Mending a Broken Heart
By Ben Brumfield | Photos by Rob Felt and Allison Carter | Illustrations by Harriss Callahan and Monet Fort | Published Feb. 14, 2019
[Disclaimer: No implements presented in this article are currently available for patient treatment.]
y this time tomorrow, your heart will have beaten 100,000 times. In an average lifetime, that’s 2.5 billion full contractions. The heart is the first organ that forms in the embryo, and life ultimately ends with its last beat.
“It’s an amazing electromechanical pump that keeps on going in some people for 60, 70, or 80 years without needing a single repair. I can’t think of any human-made device, be it a valve, a pump, or anything, that can do that without breaking down,” said Ajit Yoganathan, a Regents Professor at the Georgia Institute of Technology and a cardiology researcher for more than 40 years.
“Obviously, though, in some cases, things do go wrong with the heart, but like any living system, it has self-repair mechanisms. It can rebuild itself after a heart attack,” Yoganathan said.
Killer No. 1
Yet, heart disease remains the number one killer, taking 610,000 lives a year. That’s more than number two, cancer, and in the United States, more than the next five causes of death combined, according to figures from the Centers for Disease Control and Prevention.
CDC Deaths and Mortality in the U.S. Data source: Centers for Disease Control and Prevention
Long-term, researchers at Georgia Tech and Emory University are exploring the root causes of major heart disorders like blocked arteries, or atherosclerosis, and valve impairment. But more immediately, translational researchers are engineering methods to detect and fix the damage that heart disease is doing.
“Some underlying heart diseases may never be eliminated, but we can delay them and extend life,” said Yoganathan, who has been a key facilitator at Georgia Tech in translating cardiological research into possible patient benefits, particularly in cooperation with Emory in their jointly run Wallace H. Coulter Department of Biomedical Engineering.
Researcher Vahid Serpooshan sets up a medical 3D printer that will print a patch engineered to strengthen heart muscle damaged in a heart attack. (Photo by Rob Felt, Georgia Tech)
6 medical advancements
Here, engineers, scientists, and doctors present emerging cardiological solutions that have the potential of one day reaching patients.
All of the following cardiological solutions are currently unavailable for patient treatment. They are in preclinical and clinical trials or other human test phases, and if they succeed, it could be years before they are available to patients.
But even if these developments never make it to market, the underlying research is readily accessible and can inspire the improvement of existing or future therapies to save more patients’ lives.
Collagen patch with regenerative protein treats infarcted myocardium
This year, nearly 800,000 people in the U.S. will suffer a myocardial infarction, also called a heart attack. When blood flow is blocked to part of the heart, muscle tissue, or myocardium, dies. Victims may feel nothing, discomfort, or pain like an elephant is stepping on their chest. They usually don’t die immediately, but many do shortly thereafter from heart failure that is sometimes dramatic. “Infarcted tissue lacks mechanical integrity,” said Vahid Serpooshan, an assistant professor in the Coulter Department. “The heart beats so fast, and there’s a chance the scarred tissue will inflate and rupture.”
Serpooshan starts the 3D printer. The screen displays a model of the myocardial infarct patch. (Photo by Rob Felt, Georgia Tech)
Just when the heart needs healing, infarction destroys blood vessels that feed damaged tissue, and it depletes the heart’s outer tissue, the epicardium, of a regenerative protein called FSTL1. The protein then concentrates in the wrong places. “FSTL1 disappears from the epicardium, but it overexpresses in myocardium far away from the infarct area,” said Serpooshan, who with colleagues devised an infarct repair patch when he was at Stanford University. He has furthered its development at Coulter’s Emory location.
Expanding preclinical trials after successful initial preclinicals. “We were able to significantly recover function of the infarct region,” Serpooshan said. “The patch really reduced the scar.” Partners are working in the U.S. and Europe to move the solution toward market. “They’re developing a minimally invasive procedure to apply the patch.”
Before the journal Nature accepted the paper on the patch, it demanded a lot of proof on the rise in number of cardiomyocytes because such robust cardiomyocyte reproduction had previously been unheard of. The use of FSTL1 in the patch hinges on previous research with cardiac cells, which die a few days after application. “Some of their therapeutic effects come from paracrine factors, chemicals they secrete,” Serpooshan said. The researchers skipped straight to the FSTL1 protein, which doesn’t die off.
