68.0 ± 11.1 | 0.03 |
| Biochemical Testing | |||
| B-type natriuretic peptide (pg/ml)* | 24.8 (2.0-141.5) | 15.4 (2.0-242.2) | 0.38 |
| 24-hour urine sodium (mmol/day) | 162.7 ± 76.8 | 149.4 ± 47.6 | 0.446 |
| 24-hour urine proteinuria (mg) | 435.2 ± 731.3 | 170.0 ± 324.5 | 0.154 |
| 24-hour urine creatinine (mg) | 1601.7 ± 662.9 | 1686.1 ± 613.0 | 0.636 |
Median (range)
Table 2.
Antihypertensive medications in patients with refractory and controlled resistant hypertension
| Antihypertensive Class | Refractory hypertension (n=24) | Controlled resistant hypertension (n=30) | p-value |
|---|---|---|---|
|
|
|||
| Angiotensin converting enzyme inhibitors | 11 (45.8%) | 17 (56.7%) | 0.303 |
| Angiotensinogen receptor blockers | 13 (54.2%) | 12 (40.0%) | 0.223 |
| Calcium channel blockers | 24 (100.0%) | 23 (76.7%) | 0.011 |
| Thiazide diuretics | 24 (100.0%) | 29 (96.7%) | 0.556 |
| Loop diuretics | 0 | 1 (3.3%) | 0.556 |
| Amiloride | 0 | 1 (3.3%) | 0.556 |
| Mineralocorticoid receptor antagonists | 24 (100.0%) | 20 (66.7%) | 0.001 |
| α blockers | 1 (4.2%) | 2 (6.7%) | 0.585 |
| β blockers | 7 (29.2%) | 11 (36.7%) | 0.387 |
| Combined α-β blockers | 12 (50.0%) | 5 (16.7%) | 0.010 |
| Central acting α2 agonists | 17 (70.8%) | 6 (20.0%) | <0.001 |
| Nitrate vasodilators | 3 (12.5%) | 0 | 0.082 |
| Other vasodilators | 6 (25.0%) | 0 | 0.005 |
| Total antihypertensive medications | 6 (5-7) | 4 (3-7) | <0.001 |
Results
A total of 224 patients were screened for study participation. After diagnostic testing, 24 patients with RfHTN were enrolled and 30 patients with controlled RHTN were recruited for the comparator group (Figure 1). RfHTN patients had a higher clinic HR and BP, were younger, and more likely to be female and African American (Table 1). By definition, RfHTN patients were on more antihypertensive agents (median [range]: 6 [5 – 7] vs. 4 [3 - 7] medications, p<0.001) (Table 2). Patients with RfHTN had a higher mean BMI and a higher prevalence of diabetes. Notably, the RfHTN group had more patients with a prior heart failure diagnosis, but no difference in known coronary artery disease, prior cerebrovascular events, or confirmed obstructive sleep apnea.
Figure 1.
Schematic of enrolled study participants.
There was no difference in the mean BNP levels between the two groups (RfHTN: 24.8 [2.0 - 141.5] pg/ml vs. controlled RHTN: 15.4 [2.0 - 242.2] pg/ml, p=0.38). There was no difference in 24-hour levels of urinary sodium excretion (RfHTN: 162.7 ± 76.8 mmol/day vs. controlled RHTN 149.4 ± 47.6 mmol/day, p=0.446)
CMR-derived Measurements
Cardiac Morphology
Patients with RfHTN had greater LV mass indexed by body surface area: (88.3±35.0 vs. 54.6 ±12.5g/m2, p<0.0001), as well as greater interventricular septal thickness (14.5 ± 3.8 vs. 10.0 ± 2.2 mm, p≤0.0001) and posterior wall thickness (10.1±3.1 vs. 7.7±1.5 mm, p=0.0005) than patients with controlled RHTN (Table 3) (Figure 2). There was no difference in LA volume indexed by body surface area (RfHTN: 31.8 ± 8.3 vs. controlled RHTN: 33.1 ± 13.1 ml/m2, p=0.68) or LV end diastolic volume (RfHTN: 142.9 ± 42.8 ml vs. controlled RHTN: 138.5 ± 36.3 ml, p=0.69) between the two groups. Patients with RfHTN had a greater LV mass/LV end diastolic volume ratio than patients with controlled RHTN (1.3 ± 0.4 gr/ml vs. 0.8 ± 0.2 gm/ml p<0.0001).
