Cardiovascular Disease: Investigating the Expanding Role of Aldosterone

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

Worldwide, 8 million deaths have been attributed to high blood pressure (hypertension) per year. This accounts for at least half of all annual deaths from cardiovascular disease (stroke, heart attacks). Despite considerable research, the underlying causes of high blood pressure in most cases remain unclear. This proposal focuses on steroid hormones produced by the human adrenal gland and uses a number of techniques to examine their role in hypertension and cardiovascular disease. In particular, the effect of variation within genes that control the production of steroid hormones will be explored in a cohort of normal volunteers in order to clarify further the genetic basis of hypertension caused by excess of a key steroid hormone, aldosterone. The potentially harmful effect of this hormone on heart structure and function will also be investigated in patients with hypertension due to aldosterone excess using detailed magnetic resonance imaging scans. Finally, how steroid hormones interact with other factors including diet and salt intake to regulate blood pressure levels will also be explored in a large group of patients from different ethnic backgrounds.

The planned studies should result in a better understanding of mechanisms that lead to hypertension and cardiovascular disease and more effective targeting of treatments as well as earlier identification of those most at risk of developing hypertension and its associated problems.

Technical Summary

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.

Publications

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Alvarez-Madrazo S (2011) Role of genetic variation in regulation of aldosterone biosynthesis. in Endocrine development

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Freel EM (2014) An unusual cause of mineralocorticoid hypertension. in Hypertension (Dallas, Tex. : 1979)

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Freel EM (2010) Adrenal venous sampling for catecholamines: a normal value study. in The Journal of clinical endocrinology and metabolism

 
Description Member of Society for Endocrinology Clinical Committee
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
 
Description Member of question writing group for MRCP (Diabetes & Endocrinology)
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Member of the American Endocrine Society Self Assessment Committee
Geographic Reach North America 
Policy Influence Type Influenced training of practitioners or researchers
Impact I am a member of an international group of clinicians selected by the American Endocrine Society. We write clinical questions designed to aid the education of endocrine trainees in passing their American Board exams as well as ensuring continuing medical education of American Endocrinologists who require to recertify with the American Board of Internal Medicine every 5-10 years.
 
Description Participated in Royal Colleges 'Research Summit'
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description CSO project grant (co-investigator)
Amount £217,570 (GBP)
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 08/2012 
End 08/2015
 
Description INSPIRE Programme
Amount £10,000 (GBP)
Organisation Academy of Medical Sciences (AMS) 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2014 
End 08/2015
 
Description Kidney Research UK Training Fellowship (co PI)
Amount £135,134 (GBP)
Funding ID TF6/2013 
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2013 
End 06/2015
 
Description MRC Centenary Award
Amount £69,450 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2012 
End 10/2013
 
Description NHS GG&C Endowment award
Amount £8,500 (GBP)
Organisation NHS Greater Glasgow and Clyde (NHSGGC) 
Department NHS Greater Glasgow and Clyde Endowments
Sector Charity/Non Profit
Country United Kingdom
Start 11/2013 
End 11/2015
 
Title Cardiac MRI in Primary Aldosteronism 
Description I have completed a study which used gadolinium enhanced cardiac MRI to identify non-ischaemic cardiac fibrosis in subjects with Primary Aldosteronism. This phenomenon was rarely seen in subjects with equivalent essential hypertension 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact My clinical practice changed- target aldosterone excess as well as blood pressure in Primary Aldosteronism 
 
Title Imaging and measurement of adrenal volume using MRI 
Description Development and validation of a tool to image and measure adrenal gland volume using Magnetic Resonance Imaging. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2009 
Provided To Others? Yes  
Impact Has resulted in formal collaboration with University of Dundee; now acting as a further recruitment centre for my principal clinical study. In addition, has resulted in 2 methodology papers currently being prepared for submission. 
 
Title Member of Glasgow BP clinic data analysis group 
Description Glasgow Blood Pressure Clinic database: contains detailed phenotypic data from > 30000 patients dating back over 40 years 
Type Of Material Database/Collection of Data/Biological Samples 
Provided To Others? No  
Impact Publication in Hypertension: Serum chloride is an independent predictor of mortality in hypertensive patients. McCallum et al Hypertension 2013 
 
Description Local PI for ADIUVO Trial 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution I am local PI for an international study termed 'Efficacy of mitotane treatment in prolonging recurrence free survival in patients with adrenocortical carcinoma at low-intermediate risk of recurrence.'
Collaborator Contribution Will lead recruitment via our tertiary adrenal oncology clinic
Impact Due to begin recruitment this month
Start Year 2013
 
Description Omics-based strategies for improved diagnosis and treatment of endocrine hypertension 
Organisation European Commission
Department Horizon 2020
Country European Union (EU) 
Sector Public 
PI Contribution One of 5 European Centres (and only 2 UK centres) contributing to this project. I am a local investigator and lead local investigator is Professor Eleanor Davies. My main role is identify and recruit patients with hypertension +/- adrenal adenoma for further study.
Collaborator Contribution Led by Professor Maria Christina Zennaro
Impact None yet
Start Year 2015
 
Description Rapid Renal Sympathetic Denervation for Resistant Hypertension Using the OneShot Renal Denervation System II 
Organisation Covidien
Country United States 
Sector Private 
PI Contribution I am local PI in this multi-centre study of renal denervation
Collaborator Contribution Will lead recruitment and safe delivery of study protocol. Only site in Scotland
Impact Recruitment has yet commence (awaiting ethical approval)
Start Year 2013
 
Description British hypertension society masterclass 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Audience consisted of lay people, researchers and health professionals. Debate around frequency of hypertension and public health messages that must be conveyed

Possible collaboration with cardiologists and multi centre study
Year(s) Of Engagement Activity 2013
 
Description Faculty member of Society for Endocrinology Career Development Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact I developed and led the new 'track 2' component of the CDW (with Dr Gareth Lavery, Birmingham). The aim was to provide support and advice to post doctoral researchers (clinical and non-clinical) to help with Intermediate Fellowship applications

Excellent feedback. Now co-ordinating a 'coaching' scheme through the Society where we fcailitate individual mentorship/coaching for applications
Year(s) Of Engagement Activity 2013
URL http://www.endocrinology.org/meetings/CDW/
 
Description Medical Education Lead: Society for Endocrinology 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact Ensure undergraduate students are aware of endocrinology as a career choice. Helped develop and edit Society for Endocrinology booklet on careers in endocrinology

A number of students have contacted me asking to do SSC in Endocrinology
Year(s) Of Engagement Activity 2014
 
Description School visit (Glasgow) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact Gave talk on medicine/science as a possible career to group of local schoolchildren

Contacted by several school pupils and have arranged several clinical/laboratory placements
Year(s) Of Engagement Activity 2013
 
Description Visit to Soroptomist Society Glasgow 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Each talk attended by 40 professional local women. All very interested to hear of local research.

Benefited from local fundraising efforts.
Increased recruitment into clinical studies
Year(s) Of Engagement Activity 2009,2010