Abstract

Drug-resistant hypertension (RH) is a very high-risk condition involving many hypertensive patients, in whom primary aldosteronism (PA) is commonly overlooked. Hence, we aimed at determining if (1) adrenal vein sampling (AVS) can identify PA in RH patients, who are challenging because of receiving multiple interfering drugs; (2) AVS-guided adrenalectomy can resolve high blood pressure (BP) resistance to treatment in these patients.

Based on a pilot study we selected from 1016 consecutive patients referred to our Centre for ‘difficult-to-treat’ hypertension those with RH, for an observational prospective cohort study. We excluded those non-adherent to treatment (by therapeutic drug monitoring) and those with pseudo-RH (by 24-h BP monitoring), which left 110 patients who met the European Society of Cardiology/European Society of Hypertension (ESC/ESH) 2013 definition for RH. Of these patients, 77 were submitted to AVS, who showed unilateral PA in 27 (mean age 55 years; male/female 19/8). Therefore, these patients underwent AVS-guided laparoscopic unilateral adrenalectomy, which resolved RH in all: 20% were clinically cured in that they no longer needed any antihypertensive treatment; 96% were biochemically cured. Systolic and diastolic BP fell from 165/100 ± 26/14 mmHg at baseline, to 132/84 ± 14/9 mmHg at 6 months after surgery (P<10−4 for both) notwithstanding the fall of number and defined daily dose (DDD) of antihypertensive drugs required to achieve BP control (P<10−4 for both). A prominent regression of cardiac and renal damage was also observed.

Thus, the present study shows the feasibility of identifying PA by AVS in RH patients, and of resolving high BP resistance to treatment in these patients by AVS-guided adrenalectomy.

Introduction

More than a hundred medications are available as single agent or in combination for the treatment of arterial hypertension (HT); yet, a substantial proportion of the hypertensive patients fail to reach the optimal blood pressure (BP) values [1]. These are high-risk patients not only because of uncontrolled BP values, but also because of the concurrence of signs of hypertension-mediated organ damage, a proxy for imminent cardiovascular events. For these reasons the European Society of Cardiology/European Society of Hypertension (ESC/ESH) and the American Heart Association (AHA), to identify patients whose high BP values are not at target level notwithstanding treatment with three drugs, including a diuretic [2], and even patients at target who require four or more drugs to this goal, have introduced the term of ‘drug-resistant hypertension’ (RH) [2–5].

Their high BP resistance to treatment is often due to secondary forms of HT, of which primary aldosteronism (PA) is the most common. The 2016 Endocrine Society Clinical Practice Guidelines [6] and the 2017 AHA Hypertension Guidelines [4] recommend that all patients with RH be screened for PA. However, this is based on small retrospective studies and a case report [7,8], none of which used adrenal vein sampling (AVS) for subtyping as a guide to treatment. By definition, patients with RH are on multiple drugs that deeply affect the renin–angiotensin–aldosterone system. Therefore, both screening and subtyping for PA would be precluded as these drugs deeply affect the aldosterone-renin ratio (ARR), the most commonly used screening method [9]. For subtyping of PA the key test is AVS [6,10,11]; whether it is feasible and clinically useful in RH patients, who are on multiple drugs, remains unexplored, but if proven, the feasibility of AVS will be of paramount importance for the clinical management of these highly challenging patients. Hence, in a proof-of-concept study we investigated if AVS could allow identification of unilateral PA as the underlying cause of RH, and if AVS-guided unilateral laparoscopic adrenalectomy could be an effective strategy to resolve BP resistance to treatment in these patients.

Methods

Study design

Considering the clinical challenges posed by the patients with ‘difficult-to-treat’ HT, at our centre a protocol for the systematic evaluation of these patients was set up, which entailed the use of 24-h BP monitoring and therapeutic drug monitoring to rule out pseudo-RH and non-adherence to treatment [12,13]. This protocol was used routinely with clinical success and constituted the basis of this prospective study, which was approved by the Institutional Review Board and followed the Helsinki recommendations. Each patient provided a written consent to participate in the study and allowed use of his/her de-identified data.

Selection of the patients

We determined beforehand to select a cohort that met the ESC/ESH 2013 definition [14] for RH from a large population of consecutive patients referred for difficult-to-control HT to the University of Padua Centre of Excellence of the ESH (Figure 1). This was because RH is listed among the features that should prompt the search for PA in the Endocrine Society Clinical Practice Guidelines [15] and the 2017 AHA Hypertension Guidelines [4]. After exclusion of those with pseudo-RH and non-adherence to treatment, as described above [12,13], we selected for further work-up those who wished to achieve surgical cure. Patients fulfilling these criteria underwent adrenal imaging by 1.5-mm-thick slices computed tomography (CT) with contrast medium to rule out adrenocortical aldosterone-secreting carcinoma [16], and to identify adrenal veins anatomy in preparation for AVS as recommended by Guidelines [6].

Flow-chart of the study for selection, recruitment and analysis of the patients

Figure 1
Flow-chart of the study for selection, recruitment and analysis of the patients

Please refer to Figure 3 for the outcome according to the PASO criteria.

Figure 1
Flow-chart of the study for selection, recruitment and analysis of the patients

Please refer to Figure 3 for the outcome according to the PASO criteria.

