Research at the Heart Institute

At Children's Hospital Colorado, we believe that every child deserves to have a happy, healthy future. Child health research and innovation is at the core of our commitment to deliver the best clinical care for kids. With each patient we see in the Heart Institute, our physicians and caregivers seek to improve outcomes and deliver world-class care.

Cardiology and heart surgery advancements

Single ventricle heart conditions

Our multidisciplinary team of pediatric subspecialists are advancing our understanding of how the Fontan circulation affects quality of life, school performance and development, as well as its impact on other organs in the body.

• As one of the first dedicated multidisciplinary clinics for children and adolescents with Fontan circulation, our team described how we created the clinic, what sort of issues our screen protocol uncovered and what interventions we recommend.
• Because achieving developmental milestones and maximizing school performance are so highly linked to quality of life, we were among the first to explore and describe the relationships between physiologic and neuropsychologic functioning.
• Our team has partnered with the bioengineering department to use cardiac MRI to evaluate the Fontan circulation and associate patterns of flow propagation with clinical outcomes, hoping to one day use MRI as a way to predict adverse events.

The doctors, scientists and nurses in our Pediatric Cardiovascular Research Laboratory perform basic and translational research that enhances understanding of the mechanisms underlying pediatric heart failure and identifies unique age- and disease-specific diagnostic, prognostic and therapeutic approaches that will improve outcomes.

The focus of our work is on the two most important causes of heart failure in children: dilated cardiomyopathy and single ventricle congenital heart disease (CHD), such as hypoplastic left heart syndrome. We are uniquely positioned to perform this research at the University of Colorado and Children’s Colorado through the use of our extensive bank of human heart tissue.

Our team works to help children live longer, return sooner to normal childhood activities, and have fewer medication side effects and complications. Research efforts to improve outcomes and quality of life for the children we care for include:

• The TEAMMATE trial, a first-of-its-kind immune suppression study in pediatric heart transplant recipients examining the effect of lower dose immune suppression medication compared to standard dosing
• Cutting-edge medication trials, including the recent trial pediatric heart failure PANORAMA-HF trial, which led to a new medication approved for use in children with heart failure symptoms and poor heart function
• Clinical outcomes studies through participation in large, multicenter learning collaborations such as the Pediatric Cardiomyopathy Registry (PCMR), ACTION (Advanced Cardiac Therapies Improving Outcomes Network) and the Pediatric Heart Transplant Society (PHTS)
• The Improving Heart Transplantation Outcomes with Sphingosine-Targeted Therapies study, which is investigating novel organ perfusion strategies in an effort to prevent graft injury following donation
• A recent study that sought to investigate myocardial CL content and composition in failing and nonfailing single right ventricle (RV) samples compared with normal control RV samples, to assess mRNA expression of CL biosynthetic and remodeling enzymes
• A review article presenting a brief overview of SV anatomy and physiology, discussion of outcomes in the current era, risk factors associated with the progression to heart failure, present state of knowledge regarding molecular alterations in end-stage SV heart failure and current therapeutic interventions

• The CICU team has run an international survey on the use of vasopressin in patients with single ventricle CHD and is finalizing two clinical studies on the use of vasopressin in this patient population.
• The CICU team is also finalizing a study that aims to develop a predicting clinical score for postoperative patients and understand its relation to outcomes.
• Thanks to the C.A.R.E. project to prevent cardiac arrest that our CICU team implemented, we now have the lowest national incidence of these events.
• Katja Gist, DO, is one of the national leaders and principal investigator in the prevention and management of acute kidney injury.
• Robert Bishop, MD, is a co-principal investigator in multicentric research on high-fidelity simulation.
• Our CICU team continues to run clinical research projects on nutrition and outcomes.

