The American Heart Association’s numbers are so staggering that they seem implausible—10 million Americans visit an ER with heart attack symptoms each year; 90 percent of out-of-hospital cardiac arrests in 2014 were fatal; 17 million people died of cardiovascular disease worldwide in 2014—implausible, that is, until the moment a loved one clutches their chest and rushes to the ER.
Even then, the diagnosis can be alarmingly inconclusive. Doctors often resort to treatments that are radioactive, invasive, and accurate in only about 70 percent of cases; or to stress tests days later, sending a patient home from the ER with an uncertain prognosis and a serious case of anxiety to go with it. There can be a spectrum of symptoms that muddies the diagnosis. There can be disease in the heart’s microvasculature that doctors are unable to detect.
In fact, this may be the most staggering statistic of all: it is the year 2019, and there is still no broadly reliable means of tracking an incipient heart attack.
But if that’s the holy grail of cardiology—and it is—a team of researchers at Drexel University may just have entered the shrine.
In a groundbreaking invention that could change how chest pain is diagnosed and treated, researchers at Drexel’s College of Engineering and Drexel’s College of Medicine have developed a novel voltage-activated contrast agent that detects heart disease by “lighting up” healthy tissue, while leaving damaged or blocked tissue dark. Called Electrast, the agent responds to the heart’s own electrical activity to become visible with ultrasound when in the presence of the myocardium, providing instant, low-cost, bedside feedback on how efficiently blood is being pumped through the heart.
A journal article in Applied Acoustics, published last fall, introduced Electrast as the first ultrasound contrast agent to take advantage of the electrical activity of the heart to provide selective activation in the coronary circulation.
The Electrast team includes Principal Investigator Steven Wrenn, PhD, professor of chemical engineering in CoE’s Department of Chemical and Biological Engineering (CBE); Dr. Brett Angel, MD, Drexel College of Medicine, Division of Cardiology; Aaron Fafarman, PhD, associate professor of chemical engineering (CBE); Andrew Kohut, MD, College of Medicine, Division of Cardiology; and College of Engineering graduate student Michael Cimorelli, who is pursuing his PhD under the mentorship of Wrenn.
Electrast has performed superbly in early trials. It has proven effective in detecting blockages during surgeries in small animals and in closed-chest infarct validation surgeries in pigs. The latter were carried out by a Drexel team as well as an independent research group at North American Science Associates, Inc (NAMSA), a contract laboratory in Minnesota.
Team members recently formed a startup to commercialize Electrast. One patent has been issued, and two are pending.
The Electrast project has also received resounding support from the Drexel-Coulter Translational Research Partnership Program here at Drexel. It has funded Electrast research for three years, the highest level of support. The entrepreneurial and innovation partnership provides funding for Drexel research that has the potential to fulfill significant unmet or underserved clinical needs. Electrast fits neatly—perhaps perfectly -- into that specification.
“We’re hoping to give doctors a better tool so they can answer that question of detection quickly and inexpensively and with minimally invasive technology,” says Wrenn. “This is not pie-in-the-sky. This is working, and the implications are huge. It doesn’t seem far-fetched that we would totally change how chest pain is diagnosed and treated.”
So what is it, exactly?
If you have seen satellite images of planet Earth at night, you can envision how Electrast works: for example, coastal cities like New York and Philadelphia are lit up like Christmas trees while the Dakotas appear as a dark void. Electrast offers that obvious a delineation between perfused and non-perfused areas of the heart.
Delivered by venous injection, this phase-change agent comprises liquid droplets formulated with a novel dual-layer—or “nested”—architecture. The first layer prevents multiple droplets from sticking to one another; the second layer, the nest, keeps the droplets “silent,” or invisible to ultrasound, until acted on by the electric field within the heart’s myocardium (the muscular tissue that makes up the wall of the heart and that causes its pumping action) to selectively brighten perfusion, or blood flow, imaged via ultrasound.
Alternatively, diseased tissue, or areas where perfusion is limited or blocked, remains dark. Those areas are therefore discernible in a way that’s instantly clear and intuitive to medical personnel.
Imagine a soap bubble the size of a red blood cell; that’s a microbubble. The medical industry already makes use of microbubble ultrasound contrast agents to monitor heart disease. However, these microbubbles are not effective in evaluating blood flow in the muscle wall for at least two pronounced reasons. One, upon entering the body, they immediately begin contrasting everywhere so that infarcted heart tissue is difficult if not impossible to distinguish. Two, these fragile agents are so abased by ultrasound that their ability to highlight diseased tissue lasts only a couple of minutes.
Electrast surpasses existing microbubble agents on both of these scores. Its specificity of activation allows doctors to evaluate perfusion in the essential area—and only in the essential area—with imaging that is both longer lasting and of unusually high quality.
“Where Electrast differs dramatically from traditional microbubbles is that in the blood pool, it travels in a kind of ‘echo stealth mode,’ totally undetectable on ultrasound exam,” says Angel. “The agent only becomes echogenic and therefore detectable in the small vessels of the heart muscle where it is activated specifically by the electrical activity of viable, living heart muscle cells and the concomitant ultrasound.”
