Title: Cardiovascular Disease: Investigating the Expanding Role of Aldosterone
Funder: Medical Research Council

Abstract: Hypertension is the most important cardiovascular risk factor, and results in substantial morbidity and mortality. Aldosterone plays an important role in the pathophysiology of hypertension and cardiovascular disease. The proposed studies will use a variety of approaches to explore the key role of aldosterone and other adrenal corticosteroids in the aetiology of hypertension and in mediating end-organ damage. Regulation of aldosterone secretion-role of activation of HPA axis: I intend to build on previous findings from my Wellcome Trust Clinical Fellowship which demonstrated an association between novel variants in steroid synthetic genes (aldosterone synthase, CYP11B2 and 11? hydroxylase, CYP11B1) and an altered ACTH/cortisol relationship. Normal subjects will be genotyped across the CYP11B locus and their hypothalamic/anterior pituitary axis will be assessed by measuring ACTH response to corticotrophic releasing hormone (CRH) stimulation. Subjects will undergo assessment of adrenal volume using magnetic resonance imaging (MRI) allowing relationships among genotype, corticosteroid production and adrenal volume to be explored. Cardiovascular consequences of primary aldosteronism (PA): The proposal that subjects with hypertension due to aldosterone excess have more cardiovascular damage than subjects with equivalent essential hypertension will be investigated in more detail. Briefly, PA subjects and individually matched subjects with essential hypertension will undergo assessment of peripheral and central vascular stiffness, plasma oxidative stress markers as well as cardiac imaging using MRI with gadolinium enhancement (to demonstrate cardiac fibrosis). Aldosterone and renal end organ damage: The interaction of urinary aldosterone and sodium in predicting progression will be examined in two cohorts:-diabetic and non-diabetic nephropathy, and in hypertensive controls. Plasma renin and aldosterone, as well as urinary sodium, aldosterone and albumin excretion will be measured at a single baseline visit and renal progression (measured by estimated glomerular filtration rate and urine albumin excretion) assessed at 1 and 2 years. In addition, I will assess oxidative stress as well as vascular stiffness at baseline and after 2 years to investigate whether there is an influence of aldosterone on rate of vascular damage in such patients. Urinary Biomarkers of hypertension and cardiovascular risk: This study, investigating the role of aldosterone as a biomarker that relates to level of blood pressure amongst individuals and its interaction with sodium in relation to blood pressure, will be performed in collaboration with Professor Paul Elliott of Imperial College, London who co-ordinated the INTERMAP study of 4600 individuals (across UK, USA, Japan and China). I plan to examine how measurements of urinary excretion of aldosterone and other corticosteroid metabolites using Gas Chromatography Mass Spectrometry (GCMS) interact with sodium status to determine blood pressure and cardiovascular risk. In addition, I intend to spend a period of three months in Imperial College under the supervision of Professor Elliott gaining experience in the management and analysis of large datasets.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR