Progress on treatment for high blood pressure

  • April 21, 2016
Progress on treatment for high blood pressure

Catherine Xie is first author on a paper on research into one of the biggest causes of hypertension.

Selective Cav1.3 blockade may be a novel way of treating primary hyperaldosteronism, especially those caused by ZG-like APAs with aldosterone-dependent hypertension, without the unwanted side effects associated with currently used medication.

Catherine Xie

Researchers led by a Gates Cambridge Scholar have identified a new way of potentially treating one of the most common curable causes of hypertension.

Some 31% of men and 28% of women in England have hypertension or high blood pressure. Long-term high blood pressure is a major risk factor for coronary artery disease, stroke, heart failure, peripheral vascular disease, vision loss and chronic kidney disease.

Aldosterone-producing adenomas (APAs) – formerly known as Conn’s Syndrome – are the most common single cause of hypertension. Early diagnosis in young patients is highly likely to cure hypertension and pre‐empt the need for a lifetime of taking medication. Despite medication use, research has shown many patients succumb to increasing lethargy, progressively difficult‐to‐control hypertension, suffer premature complications like atrial fibrillation, myocardial infarction and stroke and may end up living shortened lives.

One of the most common curable causes of hypertension, APAs account for approximately half of primary aldosteronism, which is estimated to be present in between five and 13% of all hypertensive patients and in at least 20% of patients with drug-resistant hypertension. However, it is likely that fewer than 10% of APAs are ever diagnosed and fewer still are removed in time to prevent the development of hypertension that has become resistant to conventional drug treatment and is no longer be curable with surgical removal of the APA. Most patients elude diagnosis until the APAs have been present for many years, by which stage ‘palliative’ medical therapy, which treats but does not cure hypertension, is usually preferred to surgery.

Arising from the adrenal cortex, APAs are a cause of primary hyperaldosteronism, which is a state of excess production of the hormone aldosterone, resulting in high blood pressure. The current medical treatment of primary aldosteronism is blockade of the aldosterone receptor. This can lead to a pathological increase in aldosterone secretion. Decades of unopposed exposure of the heart and arteries to excessive aldosterone levels leads to high blood pressure, which takes a toll, creating patients with hypertension which is increasingly resistant to medical therapy and surgical intervention. This makes a selective and targeted blockade a potentially valuable therapeutic target.

University of Cambridge researchers had previously discovered multiple somatic mutations in an adrenal L-type calcium channel called Cav1.3 in APAs from patients with hypertension.

Gates Cambridge Scholar Catherine Xie is the first author of a paper published online in Scientific Reports this week about further research about the role of Cav1.3 in aldosterone production. Cav1.3 mutations are a common genotypic characteristic of a subtype of APAs that arise from the zona glomerulosa (ZG), the outermost layer of the adrenal gland where aldosterone is synthesised and secreted. The research team showed that the mutations in Cav1.3 channel increased aldosterone production and that this increase in aldosterone can be reversed by the blockade of calcium entry through the Cav1.3 channel using an investigational Cav1.3 channel blocker.

Catherine [2013] did the research for her MPhil in Clinical Science with Professor Morris Brown's laboratory at the University of Cambridge.  Now an MD-PhD candidate at Yale School of Medicine, she says: "Our discoveries show that Cav1.3 plays a role in the synthesis of aldosterone and suggest that Cav1.3 can provide a novel mechanism and target for regulating the excess aldosterone secretion from APAs, which results in high blood pressure that becomes resistant to conventional medical therapy and cannot be cured with surgical removal. Selective Cav1.3 blockade may be a novel way of treating primary hyperaldosteronism, especially those caused by ZG-like APAs with aldosterone-dependent hypertension, without the unwanted side effects associated with currently used medication."

She added: "Through working at the forefront of making cutting-edge scientific discoveries on disease pathogenesis and translating this new knowledge into novel and superior therapeutics, I have gained invaluable insights into the exciting connection between basic science and clinical medicine. My experience as a Gates Scholar invigorated my enthusiasm for human translational research and provided me with an essential foundation to become a physician-scientist, bridging the boundaries of the lab and clinic.”

Picture credit: Wikimedia.

Catherine Xie

Catherine Xie

  • Alumni
  • United States
  • 2013 MPhil Clinical Science
  • Trinity College

Growing up, I not only gained a deep appreciation for cultural diversity through living in four different countries (China, Australia, Canada, and the USA), but also became motivated by my fascination with the study of life to discover new knowledge. My innate curiosity and passion for scientific research led me to pursue a B.S. in Bioengineering at the California Institute of Technology, where I gained cutting-edge insights into complex modern diseases and pursued extensive investigations to find therapies for leukemia and diabetes. At Cambridge, my MPhil in Clinical Science (Translational Medicine and Therapeutics) will provide me with valuable knowledge and training in applying knowledge of disease mechanisms to guide powerful therapeutic drug development. I will gain an ideal foundation to become a physician-scientist, translating my research findings into more effective healthcare and providing people with the knowledge and treatments to battle their diseases.

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