Table 3.
CMR-based cardiac anatomy of patients with refractory and controlled resistant hypertension
| Cardiac Parameters | Refractory hypertension (n=24) | Controlled resistant hypertension (n=30) | p-value |
|---|---|---|---|
| Left Ventricle | |||
| Left ventricular mass (g) | 179.4 ± 75.0 | 115.2 ± 37.9 | 0.0002 |
| Left ventricular mass index (g/m2) | 88.3 ± 35.0 | 54.6 ± 12.5 | <0.0001 |
| Left ventricle end systolic volume (ml) | 54.5 ± 26.4 | 52.0 ± 20.8 | 1.0 |
| Left ventricle end diastolic volume (ml) | 142.9 ± 42.8 | 138.5 ± 36.3 | 0.69 |
| Left ventricle end diastolic volume indexed body surface area (ml/m2) | 70.7 ± 17.2 | 67.0 ± 12.5 | 0.375 |
| Left ventricle end systolic dimension (mm) | 32.8 ± 8.6 | 32.8 ± 6.4 | 0.99 |
| Left ventricle end diastolic dimension (mm) | 47.3 ± 6.7 | 48.9 ± 5.4 | 0.34 |
| Left ventricle posterior wall thickness (mm) | 10.1 ± 3.1 | 7.7 ±1.5 | 0.0005 |
| Inter ventricular septum thickness (mm) | 14.5 ± 3.8 | 10.0 ± 2.2 | <0.0001 |
| Left ventricular mass/Left ventricular end diastolic volume (g/ml) | 1.3 ± 0.4 | 0.8 ± 0.2 | <0.0001 |
| Left Atrium | |||
| Left atrium volume (ml) | 65.8 ± 21.6 | 67.9 ± 29.3 | 0.77 |
| Left atrium volume indexed by body surface area (ml/m2) | 31.8 ± 8.3 | 33.1 ± 13.1 | 0.68 |
| Right Ventricle | |||
| Right ventricle end systolic volume (ml) | 57.4 ± 18.8 | 65.6 ± 24.1 | 0.19 |
| Right ventricle end diastolic volume (ml) | 135.1 ± 40.6 | 147.2 ± 37.4 | 0.27 |
| Right ventricle end diastolic volume indexed body surface area (ml/m2) | 66.8 ± 16.1 | 71.1 ± 12.1 | 0.268 |
| Right ventricle end diastolic dimension (mm) | 36.5 ± 6.5 | 40.7 ± 7.1 | 0.03 |
| Right Atrium | |||
| Right atrium dimension (mm) | 41.1 ± 8.0 | 48.0 ± 7.3 | 0.009 |
| Inferior vena cava (mm) | 18.7 ± 5.5 | 20.6 ± 4.2 | 0.52 |
Figure 2.
Representative cardiac MRI images from patients with refractory hypertension (A), demonstrating increase ventricular wall thickness with similar end diastolic volumes when compared to patients with controlled resistant hypertension (B).
A modest linear association within the 2 groups was found between SBP and LV mass (Pearson correlation 0.308 p=0.023), along with DBP and LV mass (Pearson correlation 0.502 p<0.001). (Supplemental figures S1A and S1B).
Systolic and Diastolic Function
Volumetric assessment by MRI did not reveal differences in right or left ventricular ejection fraction among groups. Furthermore, flow assessment across ascending aorta did not reveal differences in cardiac output or stroke volume (Table 4). Although most of the diastolic function parameters were not different between groups, the RfHTN group showed impaired diastolic function evidenced by a lower peak filling rate (normalized by LV stroke volume) compared to the RHTN group (Table 3). RfHTN patients had higher resting heart rates, which was reflected by a trend towards a shorter time in diastole (497.3 ± 95.9 msec vs. 564.7 ± 128.7 msec p=0.04).
Table 4.