However, for this proof-of-concept study, considering the limited availability of AVS, we selected the patients who had one or more additional clues of PA according to the Guidelines, which included spontaneous or diuretic-induced hypokalaemia, adrenal nodules on imaging, and obstructive sleep apnea [6]. The finding of low (≤2 mIU/l) plasma active renin concentrations (DRCs) while on drugs as angiotensin-converting enzyme (ACE) inhibitors (ACEI), angiotensin II receptor blockers (ARBs) or diuretics that are expected to raise renin, and/or of elevated plasma aldosterone concentration (PAC) on treatments with ACEI or ARBs that lower aldosterone secretion were held to be additional clues to the presence of PA. However, in the patients on β-blockers, raised PAC values were considered a conditio sine qua non for further testing because these drugs blunt DRC, and thus factitiously raise the ARR.

As a test to allocate patients for adrenalectomy, AVS was offered only to the patients who were reasonable candidates for general anaesthesia and surgery following the Endocrine Society Clinical Practice Guidelines [6]. Consenting patients underwent the test while on multiple antihypertensive drugs, including mineralocorticoid receptor antagonists (MRAs), ACEs or ARBs, calcium channel blockers and doxazosin, as described in detail [17–19].

For each patient, at baseline, and at 1- and 6-month follow-up after adrenalectomy, we determined the antihypertensive drugs burden, as estimated by both number and defined daily doses (DDDs) of antihypertensive drugs, i.e. the assumed average maintenance dose per day for a drug used for the indication of high BP in adults as defined by the WHO [20]. The DDD for drugs used by each individual patient was calculated using the following equation:  
DDD=number of pills × quantity of the drug per pillWHO assigned DDD for that drug [20]
The total DDD of each patient was then calculated as sum of the DDD of the different drugs administered.

AVS

AVS was performed by highly experienced radiologists using catheters shaped for each adrenal vein and the bilaterally simultaneous technique. Blood was collected by gravity from the right and left adrenal veins and from the infrarenal inferior vena cava for the measurements of PAC, plasma cortisol concentration and androstenedione [19]. It was performed under unstimulated conditions, because cosyntropin, while facilitating the ascertainment of catheterisation success, induces heterogeneous responses [21–23], and lowers the lateralisation index (LI), as confirmed in the largest available series of PA patients who underwent AVS both under unstimulated conditions and during cosyntropin-stimulation in the AVIS-2 Study [24].

AVS was used for diagnosis only if bilaterally successful, as defined by a selectivity index > 2.0; unilateral PA was diagnosed and used to refer the patients for laparoscopic adrenalectomy if the LI exceeded 2.0. The use of this seemingly permissive LI cut-off is supported by results of the largest study on AVS [24], and was held to be clinically justified by the fact that those patients had RH. Moreover, these cut-off values for the selectivity and lateralisation index were recommended in an expert consensus document [11] and were validated in studies that followed the STARD recommendations in that they used an unambiguous diagnosis of aldosterone-producing adenoma (APA) as reference [12,19,24].

Biochemical and haemodynamic evaluation and diagnostic criteria

At baseline, all patients underwent a full biochemical and clinical assessment, which included measurement of serum sodium and potassium, 24-h urine sodium and potassium excretion, direct measurement of DRC, PAC (LIAISON Direct Renin™ and Aldosterone Kits™, both from Diasorin, Saluggia, Italy), and calculation of the ARR. All were tested again at 1- and 6-month follow-up post-adrenalectomy in an identical way, if possible without potentially confounding antihypertensive medications, i.e. while they were taking only a long-acting calcium channel blocker and/or doxazosin.

For the analysis of BP outcome, attended BP values were measured with automated devices in the office considering the average of at least three measurements taken 3-min apart following the recommendations of the 2013 ESC/ESH Guidelines [14].

The diagnosis of APA was established unambiguously by the strictest available criteria, which besides a biochemical diagnosis of PA, require biochemical cure, e.g. normalisation of plasma renin and PAC after adrenalectomy [25], and immunochemical demonstration of an aldosterone synthase positive adenoma at immunostaining with a monoclonal antibody for human CYP11B2 [26].

Evaluation of hypertension -mediated organ damage

Hypertension-mediated organ damage was determined by Doppler echocardiography. Briefly, left ventricular (LV) hypertrophy (LVH), geometry and end-systolic and end-diastolic volume, stroke work, LV work, Doppler-flow velocity indexes of early (E wave) and late (A wave) LV filling, the E/A wave ratio, the tissue-Doppler E/e′, and the mitral E wave deceleration time (mDecT) were measured by the same expert cardiologist (M.C.), following the American Society of Echocardiography guidelines as reported [27]. LVH was defined according to the ESC/ESH cutoffs, i.e. LV mass (LVM)/height ≥50 g/m2.7 for men and ≥47 g/m2.7 for women [14]. The mDecT was normalised for heart rate because of its dependence on the duration of diastole.

Hypertension-mediated organ damage in the kidney was assessed by 24-h urinary excretion of albumin normalised per gram of excreted creatinine and estimated glomerular filtration rate (eGFR with the CKD-EPI equation), and categorised in chronic kidney disease (CKD) classes.