Kawasaki disease (KD) is the number one acquired heart disease in the developed country. Our Kawasaki Disease Clinic is a multidisciplinary clinic between the Heart Institute and our Infectious Disease Program. The collaboration between these two departments has enabled us to take a unified approach in taking care of these patients and improved our treatment plan for KD patients. We are actively involved in the following KD research to help improve patient quality, management and outcomes:

• Participation in the American College of Cardiology Quality Network (ACC QNet) to improve outpatient quality metrics in taking care of KD patients
• American Heart Association-funded grant to study microRNA in distinguishing KD from other febrile illness; a study that has helped us differentiate KD and other febrile illness from childhood
• International Kawasaki Disease Registry (IKDR): collection of data on outcomes in KD coronary artery aneurysms and medical management.
• Kawasaki Disease Comparative Effectiveness (KIDCARE) Trial: a randomized trial of second intravenous immunoglobulin versus infliximab for resistant KD

Multisystem inflammatory syndrome in children (MIS-C) is a severe multisystem hyperinflammatory illness temporally associated with preceding severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection or exposure. Patients have cardiac dysfunction and coronary artery dilations or aneurysms similar to KD patients. Our research has demonstrated that MIS-C patients have better recovery and outcomes after receiving dual therapy (intravenous immunoglobulin and infliximab) at diagnosis. MIS-C patients are less likely to require additional therapy, have decreased development of heart dysfunction, have a more rapid decline in inflammation, and have a decreased intensive care unit length of stay.

Pei-Ni Jone, MD, is the Children’s Colorado site principal investigator in enrolling MIS-C patients into the two national clinical trials:

• Characterization of Multisystem Inflammatory Syndrome in Children and its Relationship to Kawasaki Disease (CHARMS study)
• Long-Term Outcomes in Multisystem Inflammatory Syndrome in Children (MUSIC study)

A review article on cardiac manifestations of COVID-19 and MIS-C is found on the American Heart Association Scientific Statement. Our team will also be participating in the multicenter observation study: The RECOVER Post Acute Sequelae of SARS-CoV-2 (PASC) Pediatric Cohort Study.

Our researchers are actively involved in interventional cardiology research that enables us to provide advanced treatment options to our patients. Because we believe that all children should benefit from our research insights, we collaborate with and share our expertise with pediatric experts across the country.

• Our 3 core attending physicians are authors on 29 peer-reviewed manuscripts over the last 18 months.
• We are among the leading study recruiters in four multicenter trials for cutting-edge equipment and procedures. We have access to all FDA-approved and in-trial percutaneous pulmonary valve devices in the United States. We have also been designated as a pulmonary valve center of excellence by Edwards’ life sciences.
• We are currently submitting manuscripts based on the use of VR in cath lab case planning; the use of percutaneous ECMO for rescue therapy due to COVID-related illness. We have developed and are publishing on risk benefit scoring for pediatric and ACHD interventional procedures.
• We are developing novel methods to minimize risk and procedural complexity in percutaneous valve implantation and the use of novel techniques to assess flow dynamics in congenital heart disease.
• We are hosting a major in-person international conference on interventional cardiology in Denver in December 2021 with a faculty of over 70 expert surgical and interventional key opinion leaders.

Our laboratory resources:

• We have the only in-house 3D printing workshop based on interventional angiography in the country. We have a flow dynamics and valve and stent bench testing lab on campus and are linked with the biomedical engineering school on a number of undergraduate and postgraduate student projects. We have had 14 scientific abstracts accepted for publication at major national and international conferences in 2021.
• We have a dedicated flow dynamics lab with an aim to minimize the need for animal and human testing by simulating complex congenital physiology on a benchtop.

Heart rhythm care for patients with CHD

Children and adults with CHD require specialized techniques to manage their unique heart rhythm abnormalities. Our electrophysiology team has led the way in developing novel strategies to diagnose, treat and manage these complex patients.

• Using machine learning and collaboration with biomedical engineering, our team has sought to discover subtle clues that can predict the onset of diastolic dysfunction and potentially prevent the development of sudden cardiac death or progressive cardiac disease.
• We were the primary international center that evaluated the subcutaneous implantable cardioverter defibrillator (SICD) in those with CHD. This novel device allows for the recognition and treatment of life-threatening arrhythmias without the need to enter the heart.