The tip of the 3D printer lays out a collagen gel that will set to a myocardial infarct patch. (Photo by Rob Felt, Georgia Tech)
Key study: Published in the journal Nature: Epicardial FSTL1 reconstitution regenerates the adult mammalian heart
Major collaborators and funders: Ke Wei of the School of Life Sciences and Technology, Tongji University; National Institutes of Health; the California Institute for Regenerative Medicine; the NIH’s National Heart, Lung, and Blood Institute; the Stanford BioX Interdisciplinary Initiatives Program; the National Science Foundation Nano-scale Science and Engineering Center; the National Basic Research Program of China; and the National Natural Science Foundation of China; special thanks to Dr. Jonathan Langberg of Emory University Medical School for performing trial procedures and to Dr. Mike Davis, also of Emory.
An RNA injection could replace electronic pacemakers
Severely slow heart rhythms threaten many adults, and some babies, who need pacemakers to stay alive. About 350,000 electronic pacemakers are implanted each year in the U.S. “They’re battery-powered generators with wires that lead through a blood vessel to give the heart an electric impulse every second,” said Hee Cheol Cho, an associate professor in the Wallace H. Counter Department of Biomedical Engineering at Georgia Tech and Emory. “They work reasonably well, but they’re invasive and based on 60-year-old technology.”
Researchers Phil Santangelo (l.) and Hee Cheol Cho in a preclinical trial angiocath procedure room at the Global Center of Medical Innovation in Atlanta. (Photo by Allison Carter, Georgia Tech)
Complications can be taxing. “Parts of the device can fail. Patients need periodic major surgery to replace the generator because of battery leakage,” Cho said. It’s a lifetime obligation to maintain an implanted device. And when babies are born with heart conditions that require pacemakers, the ordeal can be soul-crushing. Their bodies are too small to implant the generator, so at first it resides outside the body. The babies grow so fast that they need repeated invasive surgeries to implant the pacemaker in the body then readjust it again and again. “The child faces catastrophic risks during and after each surgery,” said cardiology and stem cell researcher Cho. “Some children realize their lives depend on this machine, and they develop a psychology of fear around it.”
A second round of preclinical trials is planned for 2019. Previous tests were promising. “We’ve been fortunate that this was successful right out of the gate,” Santangelo said.
Cho, then at Cedars-Sinai’s Smidt Heart Institute, discovered the TBX18 gene’s ability to reprogram heart muscle into a pacemaker. His team used an augmented virus, a viral vector, to deliver TBX18 DNA into the heart wall, but there was a snag. “Viral vectors are good research tools but not plausible in therapeutics. The immune system attacks them,” Cho said. “The mRNA hardly triggers any immune reaction,” Santangelo added, “and it works transiently, which is great for this application where you don’t need permanent gene expression.”
Major funders and collaborators: Particular thanks to Emory’s Director of Cardiac Electrophysiology Jonathan Langberg, who is collaborating in preclinical procedures.
Pieces for the implantation of current mechanical pacemakers. They work reasonably well but come with significant risks and require repeated invasive procedures to maintain. The new mRNA injection could someday replace this. (Photo by Allison Carter, Georgia Tech)
Stem cell injections may strengthen babies’ hearts as they face multiple life-saving cardiac operations
Babies born without a left side of the heart have what’s called hypoplastic left heart syndrome. “If they don’t have surgery within a week, they’ll die,” said Michael Davis, an associate professor at the Coulter Department's Emory location. “They get three surgeries over the course of three years to re-route all their blood through their right heart, because it’s the only ventricle they have.”
Researchers Manu Platt and Michael Davis in a patient room at Children’s Healthcare of Atlanta. (Photo by Allison Carter, Georgia Tech)
“That puts a lot more stress on that ventricle, and it can fail,” Davis said. “If children survive, the condition can keep them from playing freely, or they can develop neurological deficits.” To make things worse, there are particular hurdles to getting new treatments to market for these babies. “There are only a couple thousand patients a year, so they don’t constitute much of a patient group. By contrast, there are about 800,000 adult heart attacks a year and thus many more patients to market a new therapy to,” said Davis, who is based at Emory.