Cardiac systolic and diastolic function properties measured with cardiac MRI in refractory and controlled resistant hypertension
| Cardiac Parameters | Refractory hypertension (n=24) | Controlled resistant hypertension (n=30) | p-value |
|---|---|---|---|
| Flow across ascending aorta | |||
| Cardiac output (l/min) | 4.8 ± 1.3 | 4.6 ± 1.5 | 0.64 |
| Stroke volume (ml/beat) | 69.6 ± 19.7 | 68.5 ± 18.0 | 0.84 |
| Left Ventricle | |||
| Left ventricle stroke volume (ml) | 88.1 ± 24.1 | 86.1 ± 22.6 | 0.76 |
| Left ventricle ejection fraction (%) | 62.9 ± 9.1 | 63.1 ± 8.2 | 0.95 |
| Early diastolic mitral inflow maximal velocity (E) (cm/s) | 47.1 ± 8.6 | 46.2 ± 12.6 | 0.79 |
| Late diastolic mitral inflow maximal velocity (A) (cm/s) | 48.6 ± 13.8 | 41.5 ± 12.6 | 0.10 |
| E/A ratio maximal velocity ratio | 1.07 ± 0.55 | 1.27 ± 0.76 | 0.12 |
| Total time in diastole (D) (msec) | 497.3 ± 95.9 | 564.7 ± 128.7 | 0.04 |
| Time to recover 80% of LV stroke volume (P) (msec) | 457.1 ± 90.2 | 519.1 ± 118.3 | 0.04 |
| Left ventricle diastolic volume recovery (P/D) | 0.92 ± 0.03 | 0.92 ± 0.07 | 0.95 |
| Left ventricle peak filling rate (ml/s) | 376.5 ± 123.5 | 422.1 ± 158.3 | 0.27 |
| Left ventricle peak filling rate normalized by stroke volume | 4.5 ± 1.0 | 5.3 ± 1.3 | 0.03 |
| Right Ventricle | |||
| Right ventricle stroke volume (ml) | 77.6 ± 24.4 | 81.5 ± 20.9 | 0.54 |
| Right ventricle ejection fraction (%) | 57.6 ± 6.0 | 56.0 ± 8.4 | 0.46 |
Discussion
There are several key findings of our study. This is the first detailed cardiovascular phenotyping of patients with RfHTN utilizing CMR, a technique considered to be the gold standard for the assessment of cardiac structure and function. Second, we found no difference in LA and LVED volume between the two study groups along with similar levels of BNP, suggesting that patients with RfHTN do not have persistent fluid retention as a cause of their antihypertensive treatment failure. Third, our study demonstrated more pronounced cardiac remodeling in RfHTN subjects as evidenced by increased LV mass and wall thickness, without significant increases in chamber volume as compared to patients with controlled RHTN. Fourth, systolic function was preserved in both groups. However, there was evidence for abnormal diastolic filling in patients with RfHTN as compared to controlled RHTN subjects.
Persistent fluid retention is thought to broadly underlie the development of RHTN. Taler et al. reported that RHTN is characterized by intravascular fluid retention, as evidenced by increased thoracic impedance and the observation that intensification of diuretic therapy facilitated better BP control in these patients6. Our group previously reported that patients with RHTN have greater end-diastolic volumes and higher BNP levels than control patients without RHTN7, 26, and that this fluid retention could be overcome with use of spironolactone7. In the current study, we did not observe any significant differences in cardiac chamber volumes or BNP levels between patients with RfHTN and patients with controlled RHTN, arguing against persistent fluid retention as the cause of the antihypertensive treatment failure. This suggests that alternative mechanisms may be driving the lack of treatment response. The higher resting heart rates and higher urinary metanephrine levels observed in earlier studies suggest heightened sympathetic activity as a potential cause of RfHTN. If so, this carries important clinical implications in that such patients failing maximal or near-maximal antihypertensive treatment may best respond to more effective sympatholytic interventions, either pharmacologic or device-based, as opposed to continued intensification of diuretic therapy, which has been generally recommended for continued lack of BP control in patients with RHTN.
The current study demonstrates that patients with RfHTN have a greater prevalence of LV hypertrophy, characterized by a greater LV mass index and wall thickness as compared to patients with controlled RHTN. Previous studies of patients with RfHTN have likewise reported a high prevalence of LV hypertrophy based on ECG criteria4 and M-mode echocardiography8. The greater LV mass is no doubt attributable, at least in part, to the longstanding, poorly controlled HTN characteristic of RfHTN.
There were no differences in systolic function between the two study groups. However, patients with RfHTN had signs of diastolic dysfunction or subclinical heart failure with preserved ejection fraction. First, the LV mass/end diastolic volume ratio in the RfHTN group was >1 g/mL and greater than in the control group, concordant with findings from prior studies in patients with heart failure with preserved ejection fraction27. Secondly, RfHTN subjects showed a delayed LV filling pattern that has been described in patients with diastolic dysfunction24, as well as in clinical heart failure, despite no differences in ejection fraction among groups.