Statistical analysis

Data with a skewed distribution were analysed after log transformation by one-way ANOVA followed by Scheffe’s post-hoc test or paired t test. If after log transformation Gaussian distribution was not achieved, the non-parametric Wilcoxon’s test was used to compare quantitative variables between groups. The distribution of categorical variables was compared by chi-square analysis. Results were expressed as absolute numbers, ratio, percentage, mean (± standard deviation (SD) or standard error (SE)) or median (range). To identify predictors of cured/improved high BP we performed a multivariable logistic regression entering age, number of drugs and total DDD required to control BP at baseline, serum potassium levels and mean BP values, using a PIN = 0.05 and POUT = 0.10. The backward (Wald) strategy was chosen for this analysis because it minimises the chances of missing identification of relevant predictors. [28]

Significance was set at two-tailed P<0.05. For the analysis, we used SPSS (version 25 for Mac; IBM Italy Spa, Rome, Italy) and GraphPad Prism (version 8.3 for Mac; GraphPad Software, La Jolla, CA) software.

Results

From September 2011 to September 2018, we evaluated for ‘difficult-to-control’ high BP values 1016 patients in our specialised centre for HT; approximately half of them were referred by their physicians and the rest presented directly after a web-based search for a specialised ESH hypertension centre. Of these patients, 906 (89%) did not fulfil the RH definition and were excluded from the present study (Figure 1). This was because they were on less than three medications, and/or were not on optimal medical treatment (18%), and/or were judged to be non-adherent to prescribed treatment based on therapeutic drug monitoring, and/or because of white-coat HT on 24-h BP monitoring. The remaining 110 patients fulfilled the 2008 AHA or the ESC/ESH definition of RH [3,14].

Of these patients, 77 Caucasian patients who showed at least an additional clue of PA, as defined above (mostly spontaneous or diuretic-induced hypokalaemia) [6], who wished to pursue surgical cure, and had no contraindications to general anaesthesia and surgery, were offered AVS. In the remaining 33 patients, 26, who had no clues of PA, were considered to have a low likelihood of the disease, and 7 did not seek surgical cure and/or were judged to be suboptimal or poor candidate for general anaesthesia and/or surgery (Supplementary Figure S1). Although all these patients underwent imaging according to Guidelines to rule out an adrenocortical carcinoma, they were not offered AVS [6].

Following recommendations of an AHA consensus of experts [11], AVS was performed after verification that their plasma renin levels were not overtly elevated because high renin can lower between-side differences of aldosterone secretion. Owing to their high BP values and the associated high risk, AVS was performed without withdrawing interfering drugs.

AVS results and allocation to surgery

AVS was performed with no intra- and post-procedural complications. By the aforementioned criteria, it was bilaterally selective in 82% of the patients and demonstrated a unilateral form of aldosteronism in 27 patients (35%) who, therefore, underwent AVS-guided laparoscopic adrenalectomy. Surgery was performed uneventfully during a 3-day hospital stay, no complications occurred. Pathology and immunohistochemistry analysis of the excised adrenal, biochemical and clinical follow-up (see next section) confirmed the diagnosis of APA in all patients (Figure 1).

Follow-up studies

We performed a comprehensive clinical and biochemical evaluation at 1-month post-adrenalectomy, as per protocol at our institution. At this time point no patients showed persistent RH (Figure 2). The BP values markedly fell by 36 mmHg systolic and 19 mmHg diastolic, from 165/100 ± 26/14 mmHg at baseline to 129/81 ± 8/6 mmHg (P<10−4 for both systolic and diastolic BP values), notwithstanding the tapering (from 4.5 ± 0.2 at baseline to 1.0 ± 0.2, P<10−4) of the average number of drugs required to achieve BP control.

Changes from baseline of systolic and diastolic BP values, number and DDD of drugs in resistant hypertensive patients (n=27) at 1- and 6-month follow-up after laparoscopic adrenalectomy

Figure 2
Changes from baseline of systolic and diastolic BP values, number and DDD of drugs in resistant hypertensive patients (n=27) at 1- and 6-month follow-up after laparoscopic adrenalectomy

*P <10-4 vs. baseline

Figure 2
Changes from baseline of systolic and diastolic BP values, number and DDD of drugs in resistant hypertensive patients (n=27) at 1- and 6-month follow-up after laparoscopic adrenalectomy

*P <10-4 vs. baseline

Six months after surgery, the BP fall was well maintained (132/84 ± 14/9 mmHg (P<10−4 for both)) despite the persistently reduced drug therapy to 1.2 ± 0.2 (P<10−4 vs. baseline) (Table 1 and Figure 2).

Table 1
Demographics and clinical characteristics of the patients with RH and unilateral PA due to an APA at baseline and after unilateral adrenalectomy
VariablesBaseline (n=27)Post-surgery (6 months) (n=27)P
Age (years) 55 ± 11 
Gender, n, male/female, (%) 19/8, (70/30) 
Atrial fibrillation, n (%) 2 (8) 
Stroke, n (%) 
Acute coronary syndrome, n (%) 
CKD, n (%) 1 (4) 
Obstructive sleep apnea, n (%) 4 (16) 
Diabetes mellitus type II, n (%) 5 (20) 
BMI (kg/m227 ± 3.5 26 ± 4.3 =0.8 
Office systolic BP (mmHg) 165 ± 26 132 ± 14 <10−4 
Office diastolic BP (mmHg) 100 ± 14 84 ± 9 <10−4 
Heart rate (bpm) 73 ± 10 72 ± 9 =0.81 
Drugs (n4.5 ± 0.2 1.2 ± 0.2 <10−4 
DDD (n5.6 ± 2.2 1.13 ± 1.3 <10−4 
APA size (mm) 16.6 ± 5.6 
VariablesBaseline (n=27)Post-surgery (6 months) (n=27)P
Age (years) 55 ± 11 
Gender, n, male/female, (%) 19/8, (70/30) 
Atrial fibrillation, n (%) 2 (8) 
Stroke, n (%) 
Acute coronary syndrome, n (%) 
CKD, n (%) 1 (4) 
Obstructive sleep apnea, n (%) 4 (16) 
Diabetes mellitus type II, n (%) 5 (20) 
BMI (kg/m227 ± 3.5 26 ± 4.3 =0.8 
Office systolic BP (mmHg) 165 ± 26 132 ± 14 <10−4 
Office diastolic BP (mmHg) 100 ± 14 84 ± 9 <10−4 
Heart rate (bpm) 73 ± 10 72 ± 9 =0.81 
Drugs (n4.5 ± 0.2 1.2 ± 0.2 <10−4 
DDD (n5.6 ± 2.2 1.13 ± 1.3 <10−4 
APA size (mm) 16.6 ± 5.6 