Phase I clinical trials are scheduled for winter 2019 at Children’s Healthcare of Atlanta.
Not all stem cells do a great job, so, in the lab, Platt had to find those that did. “We identified stem cells carrying microRNAs that robustly improved heart tissue,” he said. MicroRNAs regulate gene expression mostly to decrease the production of some proteins and increase production of others. “I used data mining to locate particularly helpful microRNAs,” Platt said. Starting with thousands of them, his team was able to narrow the range to a few dozen microRNAs, making the selection of effective stem cells easier. The researchers also found that treating the cells with hypoxia — strategically depriving them of oxygen — got the most robust response from heart tissue the cells were injected into.
Major funders and collaborators: The Betkowski Family Research Fund; the Darryl M. Ceccoli Research Fund; clinical trials will be funded by the Marcus Foundation.
Michael Davis is also the associate chair for Graduate Studies and director of the Children's Heart Research and Outcomes (HeRO) Center, a research collaboration with Georgia Tech, Emory, and Children’s Healthcare of Atlanta.
Effective atrial fibrillation medication delivered without its high toxicity
Most patients admitted to the hospital with heart problems have atrial fibrillation (a-fib) as at least one of their ailments. “I would say nearly 80 percent,” said Rebecca Levit, physician and assistant professor of cardiology at Emory. A-fib occurs when the atria quiver or beat irregularly. People tend to develop the disorder as adults and then live with it for a long time. But a-fib can cause dizziness, fatigue, shortness of breath, stroke, heart failure, and death.
“A-fib has a lot of causes, so there’s not just one thing you can fix,” said Levit, who is also a member of the Coulter Department. The anti-fibrillation drug Amiodarone, in use since the 1980s, has proven the most effective therapy. “Many other drugs were tested but just don’t work as well. Some were even found to be dangerous,” Levit said. But Amiodarone has a big drawback: It’s toxic to liver, lungs, and thyroid. “Less than 1 percent of the drug goes to the heart when it’s given as a pill or infusion. The rest builds up in high concentrations in these off-target organs,” Levit said. And that increases the risk of death.
Researchers Andres García and Rebecca Levit in García’s lab at Georgia Tech. (Photo by Allison Carter, Georgia Tech)
One-month-long preclinical trials were successful, and the team wants to extend them. If the therapy moves to clinical trials, it will have the advantages of hydrogels’ long safety record and the fact that pericardial catheterization is an established medical procedure. Also, Amiodarone is an FDA-approved drug.
Hydrogels are made mostly of water, and Amiodarone is hydrophobic, so embedding it in the gel was challenging. “A hydrogel is also a molecular network, or net, so we found the answer by clustering the Amiodarone into large chunks and making the net’s mesh tight enough to hold them,” García said. The Amiodarone chunks slowly break up and the drug enters the tissue, and then the gel bio-decays.
Major funders and collaborators: The Wallace H. Coulter Foundation, Georgia Research Alliance
Andrés García is also a Regents Professor in the George W. Woodruff School of Mechanical Engineering, and Rae and Frank H. Neely Chair in Mechanical Engineering.
A minimally invasive heart catheter procedure places the medication in a targeted location, preventing its spread through the body and minimizing side effects. (Photo by Allison Carter, Georgia Tech)
Researchers are working toward a wearable seismocardiography that alerts patients and doctors when it’s time to adjust congestive heart failure medications
Five million Americans suffer from congestive heart failure, in which fluid backs up in the body — commonly the lungs, legs, or hands — because the heart is not pumping enough blood. Patients battle the ups and downs of fluid congestion by adjusting their medications. Increasing diuretic meds at the right time to make patients excrete excess water is crucial, since worsening congestion can become fatal.
Currently, a lot of in-patient observation is required. “Hospitalizations for congestive heart failure are frequent and very costly. They’re one of the highest Medicare costs,” said Omer Inan, an associate professor in Georgia Tech’s School of Electrical and Computer Engineering. “Being in the hospital every three months also dramatically reduces a patient’s quality of life. They go home, get full of fluid again, can’t breathe and have to go back to the hospital for two more weeks.”
