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Cause and Potential Cure for Common Type of Hypertension

Both the cause and a potential cure for the most common identifiable and specifically treatable cause of hypertension – aldosterone-producing adenomas (APAs) – have been revealed by researchers from Queen Mary University of London and Barts Hospital.

In most people with hypertension, the cause is unknown, and the condition requires life-long treatment by drugs. However, primary aldosteronism is common among known causes of hypertension. Previous research by the group at Queen Mary discovered that in 5-10% of people with hypertension, the cause is an APA, which results in excessive aldosterone production, leading to salt retention and driving up blood pressure. 

Approximately 30% of patients with primary aldosteronism have unilateral forms correctable by unilateral laparoscopic adrenalectomy, and 70% have bilateral forms in which the hypertension responds well to aldosterone antagonists.

'Hallmark Somatic Mutations'

"Whereas physiological adrenal secretion of aldosterone is regulated by (and inversely related to) salt intake, the autonomous aldosterone production by APAs is due to hallmark somatic mutations," the researchers explained. When this is the case, the hypertension is surgically curable by removing the affected adrenal, they said. 

The discovery of deleterious mutations in APAs led them to "several unsuspected pathways of aldosterone regulation". Their new study, published in Nature Genetics, revealed a gene variant in some of the APA nodules affecting a protein called CADM1, a member of the immunoglobulin superfamily, that inhibits gap junction intercellular communications, in turn inhibiting the hormone feedback loop that tells the body when to cease aldosterone production. This leads to a vast, but intermittent, over-production of aldosterone that at its peak causes salt overload and hypertension. 

Aldosterone Release Fluctuates Substantially 

However the release of aldosterone fluctuates substantially throughout the day, so the person's blood pressure is not consistently elevated, which can mask the problem and make it harder to diagnose. "This fluctuation explains why patients with the gene variant can elude diagnosis, unless they happen to have blood tests at different times of day," the authors explained.

Their discovery was made after a single patient participating in a clinical trial of treatments for 'difficult' hypertension was noticed to have fluctuating aldosterone levels. Morris Brown, co-senior author of the study and professor of endocrine hypertension at Queen Mary University of London, said: "This story illustrates benefits from the virtuous circle of science and medicine. Most patients consent to our undertaking non-routine molecular analyses of their surgical samples, from which we discover how their hypertension was caused, and how to cure it in future patients."

Form of Hypertension Cured by Unilateral Adrenalectomy

Patients with excess aldosterone are resistant to treatment with common anti-hypertensives and are at increased risk of heart attacks and strokes. The researchers also discovered that this form of hypertension could be cured by unilateral adrenalectomy. In two patients whose previously severe hypertension had persisted despite treatment with multiple drugs, both their periodic primary aldosteronism and the hypertension disappeared after adrenal removal, with no further treatment required through many subsequent years of observation, the team said.

"Somatic mutations of CADM1 cause reversible hypertension and reveal a role for gap junction communication in suppressing physiological aldosterone production," they concluded.

Their research also suggests a route to improved diagnosis. Aldosteronism is currently underdiagnosed because it does not have a specific, easily identifiable feature, and there is low clinician awareness of the disease. This means that patients miss out on targeted treatments that could prevent cardiovascular complications. The current screening test relies on measuements of the plasma aldosterone-to-renin ratio, but testing may not be accurate (due to interfering medications) or available (in less resourced settings), hence many cases are missed.

24-Hour Urinalysis Could Detect More Patients

The Queen Mary team noted that fewer than 1% of people with -induced hypertension are currently identified, and said this is because aldosterone is not routinely measured as a possible cause – something they argued should change, as it means many patients with potentially curable hypertension currently go undiagnosed. They recommend that clinicians measure aldosterone with 24-hour urinalysis rather than random blood samples, as this has been shown to find a much higher prevalence of primary aldosteronism than single time measurements.

Prof Brown added: "Because the aldosterone nodules in this study were so small, we are now investigating whether momentary cauterisation of the nodule is an alternative to surgical removal of the whole adrenal gland."

The research at Queen Mary was funded by Barts Charity and undertaken by research fellows funded by the British Heart Foundation, National Institute of Health Research, Medical Research Council and Royal Society. The team collaborated with international laboratories to seek more people carrying the variant.  


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