When a heart transplant occurs at the University of Colorado Anschutz campus, an outsider might think the patient’s diseased, explanted heart is no longer needed and should be discarded — but for researchers, the opposite is true. These hearts may hold answers to lingering questions of how the disease occurs and ways to improve treatments, which is why a team of clinicians and investigators regularly collaborate, with patient permission, to collect blood and tissue samples during transplant procedures.
Many of these samples are frozen and stored in the pediatric and adult cardiac tissue and blood biobanks, which are overseen by faculty in the Division of Cardiology at the CU Anschutz Department of Medicine and the CU Anschutz Department of Pediatrics. More than 1,400 heart samples and 500 blood specimens have been stored in the adult biobank, making it one of the largest adult cardiac tissue biobanks in the United States. The pediatric bank holds nearly 500 pediatric tissue samples and over 2,000 blood specimens.
“The biobank accelerates our research because it provides high-quality human biospecimens linked to clinical data. This allows investigators like me to ask precise questions that, over time, lead us to a better understanding of the disease and implement more targeted therapies to improve patient care,” says Benjamin Kopecky, MD, PhD, an assistant professor of cardiology who, along with cardiologist Amrut Ambardekar, MD, co-leads the adult blood and tissue biobank.
The biobank samples have been instrumental to researchers like Kopecky, who focus on conditions affecting adults, and investigators who focus on children, such as Kika Sucharov, PhD, a professor of cardiology and director of the Pediatric Cardiovascular Research Laboratory.
“By doing these experiments, the discoveries we’ve made in the lab have helped move science forward,” Sucharov says.
Kika Sucharov, PhD, and Benjamin Kopecky, MD, PhD, are helping advance critical research on heart failure at the CU Anschutz campus. Image by Christina Patsiokas of Green Lion Images.
The biobanks would not exist without the collaboration of clinicians — including transplant cardiologists, cardiac surgeons, anesthesiologists, and pathologists — as well as researchers, staff, and patients at CU Anschutz, UCHealth, and Children’s Hospital Colorado, Kopecky explains.
The process starts with a clinical trials team that meets with patients, as well as their guardians if the patients are minors, to inform them about the biobank and ask if they are interested in donating samples.
“They explain that this biobank is a repository for us to collect and store biological samples as well as clinical information, but all of this information is secure and de-identified so that patient confidentiality is preserved,” Kopecky says. “These contributions from patients are incredibly valuable. We are so grateful, because they are essential to improving outcomes and developing the next generation of therapies.”
If a patient agrees, then after their heart donor has been secured, a biobank procurement team is contacted. The team coordinates with the transplanting team and operating room staff so they can be present to collect cardiac tissue from the explanted heart and blood samples.
“The samples are cryopreserved, meaning they are frozen indefinitely,” Kopecky says. “This preserves the integrity of the information we can learn from these samples.”
The biobank was established in the 1980s by Michael Bristow, MD, PhD, a former cardiology division head who, using resources from the biobank, helped pioneer the use of beta blockers as a first-line therapy for patients. Due to the longstanding history and proactive procurement of tissues, researchers now have access to a diverse array of samples, including those of rare diseases.
“There is so much variability in humans, and the only way we can really discover the causes of diseases or changes that happen in people’s hearts is by evaluating more samples,” Sucharov says. “That is why the biobank is so important.”
Researchers use samples from the cardiac tissue biobanks to conduct research at CU Anschutz. Image by Christina Patsiokas of Green Lion Images.
As a physician-scientist, Kopecky conducts research while simultaneously caring for patients.
“Heart failure is very complex. We do not have all the answers, and we cannot take a one-size-fits-all approach to therapy,” he says. “Biomedical research directly informed by human biology can improve our patient-centered approach and outcomes.”
Kopecky specializes in advanced heart failure and transplant cardiology, helping patients whose hearts can no longer pump efficiently. These patients may receive advanced therapies such as a mechanical circulatory support device or a heart transplant.
His work is multidisciplinary, as he collaborates with other physicians, advanced practice providers, and staff members to support patients before and after their procedures.
“We provide care before and after heart transplantation. After a transplant, we carefully monitor their immunosuppressive medications. These medications prevent transplant rejection, but they can also cause many side effects,” he says.
Kopecky says his patients inform his research by revealing potential gaps in knowledge. His translational lab aims to understand the biological mechanisms of heart failure and heart transplant rejection. A priority is to learn how the immune system specifically impacts the heart, particularly looking at the interactions between immune and stromal cells (cells that make up types of connective tissues).
“One of the strengths of being a physician-scientist is having a hand in each of these realms. I can turn lessons learned from patient care into an opportunity for discovery,” he says. “When a question arises from treating patients, I have access to biobank samples that fuel investigations. This research can lead to new hypotheses with the ultimate goal of developing new therapies or therapeutic approaches that can improve our care for patients.
“It’s a continuous feedback loop — from bedside, to bench, back to bedside.”
The biobank has also inspired and helped train potential future physician-scientists. Ambardekar says that numerous trainees of all levels (including undergraduate students, graduate/medical students, and post-doctoral and clinical fellows) as well as junior faculty have collaborated on projects from the biobank.
