scholarly journals Mouse Models of Primary Aldosteronism: From Physiology to Pathophysiology

Endocrinology ◽  
2017 ◽  
Vol 158 (12) ◽  
pp. 4129-4138 ◽  
Author(s):  
Leticia Aragao-Santiago ◽  
Celso E Gomez-Sanchez ◽  
Paolo Mulatero ◽  
Ariadni Spyroglou ◽  
Martin Reincke ◽  
...  
Keyword(s):  
Mouse Models ◽  
Primary Aldosteronism ◽  
Genetic Basis ◽  
Plasma Renin ◽  
Adrenal Hyperplasia ◽  
Endocrine Hypertension ◽  
Bilateral Adrenal Hyperplasia ◽  
Human Disorder ◽  
Aldosterone Producing Adenoma ◽  
Functional Mechanisms

Abstract Primary aldosteronism (PA) is a common form of endocrine hypertension that is characterized by the excessive production of aldosterone relative to suppressed plasma renin levels. PA is usually caused by either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. Somatic mutations have been identified in several genes that encode ion pumps and channels that may explain the aldosterone excess in over half of aldosterone-producing adenomas, whereas the pathophysiology of bilateral adrenal hyperplasia is largely unknown. A number of mouse models of hyperaldosteronism have been described that recreate some features of the human disorder, although none replicate the genetic basis of human PA. Animal models that reproduce the genotype–phenotype associations of human PA are required to establish the functional mechanisms that underlie the endocrine autonomy and deregulated cell growth of the affected adrenal and for preclinical studies of novel therapeutics. Herein, we discuss the differences in adrenal physiology across species and describe the genetically modified mouse models of PA that have been developed to date.

scholarly journals Angiotensin II Type 1 Receptor Autoantibodies in Primary Aldosteronism

2020 ◽  
Vol 52 (06) ◽  
pp. 379-385
Author(s):  
Lucie S. Meyer ◽  
Siyuan Gong ◽  
Martin Reincke ◽  
Tracy Ann Williams
Keyword(s):  
Angiotensin Ii ◽  
Primary Aldosteronism ◽  
Functional Role ◽  
Adrenal Hyperplasia ◽  
Endocrine Hypertension ◽  
Bilateral Adrenal Hyperplasia ◽  
Aldosterone Producing Adenoma ◽  
Agonistic Autoantibodies

AbstractPrimary aldosteronism (PA) is the most common form of endocrine hypertension. Agonistic autoantibodies against the angiotensin II type 1 receptor (AT1R-Abs) have been described in transplantation medicine and women with pre-eclampsia and more recently in patients with PA. Any functional role of AT1R-Abs in either of the two main subtypes of PA (aldosterone-producing adenoma or bilateral adrenal hyperplasia) requires clarification. In this review, we discuss the studies performed to date on AT1R-Abs in PA.

scholarly journals Increased Diagnosis of Primary Aldosteronism, Including Surgically Correctable Forms, in Centers from Five Continents

2004 ◽  
Vol 89 (3) ◽  
pp. 1045-1050 ◽  
Author(s):  
Paolo Mulatero ◽  
Michael Stowasser ◽  
Keh-Chuan Loh ◽  
Carlos E. Fardella ◽  
Richard D. Gordon ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Screening Test ◽  
Detection Rate ◽  
Activity Ratio ◽  
Plasma Renin ◽  
Fold Increase ◽  
Hypertensive Patients ◽  
Endocrine Hypertension ◽  
Before And After ◽  
Aldosterone Producing Adenoma

Abstract Primary aldosteronism (PA) is a common form of endocrine hypertension previously believed to account for less than 1% of hypertensive patients. Hypokalemia was considered a prerequisite for pursuing diagnostic tests for PA. Recent studies applying the plasma aldosterone/plasma renin activity ratio (ARR) as a screening test have reported a higher prevalence. This study is a retrospective evaluation of the diagnosis of PA from clinical centers in five continents before and after the widespread use of the ARR as a screening test. The application of this strategy to a greater number of hypertensives led to a 5- to 15-fold increase in the identification of patients affected by PA. Only a small proportion of patients (between 9 and 37%) were hypokalemic. The annual detection rate of aldosterone-producing adenoma (APA) increased in all centers (by 1.3–6.3 times) after the wide application of ARR. Aldosterone-producing adenomas constituted a much higher proportion of patients with PA in the four centers that employed adrenal venous sampling (28–50%) than in the center that did not (9%). In conclusion, the wide use of the ARR as a screening test in hypertensive patients led to a marked increase in the detection rate of PA.

