Every year, nearly 800,000 people in the United States alone suffer a stroke. The vast majority of these strokes are ischemic strokes, in which blood flow is blocked, and the brain is denied the full supply of oxygen it needs to perform all of its life-sustaining functions. While the serious long-term disabilities that result from ischemic strokes are associated with the brain, embolic strokes originate outside the brain – often in the heart.
Approximately one-third of ischemic strokes occur in patients who have an abnormal heartbeat condition known as atrial fibrillation, or Afib for short. Healthy hearts beat in an even rhythm. With each contraction, blood moves from the atria to the ventricles, then to the rest of the body. In Afib hearts, faulty electrical signaling disrupts this flow. The heart beats too quickly and blood clots form, creating the conditions for a stroke.
Physicians can diagnose Afib with an EKG and treat Afib with medication or minimally invasive procedure. However, there is a need for tools to help doctors more accurately predict a patient’s risk for stroke – and to know which treatment plan to pursue depending on a patient’s risk profile. Adding to the uncertainty, another 30% of ischemic strokes are characterized as cryptogenic, a category that includes embolic stroke of undetermined source (ESUS). In these cases, a person will experience a stroke with no history or indication of Afib.
Patrick Boyle, PhD, is an Assistant Professor of Bioengineering, a faculty member in the Institute for Stem Cell and Regenerative Medicine (ISCRM), and the Director of the UW Cardiac Systems Simulation Laboratory. Boyle and his research team are on a mission to improve outcomes for patients with Afib and other cardiac arrhythmias by harnessing advances in artificial intelligence, computational biology, and stem cell technology.
Recently, Boyle and his lab have developed a keen interest in fibrotic remodeling, the natural wound healing process that has long been viewed as a precursor to ischemic strokes. “The conventional wisdom is that fibrosis in the left atrium creates the conditions for fibrillation, which, in turn causes the clots that often lead to strokes,” says Boyle. “We believe the relationship between fibrosis, Afib, and stroke is more complex, and that a more thorough understanding of this relationship will contribute to improved patient care.”
Now, a five-year, $2.9 million grant from the National Heart, Lung, and Blood Institute will allow Boyle and his collaborators to detail the interplay of these factors with unprecedented precision and to validate their findings in a proof-of-concept clinical study – outcomes they hope will provide doctors with improved individualized strategies for diagnosing and treating strokes. Crucially, the grant combines engineering and clinical perspectives. Joining Boyle on the NHLBI grant are Nazem Akoum, MD, an Associate Professor of Medicine and the director of the UW Atrial Fibrillation Program and Juan Carlos del Alamo, PhD, Professor of Mechanical Engineering.
A 2019 paper, led by Akoum, and published in the journal Neurology, helped lay the groundwork for the grant. In that study, Akoum monitored a cohort of stroke patients who had the diagnostic criteria of patients with Afib, but without the actual Afib. Boyle explains that the mere existence of this patient profile illustrates the problem that he, Akoum, and del Alamo are trying to solve.
“The fact that these patients experience a stroke without having the underlying problems that a clinician would expect to see in a stroke victim presents physicians with a challenge. Should they send the patient home and hope it was an isolated incident? Or prescribe medication that may not work or have unpleasant side effects? Neither are great options, which is why we need to understand the complex factors that contribute to strokes.”
One of the factors that intrigues the investigators is geometry – specifically, the shape of the atrial appendage, a vestigial structure that hangs off the top of the left atrium. Almost everyone has this appendage, but the shape varies widely. While it has been studied by clinicians, it has not been closely examined through an engineering lens.
Boyle explains how the grant will change that. “We are going to use imaging data from stroke patients to characterize the varying geometries and to look for a connection between the shape of the appendage, the pattern of fibrotic remodeling, and stroke risk. Conducting a multiscale simulation of the electrophysiology, biomechanics, and hemodynamics will help us see how all those pieces go together and how to design a more personalized representation of the risk factors so that physicians can make more informed decisions.”
To help them calibrate the model, Boyle and his collaborators will gather blood flow data from five patients with Afib and from a control group of five patients who have a different type of arrhythmia – and who they suspect have less fibrosis. This process will help the researchers gauge how best to represent biomechanical contractions of the atrium, and will provide the participating patients and their doctors with more information than they would normally receive.
“We can take intra cardiac Doppler measurements to look at flow rates across the different valves and veins that are connected to the left atrium,” say Boyle. “Then we can use that information to calibrate really detailed, beautifully refined electrophysiological cardiac biomechanics and hemodynamic models for those individuals. It is an unprecedented level of knowledge.”
To further validate the model, the investigators will recruit 60 ESUS patients, who will undergo a cardiac MRI scan and two brain scans. The goal of this step is to show that the computational model accurately predicts of thrombosis risk. Ultimately, the hope is to lay the groundwork for a clinical study, a prospect that motivates Boyle.
“We are at the intersection of bench technology and the clinic, which means we have an opportunity to integrate ingenious scientific tools and principles of systems engineering into actual patient care. That’s what makes me tick.”