“Their experience has resulted in successful future academic careers,” Ambardekar says. “In addition, we have had many professional research associates over the years work with us who have subsequently gone on to medical school and graduate school.”
Blood samples and cardiac tissues from explanted hearts are cryopreserved at CU Anschutz for researchers to analyze. Image by Christina Patsiokas of Green Lion Images.
The pediatric biobank has helped researchers answer questions that cannot be explored through adult studies alone.
Although the prevalence of heart failure in children is relatively low, research shows there is a high rate of associated morbidity and mortality. Heart disease can impact children differently than adults, but many current treatment approaches are based on clinical trials involving adults. It underscores the importance of investigations by the Pediatric Cardiovascular Research Laboratory.
Sucharov, whose research career began in her home country of Brazil before she moved to the U.S., co-directs the lab along with Shelley Miyamoto, MD, chair of pediatric cardiology at Children’s Colorado, and Brian Stauffer, MD, chief of cardiology at the Denver Health Medical Center. Miyamoto was the original principal investigator of the pediatric tissue bank, which is now under the oversight of Stephanie Nakano, MD.
The lab began with an investigation into why beta blockers, which helped adults with heart failure, did not provide the same improvement in pediatric patients. Sucharov and her colleagues found that the beta-adrenergic system was different in pediatric patients, which helps explain why response to therapy is different in children and adults.
“That’s where the biobank came in,” Sucharov says. “We used samples to investigate what occurred in pediatric hearts compared to adult hearts to explain those different responses. That study was just the beginning.”
A close-up visual of the different tools used by cardiology researchers at CU Anschutz. Image by Christina Patsiokas of Green Lion Images.
The multidisciplinary lab now has over 10 members and multiple ongoing projects. One of their many important discoveries was finding that children with heart failure do not experience cardiac overt fibrosis (buildup of scar tissue in the heart muscle) while adults do.
“Even though the fibrosis is minimal, the pediatric hearts are still very stiff, so now we’re trying to understand what causes this stiffness,” she says. “By doing this, we may be able to target that stiffness instead of relying on drugs intended to treat fibrosis.”
Lab researchers are also investigating single ventricle heart disease, where patients are born with only one ventricle and need three stages of surgery to establish systemic circulation. However, surgery is not always successful, and some of these patients develop heart failure.
“Investigators are examining the role of mitochondria, because mitochondria in heart failure are dysfunctional,” Sucharov says.
Through a close collaboration with Children’s Colorado, the lab receives a fresh — not frozen — piece of the explanted heart following a transplant. The lab has a machine that can measure the function of mitochondria in this fresh tissue. This allows investigators to test different drugs that target the mitochondria and assess if there are ways to improve mitochondrial function in hopes of preventing heart failure.
“Overall, the intent is to develop more specific treatments,” Sucharov says. “Securing funding for this type of pediatric research can be challenging. What we have at CU Anschutz is rare because our resources are extensive.”
Researchers frequently collaborate to analyze and study the cardiac tissue samples from the biobanks at CU Anschutz. Image by Christina Patsiokas of Green Lion Images.
As part of a research program sponsored by the National Institutes of Health, cardiology professors Luisa Mestroni, MD, and Matthew Taylor, MD, PhD, used biobank samples to study genetic cardiomyopathy, a heart muscle disease that limits the ability of the heart to pump properly.
Because of their research, genome sequencing — a process of determining the exact genetic makeup and DNA sequencing of an organism — was performed on hundreds of biobank samples that did not have genetic cardiomyopathy according to traditional testing methods. However, the sequencing led them to “identify new mutations that had not previously been identified,” Kopecky says.
“This does not directly impact patient care yet, but it does tell us that genetic cardiomyopathy is more prevalent than what our clinical testing would suggest. It also allows us to identify specific pathogenic mutations,” Kopecky says. “Through their work, we can potentially identify different genetic mutations, examine if they can be addressed before transplant surgery, and explore whether gene therapy may help.”
Taylor says that in addition to genetic sequencing of DNA, the researchers have an NIH-funded program to complete RNA sequencing and proteomics (protein studies) on roughly 1,000 hearts. Additional studies of methylation and metabolomics are also planned.
“This work has generated over a dozen collaborations, and the de-identified data are also available to other NIH researchers, which extends the reach and impact of the data from the patients who support the tissue bank,” Taylor says.
DNA sequencing has also been important in Sucharov’s lab. From the pediatric biobank, she and her colleagues identified tissues that had genetic mutations. Then, they separated those tissues by the type of mutation — if the mutation was in the ability of the heart to contract or if it was within the structure of the heart itself. This separation is important, she explains, because the cells appear to be different depending on the mutation type.
“The only reason we can even ask these questions is because we have so many samples in our biobank,” she says. “We’re finding a lot of interesting differences that I believe, once we put all of this together, should inform how to best treat these patients depending on the mutation they have.”
Given the complexity of heart disease in adults and children, identifying and implementing new treatment approaches takes time. Sucharov and Kopecky hope that the incremental steps they are taking today will lead to life-changing interventions for future generations.
“All of these discoveries, large and small, lay the foundation for future studies,” Kopecky says. “It builds upon the work we’ve done, all toward the goal of impacting and improving patient care.”