In newly diagnosed hypertensive patients referred to hypertension centers, the prevalence of APA is high (4.8%). The availability of AVS is essential for an accurate identification of the adrenocortical pathologies underlying PA.

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...