scholarly journals The syndromes of low-renin hypertension: "separating the wheat from the chaff"

2004 ◽  
Vol 48 (5) ◽  
pp. 674-681 ◽  
Author(s):  
Claudio E. Kater ◽  
Edward G. Biglieri
Keyword(s):  
Receptor Antagonist ◽  
Myocardial Fibrosis ◽  
Cardiac Remodeling ◽  
Primary Aldosteronism ◽  
Renin Activity ◽  
Adrenal Hyperplasia ◽  
Test Characteristics ◽  
Low Renin Hypertension ◽  
Bilateral Adrenal Hyperplasia ◽  
Aldosterone Producing Adenoma

Primary aldosteronism (PA) is characterized by hypertension and suppressed renin activity with or without hypokalemia and comprises the aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia or idiopatic hyperaldosteronism (IHA). In recent series employing the aldosterone (aldo, ng/dL):renin (ng/mL·h) ratio (ARR) for screening, prevalence of PA among hypertensives soars to 8-20%; current predominance of IHA (>80%) over APA suggests the inclusion of former low-renin essential hypertensives (LREH), in whom plasma aldo can be reduced by suppressive maneuvers. We evaluated the test characteristics of the ARR obtained retrospectively from 127 patients with PA (81 APA; 46 IHA) and 55 with EH (30 LREH; 25 NREH) studied from 1975 to 1990. Using the combined ROC-defined cutoffs of 27 for the ARR and 12ng/dL for aldo, we obtained 89.8% sensitivity (Ss) and 98.2% specificity (Sp) in discriminating PA from EH: all APA and 72% of the IHA patients had values above these limits, but only one (3%) with LREH. Among the 46 IHA patients, 10 (21.7%) had ARR <27, four of whom with aldo <12ng/dL, virtually indistinguishable from LREH. Use of higher cutoff values (ARR >100; aldo >20) may attain 84%Ss and 82.6%Sp in separating APA from IHA. Because IHA and LREH ("the chaff") may be spectrum stages from the same disease, definite discrimination between these entities seems immaterial. However, precise identification of the APA ("the wheat") is critical, since it is the only surgically curable form of PA. Thus, while patients who may harbor an APA must be thoroughly investigated and surgically treated, non-tumoral disease (IHA and LREH) may be best treated with an aldo-receptor antagonist that will also prevent the aldo-mediated inflammatory effects involved in myocardial fibrosis and abnormal cardiac remodeling.

scholarly journals Primary Aldosteronism: The Next Five Years

2017 ◽  
Vol 49 (12) ◽  
pp. 977-983 ◽  
Author(s):  
John Funder
Keyword(s):  
Primary Aldosteronism ◽  
Germline Mutations ◽  
Adrenal Hyperplasia ◽  
Bilateral Disease ◽  
The Past ◽  
Wide Range ◽  
Unilateral Disease ◽  
Bilateral Adrenal Hyperplasia ◽  
Aldosterone Producing Adenoma ◽  
Current Guidelines

AbstractThe management of primary aldosteronism is widely varied within various published guidelines, with very little in the way of data supporting the choice of one variation over others. Current estimates of prevalence are probably accurate for aldosterone producing adenoma, but fall very short of that for bilateral adrenal hyperplasia. Discovery at the level of basic science has proven illuminating over the past 6 years in terms of unilateral disease and both somatic and germline mutations, with much less focus on the much more common bilateral disease; Attempts at harmonization have begun – for example, criteria for complete/partial/absent cure after adrenalectomy for unilateral disease; again focus on bilateral disease is muted. A number of possibilities are suggested as agenda for active consideration and change, across a wide range of areas – referral patterns, screening, confirmation and lateralization, what will be needed is discussion and agreement, to fill the lacunae within the current guidelines. Those involved will want to change to make such an agenda possible.

MicroRNAs and Adrenocortical Tumors: Where do we Stand on Primary Aldosteronism?

