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Archives of cardiovascular diseases
Volume 111, n° 10
pages 564-572 (octobre 2018)
Doi : 10.1016/j.acvd.2018.01.004
Received : 27 July 2017 ;  accepted : 17 January 2018
Clinical research

Arterial stiffness evaluated by pulse wave velocity is not predictive of the improvement in hypertension after adrenal surgery for primary aldosteronism: A multicentre study from the French European Society of Hypertension Excellence Centres
La vitesse de l’onde de pouls n’est pas prédictive de la normalisation tensionnelle après surrénalectomie pour hyperaldostéronisme primaire : étude multicentrique du réseau des Centres français d’excellence en HTA européens – ESH excellence centres

Béatrice Bouhanick a, b, , Jacques Amar a, c, Laurence Amar d, Philippe Gosse e, Xavier Girerd f, Yves Reznik g, Claire Mounier-Vehier h, Jean Philippe Baguet i, Pierre Boutouyrie j, k, Benoit Lepage b, l, Pierre Lantelme m, Bernard Chamontin a

on behalf of the investigators of the ASAPAS study1

  The list of investigators is included in the Appendix.

a Department of Therapeutics and Hypertension, Rangueil University Hospital, 31059 Toulouse, France 
b UMR 1027 INSERM Toulouse 3 University, 31000 Toulouse, France 
c INSERM 1048 Toulouse 3 University, 31432 Toulouse, France 
d Hypertension Unit, hôpital Européen-Georges-Pompidou, université Paris Descartes, Assistance publique–Hôpitaux de Paris, 75908 Paris, France 
e Department of Cardiology and Hypertension, Bordeaux University Hospital, 33076 Bordeaux, France 
f Unité de prévention cardiovasculaire, University Hospital Pitié-Salpêtrière, 75651 Paris, France 
g Department of Endocrinology, Côte de Nacre Regional Hospital Center, University of Caen, 14033 Caen, France 
h Service de médecine vasculaire et HTA, University Hospital Lille, 59037 Lille, France 
i Department of Cardiology, Mutualist hospital Group, 38100 Grenoble, France 
j Inserm, U970, Pharmacology Unit, hôpital Européen Georges-Pompidou, AP–HP, 75908 Paris, France 
k Cardiovascular Research Center PARCC, University Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France 
l Department of Epidemiology, Toulouse University Hospital, 31000 Toulouse, France 
m Cardiology Department, hospices civils de Lyon, hôpital de la Croix-Rousse, 69004 Lyon, France 

Corresponding author. Service d’hypertension et de thérapeutique, CHU Rangueil, 1, avenue du Professeur-Jean Poulhès, TSA 50032, 31059 Toulouse cedex 9, France.Service d’hypertension et de thérapeutique, CHU Rangueil, 1, avenue du Professeur-Jean Poulhès, TSA 50032, 31059 Toulouse cedex 9, France.

Predictive factors associated with normal blood pressure (BP) after unilateral adrenalectomy for primary aldosteronism (PA) are not clearly identified.


To evaluate the predictive value of arterial stiffness before surgery on BP after surgery.


During 2009–2013, 96 patients with PA due to unilateral adrenal adenoma who underwent surgery were enrolled in a multicentre open-label, prospective study. Aortic pulse wave velocity (PWV) was assessed before surgery. Patients underwent ambulatory blood pressure monitoring (ABPM) before surgery and 6 and 12months after surgery. Twenty-four h SBP/DBP values were compared in subjects with PWV<vs. ≥10m/s. The primary outcome was 24-hour ABPM<130/80mmHg 6 months after adrenalectomy.


