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.
Despite carrying a minimal risk of adrenal vein rupture and at variance with the guidelines, AVS is not used systematically at major referral centers worldwide. These findings represent an argument for defining guidelines for this clinically important but technically demanding procedure.
Abstract-Primary aldosteronism is the most common form of secondary hypertension. Mutations in the KCNJ5 gene have been described recently in aldosterone-producing adenomas (APAs). The aim of this study was to investigate the prevalence of KCNJ5 mutations in unselected patients with primary aldosteronism and their clinical, biological and molecular correlates. KCNJ5 sequencing was performed on somatic (APA, nϭ380) and peripheral (APA, nϭ344; bilateral adrenal hyperplasia, nϭ174) DNA of patients with primary aldosteronism, collected through the European Network for the Study of Adrenal Tumors. Transcriptome analysis was performed in 102 tumors. Somatic KCNJ5 mutations (p.Gly151Arg or p.Leu168Arg) were found in 34% (129 of 380) of APA. They were significantly more prevalent in females (49%) than males (19%; PϽ10 Ϫ3) and in younger patients (42.1Ϯ1.0 versus 47.6Ϯ0.7 years; PϽ10 Ϫ3 ) and were associated with higher preoperative aldosterone levels (455Ϯ26 versus 376Ϯ17 ng/L; Pϭ0.012) but not with therapeutic outcome after surgery. Germline KCNJ5 mutations were found neither in patients with APA nor those with bilateral adrenal hyperplasia. Somatic KCNJ5 mutations were specific for APA, because they were not identified in 25 peritumoral adrenal tissues or 16 cortisol-producing adenomas. Hierarchical clustering of transcriptome profiles showed that APAs with p.Gly151Arg or p.Leu168Arg mutations were indistinguishable from tumors without KCNJ5 mutations. In conclusion, although a large proportion of sporadic APAs harbors somatic KCNJ5 mutations, germline mutations are not similarly causative for bilateral adrenal hyperplasia. KCNJ5 mutation carriers are more likely to be females; younger age and higher aldosterone levels at diagnosis suggest that KCNJ5 mutations may be associated with a more florid phenotype of primary aldosteronism. H ypertension is a major cardiovascular risk factor that affects between 10% and 40% of the population in industrialized countries. Detection of secondary forms of hypertension is particularly important because it allows for the targeted management of the underlying disease. Primary aldosteronism (PA) is the most common form of secondary hypertension, with an estimated prevalence between 6% and 12% of hypertensives and as high as 20% in patients with resistant hypertension. 1-5 PA occurs as the result of a dysregulation of the mechanisms controlling adrenal aldosterone production, ultimately leading to hypertension with low plasma renin and elevated aldosterone sometimes associated with hypokalemia. Among subtypes of PA, aldosteroneproducing adenoma (APA) and bilateral adrenal hyperplasia (BAH; also known as idiopathic hyperaldosteronism) together account for Ϸ95% of cases. [1][2][3] Aldosterone production from the adrenal zona glomerulosa is tightly controlled to maintain electrolyte and fluid homeostasis by the kidney. Thus, the two most important physiological stimuli of aldosterone secretion are angiotensin II and serum potassium. Glomerulosa cell membrane depolarization leads to openi...
Abstract-In comparison with essential hypertension, primary aldosteronism (PA) is associated with an increased risk of cardiovascular morbidity. To date, no data on mortality have been published. We assessed mortality of patients treated for PA within the German Conn's registry and identified risk factors for adverse outcome in a case-control study.Patients with confirmed PA treated in 3 university centers in Germany since 1994 were included in the analysis. All of the patients were contacted in 2009 and 2010 to verify life status. Subjects from the population-based F3 survey of the Cooperative Health Research in the Region of Augsburg served as controls. Final analyses were based on 600 normotensive controls, 600 hypertensive controls, and 300 patients with PA. Kaplan-Meyer survival curves were calculated for both cohorts. Ten-year overall survival was 95% in normotensive controls, 90% in hypertensive controls, and 90% in patients with PA (P value not significant). In multivariate analysis, age (hazard ratio, 1.09 per year [95% CI, 1.03-1.14]), angina pectoris (hazard ratio, 3.6 [95% CI, 1.04 -12.04]), and diabetes mellitus (hazard ratio, 2.55 [95% CI, 1.07-6.09]) were associated with an increase in all-cause mortality, whereas hypokalemia (hazard ratio, 0.41 per mmol/L [95% CI, 0.17-0.99]) was associated with reduced mortality. Cardiovascular mortality was the main cause of death in PA (50% versus 34% in hypertensive controls; PϽ0.05). These data indicate that cardiovascular mortality is increased in patients treated for PA, whereas all-cause mortality is not different from matched hypertensive controls. (Hypertension. 2012;60:618-624.) • Online Data Supplement Key Words: Conn syndrome Ⅲ aldosterone Ⅲ renin Ⅲ cardiovascular Ⅲ morbidity Ⅲ mortality A ldosterone is a key regulator of fluid and electrolyte balance in human physiology. Aldosterone excess in the presence of a high-sodium diet raises blood pressure. High blood pressure, together with direct proinflammatory and profibrotic effects of aldosterone on the vessel wall, causes and sustains cardiovascular atherosclerosis. 1,2 In keeping with these findings, high aldosterone levels are associated with mortality in heart failure cohorts, 3 and blockade of the renin-angiotensin-aldosterone system by mineralocorticoid antagonists improves outcome in heart failure and after myocardial infarction. 4,5 The contribution of aldosterone to the development of arterial hypertension in the general population has been suggested by the Framingham Offspring Study, in which plasma aldosterone levels in normotensive subjects predicted subsequent increases in blood pressure and the development of hypertension. 6 Recent evidence suggests that primary aldosteronism (PA) is more common than previously thought. 7 Several studies have provided evidence that patients with PA are especially prone to cardiovascular and renal complications. In a recent study by Catena et al, 8 aldosterone excess caused left ventricular hypertrophy and diastolic dysfunction independent of blood pressu...
