Publications

The Primary Aldosteronism Foundation maintains a list of salient publications. Topics range from pathogenesis to the implications of excess aldosterone. We regularly update the list with new topics, and new articles are added as they become public.

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Abstract/Summary:

Primary aldosteronism (PA) is characterized by inappropriate aldosterone production. Chronic aldosterone excess has detrimental effects on cardiovascular system, including endothelial dysfunction and vascular inflammation. Circulating extracellular vesicles (EVs) are central players in the crosstalk between endothelium, vascular structures, and inflammatory cells. The aim of the study was to assess the potential role of EVs in aldosterone-related vascular damage by evaluating a comprehensive panel of 37 EV surface antigens. Serum EVs were isolated by immunocapture from 32 patients with PA, 29 patients with essential hypertension and from 22 normotensive controls. EVs were characterized by Western blotting, nanoparticle tracking analysis, transmission electron microscopy, and flow cytometry. Particle concentration was higher and diameter lower in patients with PA compared with controls and the number of particles decreased after unilateral adrenalectomy. Nineteen EV surface antigens were differentially expressed in patients with PA compared with patients with essential hypertension or normotensive controls, including markers of activated platelets, endothelial and immune/inflammatory cells. The specific EV surface signature discriminated patients with PA from controls, whereas after specific PA treatment the profile became similar to essential hypertension. Stimulation of human endothelial cells with PA-derived EVs resulted in the overexpression of 5 selected genes (AKT1-CALR-CSNK2A1-FN1-PIK3R1), previously identified by bioinformatic analysis as targets of differentially expressed EV antigens. Overexpression of CALR and FN1 was confirmed also at protein level. Our data suggest that EVs represent biomarkers of vascular inflammation and endothelial dysfunction in patients with PA and also potential biovectors contributing to accelerated organ damage by multiple signaling processes.

Authors: Jacopo Burrello, Martina Tetti, Vittorio Forestiero, Vanessa Biemmi, Sara Bolis, Margherita Alba Carlotta Pomatto, Martina Amongero, Dario Di Silvestre, Pierluigi Mauri, Giuseppe Vassalli, Giovanni Camussi, Tracy Ann Williams, Paolo Mulatero, Lucio Barile, Silvia Monticone
Keywords: extracellular vesicles, cardiovascular disease, inflammation
DOI Number: 10.1161/HYPERTENSIONAHA.121.17136
Publication Year: 2021

Abstract/Summary:

This international multicenter study took place in tertiary referral centers. A total of 1625 PA patients seeking surgical cure were enrolled in an international study involving 19 centers in North America, Europe, Asia, and Australia. Of these, 1311 (81%) had imaging data available and 369 (23%), who received a final diagnosis of surgically cured unilateral PA, were examined. Patients underwent AVS and imaging by computed tomography and/or magnetic resonance imaging. The accuracy of detection of unilateral PA at imaging was estimated by the area under the receiver operator characteristics curve using cure (biochemical and/or full clinical success) as the reference at follow-up after unilateral adrenalectomy. In the cohort of 1311 patients with imaging data available, 34% and 7% of cases showed no detectable or bilateral nodules, respectively. Imaging did not detect the culprit adrenal in 28% of the surgically cured unilateral PA patients. Moreover, the clinical outcome did not differ significantly between the imaging-positive and imaging-negative patients. Cross-sectional imaging did not identify a lateralized cause of disease in around 40% of PA patients and failed to identify the culprit adrenal in more than one-fourth of patients with unilateral PA.

Authors: Gian Paolo Rossi, Filippo Crimì, Giacomo Rossitto, Laurence Amar, Michel Azizi, Anna Riester, Martin Reincke, Christoph Degenhart, Jiri Widimsky, Mitsuhide Naruse, Jaap Deinum, Leo Schultze Kool, Tomaz Kocjan, Aurelio Negro, Ermanno Rossi, Gregory Kline, Akiyo Tanabe, Fumitoshi Satoh, Lars Christian Rump, Oliver Vonend, Holger S Willenberg, Peter J Fuller, Jun Yang, Nicholas Yong Nian Chee, Steven B Magill, Zulfiya Shafigullina, Marcus Quinkler, Anna Oliveras, Vin Cent Wu, Zuzana Kratka, Giulio Barbiero, Teresa Maria Seccia, Michele Battistel
Keywords: CT, MRI, imaging, diagnosis
DOI Number: 10.1210/clinem/dgab482
Publication Year: 2021

Abstract/Summary:

A total of 156 patients with PA who underwent LADX in a single institution were enrolled in this prospective cohort study. The patients were divided into 2 groups, with a boundary of 60 years. The HRQoL was evaluated using the Medical Outcomes Study’s 36-Item Short-Form Health Survey version 2 (SF-36v2) questionnaire before and after LADX. Demographics, clinical features, antihypertensive drugs before and after surgery, and perioperative evaluation were recorded. We compared all scale scores and summed scores between groups. Multivariate regression models were used to determine the associations between various covariables and the HRQoL. In the older PA patients, most subscales of HRQoL at baseline were lower than the national standard values. The antihypertensive drug-free rate by LADX was only 21% in older patients, compared to 58% in younger patients. However, a significant improvement in mental HRQoL was observed after LADX (p = 0.002). The much preoperative antihypertensive drugs, lower preoperative potassium level, and smaller degree of comorbidities were predictors of improved mental HRQoL by LADX on multivariate analyses. The older PA patients showed lower mental HRQOL than the national standard populations. Although antihypertensive effects were limited for these patients, LADX was beneficial as PA treatment via improvement of mental HRQoL.