BP and PWV were available for 82 patients (mean age 49±12years). Mean 24-hour systolic/diastolic BP (SBP/DBP) values decreased from 144±15/91±9 before surgery to 131±15/84±11mmHg 6months after surgery. At 6months, mean 24-hour SBP did not differ significantly between high versus low PWV groups (SBP–0.8mmHg, 95% confidence interval–6.9 to 5.2, P =0.79). A total of 42.3% of women versus 20.0% of men had 24-hour SBP/DBP<130/80mmHg at 6months (P =0.07) and 57.9% vs. 23.8% at 12months (P =0.03). Higher SBP/DBP was recorded for men versus women after 6months (P =0.01/0.001) and 1year (P =0.04/0.05).


Preoperative arterial stiffness does not predict a beneficial effect of adrenalectomy on BP values.

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Les facteurs prédictifs associés à la normalisation tensionnelle après une surrénalectomie unilatérale pour hyperaldostéronisme primaire (HAP) ne sont pas clairement identifiés.


Décrire la valeur prédictive de la mesure préalable de rigidité artérielle sur le devenir de la pression artérielle (PA) après chirurgie.


Entre 2009 et 2013, 96 patients avec un HAP lié à un adénome surrénalien unilatéral ayant bénéficié d’une surrénalectomie sont inclus dans un essai prospectif multicentrique ouvert. La Vitesse de l’onde de pouls (VOP) est mesurée avant chirurgie. Les patients ont une Mesure ambulatoire de la pression artérielle (MAPA) avant chirurgie puis à 6 et 12 mois après chirurgie. Les PAS/PAD des 24h en, MAPA sont comparées chez les sujets ayant des VOP<10m/s ou ≥10m/s. Le critère principal de jugement est une PAS/PAD des 24h<130/80mmHg à 6 mois de la chirurgie.


Les PA et les VOP sont évaluables chez 82 patients (âge moyen 49±12 ans), à 6 mois, la PAS/PAD des 24h baisse : de 144±15/91±9 à 131±15/84±11mmHg. À 6 mois, les PAS des 24h ne sont pas statistiquement différentes dans le groupe ayant une VOP élevée et dans celui avec une VOP basse (PAS : –0,8mmHg ; 95 % IC : –6,9 à 5,2 ; p =0,79). Au total, 42,3 % des femmes et 20,0 % des hommes ont des PAS/PAD des 24h<130/80mmHg à 6 mois (p =0,07) et 57,9 % vs 23,8 % à 12 mois (p =0,03). Les PAS/PAD sont plus élevées chez les hommes que chez les femmes à 6 mois (p =0,01/0,001) et à 1 an (p =0,04/0,05).


La mesure de la rigidité artérielle préopératoire n’est pas prédictive d’un effet bénéfique sur les PA après surrénalectomie.

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Keywords : Primary aldosteronism, Pulse wave velocity

Mots clés : Hyperaldostéronisme primaire, Vitesse de l’onde de pouls

Abbreviations : ABPM, APA, BP, DBP, PA, PWV, ROC, SBP


The cardiovascular effects of aldosterone are well documented – this hormone is likely to be involved in changes in endothelial vasodilatation, which can also contribute to inflammation and vascular and myocardial remodelling. Studies comparing patients with primary aldosteronism (PA) to those diagnosed with essential hypertension have highlighted target organ distress beyond that anticipated for the blood pressure (BP) levels in question, namely the presence of endothelial dysfunction, accelerated pulse wave velocity (PWV) and an increase in carotid intima-media thickness [1, 2, 3, 4]. These findings appear to be reversible with specific treatment to alleviate hyperaldosteronism and it has thus been suggested that accelerated collagen turnover and the onset of fibrosis are due to the action of aldosterone [5].

The conventional treatment of adrenal adenoma in the presence of PA involves unilateral adrenal surgery. The anticipated benefit of the latter is a return to normal – or improvement in – BP values in 50% of cases, the disappearance of hypokalaemia, and the cure of PA [6, 7]. Age, a family history of PA, evidence of the lateralization of aldosterone secretion during adrenal venous catheterization and the BP response to spironolactone have been put forward as predictive factors of success to date whereas, from a haemodynamic perspective, adrenal surgery would also reduce aortic stiffness (reduction in PWV from 9.5 to 7.6m/s) [2].