Data reported as absolute numbers, percentage and mean (±SD) as appropriate. Abbreviations: BMI, body mass index; CKD, chronic kidney disease; BP, blood pressure; DDD, defined daily dose; APA, aldosterone-producing adenoma .

By internationally accepted criteria [25], all patients showed a clear-cut clinical benefit: 5 (20%) were completely cured, i.e. were normotensive on no antihypertensive drugs, 22 (80%) showed a partial clinical success (Figure 3).

Clinical and biochemical outcomes after AVS-guided unilateral laparoscopic adrenalectomy in 27 patients with resistant hypertension by the PASO criteria [25] as defined below

Figure 3
Clinical and biochemical outcomes after AVS-guided unilateral laparoscopic adrenalectomy in 27 patients with resistant hypertension by the PASO criteria [25] as defined below

Absent clinical success: unchanged or increased BP [unchanged difference (pre- vs post-surgery) in systolic/diastolic BP of < 20/10 mmHg or increased in systolic/diastolic BP ≥ 20/10 mmHg respectively] with either the same amount or an increase in antihypertensive medication [unchanged difference is n defined as less than 0.5 of the DDD or an increase in 0.5 or more times the DDD between pre- and post-surgery]. Partial clinical success: the same BP as before surgery [difference (pre- vs post-surgery) in systolic/diastolic BP of < 20/10 mmHg respectively] with less antihypertensive medication [defined as less than 0.5 times the DDD between pre- and post-surgery] or reduction in BP [defined as a difference in systolic and/or diastolic BP of ≥ 20/10 mmHg respectively] with either the same amount or less antihypertensive medication [unchanged antihypertensive medication is defined as a change (decrease or increase) in less than 0.5 times the DDD; less antihypertensives defined as a decrease of 0.5 or more times the DDD between pre- and post-surgery]. Complete clinical success: defined as office systolic/diastolic BP < 140/90 mmHg respectively without the aid of antihypertensive medication. Absent biochemical success: persistent hypokalaemia [defined as K+ < 3.6 mmol/l after surgery] and/or persistent raised ARR [defined as ARR ≥ 26 (ng/dl)*(ng/ml/h)−1 after surgery]. Partial biochemical success: correction of hypokalaemia [defined as K+ ≥ 3.6 mmol/l after surgery] and a raised ARR with ≥ 50% decrease in baseline PAC [defined as ARR ≥ 26 (ng/dl)*(ng/ml/h)−1 and PAC ≥ 15 ng/dl after surgery]. Complete biochemical success: correction of hypokalaemia [defined as K+ ≥ 3.6 mmol/l after surgery] and normalisation of ARR [defined as ARR < 26 (ng/dl)*(ng/ml/h)−1].

Figure 3
Clinical and biochemical outcomes after AVS-guided unilateral laparoscopic adrenalectomy in 27 patients with resistant hypertension by the PASO criteria [25] as defined below

Absent clinical success: unchanged or increased BP [unchanged difference (pre- vs post-surgery) in systolic/diastolic BP of < 20/10 mmHg or increased in systolic/diastolic BP ≥ 20/10 mmHg respectively] with either the same amount or an increase in antihypertensive medication [unchanged difference is n defined as less than 0.5 of the DDD or an increase in 0.5 or more times the DDD between pre- and post-surgery]. Partial clinical success: the same BP as before surgery [difference (pre- vs post-surgery) in systolic/diastolic BP of < 20/10 mmHg respectively] with less antihypertensive medication [defined as less than 0.5 times the DDD between pre- and post-surgery] or reduction in BP [defined as a difference in systolic and/or diastolic BP of ≥ 20/10 mmHg respectively] with either the same amount or less antihypertensive medication [unchanged antihypertensive medication is defined as a change (decrease or increase) in less than 0.5 times the DDD; less antihypertensives defined as a decrease of 0.5 or more times the DDD between pre- and post-surgery]. Complete clinical success: defined as office systolic/diastolic BP < 140/90 mmHg respectively without the aid of antihypertensive medication. Absent biochemical success: persistent hypokalaemia [defined as K+ < 3.6 mmol/l after surgery] and/or persistent raised ARR [defined as ARR ≥ 26 (ng/dl)*(ng/ml/h)−1 after surgery]. Partial biochemical success: correction of hypokalaemia [defined as K+ ≥ 3.6 mmol/l after surgery] and a raised ARR with ≥ 50% decrease in baseline PAC [defined as ARR ≥ 26 (ng/dl)*(ng/ml/h)−1 and PAC ≥ 15 ng/dl after surgery]. Complete biochemical success: correction of hypokalaemia [defined as K+ ≥ 3.6 mmol/l after surgery] and normalisation of ARR [defined as ARR < 26 (ng/dl)*(ng/ml/h)−1].

