CTSA Program Supports Early Development and De-Risking of Innovative Heart Valve Technology

Translational Science Highlight

  • NCATS’ Clinical and Translational Science Awards Program support enabled the early development and “de-risking” of an innovative device that may be more durable and help patients avoid complications of heart valve replacement.

The aortic valve keeps blood flowing out of the heart to the rest of the body. Calcium deposits form on the valve with age, narrowing the valve opening and disrupting blood flow. Traditionally, replacing the aortic valve meant having open-heart surgery, a risky and invasive procedure. But in 2011, the Food and Drug Administration (FDA) approved the first device for a procedure called transcatheter aortic valve replacement (TAVR).

For TAVR, a cardiologist makes a small cut somewhere else in the body, such as in the groin, and threads a catheter containing the replacement valve through a large blood vessel up to the heart, where the valve is set in place. The procedure is much less invasive than traditional open-heart surgery, and patients recover more quickly. However, patients who receive TAVR may have a higher risk of complications, such as blood clots on the heart valve, than people who have the valve replaced surgically.

Arash Kheradvar, M.D., Ph.D., a biomedical engineer at the University of California (UC), Irvine, has an idea about why: Squeezing the replacement valve down to a size that fits through the artery in the groin appears to damage the valve and may make it easier for blood clots to form on its surface. With support from the NCATS Clinical and Translational Science Awards (CTSA) Program hub at UC Irvine, Kheradvar began developing a device called FoldaValve that folds differently to minimize or even avoid damage to the valve.

Kheradvar hopes that FoldaValve will further lower risks for patients, increase the working lifespan of the replacement valve and make TAVR available to more people. Currently, TAVR is not approved for patients at lower risk from surgery or patients younger than 65, mainly because of concerns about the durability of the valve.

Understanding Valve Damage

A replacement heart valve

FoldaValve, a replacement heart valve with leaflets attached. (KLAB: Kheradvar Research Group Photo)

A replacement valve for TAVR consists of two parts. The leaflets, which flap open and shut with each heartbeat, are affixed to a stent that sits in the opening of the aorta. For the replacement valves currently on the market, the stent is compressed, or crimped, with the leaflets inside, just before the procedure. Before crimping, the replacement valve is often more than an inch across, yet it must fit into an artery that is less than half an inch across.

“If you are going to significantly crimp these valves inside the stent, what will happen to the leaflets?” Kheradvar asked. He was a bioengineering graduate student at the California Institute of Technology when TAVR was being studied as an experimental procedure in the 2000s. He was studying how blood flows through heart valves. “Everybody was super excited, but I was thinking, ‘In its current form, this invention may be costing the durability of these valves.’”

In a 2014 study, Kheradvar and his colleagues showed that crimping a valve’s delicate leaflets inside the stent causes irreversible damage. Since then, other researchers have reported several cases in which calcium deposits formed on TAVR valves within about two years. Another study revealed that blood clots seem to be more likely on valves that were placed via catheter. Kheradvar suspects that the damage to the leaflets makes it easier for clots to form. These clots may lead to stroke or other health problems if not treated in time, and damage to the leaflet can shorten the lifespan of the valve and subject patients to another replacement procedure.

Working from the Outside In

In 2011, with support through the CTSA Program, UC Irvine awarded Kheradvar a pilot grant, which he used to develop a different TAVR technology called FoldaValve. With this approach, the leaflets are extended outside the stent for the trip from the groin to the heart. The valve is designed so that the leaflets turn inside and start working when the stent is expanded.

The CTSA Program pilot funding also helped Kheradvar secure a larger grant from the Wallace H. Coulter Foundation, which enabled him to develop a delivery system for FoldaValve. So far, the valve has been implanted successfully in animals.

FoldaValve solves another problem with existing valve replacement systems: The calcium deposits on the diseased aortic valves form in random places, so it can be difficult to tell where exactly the valve should be placed. “For a conventional valve, when you implant it, you’re fitting a cylinder into a bed that is not circular, due to randomly deposited calcium,” Kheradvar said. “You get gaps between your stent and that calcium, which results in leaks around the valve.”

Replacement heart valves solve this problem by adding a skirt, which is very effective. In addition to having a skirt, FoldaValve is designed so that the cardiologist can reposition the valve for optimal placement to avoid leaks. If the valve is not going to work at all — or if the patient feels unwell during the procedure — it can be refolded and removed. Additionally, FoldaValve’s unique folding makes it narrower than other valves used for TAVR, which means it should be safer for patients with thin, delicate arteries.

Improving Imaging

FoldaValve in action

FoldaValve in action (KLAB: Kheradvar Research Group Photo)

Using grant support from NIH’s National Institute of Biomedical Imaging and Bioengineering, Kheradvar is also working on improving imaging during the valve replacement process. Normally, a cardiologist guides the valve using fluoroscopy, a kind of x-ray imaging that shows a continuous video of the action inside the body. In contrast, Kheradvar has mounted a tiny ultrasound probe on the catheter —  something that has previously been done to position stents in the arteries that supply blood to the heart muscle. “When you see the catheter under the x-ray, it’s like you’re standing on the street and a car passes by,” Kheradvar said. “But if you have an ultrasound system on your catheter, it is like you are driving the car.”

Mohammad Sarraf, M.D., a cardiologist at the University of Alabama at Birmingham, is working with Kheradvar to help further refine and test FoldaValve. Sarraf routinely performs TAVR with the two existing FDA-approved replacement valve systems, and he said that having more options on the market would be useful. “We’re learning from our patients and their complications,” he said. “It’s difficult to say that one valve system is best for all patients. Having three or four TAVR systems on the market will give us more tools to serve our patients better.”

Looking Ahead

Kheradvar has formed a company to further develop FoldaValve. He is currently raising private funding to move the technology forward and ensure safety and efficacy. He hopes to implement the first human trials of the valve in Europe and eventually get approval for the device from both the European Union regulatory agency and the FDA.

“This project demonstrates how CTSA Program support of innovative ideas can lead to new technologies that benefit patients,” said Michael G. Kurilla, M.D., Ph.D., director of the NCATS Division of Clinical Innovation. “A small infusion of CTSA Program funding seven years ago may eventually have a big impact: a better valve replacement for patients.”

“Everything starts from something,” Kheradvar said. “I’m thankful for the early CTSA Program funding, because it was crucial to securing additional funds and moving forward with the development.”

Posted October 2018