Prolonged hyperaldosteronism could therefore trigger vascular fibrosis, taking into consideration excess arterial stiffness with a potential negative impact on the anticipated benefits of adrenal surgery. We therefore suggest that arterial stiffening could partially account for the limitations in the surgical treatment of Conn's adenoma.

The aim of the study was, therefore, to assess whether preoperative PWV – as a measure of arterial stiffness – could predict response to adrenalectomy in patients with PA due to unilateral adrenal adenoma.

Patient selection

Between January 2009 and December 2013, we enrolled a prospective multicentre French cohort of 96 patients with PA due to unilateral adrenal adenoma who underwent adrenal surgery. All patients included in the study had an aldosterone-producing adenoma (APA) confirmed by histopathological investigation. The study was carried out in eight French Hypertension Excellence Centres in Toulouse, Paris (2 centres), Bordeaux, Lyon, Caen, Lille, and Grenoble.

The local Ethics Committee (Comité de protection des personnes Midi Pyrénées ) approved the study. Written information was given to patients, including conditions governing anonymity and study withdrawal. Written consent was obtained from all patients.

Study design

Twenty-hour-hour ambulatory blood pressure monitoring (ABPM) (Spacelab® device Healthcare SAS, France) was performed before surgery with the patients taking conventional antihypertensive treatment except spironolactone, and 6 and 12months after surgery. The diagnostic work-up of APA included the biochemical diagnosis of PA, evidence of adrenocortical adenoma on a CT scan and/or unequivocal evidence of lateralized aldosterone secretion if adrenal venous sampling was available, and histopathological investigation after surgery. On completion of the diagnostic work-up, the lead investigators of each hypertension centre determined whether patients had PA.

Plasma aldosterone concentrations were measured by radioimmunoassay. Depending on the centre, direct renin concentration was measured by chemiluminescent immunoassay or plasma renin activity was measured by radioimmunoassay. Samples were collected in the supine position or after 15min in the sitting position. As recommended [8], a minimum renin value of 5 mIU/L was used to calculate the aldosterone to renin ratio. All drugs interfering with the renin – aldosterone system were withdrawn approximately 2 weeks before evaluation (6 weeks for spironolactone). The aldosterone to renin ratio cut-off value of 23 (plasma aldosterone in pg/mL and direct renin in mIU/L) or 64 (plasma aldosterone in pmol/L and direct renin in mIU/L) was used as the reference for suspected PA and was repeated twice [8]. Confirmatory testing in the form of a saline infusion test was performed, as required, depending on centre practice.

Arterial stiffness was assessed by measuring carotid-femoral PWV prior to adrenalectomy. No patient received aldosterone antagonists. The measurements were obtained with a Complior® device (Alam Medical Garge les Gonesse, France) in each centre. PWV was automatically measured by recording simultaneous pulse waves captured by external sensors on carotid and femoral arterial segments, divided by the time taken to travel between the two points, representing the pulse wave propagation along the aorta, provided by the device software. The use of direct distance, measured over the body surface, leads to overestimation of the real PWV, and a scaling factor of 0.8 was used to convert PWV obtained using direct distances to real PWV, as recommended [9, 10]. The gain in each waveform was automatically analysed and good quality curves were selected. The time delay between the two carotid-femoral points was automatically determined. The quality of the site records was monitored centrally. The consensus documents on the measurement procedures recommend 10m/s as the new cut-off value for carotid-femoral PWV to identify patients at high cardiovascular risk [9, 11].

Therapeutic decision-making was based on standard centre criteria. All patients included in the study analysis were candidates for surgery and were managed by laparoscopic adrenalectomy.

Adverse events were recorded routinely.