Air pollution is an important risk factor for global burden of disease. There has been recent interest in its possible role in the etiology of diabetes mellitus. Experimental evidence is suggestive, but epidemiological evidence is limited and mixed. We therefore explored the association between air pollution and prevalent diabetes, in a population-based Swiss cohort. We did cross-sectional analyses of 6392 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults [SAPALDIA], aged between 29 and 73 years. We used estimates of average individual home outdoor PM10 [particulate matter <10μm in diameter] and NO2 [nitrogen dioxide] exposure over the 10 years preceding the survey. Their association with diabetes was modeled using mixed logistic regression models, including participants' study area as random effect, with incremental adjustment for confounders. There were 315 cases of diabetes (prevalence: 5.5% [95% confidence interval (CI): 2.8, 7.2%]). Both PM10 and NO2 were associated with prevalent diabetes with respective odds ratios of 1.40 [95% CI: 1.17, 1.67] and 1.19 [95% CI: 1.03, 1.38] per 10μg/m(3) increase in the average home outdoor level. Associations with PM10 were generally stronger than with NO2, even in the two-pollutant model. There was some indication that beta blockers mitigated the effect of PM10. The associations remained stable across different sensitivity analyses. Our study adds to the evidence that long term air pollution exposure is associated with diabetes mellitus. PM10 appears to be a useful marker of aspects of air pollution relevant for diabetes. This association can be observed at concentrations below air quality guidelines.
Abstract-Primary aldosteronism is the most frequent cause of endocrine hypertension. Three forms of familial hyperaldosteronism (FH) have been described, named FH-I to -III. Recently, a mutation of KCNJ5 has been shown to be associated with FH-III, whereas the cause of FH-II is still unknown. In this study we searched for mutations in KCNJ5 in 46 patients from 21 families with FH, in which FH-I was excluded. We identified a new germline G151E mutation in 2 primary aldosteronism-affected subjects from an Italian family and 3 somatic mutations in aldosterone-producing adenomas, T158A described previously as a germline mutation associated with FH-III, and G151R and L168R both described as somatic mutations in aldosterone-producing adenoma. The phenotype of the family with the G151E mutation was remarkably milder compared with the previously described American family, in terms of both clinical and biochemical parameters. Furthermore, patients with somatic KCNJ5 mutations displayed a phenotype indistinguishable from that of sporadic primary aldosteronism. The functional characterization of the effects of the G151E mutation in vitro showed a profound alteration of the channel function, with loss of K ϩ selectivity, Na ϩ influx, and membrane depolarization. These alterations have been postulated to be responsible for voltage gate Ca 2ϩ channel activation, increase in cytosolic calcium, and stimulation of aldosterone production and adrenal cell proliferation. In conclusion, we describe herein a new mutation in the KCNJ5 potassium channel associated with FH-III, responsible for marked alterations of channel function but associated with a mild clinical and hormonal phenotype. (Hypertension. 2012;59: 235-240.) • Online Data Supplement Key Words: familial hyperaldosteronism Ⅲ endocrine hypertension Ⅲ primary aldosteronism Ⅲ aldosterone Ⅲ KCNJ5 P rimary aldosteronism (PA) is the most frequent cause of secondary hypertension, and its prevalence increases with blood pressure severity. 1 PA diagnosis is of paramount importance for the patient, not only because specific therapy is available, mineralocorticoid receptor antagonists for bilateral forms and adrenalectomy for unilateral forms, 2 but also because aldosterone causes detrimental effects on the cardiovascular system that are at least partly independent of blood pressure levels. 3,4 Current guidelines of the Endocrine Society recommend the confirmation or exclusion of PA in all groups of patients with an increased risk of the disease, 1 which include hypertensive patients with a family history of early onset hypertension or cerebrovascular events at a young age and all hypertensive first-degree relatives of patients with PA. These indications recognize the importance of testing for PA in patients at risk for familial hyperaldosteronism (FH). Three forms of FH have been described to date, named FH-I to -III. 5-8 FH-I, also known as glucocorticoid-remediable aldosteronism (GRA), is attributed to a chimeric CYP11B1/ CYP11B2 gene encoding a hybrid enzyme able to synthesize al...
Persistent postoperative hypoaldosteronism with hyperkalemia occurs in 5% of adrenalectomized PA patients through prolonged ZG insufficiency, requiring long-term fludrocortisone treatment. Potassium levels after adrenalectomy must be monitored to avoid life-threatening hyperkalemia.
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