Authors: Kawasaki Y, Ishidoya S, Morimoto R, Ono Y, Omata K, Tezuka Y, Kawamorita N, Yamashita S, Mitsuzuka K, Satoh F, Ito A
Keywords: laparoscopic adrenalectomy, health-related quality of life
DOI Number: 10.1159/000518165
Publication Year: 2021

Abstract/Summary:

Spironolactone, a steroidal mineralocorticoid receptor antagonist, is recommended as add-on therapy for treatment-resistant/uncontrolled hypertension. However, caution is advised in patients with advanced chronic kidney disease (CKD) due to an increased risk for hyperkalemia. KBP-5074 is a nonsteroidal mineralocorticoid receptor antagonist under investigation for the treatment of treatment-resistant and uncontrolled hypertension in patients with moderate-to-severe CKD. BLOCK-CKD is a phase 2, international, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of KBP-5074, on top of current therapy, in patients with stage 3B/4 CKD (estimated glomerular filtration rate ≥15 and ≤44 mL/[min·1.73 m2]) and resistant hypertension (trough cuff seated systolic blood pressure ≥140 mm Hg, despite treatment with maximally tolerated doses of 2 or more antihypertensive medicines with complementary mechanisms). Patients (n=240) will be randomized 1:1:1 to once-daily treatment with KBP-5074 0.25 mg, KBP-5074 0.5 mg, or placebo, stratified by estimated glomerular filtration rate (≥30 versus <30 mL/[min·1.73 m2]) and systolic blood pressure (≥160 versus <160 mm Hg). Approximately 30% of enrolled patients should have an estimated glomerular filtration rate of 15 to 29 mL/(min·1.73 m2). The primary efficacy analysis is the change in trough cuff seated systolic blood pressure from baseline to day 84 for the KBP-5074 doses compared with placebo. Changes in urinary albumin-creatinine ratio will be assessed along with changes in serum potassium/incidence of hyperkalemia and changes in estimated glomerular filtration rate and serum creatinine. BLOCK-CKD will determine whether the addition of KBP-5074 will effectively lower blood pressure without an increased risk of hyperkalemia in patients who are not candidates for steroidal mineralocorticoid receptor antagonists due to advanced CKD.

Authors: George Bakris, Y Fred Yang, Bertram Pitt
Keywords: albuminuria, creatinine, drug resistance, glomerular filtration rate, chronic renal insufficiency, KBP-5074
DOI Number: 10.1161/HYPERTENSIONAHA.120.15199
Publication Year: 2020

Abstract/Summary:

During a median follow-up of 2.6 years, a primary outcome event occurred in 504 of 2833 patients (17.8%) in the finerenone group and 600 of 2841 patients (21.1%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.93; P=0.001). A key secondary outcome event occurred in 367 patients (13.0%) and 420 patients (14.8%) in the respective groups (hazard ratio, 0.86; 95% CI, 0.75 to 0.99; P=0.03). Overall, the frequency of adverse events was similar in the two groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone than with placebo (2.3% and 0.9%, respectively). In patients with CKD and type 2 diabetes, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo.

Authors: George L. Bakris, Rajiv Agarwal, Stefan D. Anker, Bertram Pitt, Luis M. Ruilope, Peter Rossing, Peter Kolkhof, Christina Nowack, Patrick Schloemer, Amer Joseph, Gerasimos Filippatos
Keywords: chronic renal insufficiency, Finerenone, diabetic nephropathies
DOI Number: 10.1056/NEJMoa2025845
Publication Year: 2020

Abstract/Summary:

The MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF; NCT01807221) is a multicentre, randomized, double-blind, active-comparator-controlled, six-parallel-group, phase 2b dose-finding study. In total, 1060 patients with HFrEF and concomitant type 2 diabetes mellitus and/or chronic kidney disease (CKD) will be randomized within 7 days of emergency presentation to hospital for worsening chronic HF to receive finerenone (one of five doses in the range 2.5-20.0 mg once daily) or eplerenone (25 mg every second day to 50 mg once daily for 90 days). The primary objective is to investigate the safety and potential efficacy (measured as the percentage of individuals with a decrease in plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP] of more than 30% relative to baseline at day 90 ± 2) of different oral doses of finerenone compared with eplerenone. Other objectives are to assess the effects of finerenone on a composite clinical endpoint (death from any cause, cardiovascular hospitalizations, or emergency presentations for worsening chronic HF), and on changes in health-related quality of life from baseline.

Authors: Bertram Pitt, Stefan D Anker, Michael Böhm, Mihai Gheorghiade, Lars Køber, Henry Krum, Aldo P Maggioni, Piotr Ponikowski, Adriaan A Voors, Faiez Zannad, Christina Nowack, So-Young Kim, Alexander Pieper, Nina Kimmeskamp-Kirschbaum, Gerasimos Filippatos
Keywords: finerenone, mineralocorticoid receptor antagonist
DOI Number: 10.1002/ejhf.218
Publication Year: 2015

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The Primary Aldosteronism Foundation is a registered 501(c)(3) public charity. Donations are tax deductible in the US.

©2021 Primary Aldosteronism Foundation

The Primary Aldosteronism Foundation is a registered 501(c)(3) public charity. Donations are tax deductible in the US.