Project 13

Endocrine forms of arterial hypertension are common, but usually overlooked. The most common form is primary aldosteronism (PA), which induces excess macro- and micro-vascular damage, and thus cardiovascular events.

In this project the researcher will develop optimised strategies for the screening, subtyping and vascular phenotyping of PA. Mutations in ion channel genes have been reported in PA, the most prevalent of which involves the KCNJ5 (Kir3.4) gene. Recent findings indicated that macrolides specifically correct the altered physiology of these channels and inhibit in vitro the biosynthesis of aldosterone in KCNJ5-mutated human Aldo-producing cells (APCs) isolated from PA patients. Hence, the hypothesis that macrolides can be used for the diagnosis and treatment of PA will be tested.

Moreover, recent evidence suggested that Na⁺-skin content is higher in PA than in normotensive patients and that such increased levels would induce macrophage and pro-inflammatory genes expression and inhibit anti-inflammatory genes in the vasculature. Starting from these premises, the hypothesis that the increased Na⁺-skin content is associated with vascular damage in PA patients will be tested.

The researcher will be trained in recruiting, screening, subtyping and vascular phenotyping of PA patients. Then, he/she will ascertain the effects of the macrolide roxithromycin administered orally on plasma levels of aldosterone, active renin, serum K⁺, and on blood pressure values when screening the patients for PA and, in those patients who will be addressed to the adrenal vein sampling (AVS), the effects of i.v. clarithromycin on the selectivity and lateralization indexes, and the relative aldosterone secretion index (RASI). Finally, he/she will assess the vascular damage and Na⁺ content in the skin and microvasculature.

He/she will receive training also in the Prof. A. Briones lab at UAM to learn how to investigate the mechanisms of vascular damage and at the Prof. Stehouwer lab at UM on the comprehensive characterisation of vascular function. Finally, the ESR will be seconded at Attoquant to train on measuring aldosterone and Angiotensin 2 in plasma of hypertensive patients before and after the exposure to roxithromycin (PA screening phase) and clarithromycin (PA subtyping phase) with LC-MS/MS.

Requirements: