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:

New approaches are needed to address the evolution of the primary aldosteronism syndrome and to increase its recognition. Herein, we review evidence indicating that primary aldosteronism is a prevalent syndrome that is mostly unrecognized, and present a pragmatic and pathophysiology-based approach to improve diagnosis and treatment. Evidence was gathered from published guidelines and studies identified from PubMed by searching for primary aldosteronism, aldosterone, renin, and hypertension. This evidence was supplemented by the authors’ personal knowledge, research experience, and clinical encounters in primary aldosteronism. The landscape of primary aldosteronism has evolved to recognize that it is a prevalent syndrome of renin-independent aldosterone production that contributes to the pathogenesis of hypertension and cardiovascular disease. Expanding screening indications and simplifying the diagnostic approach will enable implementation of targeted treatment for primary aldosteronism.

Authors: Anand Vaidya, Robert M Carey
Keywords: aldosterone, renin, adrenal, diagnostic techniques, hyperaldosteronism, primary aldosteronism, hypertension, mass screening, prevalence
DOI Number: 10.1210/clinem/dgaa606
Publication Year: 2020

Abstract/Summary:

The prevalence of obesity, diabetes, hypertension, and cardiovascular and chronic kidney disease is increasing in developed countries. Obesity, insulin resistance, and hypertension commonly cluster with other risk factors for cardiovascular and chronic kidney disease to form the metabolic syndrome. Emerging evidence supports a paradigm shift in our understanding of the renin-angiotensin-aldosterone system and in aldosterone’s ability to promote insulin resistance and participate in the pathogenesis of the metabolic syndrome and resistant hypertension. Recent data suggest that excess circulating aldosterone promotes the development of both disorders by impairing insulin metabolic signaling and endothelial function, which in turn leads to insulin resistance and cardiovascular and renal structural and functional abnormalities. Indeed, hyperaldosteronism is associated with impaired pancreatic beta-cell function, skeletal muscle insulin sensitivity, and elevated production of proinflammatory adipokines from adipose tissue, which results in systemic inflammation and impaired glucose tolerance. Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated in part by aldosterone acting on the mineralocorticoid receptor. Although we have known that mineralocorticoid receptor blockade attenuates cardiovascular and renal injury, only recently have we learned that mineralocorticoid receptor blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation. In summary, aldosterone excess has detrimental metabolic effects that contribute to the metabolic syndrome and endothelial dysfunction, which in turn contribute to the development of resistant hypertension as well as cardiovascular disease and chronic kidney disease.

Authors: James R Sowers, Adam Whaley-Connell, Murray Epstein
Keywords: aldosterone, cardiovascular disease, endothelium, metabolic syndrome, insulin resistance
DOI Number: 10.7326/0003-4819-150-11-200906020-00005
Publication Year: 2009

Abstract/Summary:

To determine the extent to which dietary sodium modulates aldosterone-induced cardiovascular damage, and to determine whether increased dietary potassium can prevent this damage, we used the Nomega-nitro-L-arginine methyl ester (L-NAME)/angiotensin II (Ang II) rat model of cardiac injury. This model is dependent on the presence of aldosterone for the occurrence of myocardial damage. Two sets of experiments were performed. In the first set, the following groups were studied: (1) 1% NaCl to drink (control group); (2) L-NAME/Ang II with water to drink (low salt group); (3) L-NAME/Ang II/1% NaCl (high salt group); (4) L-NAME/Ang II/1% NaCl/eplerenone (eplerenone group). Systolic blood pressure increased similarly in all groups compared with controls. Compared with the controls, the high salt group, but not the low salt or eplerenone groups, developed significant myocardial damage. In the second set of experiments three groups of animals were studied: (1) L-NAME/Ang II/1%NaCl (high salt group) (2) L-NAME/Ang II/1%NaCl/eplerenone (eplerenone group), and (3) L-NAME/Ang II/1%NaCl with an extra 1% KCl in food (high dietary potassium group). Eplerenone, but not dietary potassium supplementation, prevented the development of cardiac damage. Thus, mineralocorticoid receptor antagonist treatment and low sodium diet were effective in preventing cardiac damage, which suggests that a minimal level of aldosterone and a moderately high sodium diet are both required for the development of the cardiovascular damage in the L-NAME/Ang II model. The inability of potassium supplementation to reduce myocardial damage suggests that eplerenone’s protective effect is not due to its potassium-sparing ability, but is rather related to some other feature of its selective aldosterone antagonism.

