MUSC study seeks drug target to treat small abdominal aortic aneurysms

Vascular surgeon Jean Marie Ruddy, M.D., is leading a study that she hopes will lead to a way to keep small abdominal aortic aneurysms from growing. It’s an important focus, because large aortic aneurysms – weak spots in the body’s largest artery – can rupture if left untreated. That causes internal bleeding and, often, death.

The study is called “Targeting biomechanical signaling in AAA.” In this Q&A, Ruddy, a professor of Surgery in the Medical University of South Carolina’s College of Medicine, explains the reasons for her research, the role of biomechanical signaling in aneurysms and how the study may help prevent small abdominal aortic aneurysms from getting dangerously large.

Q: Your study seeks to find a target for a drug to treat small abdominal aortic aneurysms. Why is it important to treat them?

A: As a dilation of the aorta in the abdomen, an abdominal aortic aneurysm, or AAA, often develops without any symptoms. As the AAA continues to grow, it can begin to leak blood, which is referred to as rupture and has a high rate of death – as high as 80%. 

There are many screening protocols to identify AAA in the early stages, and currently, we treat patients with medications to reduce overall cardiovascular risk. However, science has been unable to develop a drug therapy that would directly impact the AAA and prevent progression. If we can identify a way to treat small AAA, we could prevent the further growth that leads to risk for rupture.

Q: How common are these aneurysms?

A: The rate of AAA is estimated at about 8% to 10% of Americans and is more common in men, although women have recently been found to be at higher risk of rupture. The natural history of an AAA is for it to slowly grow over time at a rate of about 2 millimeters per year, but that does vary from patient to patient. 

Q: Why isn’t there an existing treatment that prevents growth? 

A: When we study AAA in the lab, there have been many times when drugs have been effective at reducing AAA growth. However, when those have been in clinical trials with patients, the same effect has not been observed. We think this is related to the complexity of human physiology and keeps us working to be more precise in identifying a target to reduce AAA growth. 

Q: Why can’t the smaller aneurysms be treated with surgery?

A: The threshold to discuss surgical therapy is based on aortic diameter and has been set at 5.5 centimeters for men and 5 centimeters for women, for several decades. The purpose of pursuing surgery for an AAA is to prevent rupture. Therefore, those thresholds have been set based on risk of surgical complication versus risk of rupture. 

Applying surgery to a smaller AAA would expose the patient to surgical risk without the same benefit. In fact, successful identification of drug therapy for a small aneurysm may mean that some patients would never require surgery.

Q: Your research focuses on biomechanical signaling and the role it plays in the growth of abdominal aortic aneurysms. Please explain what that means and why it’s important.

A: The wall of the aorta undergoes stress with every heartbeat. Much of the impact is absorbed by the matrix and fibers of the aortic wall. However, there is also evidence that the individual cells react to this stretch effect. 

While this mechanical stress may not be the factor that starts the AAA, as the size of the aorta grows, the aortic wall is exposed to higher stress. That impacts the cells within that structure. We believe that the ongoing increase in stress then promotes changes in gene production that are detrimental to the aortic wall and therefore promote growth of the AAA.

Q: How are you trying to figure out how to disrupt that signaling?

A: Using a lab-based model, we can develop an aneurysm and utilize ultrasound to assess the mechanics. Through prior testing, I have identified a key protein for dedicated study. We have been interrogating this protein to “map” how it influences the mechanical signaling to basically be a transmitter for producing more aneurysm growth. 

My current grant (research funding) is then to pair that activity with a collection of protein levels that can be easily measured in the blood of patients while looking at the mechanics of their aorta by ultrasound. This prospective enrollment of patients maintains an important direct clinical translation. We're collecting data to make sure that what we're seeing in the lab is matching what happens in patients.

Q: Where do you see this research going in the next 10 to 20 years?

A: I believe that as we learn more about the protein and gene activities in the wall of small AAA, we will develop a stage-specific treatment protocol. We already know that single drug treatments across a catchment of patients with small AAA are not effective, likely because categorizing by size can’t capture the activity of the aneurysm. 

Mirroring what is done with cancer therapy, stage-specific drug regimens would enable targeting the most impactful proteins and pathways for that patient, at that time, thereby individualizing drug therapy for small AAA to be patient-centric to provide the most benefit.