Aldosterone regulation in aldosterone-producing cell clusters and its impact on medical management of primary aldosteronism

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Looking for clues to curing a very common cause of high blood pressureA quarter of the world's adult population has high blood pressure, or hypertension. One in ten of those people have an hormonal cause; an excess of the hormone which causes blood pressure to increase. This hormone is called aldosterone and the condition in which people have an excess of it is called primary aldosteronism (PA). There are many root causes of PA, but most cases are caused by one of two problems: 1- a nodule in the adrenal gland which releases excess aldosterone, an 'aldosterone producing adenoma' (APA) and 2- general enlargement of both adrenal glands; 'bilateral adrenal hyperplasia'. Currently, the patient journey to curing PA is long and difficult; it starts with a GP recognising the signs of PA and doing specialist blood tests to look for it. If the blood tests indicate the excess levels of aldosterone, the patient must then have further specialist tests to confirm it, and then go through a process of changing their blood pressure medications, then have a specialist, invasive blood sampling procedure; adrenal vein sampling (AVS). During the AVS, a specialist doctor samples blood from veins which drain each of the adrenal glands, using X-ray guidance. The purpose is to determine whether the source of the hormone excess is from only one adrenal, since in such cases, the patient is offered surgery to remove the culprit adrenal gland. However, interpretation of the results is not straightforward and frequently high levels of aldosterone are present on both sides, even if the amount of aldosterone coming from one gland is higher than the other. We think this may be why, sadly only 50% of patients who get as far as having their adrenal gland removed are cured. Recently there has been a rush of research into PA because evidence has shown it is much more common than we previously thought and new markers, which aid the investigation of PA, have been discovered. These markers have shown that there are clusters of cells which produce excess aldosterone, called aldosterone producing cell clusters (APCCs), which are too small to see on scans. APCCs have been found in a third of "normal" adrenal glands, and increase in frequency with age. They release aldosterone of their own accord and do not respond to the usual messages in the body to stop. We believe that APCCs are the beginnings of APAs. We also believe that they contribute to the ongoing problem of hypertension in the patients who are not cured after their APA is removed, rather than general enlargement of the glands. By doing laboratory experiments, this project aims to find out the details of APCCs, for example - what is involved in their release of aldosterone- what can be done to stop them producing aldosterone- if there is a way to stop them producing aldosterone, or killing them off altogetherWe believe that some molecules might have an impact on the function of APCCs. The molecules have been identified by examination of DNA and immune staining of APCC cells and an example is DPP4, which is the target of a common class of diabetes medications. I will be looking for effects of some of these molecules on cells in petri dishes and on slices of adrenal glands from humans who have had them removed to treat their PA. I will also be looking for these molecules, and other markers such as DNA, in the blood taken during AVS, to see whether they provide any clues to predict which patients would benefit, or not, from surgery. This research is important because it will bring us closer to finding a medical treatment for PA and will help to avoid many patients having unhelpful surgery. It will be carried out primarily by me, a clinical research fellow, supervised and supported by my research team at the Queen Mary University of London's William Harvey Research Institute, which is led by world-leading expert in endocrine hypertension, Professor M Br