2020 ◽  
Vol 52 (06) ◽  
pp. 394-403
Author(s):  
Zsófia Tömböl ◽  
Péter István Turai ◽  
Ábel Decmann ◽  
Peter Igaz
Keyword(s):  
Rna Interference ◽  
Primary Aldosteronism ◽  
Expression Profiles ◽  
Microrna Expression ◽  
Circulating Microrna ◽  
Adrenal Hyperplasia ◽  
Aldosterone Secretion ◽  
Adrenocortical Tumors ◽  
Bilateral Adrenal Hyperplasia ◽  
Aldosterone Producing Adenoma

AbstractMicroRNAs, the endogenous mediators of RNA interference, interact with the renin-angiotensin-aldosterone system, regulate aldosterone secretion and aldosterone effects. Some novel data show that the expression of some microRNAs is altered in primary aldosteronism, and some of these appear to have pathogenic relevance, as well. Differences in the circulating microRNA expression profiles between the two major forms of primary aldosteronism, unilateral aldosterone-producing adenoma and bilateral adrenal hyperplasia have also been shown. Here, we present a brief synopsis of these findings focusing on the potential relevance of microRNA in primary aldosteronism.

scholarly journals Progress on Genetic Basis of Primary Aldosteronism

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1708
Author(s):  
Izabela Karwacka ◽  
Łukasz Obołończyk ◽  
Sonia Kaniuka-Jakubowska ◽  
Michał Bohdan ◽  
Krzysztof Sworczak
Keyword(s):  
Primary Aldosteronism ◽  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Genetic Disorders ◽  
Plasma Renin ◽  
Cardiovascular Complications ◽  
High Rate ◽  
Type I ◽  
Familial Hyperaldosteronism ◽  
Bilateral Adrenal Hyperplasia

Primary aldosteronism (PA) is a heterogeneous group of disorders caused by the autonomous overproduction of aldosterone with simultaneous suppression of plasma renin activity (PRA). It is considered to be the most common endocrine cause of secondary arterial hypertension (HT) and is associated with a high rate of cardiovascular complications. PA is most often caused by a bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA); rarer causes of PA include genetic disorders of steroidogenesis (familial hyperaldosteronism (FA) type I, II, III and IV), aldosterone-producing adrenocortical carcinoma, and ectopic aldosterone-producing tumors. Over the last few years, significant progress has been made towards understanding the genetic basis of PA, classifying it as a channelopathy. Recently, a growing body of clinical evidence suggests that mutations in ion channels appear to be the major cause of aldosterone-producing adenomas, and several mutations within the ion channel encoding genes have been identified. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D) have been identified in nearly 60% of the sporadic APAs, while germline mutations in KCNJ5 and CACNA1H have been reported in different subtypes of familial hyperaldosteronism. These new insights into the molecular mechanisms underlying PA may be associated with potential implications for diagnosis and therapy.

Abstract 12591: Impact of Aldosterone Producing Adenoma on Endothelial Function and Rho-Associated Kinase Activity in Patients With Primary Aldosteronism

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Takeshi Matsumoto ◽  
Yukihito Higashi ◽  
Nozomu Oda ◽  
Akimichi Iwamoto ◽  
Yumiko Iwamoto ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Primary Aldosteronism ◽  
Vascular Function ◽  
Cardiovascular Events ◽  
Plasma Renin ◽  
Secondary Hypertension ◽  
Plasma Aldosterone Concentration ◽  
Significant Difference ◽  
Aldosterone Producing Adenoma ◽  
Rock Activity

Background: Hypertension is associated with endothelial dysfunction and activated Rho-associated kinases (ROCKs) activity. Primary aldosteronism (PA) is a most common cause of secondary hypertension. Recent studies have shown that risk of cardiovascular events is higher in patients with PA than in patients with essential hypertension (EH). However, there is little information on the relationship between subtype of PA and the grade of atherosclerosis. The purpose of this study was to evaluate the vascular function and ROCK activity in patients with PA. Methods: Vascular function, including flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation, and ROCK activity in peripheral leukocytes were evaluated in 21 patients with aldosterone producing adenoma (APA) group (50.7±14.3 years, 9 males), 23 patients with idiopathic hyperaldosteronism (IHA) group (55.8±9.9 years, 12 males), and 33 age-, gender-, and blood pressure-matched EH group (54.9 ± 10.7 years, 18 males). Results: FMD was significantly lower in the APA group than in the IHA group and EH group (3.2±2.0% vs. 4.6±2.3% and 4.4±2.2%, P<0.05, respectively), whereas there was no significant difference in FMD between the IHA group and EH group. There was no significant difference in the response of nitroglycerine in three groups. ROCK activity was significantly higher in the APA group than in the IHA group and EH group (1.29±0.57 vs. 1.00±0.46 and 0.81±0.36, P<0.05 and P<0.001, respectively), whereas there was no significant difference in ROCK activity between the IHA group and EH group. FMD correlated with age (r=-0.31, P<0.01), brachial arterial diameter (r=-0.44, P<0.01), plasma aldosterone concentration (PAC) (r=-0.35, P<0.01) and plasma renin activity ratio (ARR) (r=-0.34, P<0.01). ROCK activity correlated with age (r=-0.24, P=0.04), PAC (r=0.33, P<0.01) and ARR (r=0.46, P<0.01). Conclusions: APA was associated with both endothelial dysfunction and increased ROCK activity compared with those in IHA and EH. These findings suggest that APA may have a higher risk of future cardiovascular events.