The number of drugs needed to achieve BP control decreased in a highly significant fashion from baseline (Tables 1 and 3 and Figure 2). These changes were paralleled by signs of biochemical correction of PA: increased serum potassium and DRC levels, and decreased PAC (Table 2). Accordingly, the vast majority (96%) of the patients showed complete biochemical cure and only one (4%) partial success [25], owing to the fact that DRC values remained very low due to treatment with β-blockers (Figure 3).

Table 2
Biochemical characteristics of the patients with RH and unilateral PA due to an APA at baseline and after unilateral adrenalectomy
VariablesBaseline n=27Post-surgery (6 months) n=27P
PRA (ng/ml/h) 0.6 (0.2–3.4) 10.5 (0.2–40.9) =6 × 10−3 
DRC (mIU/l) 4.9 (2.0–27.9) 36.8 (2.0–334.6) =6 × 10−3 
PAC (ng/dl) 32 (14–152) 7 (2.6–13.1) <10−4 
ARR ([ng/dl]*[(ng/ml/h)−1]) 168 (30– 624) 9.3 (0–40) <10−4 
Serum Na+ (mmol/l) 142 ± 2.6 140 ± 2 =0.02 
Serum K+ (mmol/l) 3.5 ± 0.8 4.6 ± 0.6 <10−4 
24-h urinary Na+ excretion (mmol/24 h) 172 ± 67 163 ± 47 =0.4 
24 h urinary K+ excretion (mmol/24 h) 78 ± 27 64 ± 22 =0.01 
UAE (mg/g creatinine) 56.5 (6–3820) 7.2 (5–1770) =0.01 
eGFR (ml/min/1.73 m277 ± 5 72 ± 5 =0.11 
VariablesBaseline n=27Post-surgery (6 months) n=27P
PRA (ng/ml/h) 0.6 (0.2–3.4) 10.5 (0.2–40.9) =6 × 10−3 
DRC (mIU/l) 4.9 (2.0–27.9) 36.8 (2.0–334.6) =6 × 10−3 
PAC (ng/dl) 32 (14–152) 7 (2.6–13.1) <10−4 
ARR ([ng/dl]*[(ng/ml/h)−1]) 168 (30– 624) 9.3 (0–40) <10−4 
Serum Na+ (mmol/l) 142 ± 2.6 140 ± 2 =0.02 
Serum K+ (mmol/l) 3.5 ± 0.8 4.6 ± 0.6 <10−4 
24-h urinary Na+ excretion (mmol/24 h) 172 ± 67 163 ± 47 =0.4 
24 h urinary K+ excretion (mmol/24 h) 78 ± 27 64 ± 22 =0.01 
UAE (mg/g creatinine) 56.5 (6–3820) 7.2 (5–1770) =0.01 
eGFR (ml/min/1.73 m277 ± 5 72 ± 5 =0.11 

Data reported as mean (±SD) or median (range) as appropriate. Abbreviations: PRA, plasma renin activity; DRC, renin concentration; PAC, plasma aldosterone concentration; ARR, aldosterone-renin ratio; UAE, urinary albumin excretion; eGFR, estimated glomerular filtration rate.

Please note that in few patients the renin levels were not suppressed likely because of the ongoing treatment with multiple drugs, including ACIs, ARBs, diuretics, that stimulate renin secretion. Normal values for the ARR = <26 ([ng/dl]*[(ng/ml/h)−1]).

Of note, in the group of patients assigned to an MRA-based antihypertensive treatment, because AVS failed bilaterally or showed bilateral PA, none were biochemically or haemodynamically cured (P< 10−3 for cure rate vs adrenalectomy).

Predictors of cure/improvement

By a multivariable logistic regression analysis we found that of the following baseline variables, i.e. age, body mass index (BMI), sex, number of drugs, total DDD and mean BP, only the latter was useful to predict clinical outcome: higher baseline mean BP values were associated with a higher chance of being improved over cured (Expß = 1.286 [95% CI: 1.013–1.632], P=0.039). A model based on mean BP predicted correct allocation of the patients in the cured/markedly improved categories in 90% of the RH patients.

Hypertension-mediated organ damage

LVM index decreased by 13% (from 60 ± 14 to 52 ± 13 g/m2.7, P<10−4) at the 6-month follow-up, mainly because of a decrease in LV end-diastolic volume and posterior wall thickness; the relative wall thickness remained unchanged (Table 4). While the left atrium size decreased significantly, the bulbar aorta did not; therefore, the change of their ratio did not attain statistical significance. There was a significant increase in the mDecT and the mDecT normalised for heart rate increased significantly from baseline (Table 5); however, the E/A ratio and the E/e′ ratio values, which were within the normal range at baseline, showed no significant changes. The LV stroke volume and LV stroke work fell significantly as a result of decreased LVM and volume (Table 5). Arterial compliance exhibited a 21%, non-significant trend to increase; systemic resistance index showed no significant changes (Table 5).

As regard to renal function, there was a significant fall of urinary albumin excretion and a slight decrease in eGFR after adrenalectomy (Table 2).