Authors: Diego V Martinez, Ricardo Rocha, Mamiko Matsumura, Eveline Oestreicher, Margarita Ochoa-Maya, Weranuj Roubsanthisuk, Gordon H Williams, Gail K Adler
Keywords: metabolism, sodium-restricted diet, heart disease, potassium, mineralocorticoid receptor antagonist
DOI Number: 10.1161/hyp.39.2.614
Publication Year: 2018

Abstract/Summary:

Primary aldosteronism (PA) is the most common cause of secondary hypertension. In this review, we discuss the diagnosis and management of PA during pregnancy based on the literature. As aldosterone and renin are physiologically increased during pregnancy and confirmation tests are not recommended, the diagnosis of PA during pregnancy relies on a repeatedly suppressed plasma renin level. Mineralocorticoid receptor antagonists (MRAs) are the most effective drugs to treat hypertension and hypokalemia in patients with PA. However, spironolactone (FDA pregnancy category C) might lead to undervirilization of male infants due to the anti-androgenic effects. Although data in the literature are very limited, treatment with spironolactone is not recommended. Eplerenone (FDA pregnancy category B) is a selective MRA without anti-androgenic potential. If MRA treatment is required in pregnancy, eplerenone appears to be a safe and effective alternative, although symptomatic treatment with approved antihypertensive drugs and supplementation with potassium is the first choice. In case of aldosterone-producing adenoma, laparoscopic adrenalectomy is a therapeutic option in the second trimester of pregnancy.

Authors: Anna Riester, Martin Reincke
Keywords: pregnancy, pregnancy complications, mineralocorticoid receptor antagonist
DOI Number: 10.1530/EJE-14-0444
Publication Year: 2015

Abstract/Summary:

We used a longitudinal population database from the Taiwan National Health Insurance system and applied a validated algorithm to identify patients with PA diagnosed between 1997 and 2009. There were 2699 patients with PA recruited, of whom 761 patients with an aldosterone-producing adenoma (APA) were identified. The incidence rate of end-stage renal disease (ESRD) was 3% in patients with PA after targeted treatments and 5.2 years of follow-up, which was comparable to the rate in controls with essential hypertension (EH). However, after taking mortality as a competing risk, we found a significantly lower incidence of ESRD when comparing patients with PA vs EH [subdistribution hazard ratio (sHR), 0.38; P = 0.007] and patients with APA vs EH (sHR 0.55; P = 0.021) after adrenalectomy; however, we did not see similar results in groups with mineralocorticoid receptor antagonist (MRA)‒treated PA vs EH. There was also a significantly lower incidence of mortality in groups with PA and APA who underwent adrenalectomy than among EH controls (P < 0.001). Regarding incident ESRD, patients with PA were comparable to their EH counterparts after treatment. After adrenalectomy, patients with APA had better long-term outcomes regarding progression to ESRD and mortality than hypertensive controls, but MRA treatments did not significantly affect outcome.

Authors: Ying-Ying Chen, You-Hsien Hugo Lin, Wei-Chieh Huang, Eric Chueh, Likwang Chen, Shao-Yu Yang, Po‐Chih Lin, Lian-Yu Lin, Yen-Hung Lin, Vin-Cent Wu, Tzong‐Shinn Chu, Kwan Dun Wu
Keywords: adrenalectomy, end-stage renal disease, mineralocorticoid receptor antagonist
DOI Number: 10.1210/js.2019-00019
Publication Year: 2019

Abstract/Summary:

The mineralocorticoid aldosterone is an important mediator of blood pressure, volume and electrolyte balance. However, excess aldosterone can be deleterious as a driver of vascular remodeling and tissue fibrosis associated with cardiometabolic diseases. Aldosterone synthase (AS) inhibitors (ASI) attenuate the production of aldosterone directly and have been proposed as an alternative to mineralocorticoid receptor (MR) antagonists (MRA) for blocking the pathological effects of excess aldosterone. Discovery of selective ASIs has been challenging because of the high sequence identity (93%) AS shares with cortisol synthase (CS), and the low identity of rodent AS compared to human (63%). Using cynomolgus (cyno) monkey-based models we identified BI 689648, a novel, highly selective ASI that exhibits an in vitro IC50 of 2 nM against AS and 300 nm against CS (150-fold selectivity) compared with the recently described ASIs FAD286 (3 nM AS; 90 nM CS; 40-fold) and LCI699 (10 nM AS; 80 nM CS; 8-fold). Following oral administration in cynos, BI 689648 (5 mg/kg) exhibits a peak plasma concentration of ~ 500 nM. For in vivo profiling we used an ACTH-challenge model in which BI 689648 was >20-fold more selective compared with FAD286 and LCI699. Since both FAD286 and LCI699 failed to provide adequate selectivity for CS when tested in patients, the desire for more selective molecules to test the ASI hypothesis remains high. Therefore, highly selective aldosterone synthase inhibitors such as BI 689648 represent an important step forward towards developing ASIs with greater potential for clinical success in cardiometabolic diseases.

Authors: Steven M. Weldon, Matthew A. Cerny, Kristina Gueneva-Boucheva, Derek Cogan, Xin Guo, Neil Moss, Jean-Hugues Parmentier, Jeremy Richman, Glenn A. Reinhart, Nicholas F. Brown
Keywords: aldosterone synthase inhibitor
DOI Number: 10.1124/jpet.116.236463
Publication Year: 2016

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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.