Image-Derived Enzymatic Adrenal Lateralisation of Primary Hyperaldosteronism (IDEAL)

High blood pressure is a serious medical condition that, over time, causes damage to the heart and blood vessels. If left untreated, high blood pressure often leads to life threatening conditions, such as heart attack, stroke (bleeding in the brain), kidney disease and dementia (memory problems). For most people, lifestyle changes, and treatment with blood pressure lowering medication, return the blood pressure to healthy levels. However, sometimes high blood pressure cannot easily be controlled. This is particularly the case when there are other underlying conditions that raise the blood pressure. In about 1 out of 10 patients with high blood pressure (over half a million people in the UK), the condition is caused by too high production of a chemical, known as aldosterone, in the body. This condition (hyperaldosteronism) is very difficult to treat, and those affected have a particularly high risk of damaging the heart, kidneys and suffering from dementia. Patients with hyperaldosteronism will often need to take a number of medications (3-5 drugs) for the rest of their life, and are likely to have reduced life quality. However, for some of these patients (about one in four), removal of the gland (adrenal) that produces too much aldosterone can cure the high blood pressure, or at the very least, help reduce the need for blood pressure reducing medication. Unfortunately, very few patients with hyperaldosteronism (about 300 per year in the UK) are offered the chance to be treated with surgery as there are no practical methods to identify those who are likely to benefit. For surgery to be successful, it is of outmost importance to know which gland to remove - the one on the left or right side of the body. This can only be determined by taking blood samples from tiny blood vessels within the left and right adrenal glands, a procedure so difficult that it can only be performed by a handful of people in the UK.
The goal of our research is to make it much easier to identify those patients with hyperaldosteronism who are likely to benefit from surgery, and to determine which gland (left or right) to remove, so that more people can be offered surgical treatment. We have developed a kind of 'chemical dye' for use with an advanced type of medical imaging, known as positron emission tomography (PET). If the 'dye' works as we hope, the PET scan will allow us to see how much aldosterone that each of the two adrenal glands (left and right) produce. This will make it possible to identify the patients who are most likely to benefit from surgery, and to determine which adrenal gland to remove. For this study, we will investigate if PET scanning with the 'dye' can be used to measure aldosterone production in adrenal glands in patients with hyperaldosteronism.

Aim: to develop a highly selective aldosterone synthase (CYP11B2) PET tracer as a diagnostic tool to better identify and stratify patients with primary hyperaldosteronism (PHA) for surgery. Hypertension is a leading cause of premature morbidity and death globally. Although most hypertension can be treated with life-long medication, some patients have "secondary" hypertension due a specific cause, the detection of which is important as it allows more targeted medication or a curative procedure. The commonest secondary cause of hypertension is PHA, characterized by excessive aldosterone production by the adrenal gland/s. PHA occurs in 5-10% of the 12 million patients with hypertension in the UK, and 15-25% of those with treatment resistant hypertension, however, in most cases this cause remains undetected. In cases with a demonstrable unilateral cause - typically an aldosterone producing adenoma (APA) - adrenalectomy substantially reduces blood pressure and medication requirements, and may result in a complete cure (30-60% of cases). Thus, although a unilateral APA is the most common, curable cause of secondary hypertension, less than 300 patients per year undergo adrenalectomy for APAs in the UK. This reflects the inefficient and often inconclusive series of tests currently used to identify APAs (screening, confirmative tests, CT scans and adrenal vein sampling (AVS)). AVS is challenging, invasive, has a poor success rate and is often not feasible as it requires patients with severe hypertension to stop medication for several weeks.
Imaging of CYP11B2 can provide a non-invasive readout of aldosterone production in each of the adrenal glands, and allow patients with suspected PHA to be stratified for surgery with a single PET/CT scan, without the need to stop medication. We have developed [18F]UCB2 as the first highly selective CYP11B2 PET tracer. The diagnostic potential of the tracer is substantial and will be evaluated in patients with PHA using PET/CT.

Patient benefits: Our hope is that the primary impact of this proposal will be on patients affected by primary hyperaldosteronism (PHA). It is estimated PHA occurs in 5-10% of the 12 million patients with hypertension in the UK. In most cases this cause remains undetected. In cases with a demonstrable unilateral cause - typically an aldosterone producing adenoma (APA) - adrenalectomy substantially reduces blood pressure and medication requirements, and may result in a complete cure (30-60% of cases). Thus, although a unilateral APA is the most common, curable cause of secondary hypertension, less than 300 patients per year undergo adrenalectomy for APAs in the UK. This reflects the inefficient and often inconclusive series of tests currently used to identify APAs (screening, confirmative tests, CT scans and adrenal vein sampling (AVS)). AVS is challenging, invasive, has a poor success rate and is often not feasible as it requires patients with severe hypertension to stop medication for several weeks. The >99% of patients who go undiagnosed are destined to lifelong treatment with a cocktail of 3-5 drugs, with high risk of complications and reduced quality of life due to cardiovascular, renal and CNS co-morbidity, and drug side-effects. Development of IDEAL PET/CT will offer the following patient benefits: (1) Practical, scalable and expedient diagnosis will allow many more PHA patients to be selected for surgery, and potentially cured. (2) By extending diagnosis to cases with aldosterone producing microadenomas, which is much more common than CT-positive APAs, surgical treatment can be offered to a larger cohort of patients. (3) It will provide a robust and operator-independent test, and thereby overcome the current 'postcode lottery' for AVS (AVS is only available at a handful of hospitals in the UK and the success rate varies markedly between centres). (4) It will allow diagnosis of the ~30% of cases for which AVS currently fails, and a proportion of the ~25% of patients for which AVS is inconclusive. (5) Diagnosis will not require patients to stop their medication, travel to attend numerous hospital visits, or undergo invasive procedures (6) Accurate diagnosis will prevent instances of failed surgery, and allow many more patients to be cured. (7) It will facilitate development of targeted ablation therapy, which will provide a less invasive treatment option for patients with demonstrable solitary APAs.
Socioeconomic benefits: IDEAL will reduce the cost of PHA to the healthcare system by providing a conclusive test, unlike the current diagnostic pathway, which is often inconclusive. IDEAL will therefore substantially reduce the diagnostic costs for each patient who is selected for surgery. Surgical treatment (~£5,000) is considered cost-effective in patients <40 years, as it saves a lifetime of medication for the 30-60% who are cured, and help reduce the need for blood pressure reducing medication in the majority of cases. IDEAL will make surgery even more cost effective by increasing the cure rate, and allow the procedure to be offered to a much larger cohort of patients. This will lead to substantial savings on medication, and reduce the healthcare burden of PHA by preventing complications from poorly controlled hypertension. IDEAL PET/CT is also likely to lead to increased efforts by pharmaceutical industry to develop new drugs for PHA due to bilateral adrenal hyperplasia (which is not amenable to surgical cure), and provide an impetus for them to bring highly selective aldosterone synthase inhibitors into the clinic (much wanted by clinicians working in this field). Ultimately, this would result in substantial additional patient benefits by providing a specific treatment stratified according to a precise diagnosis. In this regard, the IDEAL scan will be a valuable tool to stratify patients for clinical trials with such experimental drugs.