The primary outcome was a therapeutic response (BP<130/80mmHg, with or without antihypertensive medication [excluding aldosterone antagonists] measured by 24-hour ABPM) 6months after adrenalectomy. Secondary outcomes were a therapeutic response (defined as for the primary outcome) 12months after adrenalectomy; a therapeutic response (a decrease in 24-hour systolic BP [SBP] of>10mmHg [12]) at 6 and 12months; and SBP/diastolic BP (DBP) values measured at 6 and 12 months by 24-hour ABPM.

Sample size calculation

The average frequency of the therapeutic response following adrenal surgery is approximately 50%. Using multiple logistic regression in which the PWV variable on the other independent variables obtained an R-squared value of 0.15, considering 10% of patients were lost to follow-up and assuming a therapeutic response in 65% of patients with low preoperative PWV values versus 35% of patients with high PWV values, the sample size needed to achieve 80% power with a 5% type I error was 110 patients.

Statistical analyses

Baseline patient characteristics are described in the whole study population and are compared between subjects with low (<10m/s) versus high (≥10m/s) PWV values (using bivariate analyses) [9, 11].

The primary and secondary outcomes are described and compared between subjects with low and high PWV values. The association between PWV values and primary or secondary outcomes was then estimated using longitudinal mixed models of the outcome on PWV values (high versus low as the reference category), adjusted for time since surgery and taking other potential confounding variables into account. Mixed logistic regressions were applied using therapeutic response as the dependent variable; mixed linear regressions were applied when the dependent variable was SBP or DBP (by 24-hour ABPM). Confounding variables were initially included in the models if they were associated with the outcome with P <0.20, then a backward step-by-step selection procedure was applied to obtain parsimonious models. Sex-PWV interaction terms were tested in the final multivariable models, using likelihood ratio tests. These analyses were firstly computed in the enrolled study population; secondly, analyses were computed separately in men and women. Statistical analyses were computed using Stata Statistical Software: Release 14.2 (StataCorp 2015, College Station, TX). Sensitivity and 1 – specificity for different cut-off values of PWV were plotted in receiver operating characteristic (ROC) curves. ROC curves of the primary and secondary outcomes were compared according to the continuous PWV value.


A total of 96 patients with APA were recruited, of whom 82 were included in the study analysis. The other 14 patients were excluded because of missing preoperative PWV values or missing primary outcomes (i.e. 24-hour ABPM missing at 6-month follow-up).

Baseline characteristics

The mean±standard deviation (SD) age of patients was 48.6±11.6years (range: 24–78years), 47.6% were women, and the mean duration of hypertension was 7.3±6.5years. Approximately half of the patients (51.2%) had PWV<10m/s. The main characteristics are shown in Table 1, in the overall study population and stratified by PWV value (<or ≥10m/s).

Primary outcome

A therapeutic response (BP<130/80mmHg on 24-hour ABPM) was observed in 30.4% of patients at 6months, with no significant difference between those with low or high PWV (Table 2). In the multivariable analysis, no statistically significant interaction was found between time and PWV (for any of the outcomes), i.e. the adjusted associations between PWV and outcome were the same at 6 and 12months. Therapeutic response (BP<130/80mmHg at 6 and 12months) tended to be less frequent in patients with high versus low PWV values, but with a large uncertainty (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.06–11.22, P =0.89) after adjustment for time since surgery, duration of hypertension at baseline, baseline SBP, and sex (Table 3). The ROC curve did not indicate an optimal cut-off point for PWV (Figure 1), showing that PWV has very low sensitivity and specificity to predict therapeutic response.

Figure 1

Figure 1. 

ROC curves for PWV values to predict BP control. 24-hour ABPM<130/80mmHg, at: A. 6months (primary outcome). B. 12months. SPB decrease of>10mmHg on 24-hour ABPM, at: C. 6months. D. 12months. ABPM: ambulatory blood pressure monitoring; BP: blood pressure; PWV: pulse wave velocity; ROC: receiver operating characteristic; SBP: systolic blood pressure.


