Heart Mechanics: TIP Awardees Investigate Models of Pulmonary Heart Dysfunction



Seventy-five years ago in 1944, researchers at Johns Hopkins made history when they performed cardiac surgery on a cyanotic one-year-old girl with a congenital heart disease known as tetralogy of Fallot. The surgery, dubbed the Blalock-Taussig shunt procedure, or Blue Baby Operation, has helped countless children by improving oxygen flow into the bloodstream. Children born today with tetralogy of Fallot—about 1,660 each year in the U.S. according to the Centers for Disease Control—are living to experience their childhood. Yet, much remains unknown about the mechanical factors that impact their hearts.

Associate Professor of Pediatrics and of Bioengineering Alison Marsden, PhD, and her colleagues are hoping to accelerate our understanding by studying pulmonary valves both in vitro and in silico. Tetralogy of Fallot is a very rare combination of four heart defects, one being a narrowing of the pulmonary valve that often needs to be replaced periodically. Dr. Marsden and her team recently received an American Heart Association (AHA) Transformational Project Award of  $300,000, which is designed to support innovative, high-impact research that could lead to major breakthroughs or advancements in cardiovascular and/or cerebrovascular research. Dr. Marsden’s award began July 1, 2019 with funding continuing through June 2022.

Like many major funding organizations, the AHA stipulates that applicants for the Transformational Project Award must submit robust preliminary data. Support from Stanford’s Maternal and Child Health Research Institute (MCHRI) was instrumental in this respect. “It gave us a seed for bringing together an interdisciplinary collaborative team to launch a new effort,” Dr. Marsden says.

MCHRI TIP awardees Drs. Alison Marsden, Doff McElhinney, and John Eaton

Dr. Marsden received MCHRI’s Transdisciplinary Initiative Program (TIP) Award in May 2017, with funding of $200,000 through April 2019, to study models of pulmonary valve dysfunction in children with tetralogy of Fallot. After initial repair early in life, children with tetralogy of Fallot often require surgery to replace the pulmonary valve in their teens. Valve prostheses routinely used today – typically a porcine or bovine pericardial variety – tend to last around 15 years; however, they often deteriorate more quickly in individuals with tetralogy of Fallot. Dr. Marsden set out to investigate what might be causing these early failures and determine how outcomes could be improved in the future.

Dr. Marsden has a long history of working on problems related to congenital heart disease, though, until recently, she had never studied tetralogy of Fallot specifically. Professor of Cardiothoraic Surgery and of Pediatric Cardiology Doff McElhinney, MD, approached her with the idea and the two worked together to develop the project. Dr. McElhinney, who was previously a MCHRI Biodesign Faculty Fellow, was named a Co-Principal Investigator on the TIP Award.

Dr. Marsden also benefited from having done her doctorate work in the Flow Physics and Computational Engineering Group, where she studied with Charles Lee Powell Foundation Professor of Engineering John Eaton, PhD, who also joined the grant as Co-Principal Investigator. Together, the three researchers worked to combine mechanical and computational modeling with clinical data, leading to insights about pulmonary valve anatomy and placement.

Right ventricular outflow tract model of a Tetralogy of Fallot anatomy (left) in a physiological flow loop inserted into an MRI (right) to measure full 3D velocity fields

A model heart

To get a closer look, Dr. Marsden and Nicole Schiavone, a PhD student in her Cardiovascular Biomechanics Computation Lab, partnered with Dr. Eaton and research engineer Chris Elkins, PhD to create an in vitro testing rig of the right side of the heart. The goal was to learn more about blood flow around the pulmonary valve: Is it asymmetric? Is blood pooling or recirculating? Any abnormalities could help explain early valve failure. They created a 3D-printed model of the right ventricle as well as models of the right ventricular outflow tract (RVOT), both normal and dilated. The dilated RVOT is characteristic of individuals with tetralogy of Fallot. Analogue blood fluid was a stand-in for the real thing.

“It took quite a bit of effort to get the flow and pressure waveforms correct and make it physiologic,” Dr. Marsden says. Indeed, seeing the scale and complexity of the completed rig gives one an appreciation not only for the work that went into its development but also for the intricacies of the compact heart.

Once satisfied with the rig, Dr. Marsden’s team brought it to Stanford’s Lucas MRI Service Center for overnight testing in the MRI machine. The result is 4-D imaging, or as Dr. Marsden says, “basically a movie of blood flow patterns as the valve is opening and closing.” The team tested a variety of configurations in the scanner; they oriented the valve in different ways and tested each orientation with both the normal and dilated RVOT.

“The bottom line is that we're seeing pretty big changes in the flow fields that are generated, and these depend on both how the RVOT is shaped and how the valve is oriented,” Dr. Marsden says. “We used the TIP money to design this whole set-up with the idea that when we went to AHA or NIH for money, we could say, ‘We've got this rig, and here's what we're planning to do.’”

Flow patterns through a bioprosthetic pulmonary valve are shown in a healthy geometry (top) and a diseased geometry (bottom) of the right ventricular outflow tract, shown at two locations in each model. The flow patterns of the two cases are drastically different, most notably with the regions of reverse flow which may impact valve performance.

Bringing it back to the bedside

In addition to the visual representation of the blood flow through the valve, Dr. Marsden and her team wanted to be able to actually measure valve performance over several years. To achieve this, they added a retrospective clinical component to the study where they pulled outcomes data on valve performance over five years from about 50 individuals with tetralogy of Fallot. Working with Stanford medical student Veronica Toro, they began to find some similarities in features in those who did and also those who didn’t have valve failure.

The next step will involve recreating the valve features they identified being related to valve success and failure using 3-D printed models. They will test fluid flow through these valve models using the rig to better understand the differences in anatomy, valve size, and placement. The hope is that based on the results of a clinical scan alone, certain features predictive of valve failure could be flagged sooner or avoided altogether by modified implant techniques.

The grant from the AHA will fund both the 3-D printing and experimentation and also computational modeling that allows Dr. Marsden and her team to build patient-specific models from image data using open source software developed in the Marsden Lab called SimVascular.

Guidelines may help boost outcomes

The ultimate goal of this next-level funding is to establish basic guidelines regarding valve sizing and orientation in order to avoid adverse hemodynamics. Even general recommendations could go a long way in helping to improve surgical outcomes.

Right now,  pediatric cardiac surgeons managing the care of children with tetralogy of Fallot rely on their own judgment when it comes to valve sizing and placement. Dr. McElhinney says it’s challenging to select a valve for a child whose anatomy will undoubtedly change. “You might put in a valve in a ten-year-old that’s too big for a 10-year-old but that’s big enough for an 18-year-old or a 15-year-old and you’re sort of looking ahead. You’re putting in a bigger valve for their future-needs, not for their today-needs. There may be downsides to that relating to the geometry and flow,” he says. “On the other end of that spectrum, if someone grows to the point where the surgical valve that’s in there is really too small, then the same sort of geometric mechanical factors could come to play.”

The data collected by Dr. Marsden and her team should help surgeons make more informed choices in the future. “The more standards or uniform guidelines one can suggest, the more likely outcomes could be unified across different centers that are performing these procedures,” she says. “We can't make those kind of recommendations if we don't understand what's causing the difference in outcomes.”

Thanks to MCHRI funding, the team was able to prove their hypothesis that valve sizing and placement produce differences in blood flow patterns. Confirming those differences exist, says Dr. McElhinney, “that’s the first important foundation towards moving into understanding the impact. Having this type of funding to help develop the preliminary data and the proof-of-concept data is essential.”