Estrogen Modulation Unlocks a Core Defense against Aortic Aneurysm

With a 2017 Nina Starr Braunwald Fellowship from TSF, Lauren V. Huckaby, MD, MS, explored how declining estrogen levels during menopause can place patients at higher risk for aortic valve aneurysm. She has since built an impressive body of research in aortic valve interventions, transplant strategies, risk estimation and more.

“I plan to tailor my career to focus on improving outcomes for patients with thoracic aortic disease through improved understanding of the pathophysiology of the disease and evidence-based risk mitigation approaches,” Dr. Huckaby told TSF. “This award provided me with a running start to develop a niche to better understand how sex differences may better guide our management of these patients.”

Gene Expression by Sex and Morphology

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Dr. Huckaby hypothesized that estradiol, the predominant circulating estrogen in female tissues, created a protective effect in thoracic aortic aneurysm by modulating oxidative stress response and extracellular matrix degeneration. Declining estrogen levels could strip this protection, impairing the oxidative stress response in the thoracic aorta and resulting in aortic dilatation.

With funding from the Braunwald Fellowship, she examined estrogen receptor gene expression in aortic tissues and smooth muscle cells from both male and female samples. She compared expression between the sexes, in patients with bicuspid aortic valve (BAV) tricuspid aortic valve (TAV) morphology, and in patients with and without thoracic aortic aneurysm.

She found that neither sex nor age significantly influenced estrogen receptor gene or protein expression in the aortic specimens, and that aortic smooth muscle cells expressed the G protein-coupled estrogen receptor (GPER) regardless of sex.

Investigating gene expression of the antioxidant enzymes superoxide dismutase (SOD)1, SOD2, and SOD3, Dr. Huckaby discovered that neither the presence of aneurysm, aortic valve morphology, nor patient sex were significant predictors.

“Interestingly, SOD3 expression in the aortic media decreased with age in both sexes,” Dr. Huckaby noted. “I observed a similar trend of decreased expression with age forfibulin-5, an anchoring protein for SOD3 that is also involved in smooth muscle cell binding to elastin fibers in the extracellular matrix.”

In the smooth muscle cells, estrogen treatment alone didn’t regulate estrogen receptor protein expression, while it did produce a dose-dependent increase in SOD2 and SOD3 expression.

“One exception was the BAV non-aneurysmal group, which exhibited minimal response to estrogen,” Dr. Huckaby observed. “This may indicate a defective downstream pathway involved in estrogen-mediated SOD2 and SOD3 upregulation in early stages of BAV aortopathy.”

A Blossoming Surgeon Scientist

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Dr. Huckaby’s work quickly garnered attention from both national and international societies, and she presented her findings at the scientific assembly of the American Heart Association, the American Association for Thoracic Surgery (AATS)’s Aortic Symposium, and the 2021 AATS Annual Meeting. Her subsequent research has underscored the need for tailored treatments for aortic dissection, sex-based transplant outcomes after bridging with LVADs, and the impact of sex on outcomes after multi vessel revascularization.

With funding from programs like TSF, Dr. Huckaby was able to take 3 years in the middle of her residency at Emory University School of Medicine to pursue her research goals. She has authored dozens of articles in journals including The Annals of Thoracic Surgery, US Cardiology Review, and the Journal of Surgical Research. In2021, she served as the lead author on a study exploring the impact of a high-risk committee for cardiac surgery decision-making.

“I plan to continue my translational research in thoracic aortic disease in my career as a cardiac surgeon,” she said. “The Nina Starr Braunwald Fellowship has been a meaningful component of my training as a surgeon-scientist and has allowed me to both build a foundation for my future career and also to contribute to our understanding of thoracic aortic aneurysms.”