Background-Although unilateral primary aldosteronism is the most common surgically correctable cause of hypertension there are no standard criteria to classify surgical outcomes.

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Background. Despite being widely recognized as the most common form of secondary hypertension, the true prevalence of primary aldosteronism (PA) and its main subtypes, aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH), among the general hypertensive population remains a matter of debate. Objectives. To determine the prevalence and clinical phenotype of PA in a large cohort of unselected hypertensive patients, consecutively referred to our Hypertension Unit, by 19 general practitioners from Torino, Italy. Methods. Patients were screened for PA using the serum aldosterone to plasma renin activity ratio after withdrawal from all interfering medications and PA was diagnosed according to the Endocrine Society guidelines. The diagnosis was confirmed/excluded by an i.v. saline infusion test or captopril challenge test and subtype differentiation was performed by adrenal CT scanning and adrenal vein sampling (AVS) using strict criteria to define both successful cannulation and lateralization of aldosterone production. Results. A total of 1,672 primary care hypertensive patients, 569 newly diagnosed hypertensives and 1,103 patients already diagnosed with arterial hypertension, were included in the study. A total of 99 patients (5.9%) were diagnosed with PA and conclusive subtype differentiation by AVS was made in 91 patients (27 patients with an APA and 64 patients with BAH). The overall prevalence of PA increased with the severity of hypertension, from 3.9% in hypertensives stage I to 11.8% in hypertensives stage III. Patients with PA more frequently displayed target organ damage and cardiovascular events compared to non-PA hypertensives, independent of confounding variables. Conclusions.The results from the present study demonstrated that PA is a frequent cause of secondary hypertension even in the general hypertensive population and indicates that the majority of hypertensive patients should be screened for PA. Keywords: Primary aldosteronism, aldosterone-producing adenoma, bilateral adrenal hyperplasiaAbbreviation list AC = aldosterone concentration APA = aldosterone-producing adenoma AVS = adrenal vein sampling ARR = serum aldosterone to plasma renin activity ratio BAH = bilateral adrenal hyperplasia CV events = cardiovascular events GP = general practitioner HT = hypertension LREH = low renin essential hypertensives MRA= mineralocorticoid receptor antagonist PA = primary aldosteronism PATO = primary aldosteronism in Torino Condensed AbstractThe prevalence of primary aldosteronism (PA) among general hypertensive population remains unknown. We screened 1,672 primary care hypertensives and 5.9% were diagnosed with PA (27 3 with an aldosterone-producing adenoma and 64 with bilateral adrenal hyperplasia). PA prevalence increased with the severity of hypertension, from 3.9% in hypertensives stage I to 11.8% in stage III. PA patients more frequently displayed target organ damage and cardiovascular events compared to non-PA hypertensives. The study demonstrated that PA is a frequent cause ...

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.

Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na(+)/K(+) ATPase α subunit) and ATP2B3 (encoding a Ca(2+) ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutation-negative cases. In summary, dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion.

A rterial hypertension is a major cardiovascular risk factor that affects 10% to 40% of the adult population in industrialized countries. Detection of secondary forms of hypertension is particularly important because it allows the targeted management of the underlying disease. Primary aldosteronism (PA) is the most common form of secondary hypertension with an estimated prevalence of ≈10% in referred patients and 4% in primary care but as high as 20% in patients with resistant hypertension. [1][2][3][4][5] PA is caused by the excessive production of aldosterone from the adrenal cortex, resulting in hypertension associated with high plasma aldosterone levels, low plasma renin activity, and varying degrees of hypokalemia and metabolic alkalosis. Long-term consequences include an increased risk of myocardial infarction, stroke, and atrial fibrillation. 6,7 Abstract-Primary aldosteronism is the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D have been described in aldosterone-producing adenomas (APAs). Our aim was to investigate the prevalence of somatic mutations in these genes in unselected patients with APA (n=474), collected through the European Network for the Study of Adrenal Tumors. Correlations with clinical and biochemical parameters were first analyzed in a subset of 199 patients from a single center and then replicated in 2 additional centers. Somatic heterozygous KCNJ5 mutations were present in 38% (180/474) of APAs, whereas ATP1A1 mutations were found in 5.3% (25/474) and ATP2B3 mutations in 1.7% (8/474) of APAs. Previously reported somatic CACNA1D mutations as well as 10 novel CACNA1D mutations were identified in 44 of 474 (9.3%) APAs. There was no difference in the cellular composition of APAs or in CYP11B2, CYP11B1, KCNJ5, CACNA1D, or ATP1A1 gene expression in APAs across genotypes. Patients with KCNJ5 mutations were more frequently female, diagnosed younger, and with higher minimal plasma potassium concentrations compared with CACNA1D mutation carriers or noncarriers. CACNA1D mutations were associated with smaller adenomas. These associations were largely dependent on the population structure of the different centers. In conclusion, recurrent somatic mutations were identified in 54% of APAs. Young women with APAs are more likely to be KCNJ5 mutation carriers; identification of specific characteristics or surrogate biomarkers of mutation status may lead to 12 Mutations in KCNJ5 and ATP1A1 affect adrenal ZG cell membrane potential and intracellular ionic homeostasis, with chronic depolarization leading to opening of voltage-dependent calcium channels and activation of calcium signaling and aldosterone production. 10,12,13 Finally, somatic mutations in the CACNA1D encoding the Ca v 1.3 channel (calcium channel, voltage dependent, L type, α-1d subunit) have been identified in APA. The altered residues are located in particular segments bordering the channel pore.14,15 These changes result in channel activation and opening at lower voltages, leading, l...

Our findings confirm a negative effect of aldosterone excess on glucose metabolism and suggest that the recently reported higher rates of cardiovascular events in primary aldosteronism than in essential hypertension might be due to increased prevalence of the metabolic syndrome in the former condition.

This study demonstrates in a large population of patients the pathogenetic role of aldosterone excess in the cardiovascular system and thus the importance of early diagnosis and targeted PA treatment.