Researchers set on grand challenge to accomplish targeted drug delivery for heart disease

Virginia Tech researcher Pavlos Vlachos and his students in the College of Engineering have a tall order to tackle: Stem the grim progression of heart disease, which kills hundreds of thousands of people each year in the United States alone.

Vlachos, an associate professor of mechanical engineering and director of the Advanced Experimental Thermofluid Engineering Research Laboratory, is waging this fight with what he calls his four children. That's not a condescending term for his researchers, but a parental pride in the series of cardiac-related projects he's working on. Vlachos literally treats these research projects as a parent would treat his or her children. "I can't just talk about one," he says of the lab experiments.

Their initiative areas are wide and include better understanding the flow of blood in and out of the heart; improving drug delivery and artery stents; and creating a system that can mimic the sounds of a diseased heart in order to develop sensors that, from vibrations, can form a diagnosis.

Each project is dedicated to reducing deaths from cardiovascular and coronary disease through noninvasive diagnostics and advanced therapies. Put it all together and, ultimately, Vlachos and his group aspire to develop a family of cardiovascular healthcare tools that are not limited to benchtop experiments but make the transition to bedside solutions to help patients and physicians.

The heart, says Vlachos, continuously adapts, even throughout one day, to accommodate exercise, stress, illnesses, or shortages that it has suffered. A person's heart also can change its beat-per-minute cycle depending on whether or not the heart is diseased, or if the person is smoking, drinking a caffeinated soda pop, or jogging or resting. Vlachos calls the heart muscle "a fire brigade assembly" and "a dynamic evolving system." That's why heart arrhythmias and other defects — holes, for instance — are difficult to trace, Vlachos says.

"If you don't know what it is, what is wrong, how can you treat it?" he asks. Vlachos and his students' hope is to answer such questions by developing novel tools and improving existing ones to diagnose, monitor, and treat heart disease. The answers may lie in the four "children."

Bioacoustics

In a project headed by Daniel Cooper, a Ph.D. student in biomedical engineering, Vlachos' lab is developing a computer model with simulated organs that one day will lead to the tracking, recording, and organizing of the exact sounds of the heart and how these sounds correlate to its health. For instance, if the sound of blood pressure flow changes can be tagged to a certain form of heart disease or a disorder, doctors then could make a diagnosis. "If you can differentiate the sound of a certain disorder, you can diagnose it," Vlachos says. This project builds on prior research that stipulates a diseased artery or heart makes distinct sounds, such as murmurs, depending on the illness that inflicts it. The trick here: Cooper's model will comprise sensors that will pick up on the vibrations created from the sounds, not the audible sound itself. Tagging those vibrations could lead to a diagnosis. This is the newest of Vlachos' projects.

Drug delivery

One would assume that medicine is like a rifle shot: If you have heart disease or grass allergies and you take medicine, the pill you pop in your mouth goes directly to your heart muscle or your sinuses, respectively. But that would be wrong. Medicine, it turns out, is more like a shotgun blasting out pellets; it ends up hitting more than the target. One result can be toxic side effects. Jaime Schmieg, also seeking a doctorate degree in biomedical engineering, is leading the experiments to cut that collateral damage. The goal: "Selectively attack the diseased tissue while leaving the surrounding healthy tissue unaffected," Vlachos says.

As in all of his cardiac-related experiments, Vlachos reaches back to his fluid mechanics work for an analogy. "The basic principles are the same," he says. "Drugs are carried by the flow in the artery inside particles that reach the organs the same way as air carries tree leaves and deposits them in your backyard."

If a drug can be made or directed to an exact spot where the stent is located for a patient who has an artery stenosis, then unintended side effects would not be a hindrance, Vlachos says. "The ramifications are huge," he says. Imagine taking medicine for pain or the flu and having no side effects, such as drowsiness or lethargy. Vlachos calls this research area a "grand challenge." Researchers elsewhere are working on many different ways to accomplish targeted drug delivery.

Stents

Simply hearing about stents and holding one in your hand are totally different experiences. Stents are small metal tubes made out of wire mesh that are inserted into an artery to open blockages and allow for the free flow of blood. But when holding one of the fragile tubes, the thought of having metal wire mesh inside your artery hits home. The process, although much less invasive than open-heart surgery, still can be extremely difficult on the body. John Charonko and Satya Karri, Ph.D. students in biomedical engineering and part of Vlachos' team, developed realistic simulations of coronary arteries, incorporating measurements of the flexibility of vessel walls, and have been investigating how blood flow is changed by different stent designs, and how small changes in design or use might lead to large changes in the forces experienced by the arterial walls, for instance. Their research has made significant strides in terms of physiologically realistic blood pressure and flow waveforms, and the use of commercial stents, of which there are many. The goal is to design more compatible stents and interventions, reducing the need for repeat procedures. Their work has been partially sponsored by and is in collaboration with Abbott Vascular Laboratories.

Cardiac diastolic dysfunction diagnosis

Contraction of the heart is easier to measure than the relaxation or diastole phase, when the heart fills with blood, ready for the next contraction to pump it to its next station. When diastolic dysfunction occurs, the heart chambers do not fill smoothly. There are several causes of diastolic dysfunction, including hypertension, or high blood pressure, from which more than 60 million Americans suffer. Some of the causes can be treated or reversed. But first the problem must be diagnosed, "and that is very hard because the heart is doing a great job compensating for the deficiency," says Vlachos.

Kelley Stewart, a doctoral student in mechanical engineering, and Charonko are working on a project in collaboration with cardiologists William Little and Rahul Kumar from the Wake Forest University School of Medicine to improve Doppler echocardiograph and MRI diagnostics for this disease. They have developed a new methodology that is based on the physics of fluid flow, which allows these existing clinical tools to present a more comprehensive picture of the heart's function. Studying how the heart's left ventricle fills, Vlachos, Stewart, and collaborators have developed an automated algorithm to analyze the stage of diastolic dysfunction and determine whether a heart is healthy or not. Preliminary results show an increase in diagnostic consistency and repeatability over conventional methods, such as ejection fraction methods used to measure the blood pumped out of the heart. It is hoped this algorithm will reduce diagnostic mistakes while delivering a reliable and robust detection tool for clinical applications.