Inan and his collaborators have completed promising studies on roughly 70 patients. Only one had to be readmitted to the hospital during test phases. Researchers benchmarked seismocardiography with right atrial pressure measurement, which is the gold standard of heart failure testing but also invasive.
A researcher in Omer Inan’s lab demonstrates the positioning of the wearable seismocardiograhy. (Photo by Rob Felt, Georgia Tech)
The seismic sensor, made with the most sensitive commercially available accelerometer, picks up tiny vibrations. “We had a technical challenge because the waves coming from patients with heart failure are weaker and often the patients are overweight, so there’s more soft tissue that dulls vibrations coming from the heart,” Inan said. A machine learning tool called graph mining takes the huge, noisy dataset and creates a more orderly indicator that alerts researchers and doctors to questionable states of a patient’s heart congestion.
Key study: Novel Wearable Seismocardiography and Machine Learning Algorithms Can Assess Clinical Status of Heart Failure Patients, in the journal Circulation: Heart Failure
Major funders and collaborators: National Heart, Lung, and Blood Institute (R01HL130619); Maziyar Baran Pouyan, Abdul Javaid, Alexis Dorier, and Ozan Bicen of Georgia Tech; Sean Dowling, Shuvo Roy, Teresa De Marco, and Liviu Klein of the University of California San Francisco; and Mozziyar Etemadi and Alex Heller of Northwestern University.
Frontline detection of coronary artery disease at a fraction of the cost via seismocardiography and a CT scan
Coronary artery disease (CAD) often sneaks up on its victims, who are unaware they have it until a heart attack strikes. Some segments of society suffer more from it. “African-Americans are particularly likely to die of CAD and urgently need early detection,” said Pamela Bhatti, an associate professor in Georgia Tech’s School of Electrical and Computer Engineering.
Research team members Jingting Yao (l.), Pamela Bhatti, and Srini Tridandapani (r.) place ECG electrodes and an accelerometer on the chest of a person positioned in a CT scanner. (Photo by Rob Felt, Georgia Tech)
The best diagnostic tool for early detection is a coronary angiogram, but the cost of up to $30,000 is prohibitive, especially for the uninsured. Some patients may also fear the procedure. “It’s invasive,” Bhatti said. “A catheter comes up through an artery, through the aorta and into the heart and injects a mildly toxic dye.” The risk of complications is low but enough to scare some patients off. Computed tomography, or CT, scans, at about $2,000, offer less costly, faster, non-invasive diagnostics. They can act as prescreens to determine if an angiogram is even necessary, which is usually not the case. But the heart is almost always in motion, and by the time a technologist can snap a good CT image of the coronary arteries, the scanner can expose the patient to three times as much radiation as an angiogram.
The accelerometer used in these tests is high-end but commercially available, which helps make this new procedure effective but also cost-effective. (Photo by Rob Felt, Georgia Tech)
Testing on human patients has shown the method to significantly raise CT heart scan precision.
Angiograms remain the best diagnostic tool, but seismo-CT could bring CAD diagnostics to those for whom the cost is prohibitive. It could also extend scans more often to older patients. “As we age, we have more anxiety about what’s happening with us, and this provides a perhaps less daunting way of assuring that things are fine or seeing if we need a more extensive test,” said Srini Tridandapani, formerly a researcher at Emory and currently a professor at University of Alabama Medical School. He is principle investigator alongside Bhatti. “Further development could bring radiation exposure down to that of an angiogram,” Tridandapani said.
Key studies: An Adaptive Seismocardiography (SCG)-ECG Multimodal Framework for Cardiac Gating Using Artificial Neural Networks (forthcoming); Seismocardiography-Based Cardiac Computed Tomography Gating Using Patient-Specific Template Identification and Detection
Major funders and collaborators: National Science Foundation (CAREER ECCS-1055801), National Center for Advancing
Translational Sciences of the National Institutes of Health (UL1TR000454), National Institute of Biomedical Imaging and Bioengineering
(K23EB013221), Jingting Yao of Georgia Tech; William Auffermann, MD, of University of Utah School of Medicine; Carson Wick of Camerad Technologies.
For media inquiries, contact Ben Brumfield, firstname.lastname@example.org