Secondary outcomes

Therapeutic response (24-hour ABPM<130/80mmHg) at 12-month follow-up was observed by 40.0% of patients, and was non-significantly higher among those with low versus high PWV values (Table 2).

Therapeutic response (SBP decrease>10mmHg) was observed in 54.0% and 60.5% of patients at 6- and 12-month follow-up, respectively (Table 2). This response tended to be observed more frequently in patients with higher PWV values, but the bivariate comparisons were not statistically significant (Table 2). In the multivariable analysis, this therapeutic response (SBP decrease>10mmHg at 6 and 12months) also tended to be more frequent in patients with high versus low PWV values, but the association was not statistically significant (OR 6.47, 95% CI 0.37–113, P =0.20 after adjustment; Table 3). For the threshold of SBP decrease>10mmHg, ROC curves did not show a significant predictive cut-off value of PWV (Figure 1).

Antihypertensive drugs at follow-up

More than half of the patients (58.8% at 6months and 55.6% at 12months) did not take any antihypertensive drugs at follow-up. Among those taking antihypertensive drugs, calcium channel blockers were the most frequent class (36.8% at 6 months and 33.9% at 12months). The mean number of antihypertensive drugs per patient was slightly higher in the high PWV group, but the difference was not statistically significant (Table 2).

Blood pressure levels and changes after adrenalectomy

In the overall study population, mean office BP was 150±21/91±15mmHg at baseline (n =82), 131±14/82±11mmHg at 6 months (n =81), and 130±16/82±11mmHg at 12months (n =61). Twenty-four-hour ABPM results at baseline and 6- and 12-month follow-up are shown in Table 2.

In multivariable analyses, mean SBP (on 24-hour ABPM) at 6 and 12months did not differ significantly between patients with high and low PWV, with a mean SBP 0.8mmHg lower (95% CI–6.9 to 5.2, P =0.79) in the high versus low PWV group (Table 3). Similarly, DPB did not differ significantly between patients with high versus low PWV (Table 3).

Comparison between men and women

At baseline, high levels of PWV (≥10m/s) tended to be more frequent in men than in women (58.1% vs. 38.5%, P =0.08). Similarly, SBP/DBP at baseline (24-hour ABPM) tended to be higher in men than in women (145±15/93±9mmHg vs. 142±15/89±8mmHg, P =0.37 for SBP and P =0.05 for DBP).

After adrenalectomy, therapeutic response (BP<130/80mmHg) was more frequent in women than in men: 42.3% vs. 20.0% (P =0.07) at 6 months and 57.9% vs. 23.8% (P =0.03) at 12months. Mean SBP/DBP (24-h ABPM) values were lower in women than in men at 6months (125±9/79±7 vs. 136±18/88±12; P =0.01 for SBP and P =0.001 for DBP) and at 12months (120±12/78±8 vs. 129±16/84±10; P =0.04 for SBP and P =0.05 for DBP).

Regarding the link between PWV and therapeutic response or BP, Figure 2 shows that, in men, high PWV values (≥10m/s) tended to be associated with a therapeutic response, with no clear correlation in women. A statistically significant sex*PWV interaction term was found in the multivariable analysis of therapeutic response (BP<130/80mmHg) (P =0.01). Sex*PWV interaction terms were not, however, statistically significant with other secondary outcomes (SBP decrease>10mmHg, mean SBP, or mean DBP, P =0.32, P =0.20, and P =0.16, respectively). In the multivariable analyses stratified by sex, there were non-statistically significant tendencies to observe more frequent therapeutic responses and a decrease in SDP and DBP levels in men with high versus low PWV. The opposite trend was observed in women (Table 3).

Figure 2

Figure 2. 

Relationship between BP responses according to PWV<or ≥10m/s in men and in women. ABPM: ambulatory blood pressure monitoring; BP: blood pressure; DBP: diastolic blood pressure PWV: pulse wave velocity; SBP: systolic blood pressure.