In essence, the Drexel team is coupling the technology of nested droplets with the electrical field of the heart and the acoustic signal of the ultrasound to highlight the myocardium with greater efficiency than ever before.
“If it’s dark, that’s a blockage. It’s really that simple,” says PhD candidate Cimorelli. “That’s basically what we’ve seen.”
The Heart is a Muscle
To explain the challenge cardiologists have in tracking heart disease, Angel offers a well-used ER expression: time, he says, is muscle.
Heart disease can begin years before symptoms appear. All too often, by the time a patient gets to the ER, damage to the heart’s muscle has advanced significantly. In addition, some 40 percent of these patients may have blockages that started in the heart’s network of micro-vessels. Current detection technologies only target the larger vessels.
“Cardiovascular disease is ultimately a silent disease until it becomes un-silent. Until someone has an event,” says Angel. “To this date, there’s very little that you can do to really try and screen for that in terms of imaging the actual blood flow through the heart muscle without exposing a patient to some degree of risk -- and without exposing the patient to some degree of ambiguity in the results. There’s a large false positive rate and false negative rate.
“Most of the technologies that we have are good at looking at the big vessels on the outside of the heart. But really, they don’t have the ability to see blood flow through the little vessels. That’s really what the holy grail of cardiology would be, to try and catch that early and be able to act on it.”
Unlike conventional microbubbles now in use, Electrast droplets can be formulated with a range of diameters in nominally hundreds of nanometers, giving them unprecedented access to the heart’s microvasculature.
That access, along with Electrast’s brightening response, are what sets the agent apart.
Wrenn and Angel describe its utility as analogous to “silencing the noise in the room,” so that doctors can hear that one voice in the back corner that has something important to say about heart health. The medical industry has been hammering away at techniques that accomplish this for some 30 years with only modest success, which is why Electrast could be “a welcome disruption” in the medical field.
“This ability to really discern different levels of tissue perfusion, viability, and compromise by latching onto the most unique aspect of living cardiac muscle is what makes Electrast such a valuable and disruptive technology,” says Angel.
Early Colloidal Research
When Wrenn first came to Drexel in the early 2000s, he was working on biological colloids, particles produced by the body ranging in size from a nanometer to about a micron. An example of a colloid is a “liposome,” a water-filled particle surrounded by a membrane. Liposomes can also be made synthetically. Wrenn developed an interest in how these structures interact with ultrasound and how microbubbles could be tethered to the outside of liposomes for controlled drug release within the body. He then had the idea to put the bubble - plus a drug - inside a specially designed liposome for a unique, dual-shell architecture now referred to as Wrenn’s nest. That architecture allows for a hardy drug delivery system.
“But there was no interest commercially,” says Wrenn. “They said, ‘that’s encapsulation; there’s nothing new here.’ But they were missing the fact that I have two coatings—I have a coating on the bubble at the interface between the gas and the water, but then I have a second shell that’s separated from that coating with water in between—so I have free-floating, coated bubbles inside of a liposome.”
Undeterred, Wrenn continued studying nesting properties and publishing his results. He generated some 19 papers over eight years on the technology, unwittingly laying the foundation for Electrast. The bubbles he was formulating, which previously dissolved in a matter of minutes, were persisting indefinitely owing to his nested architecture.
Then, three years ago, Wrenn got a phone call from a complete stranger with a pressing question. That stranger was Angel, calling in his excitement from a CVS parking lot.
“It was June 3 of 2015,” Wrenn says. “Brett called me and I had no idea who he was. He was really excited. He had read some of my papers and wanted to know, could I create an agent that could let us see a heart attack in real time? And the main challenge was, could you make it so that it worked with the electrical activity of the heart?
“So I met with him a few times. I began to read and learn about the heart’s physiology. I spent about six months thinking about it before arriving at an idea I thought could work.” says Wrenn. “Then I shared the idea with Aaron (Fafarman) because of his prior experience working with electric fields, and we sketched the idea out on the whiteboard in my office.”
The idea they sketched out on Wrenn’s whiteboard was that nanodrops could be nested within a voltage-sensitive bilayer of FDA-approved ingredients for an innocuous phase-change agent that could be deployed in the very region cardiologists must image to detect heart disease, especially early-stage heart disease.
Research began almost immediately in Wrenn’s College of Engineering-based laboratory, the Wrenn Research Group, which bet on the idea that, with Electrast, cardiologists could get localized, high-resolution imaging exactly where it’s needed.
“The heart attack is happening due to a blockage in the muscle. So, you want a way to distinguish the blood that’s in the muscle from the blood that’s being pumped by the muscle to keep the heart going. You need to be dark in the chamber, bright in the wall,” says Wrenn. “The heart’s depolarization wave is happening roughly once a second—lub-dub, lub-dub. It is confined to the tissue of the heart; it’s like dominoes falling, and that signal cascades down and it makes the muscle contract, and that makes the heart pump.