Discussion

Biochemical cure, and cure or improvement of HT with AVS-guided adrenalectomy have been documented in several previous studies of PA patients [29–32], but none has been focused specifically on patients with RH. Thus, this is the first study, to the best of our knowledge, to prove the concept that AVS provides an accurate identification of unilateral PA in high-risk RH patients notwithstanding their being on multiple potentially interfering antihypertensive drugs.

Albeit obtained in a small observational study, the present study also proves, for the first time, the concept that AVS-guided unilateral laparoscopic adrenalectomy allowed resolution of RH in all patients and total biochemical cure of PA in the vast majority of them (Tables 1 and 2). We consider these results extremely important as they demonstrate that RH can be resolved and even completely cured as the BP values were brought down to target levels after surgery notwithstanding the significant fall of the antihypertensive medications burden, both in terms of number and of DDD needed to control HT (Tables 1 and 3 and Figure 2).

Table 3
Antihypertensive drugs at the initial screening and after adrenalectomy
Antihypertensive drugsDDDAt screeningPost-adrenalectomy
nPatients (%)nPatients (%)
Calcium-channel blockers      
 0.75 31 15 
 1.0 10 38 62 
 2.0 31 23 
Total  26 100 13 100 
β-blockers      
 0.17 
 0.5 67 
 0.6 26 
 1.0 58 33 
Total  12 100 3 100 
Diuretics      
• Thiazides or Furosemide      
 0.25 24 
 0.5 41 
 1.0 35 100 
Total  17 100 2 100 
• Amiloride      
 1.0 100 
Total  4 100   
• Mineralcorticoid receptor antagonists      
 0.3 2 9.5 0 
 1.2 2 9.5 0 
 1.25 12 57 0 
 2.5 5 24 0 
Total  21 100   
α1-blockers      
 0.5 42 67 
 1.0 10 53 33 
 2.0 
Total  19 100 3 100 
Angiotensin-type I receptors blockers      
 1.0 60 
 2.0 40 100 
Total  15 100 1 100 
Antihypertensive drugsDDDAt screeningPost-adrenalectomy
nPatients (%)nPatients (%)
Calcium-channel blockers      
 0.75 31 15 
 1.0 10 38 62 
 2.0 31 23 
Total  26 100 13 100 
β-blockers      
 0.17 
 0.5 67 
 0.6 26 
 1.0 58 33 
Total  12 100 3 100 
Diuretics      
• Thiazides or Furosemide      
 0.25 24 
 0.5 41 
 1.0 35 100 
Total  17 100 2 100 
• Amiloride      
 1.0 100 
Total  4 100   
• Mineralcorticoid receptor antagonists      
 0.3 2 9.5 0 
 1.2 2 9.5 0 
 1.25 12 57 0 
 2.5 5 24 0 
Total  21 100   
α1-blockers      
 0.5 42 67 
 1.0 10 53 33 
 2.0 
Total  19 100 3 100 
Angiotensin-type I receptors blockers      
 1.0 60 
 2.0 40 100 
Total  15 100 1 100 

Data reported by absolute numbers and % refer to each single class of drugs both at baseline and after adrenalectomy.

We identified the baseline predictors of cure of HT by a multivariable logistic regression technique. In spite of being limited in power by the small sample size of our cohort, this analysis showed that in RH patients the higher baseline mean BP values (while on multiple treatment), the lower the chances of getting complete cure of HT.

Of note, medical treatment of PA with MRAs was reported to be associated with regression of the hyperaldosteronism in two independent reports [33,34]. At variance with those findings we could find no signals for this phenomenon to occur in our cohort of RH patients as none of our medically treated patients showed any signs of biochemical or haemodynamic cure improvements.

It is worth noting that all our adrenalectomised RH patients showed an adenoma (average diameter 16.6 ± 5.6 mm) at pathology examination. This tumour was conclusively identified as aldosterone-producing at immunohistochemistry with a monoclonal antibody specific for CYP11B2 [35]. Thus, a surgically curable tumour was the underlying cause of resistance to treatment in 27 (24.5%) of our 110 patients with RH, a proportion that raised to 35% when considering the 77 patients, who were held to be eligible for AVS. The fact that AVS allowed identification of these small tumours in RH patients, despite their being on multiple potentially interfering drugs, and that removal of this tumour led to resolution of RH in all of our patients, are clinically important findings that can lead to changing practice as discussed later.

Our results also indicate that in patients with RH the removal of the culprit adrenal gland furnished an impressive regression of cardiac and renal damage, when present (Tables 4 and 5). This observation agrees with the findings of Gaddam et al. in a 46% African-Americans cohort of RH patients where force-titrated spironolactone treatment induced rapid reversal of LVH in those with high aldosterone [36]. Thus, correction of the hyperaldosteronism and the ensuing favourable haemodynamic changes are fundamental measures to lower the overall cardiovascular risk of the patients. Noteworthy, the reduction in LVM index occurred early, e.g. within 6 months after adrenalectomy, and involved mostly an inward type of remodelling, i.e. rearrangement of the LV around a smaller cavity (Table 4), a finding consistent with previous observations [29], and with the view that PA involves a slight expansion of blood volume [37] that is corrected when biochemical cure is accomplished. From the functional standpoint, the decrease in LVM and volume has sound implications in terms of myocardial susceptibility to ischaemia, as it implies a highly significant decrease in LV stroke work and, therefore, LV myocardial O2 consumption.