It has been suggested that long-term exposure to high levels of aldosterone induces cardiovascular damage extending beyond the effects of arterial hypertension per se [5, 13]. Overproduction of aldosterone contributes to arterial wall fibrosis – regardless of any haemodynamic effects – and aldosterone has been considered capable of triggering collagen deposits [14] leading to increased arterial wall stiffness, increased intima-media thickness, and endothelial dysfunction [5]. Compared to patients with essential hypertension, hypertensive patients with PA present with more arterial wall damage, accompanied by a thicker intima-media layer and increased arterial stiffness [15].

The benefit of adrenalectomy on arterial stiffness evaluated by PWV measurements has been demonstrated [2]; and the reversal of arterial stiffening in patients with APA has been shown to occur early after adrenalectomy [16]. Patients with PA tend to have an increased risk of cardiovascular events, including coronary artery disease, stroke, and atrial fibrillation [13, 17]. Thus, PWV could be a relevant intermediate criterion for predicting the anticipated benefit from adrenalectomy in patients with APA. Long-term excess aldosterone can induce increased arterial stiffness and potentially jeopardise the benefits of surgery. However, our study did not confirm this hypothesis and shows that arterial stiffness evaluated by PWV measurements was not linked – to any significant extent – with improved BP following the removal of aldosterone-producing adenoma at 6- or 12-month follow-up. The predictive value of the benefits of adrenalectomy based on PWV cannot be applied for the management of hypertensive patients with PA due to APA.

However, the change in BP during adrenalectomy follow-up appeared more favourable in women than in men. The study therefore shows that the association between PWV and BP response differed in men and women, albeit not to a significant extent. Contrary to our hypothesis, a high PWV did not appear to compromise the benefit of adrenalectomy, particularly in men. As suggested by Strauch et al. [2] – and according to our results – decreased aldosterone levels via adrenalectomy could have a beneficial effect on aortic stiffness and BP response, even in patients presenting a high PWV on admission.

Based on our results, future studies should be conducted in men and women separately. Finally, the evaluation of aortic stiffness by PWV measurement does not highlight the characteristics of BP responders to adrenal surgery in patients with PA. It remains to be seen whether PWV helps to assess the cardiovascular benefit of adrenalectomy in patients with PA.

Study limitations

The main limitation of the study is the number of the patients included: of 96 patients, 14 patients with missing ABPM were excluded from the analysis. Also, PWV measurements were only performed once. However, despite this limitation, arterial stiffness was analysed according to a standardized process and only good quality curves were selected. The quality of the site records was monitored centrally.


In our multicentre study, arterial stiffness reflected by pre-operative PWV measurements did not predict the beneficial effects of adrenalectomy on BP values after APA removal with follow-up at 6 and 12months.

The predictive value of adrenalectomy through PWV cannot be applied for the management of hypertensive patients due to APA-induced PA. However, the change in BP during adrenalectomy follow-up appears to be more favourable in women than in men.

Sources of funding

The Fondation de Recherche sur l’Hypertension Artérielle (FRHTA; Research Foundation for Hypertension) provided funding for the study.

Disclosure of interest

The authors declare that they have no competing interest.


The authors wish to thank the ASAPAS study participants, trial staff and investigators for their participation and the CARDIOMET team for technical assistance.

Appendix A. ASAPAS investigators

French ESH Excellence Centres: Bordeaux: A Cremer (Department of Cardiology and Hypertension); A Tabarin (Department of Endocrinology); Grenoble: O Chabre (Department of Endocrinology); Lille: C Douillard (Service Médecine vasculaire et HTA); JL Wemeau (Service d’Endocrinologie); Lyon: PY Courand, C Berge (Cardiology Department), Paris: PF Plouin (Université Paris Descartes, Hypertension Unit APHP Hôpital Européen Georges Pompidou Hypertension Unit).


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1  The list of investigators is included in the Appendix.

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