“So, if you can make an agent that is sensitive to that signal, then only the agent that’s in the muscle will be activated and not the stuff that’s farther away. That’s what we’ve done here.”
Coulter-Drexel Steps In
The Electrast team formed in earnest in 2016 with the first installment of funding from the Coulter-Drexel partnership. Studies followed at Hahnemann, in Minnesota, and at the University of Pittsburgh where they will continue this summer.
“We give $800K a year to between four and six projects to de-risk them for funding milestones on the path to commercialization,” says Coulter Program Director Kathie Jordan, PhD. “Because we fund early, we really are a concierge service. What we do depends on what is needed, whether it’s regulatory consulting or finding a CEO—any number of things that it takes so that the project can hit a commercial market.
“Steve was exactly what we look for in projects,” she adds. “He was incredibly engaged and excited in the project. One of the things we look for is the strength of the clinical and engineering collaboration, and it was clear right from the beginning that we had a top-notch team.”
Cimorelli says the key to a good team is simply matter of bringing the problem-solvers, or engineers, together with the day-to-day practitioners, or doctors and medical staff, for maximum proficiency.
“That’s what this project truly is,” Cimorelli says. “We have two great doctors who really understand the disease states and two amazing engineers with great technical foundations. I think that’s why this project has been so successful in just two-and-a-half years.”
Coulter funding follows a six-month proposal process that seeks to gauge market need and commercial viability. Since the inception of the Coulter program at Drexel University in 2005, 58 projects have received a total of $9.4 million in support. However, the Electrast project is one of only a handful to receive three full years of funding. The Coulter partnership has provided Electrast with $600K in funding to date. That funding runs through the end of September with the likelihood of a no-cost extension.
The Electrast team met with a Coulter oversight committee several months ago to present a film of the surgery being performed at the lab in Minnesota. In the film, the research group performed a progressive series of animal studies to get a sharper image and demonstrate how effective Electrast is in predicting heart attacks. In one surgery, Electrast was deployed via bolus injection. It immediately brightened the subject’s myocardium, leaving a dark spot where the “heart attack” had been created. The brightness was obvious even to an untrained eye.
“After talking with our oversight committee, it became pretty clear that what venture capitalists want to see is, can you detect a heart attack? They told us: replicate it in the lab, replicate it in the rat, replicate it in the pig. We’ve done all that now,” says Wrenn.
“Particularly with university research, investors want to see that the agent will work in someone else’s hands,” says Jordan. “That was the point of doing studies at an outside contract research organization like NAMSA. That went very well.”
One of the World’s Fastest Cameras
Electrast research will proceed simultaneously through several next-step stages. One of them is the startup process, as team members introduce their phase-change agent at cardiology conclaves around the world and begin funding discussions with venture capitalists. Another is a series of video microscropy studies at the University of Pittsburgh, which are underway. There, one of the world’s fastest cameras (25 MHz, or 25 million pictures per second) provides the team with a frame-by-frame view of exactly how their phase change agent changes.
Electrast is working, says Cimorelli. But they are not clear on exactly how the ultrasound’s impact can be tweaked and modified for maximum clarity. They want to establish a nesting efficiency that will give them the best acoustic signature.
“The camera speed is tied to the speed and frequency of the ultrasound,” explains Wrenn. “Typically, when you’re looking at our samples, you’re seeing some brightness but you’re not seeing what’s providing that brightness. Our agent that’s providing the signal is doing things on a megahertz frequency scale—which means millions of times per second, but you’re not seeing that with your eyes, obviously. This camera at Pitt lets you see the actual oscillations, and then you can play it back frame-by-frame and see what is happening each cycle of ultrasound.
“We’re attempting not only to optimize the formulation, but fully understand it scientifically,” he adds. “How does the performance respond to all these changes in the chemistry? And then ultimately, we’ll know what combinations to use under certain circumstances.”
The contrast agent will proceed to commercialization at the same time as its mechanism is being more deeply investigated. As team members explain it, the FDA is less concerned with exactly how the phase change agent behaves than that it won’t cause any harm in the body and that it works better than anything else on the market. For Cimorelli, it’s another matter. He wants to see and understand exactly what is happening. “It bugs me like crazy,” he says. “I’m spending 60 hours a week working on this. I think it’s valuable to know before it goes to a commercial step. But that’s me.”
Because Electrast is less expensive, non-invasive, highly portable, and able to be wielded with a minimum of training by medical technicians, Wrenn hopes it could someday be used as an annual screening tool. Instead of waiting for an ER episode, general practitioners might use it in regular office visits to track how a patient with cardiovascular vulnerability is doing from year to year.
Waxing poetic about the opportunities the team’s contrast agent could afford, Wrenn concludes: “I foresee a day when Electrast is as familiar as an EKG; when hearts brighten on the edge of darkness; when patients leave a doctor’s office—amazed and perfused.”