Table 4
Cardiac remodelling indexes of the patients with RH and unilateral PA due to an APA at baseline and after unilateral laparoscopic adrenalectomy
VariablesBaseline n=27Post-surgery (6 months) n=27P
Cardiac remodelling 
LVED diameter (mm) 50 ± 4 48 ± 4 <10−4 
LVES diameter (mm) 30 ± 4 29 ± 4 NS 
IVSd (mm) 1.32 ± 0.18 1.27 ± 0.17 =6 × 10−3 
PWd (mm) 1.30 ± 0.17 1.21 ± 0.13 =4 × 10−3 
LVED volume (ml) 122 ± 24 107 ± 20 <0.05 
LVES volume (ml) 37 ± 14 35 ± 10 NS 
LVMI (g/m2.760 ± 14 52 ± 13 <10−4 
RWT 0.52 ± 0.05 0.55 ± 0.08 NS 
Left atrial size (mm) 38.8 ± 0.5 36.9 ± 0.5 =10−4 
Aorta (mm) 36.2 ± 0.3 35.7 ± 0.3 NS 
Aorta/Left atrial size 1.07 ± 0.14 1.04 ± 0.14 NS 
VariablesBaseline n=27Post-surgery (6 months) n=27P
Cardiac remodelling 
LVED diameter (mm) 50 ± 4 48 ± 4 <10−4 
LVES diameter (mm) 30 ± 4 29 ± 4 NS 
IVSd (mm) 1.32 ± 0.18 1.27 ± 0.17 =6 × 10−3 
PWd (mm) 1.30 ± 0.17 1.21 ± 0.13 =4 × 10−3 
LVED volume (ml) 122 ± 24 107 ± 20 <0.05 
LVES volume (ml) 37 ± 14 35 ± 10 NS 
LVMI (g/m2.760 ± 14 52 ± 13 <10−4 
RWT 0.52 ± 0.05 0.55 ± 0.08 NS 
Left atrial size (mm) 38.8 ± 0.5 36.9 ± 0.5 =10−4 
Aorta (mm) 36.2 ± 0.3 35.7 ± 0.3 NS 
Aorta/Left atrial size 1.07 ± 0.14 1.04 ± 0.14 NS 

Data reported as mean ± SE. Abbreviations: LVED, LV end-diastolic; LVES, LV end-systolic; IVSd, interventricular septum thickness at diastole; PWd, posterior wall thickness in diastole; LVMI, LV mass index; RWT, relative wall thickness.

Table 5
Haemodynamic parameters of the patients with RH and unilateral PA due to an APA at baseline and after unilateral laparoscopic adrenalectomy
VariablesBaseline n=27Post-surgery (6 months) n=27P
Haemodynamic parameters 
LV stroke volume (ml/beat) 85 ± 14 72 ± 14 <10−4 
LV stroke work (g/m) 192 ± 43 142 ± 29 =3 × 10−3 
Cardiac index (l/min/m22.87 ± 5.02 2.56 ± 7.30 =0.05 
Mitral deceleration time (ms) 239 ± 64 282 ± 80 =0.02 
Mitral deceleration time normalised for HR (ms/beat) 3.5 ± 1.2 4.2 ± 1.1 =0.03 
Systemic resistance index (din s/cm5m23083 (2576–3590) 3075 (2568–3582) NS 
Arterial compliance (ml/mmHg) 1.32 ± 0.41 1.60 ± 0.38 NS 
VariablesBaseline n=27Post-surgery (6 months) n=27P
Haemodynamic parameters 
LV stroke volume (ml/beat) 85 ± 14 72 ± 14 <10−4 
LV stroke work (g/m) 192 ± 43 142 ± 29 =3 × 10−3 
Cardiac index (l/min/m22.87 ± 5.02 2.56 ± 7.30 =0.05 
Mitral deceleration time (ms) 239 ± 64 282 ± 80 =0.02 
Mitral deceleration time normalised for HR (ms/beat) 3.5 ± 1.2 4.2 ± 1.1 =0.03 
Systemic resistance index (din s/cm5m23083 (2576–3590) 3075 (2568–3582) NS 
Arterial compliance (ml/mmHg) 1.32 ± 0.41 1.60 ± 0.38 NS 

Data reported as mean ± SE, or median (range) as appropriate. Abbreviations: LV, left ventricular; HR, heart rate; NS, not significant.

Of interest, in this cohort of Caucasian patients the indexes of LV filling were normal at baseline notwithstanding the presence of LVH, which likely explains why they did not decrease along with the changes in LVM and volumes. Nonetheless, the left atrium size decreased significantly, suggesting an improvement of LV filling and an ensuing decrease in left atrial pressure, a contention supported by the significant prolongation of the mitral valve deceleration time (Table 5). These modifications suggest an enhancement of LV emptying, in keeping with what observed in PA patients without RH [38]. Given the prominent fall of systolic and diastolic BP and the trend toward an increase in arterial compliance (Table 5), it was puzzling to observe that total systemic vascular resistance did not change significantly. This is an unexpected finding that deserves further scrutiny in larger cohorts of RH patients.

As regards to renal damage, microalbuminuria decreased significantly after surgery because of the decrease in BP, as its changes correlated significantly with the fall of mean BP, and the correction of hypertension- and hyperaldosteronism-induced hyperfiltration [39]. Due to the same mechanisms, estimated GFR showed a trend towards a decrease, in keeping with observations in larger series of PA patients, who were not selected because of RH [40].