Although we did not detect differences between the two study groups, the small sample size of patients with RfHTN reduces the statistical power of the analysis, increasing risk of a type II error. Study limitations include the small number of patients with RfHTN. Study strengths include the rigorous characterization of the two phenotypes based on extensive biochemical testing, ambulatory BP monitoring, and cardiac MRI imaging.
In conclusion, the current study demonstrates similar intracardiac chamber volumes and BNP levels in patients with RfHTN and controlled RHTN, suggesting that antihypertensive treatment failure in these patients is not from lack of effective diuresis when treated with chlorthalidone and spironolactone. Instead, it suggests a mechanism of treatment failure separate from persistent fluid retention, such as increased sympathetic tone1. Further, patients with RfHTN have evidence of adverse cardiovascular remodeling compared to controlled RHTN, placing them at increased risk for adverse cardiovascular events1, 28.
Perspectives
Patients with RfHTN represent a subset of individuals with hypertension that remains uncontrolled despite maximal antihypertensive treatment, including use of long-acting thiazide diuretics and mineralocorticoid receptor antagonists. Our detailed cardiac phenotyping analysis using CMR demonstrated greater ventricular wall thickness without chamber enlargement in patients with RfHTN compared to patients with controlled RHTN. These findings are in agreement with prior studies from our group, suggesting that the failure of antihypertensive failure to control BP in RfHTN is not attributable to persistent fluid retention, but instead is mediated by other mechanisms, such as increased sympathetic tone.
Supplementary Material
Novelty and Significance.
1. What Is New
Patients with refractory hypertension have increased cardiac damage compared to controlled resistant hypertension.
Cardiac MRI showed evidence of increased LV mass and wall thickness without cardiac chamber enlargement in refractory hypertension patients.
2. What Is Relevant?
In patients with resistant hypertension, lack of blood pressure control despite multiple medications is associated with adverse cardiovascular remodeling.
There is no evidence of chamber enlargement in refractory hypertension patients to suggest persistent excess intravascular volume as a cause of antihypertensive treatment failure.
Summary.
Patients with refractory hypertension have greater LV mass and adverse vascular remodeling compared to controlled resistant hypertension patients, without evidence of greater intravascular volume to explain their antihypertensive treatment failure.
Acknowledgments
None
Source(s) of Funding:
The National Institutes of Health (NIH R01 HL113004) and the American Heart Association Strategically Focused Research Network (AHA 5SFRN2390002) supported this research.
Footnotes
Conflict(s) of Interest/Disclosure(s): None
References
- 1.Dudenbostel T, Acelajado MC, Pisoni R, Li P, Oparil S, Calhoun DA. Refractory hypertension: Evidence of heightened sympathetic activity as a cause of antihypertensive treatment failure. Hypertension. 2015;66:126–133. doi: 10.1161/HYPERTENSIONAHA.115.05449. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM, American Heart Association Professional Education C 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. Circulation. 2008;117:e510–526. doi: 10.1161/CIRCULATIONAHA.108.189141. [DOI] [PubMed] [Google Scholar]
- 3.Acelajado MC, Pisoni R, Dudenbostel T, Dell’Italia LJ, Cartmill F, Zhang B, Cofield SS, Oparil S, Calhoun DA. Refractory hypertension: Definition, prevalence, and patient characteristics. Journal of clinical hypertension. 2012;14:7–12. doi: 10.1111/j.1751-7176.2011.00556.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Calhoun DA, Booth JN, 3rd, Oparil S, Irvin MR, Shimbo D, Lackland DT, Howard G, Safford MM, Muntner P. Refractory hypertension: Determination of prevalence, risk factors, and comorbidities in a large, population-based cohort. Hypertension. 2014;63:451–458. doi: 10.1161/HYPERTENSIONAHA.113.02026. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Siddiqui M, Judd EK, Oparil S, Calhoun DA. White coat effect is uncommon in patients with refractory hypertension. Hypertension. 2017 doi: 10.1161/HYPERTENSIONAHA.117.09464. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Taler SJ, Textor SC, Augustine JE. Resistant hypertension: Comparing hemodynamic management to specialist care. Hypertension. 2002;39:982–988. doi: 10.1161/01.hyp.0000016176.16042.2f. [DOI] [PubMed] [Google Scholar]