scholarly journals Unanswered Questions in the Genetic Basis of Primary Aldosteronism

2017 ◽  
Vol 49 (12) ◽  
pp. 963-968 ◽  
Author(s):  
Ute Scholl
Keyword(s):  
Primary Aldosteronism ◽  
Genetic Basis ◽  
Rare Variants ◽  
Beta Catenin ◽  
Major Question ◽  
Serum Factors ◽  
Germline Variants ◽  
Number Variation ◽  
Bilateral Adrenal Hyperplasia

AbstractOver the past six years, the genetic basis of a significant fraction of primary aldosteronism (PA) cases has been solved. Breakthrough discoveries include the role of somatic variants in the KCNJ5, CACNA1D, ATP1A1, and ATP2B3 genes as causes of aldosterone-producing adenomas (APAs), and the recognition of three novel hyperaldosteronism syndromes with germline variants in the KCNJ5, CACNA1D, and CACNA1H genes. The description of somatic variants in CACNA1D and ATP1A1 in aldosterone-producing cell clusters (APCCs) suggests that these clusters are precursors of some aldosterone-producing adenomas. Yet, a number of questions remain unanswered. These include the genetic basis of about 40% of APAs without somatic variants in known genes. Do technical issues explain this finding, or are the unexplained APAs due to somatic copy number variation or rare variants in thus-far undiscovered genes? Similarly, the role of CTNNB1 (beta catenin) variants in APA pathogenesis is still unclear. The major question to be solved is the genetic basis of bilateral adrenal hyperplasia (BAH). Is BAH due to the bilateral occurrence of APCCs, to germline variants, or perhaps due to unknown serum factors? Lastly, the etiology of unsolved cases of apparently familial hyperaldosteronism remains to be discovered. It is expected that genetic studies over the next few years will lead to answers to at least some of the questions raised.

The relation among aldosterone, galectin-3, and myocardial fibrosis: a prospective clinical pilot follow-up study

2016 ◽  
Vol 64 (6) ◽  
pp. 1109-1113 ◽  
Author(s):  
Che-Wei Liao ◽  
Yen-Tin Lin ◽  
Xue-Ming Wu ◽  
Yi-Yao Chang ◽  
Chi-Sheng Hung ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Primary Aldosteronism ◽  
Plasma Renin ◽  
Secondary Hypertension ◽  
Left Ventricular ◽  
Galectin 3 ◽  
Registration Number ◽  
Cyclic Variations ◽  
Pressure Concentration ◽  
Aldosterone Producing Adenoma

Primary aldosteronism has been associated with myocardial fibrosis, and is the most common cause of secondary hypertension. We previously showed that aldosterone can induce the secretion of galectin-3. The aim of this study was to investigate the association between myocardial fibrosis and plasma galectin-3 level in patients with primary aldosteronism. We prospectively analyzed 11 patients with aldosterone-producing adenoma (APA) who received adrenalectomy from December 2006 to October 2008, and 17 patients with essential hypertension as controls. Levels of plasma galectin-3 were determined in both groups, and both groups underwent echocardiography with cyclic variations of integrated backscatter (CVIBS) to characterize tissue initially and 1 year after surgery in the APA group. Diastolic blood pressure, concentration of plasma aldosterone and aldosterone-renin ratio were significantly higher, and serum potassium level and plasma renin activity significantly lower in the APA group compared to the controls. In addition, left ventricular mass index was significantly higher and CVIBS significantly lower in the APA group (7.3±2.0 vs 9.2±1.7 dB, p=0.015). Furthermore, the concentration of plasma galectin-3 was significantly higher in the APA group (2.1±0.9 vs 1.1±0.6 ng/mL, p=0.005) compared to the controls. CVIBS was correlated to plasma galectin-3 level. In the APA group, CVIBS increased significantly (7.3±2.0 to 9.2±2.4 dB, p=0.032) and plasma galectin-3 decreased (2.1±0.9 to 1.2±0.6, p=0.049) 1 year postadrenalectomy. The patients with APA had increased myocardial fibrosis, and this was associated with a higher plasma galectin-3 level. Both increased myocardial fibrosis and plasma galectin-3 level recovered at least partially after adrenalectomy.Trial registration number200611031R; Results.

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