Both the last European and American Guidelines on hypertension [2,5], considering the results of studies with MRAs agents in RH patients, [41–46] now recommend prescription of MRAs in RH patients. Along with the results of the EMIRA Study, which documented the feasibility of diagnosing PA without withdrawal of MRAs [47], and with previous findings of Gaddam et al. [36], our study provided further compelling evidence in support of a key role of hyperaldosteronism in RH and, moreover, documented the possibility of diagnosing unilateral surgical curable PA in patients receiving these drugs as long as renin was not stimulated.

The observational design, the relatively small size and the absence of a control group to rule out a Hawthorne effect [48] could be seen as possible weaknesses of this study, which, however, are offset by numerous strengths. The latter entail a clinically validate protocol and the painstaking evaluation of hypertension-mediated organ damage allowed to conclusively rule out pseudo-RH, the prospective design, the careful AVS-centred diagnostic work-up, and use of a conclusive diagnosis of APA based on pathology, immunohistochemistry and follow-up data, as gold reference.

In summary, this proof-of-concept study provided three sets of novel observations that are important for the clinical management of the patients with RH: (i) the demonstration that AVS allows identification of unilateral PA in RH patients notwithstanding treatment with multiple potentially interfering drugs; (ii) the finding that AVS-guided adrenalectomy allowed resolution of the RH patients with underlying unilateral PA; (iii) the accomplishment of a prominent regression of cardiac and renal damage with AVS-guided adrenalectomy. The high rate of biochemical cure, the 20% rate of complete cure of HT and the marked improvement in the rest (Figure 3), allowed a highly significant decrease in the drug burden (Figure 2), with obvious implications for life-long treatment costs and quality of life.

Accordingly, we would like to contend that patients with RH should be referred to centres that not only can rule out pseudo-RH and non-adherence to treatment, but also are able to successfully perform and interpret AVS and thereby can identify the PA patients, who benefit from unilateral laparoscopic adrenalectomy. From the practical standpoint, based on the EMIRA Study [47] and the present results, at our Centre we now do not withdraw MRAs unless renin is stimulated. This has made the preparation and management of our PA patients, and particularly those with RH, through the AVS procedure much safer, simpler and easier.

Clinical perspectives

  • Background as to why the study was undertaken. We wished to investigate if patients with RH, who are on multiple interfering drugs, can receive a diagnosis of PA with AVS and if AVS-guided adrenalectomy can thereby resolve their resistance to treatment.

  • A brief summary of the results. In 27 of 110 patients with RH we could diagnose unilateral PA by AVS and perform AVS-guided adrenalectomy, which was followed by resolution of RH in all patients, biochemical cure in 96% of them, and regression of cardiac and renal organ damage.

  • The potential significance of the results to human health and disease. AVS is feasible and allows to make a diagnosis of unilateral PA in patients with RH. AVS-guided adrenalectomy provides resolution of RH and biochemical cure of PA.

Data Availability

The datasets generated during and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by the Ministry of Health [grant number RF2011-02352318]; and the University of Padua [grant numbers DOR1625891/16, DOR1670784/16, BIRD163255/16].

Author Contribution

G.P.R. conceived the study, recruited the patients, analysed the data and drafted the manuscript. F.T. collected the data, participated in the analysis of the data, preparation of the results the manuscript for publication. S.L. collected the data. G.R. and V.B. contributed to collection of the data and preparation the results. G.M., M.C. and T.M.S. contributed to recruitment of the patients and collected the follow-up variables. M.I. and F.T. operated the patients and planned the 1-month follow-up. R.Z. contributed to collection the data and search of the relevant literature for preparation of the manuscript.

Acknowledgements

We are grateful to Mrs. Chiara Berton for her precious help in collecting blood samples, and Dr. Michele Battistel and Dr. Giulio Barbiero of the Radiology Institute of the University of Padua for performing AVS.

Abbreviations

     
  • ACE

    angiotensin-converting enzyme

  •  
  • ACEI

    angiotensin-converting enzyme inhibitors

  •  
  • AHA

    American Heart Association

  •  
  • APA

    aldosterone-producing adenoma

  •  
  • ARBs

    angiotensin II receptor blockers

  •  
  • ARR

    aldosterone-renin ratio

  •  
  • AVS

    adrenal vein sampling

  •  
  • BP

    blood pressure

  •  
  • CKD

    chronic kidney disease

  •  
  • CKD-EPI

    Chronic Kidney Disease Epidemiology Collaboration

  •  
  • DDD

    defined daily dose

  •  
  • DRC

    renin concentration

  •  
  • eGFR

    estimated glomerular filtration rate

  •  
  • ESC/ESH

    European Society of Cardiology/European Society of Hypertension

  •  
  • HT

    arterial hypertension

  •  
  • LI

    lateralisation index

  •  
  • LV

    left ventricular

  •  
  • LVH

    LV hypertrophy

  •  
  • LVM

    LV mass

  •  
  • mDecT

    mitral E wave deceleration time

  •  
  • MRA

    mineralocorticoid receptor antagonist

  •  
  • PA

    primary aldosteronism

  •  
  • PAC

    plasma aldosterone concentration

  •  
  • PRA

    plasma renin activity

  •  
  • RH

    drug-resistant hypertension

  •  
  • UAE

    urinary albumin excretion

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Supplementary data