- 7.Gaddam K, Corros C, Pimenta E, Ahmed M, Denney T, Aban I, Inusah S, Gupta H, Lloyd SG, Oparil S, Husain A, Dell’Italia LJ, Calhoun DA. Rapid reversal of left ventricular hypertrophy and intracardiac volume overload in patients with resistant hypertension and hyperaldosteronism: A prospective clinical study. Hypertension. 2010;55:1137–1142. doi: 10.1161/HYPERTENSIONAHA.109.141531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Modolo R, de Faria AP, Sabbatini AR, Barbaro NR, Ritter AM, Moreno H. Refractory and resistant hypertension: Characteristics and differences observed in a specialized clinic. Journal of the American Society of Hypertension: JASH. 2015;9:397–402. doi: 10.1016/j.jash.2015.03.005. [DOI] [PubMed] [Google Scholar]
- 9.Terent A, Breig-Asberg E. Epidemiological perspective of body position and arm level in blood pressure measurement. Blood pressure. 1994;3:156–163. doi: 10.3109/08037059409102246. [DOI] [PubMed] [Google Scholar]
- 10.Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps SG, Roccella EJ. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: Blood pressure measurement in humans: A statement for professionals from the subcommittee of professional and public education of the american heart association council on high blood pressure research. Circulation. 2005;111:697–716. doi: 10.1161/01.CIR.0000154900.76284.F6. [DOI] [PubMed] [Google Scholar]
- 11.Manning DM, Kuchirka C, Kaminski J. Miscuffing: Inappropriate blood pressure cuff application. Circulation. 1983;68:763–766. doi: 10.1161/01.cir.68.4.763. [DOI] [PubMed] [Google Scholar]
- 12.Beckett L, Godwin M. The bptru automatic blood pressure monitor compared to 24 hour ambulatory blood pressure monitoring in the assessment of blood pressure in patients with hypertension. BMC cardiovascular disorders. 2005;5:18. doi: 10.1186/1471-2261-5-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Wright JM, Mattu GS, Perry TL, Jr, Gelferc ME, Strange KD, Zorn A, Chen Y. Validation of a new algorithm for the bpm-100 electronic oscillometric office blood pressure monitor. Blood pressure monitoring. 2001;6:161–165. doi: 10.1097/00126097-200106000-00008. [DOI] [PubMed] [Google Scholar]
- 14.Mattu GS, Heran BS, Wright JM. Overall accuracy of the bptru–an automated electronic blood pressure device. Blood pressure monitoring. 2004;9:47–52. doi: 10.1097/00126097-200402000-00009. [DOI] [PubMed] [Google Scholar]
- 15.Culleton BF, McKay DW, Campbell NR. Performance of the automated bptru measurement device in the assessment of white-coat hypertension and white-coat effect. Blood pressure monitoring. 2006;11:37–42. doi: 10.1097/01.mbp.0000189794.36230.a7. [DOI] [PubMed] [Google Scholar]
- 16.Myers MG, Kaczorowski J, Paterson JM, Dolovich L, Tu K. Thresholds for diagnosing hypertension based on automated office blood pressure measurements and cardiovascular risk. Hypertension. 2015;66:489–495. doi: 10.1161/HYPERTENSIONAHA.115.05782. [DOI] [PubMed] [Google Scholar]
- 17.Wohlfahrt P, Cifkova R, Movsisyan N, Kunzova S, Lesovsky J, Homolka M, Soska V, Bauerova H, Lopez-Jimenez F, Sochor O. Threshold for diagnosing hypertension by automated office blood pressure using random sample population data. Journal of hypertension. 2016;34:2180–2186. doi: 10.1097/HJH.0000000000001076. [DOI] [PubMed] [Google Scholar]
- 18.O’Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, Clement D, de la Sierra A, de Leeuw P, Dolan E, Fagard R, Graves J, Head GA, Imai Y, Kario K, Lurbe E, Mallion JM, Mancia G, Mengden T, Myers M, Ogedegbe G, Ohkubo T, Omboni S, Palatini P, Redon J, Ruilope LM, Shennan A, Staessen JA, vanMontfrans G, Verdecchia P, Waeber B, Wang J, Zanchetti A, Zhang Y, European Society of Hypertension Working Group on Blood Pressure M European society of hypertension position paper on ambulatory blood pressure monitoring. Journal of hypertension. 2013;31:1731–1768. doi: 10.1097/HJH.0b013e328363e964. [DOI] [PubMed] [Google Scholar]
- 19.Pickering T. Recommendations for the use of home (self) and ambulatory blood pressure monitoring. American society of hypertension ad hoc panel. American journal of hypertension. 1996;9:1–11. doi: 10.1016/0895-7061(95)00341-x. [DOI] [PubMed] [Google Scholar]
- 20.Ahmed MI, Desai RV, Gaddam KK, Venkatesh BA, Agarwal S, Inusah S, Lloyd SG, Denney TS, Jr, Calhoun D, Dell’italia LJ, Gupta H. Relation of torsion and myocardial strains to lv ejection fraction in hypertension. JACC Cardiovascular imaging. 2012;5:273–281. doi: 10.1016/j.jcmg.2011.11.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ, Chamber Quantification Writing G, American Society of Echocardiography’s G, Standards C, European Association of E Recommendations for chamber quantification: A report from the american society of echocardiography’s guidelines and standards committee and the chamber quantification writing group, developed in conjunction with the european association of echocardiography, a branch of the european society of cardiology. J Am Soc Echocardiogr. 2005;18:1440–1463. doi: 10.1016/j.echo.2005.10.005. [DOI] [PubMed] [Google Scholar]
- 22.Lawson MA, Blackwell GG, Davis ND, Roney M, Dell’Italia LJ, Pohost GM. Accuracy of biplane long-axis left ventricular volume determined by cine magnetic resonance imaging in patients with regional and global dysfunction. Am J Cardiol. 1996;77:1098–1104. doi: 10.1016/s0002-9149(96)00140-3. [DOI] [PubMed] [Google Scholar]
- 23.Feng W, Nagaraj H, Gupta H, Lloyd SG, Aban I, Perry GJ, Calhoun DA, Dell’Italia LJ, Denney TS., Jr A dual propagation contours technique for semi-automated assessment of systolic and diastolic cardiac function by cmr. Journal of cardiovascular magnetic resonance: official journal of the Society for Cardiovascular Magnetic Resonance. 2009;11:30. doi: 10.1186/1532-429X-11-30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Kawaji K, Codella NC, Prince MR, Chu CW, Shakoor A, LaBounty TM, Min JK, Swaminathan RV, Devereux RB, Wang Y, Weinsaft JW. Automated segmentation of routine clinical cardiac magnetic resonance imaging for assessment of left ventricular diastolic dysfunction. Circ Cardiovasc Imaging. 2009;2:476–484. doi: 10.1161/CIRCIMAGING.109.879304. [DOI] [PubMed] [Google Scholar]
- 25.Daneshvar D, Wei J, Tolstrup K, Thomson LE, Shufelt C, Merz CN. Diastolic dysfunction: Improved understanding using emerging imaging techniques. American heart journal. 2010;160:394–404. doi: 10.1016/j.ahj.2010.06.040. [DOI] [PubMed] [Google Scholar]
- 26.Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, Pimenta E, Aban I, Oparil S, Calhoun DA. Characterization of resistant hypertension: Association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Archives of internal medicine. 2008;168:1159–1164. doi: 10.1001/archinte.168.11.1159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Prasad A, Hastings JL, Shibata S, Popovic ZB, Arbab-Zadeh A, Bhella PS, Okazaki K, Fu Q, Berk M, Palmer D, Greenberg NL, Garcia MJ, Thomas JD, Levine BD. Characterization of static and dynamic left ventricular diastolic function in patients with heart failure with a preserved ejection fraction. Circulation. Heart failure. 2010;3:617–626. doi: 10.1161/CIRCHEARTFAILURE.109.867044. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M, Caulfield MJ, Cifkova R, Clement D, Coca A, Dominiczak A, Erdine S, Fagard R, Farsang C, Grassi G, Haller H, Heagerty A, Kjeldsen SE, Kiowski W, Mallion JM, Manolis A, Narkiewicz K, Nilsson P, Olsen MH, Rahn KH, Redon J, Rodicio J, Ruilope L, Schmieder RE, Struijker-Boudier HA, van Zwieten PA, Viigimaa M, Zanchetti A, European Society of H Reappraisal of european guidelines on hypertension management: A european society of hypertension task force document. Journal of hypertension. 2009;27:2121–2158. doi: 10.1097/HJH.0b013e328333146d. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.