Genetics

Cardiovascular genetics is a new and rapidly evolving field within pediatric cardiology. Our active research programs are focused on several projects, including genetic contribution to heart failure in dilated cardiomyopathy and hypoplastic left heart syndrome, the role of genetic diagnosis in heart transplant patients, and outcomes of multidisciplinary care in Turner syndrome. In addition, our program is investigating the role of disease-specific treatment of cardiac, vascular and lymphatic disease in RASopathy disorders.

Advanced cardiac imaging

The advanced cardiac imaging team, made up of cardiologists, radiologists and bioengineers, has been developing new techniques and novel frameworks for understanding acquired and congenital heart disease in innovative and clinically useful ways. We have made major advancements in understanding single ventricle heart disease and pulmonary hypertension:

• In single ventricle heart disease, our team has been able to use cardiac MRI to link ventricular dyssynchrony, aortic arch geometry and flow propagation through the body to important clinical outcomes. This provides important insights into how CMR could be used to help predict adverse outcomes.
• In children and adolescents with pulmonary hypertension, our team has used a combination of 2D, 3D and 4D imaging based on echocardiography and cardiac MRI platforms to validate new ways to measure the many facets of cardiac muscle function. Following these metrics over time helps us identify patients at risk for acute events before they happen.
• Pre-surgical planning of congenital heart disease using 3D echocardiography has advanced our understanding of heart valve repairs and complex surgical baffle repairs for complex congenital heart disease. We are the primary research site for the 3D consortium in the nation and a leading site within the industry to develop pediatric 2D and 3D ultrasound probes.
• 3D echocardiography-guided catheter interventions in congenital heart disease has reduced radiation use. Our team uses fusion imaging to reduce the amount of radiation exposure of our congenital heart disease patients and we are the leading research program in developing this advanced fusion imaging tool to better understand congenital heart disease and structural heart interventions.

Congenital heart disease research

Children’s Colorado is a national leader in CHD research and a member of Cardiac Networks United, a group of collaboratives aimed at improving the outcomes of patients with congenital and acquired heart disease. These collaboratives include:

• Pediatric Cardiac Critical Care Consortium (PC⁴)
• Pediatric Acute Care Cardiology Collaborative (PAC3)
• Cardiac Neurodevelopmental Outcomes Collaborative (CNOC)
• National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC)
• Advanced Cardiac Therapies Improving Outcomes Network (ACTION)
• PediPERForm Learning Network (PLN)
• HLHS Consortium
• Pediatric Heart Network
• STeroids to REduce Systemic inflammation After Neonatal Heart Surgery (STRESS trial) Study

Through our work in these multi-institutional collaboratives, we have helped improve the care of with CHD, not only at Children’s Colorado, but across the nation. Our work in these networks has allowed us to identify practice variation between centers and best practices for diagnosis, treatment and prevention of morbidity and mortality.

Through our participation in the Cardiac Networks United, we have successfully decreased our cardiac arrest rate, decreased postoperative chest tube duration, improved outcomes for our single ventricle population and improved outcomes for our patients with ventricular assist devices. We are currently participating in multicenter quality improvement initiatives to:

• Identify and improve health care equity and decrease disparities
• Decrease emergent transfers from the acute care unit to the cardiac intensive care unit
• Define best practice for treatment of chylothorax
• Implement programs in the early postoperative period to enhance long-term neurodevelopmental outcomes

What our heart research means for kids

The Heart Institute is actively engaged in research to determine the best ways to take care of children with congenital or acquired heart disease. There are approximately 75 research studies occurring within the Heart Institute with more than half that are actively enrolling. These studies range from examining cells in the heart to clinical trials of new medications or devices used to treat heart problems in kids.

Funding for the Heart Institute research portfolio comes from many different sources These sources include grants from the National Institutes of Health, American Heart Association and other research organizations, industry departments, internal awards and from the department itself. The Heart Institute is eternally thankful for all the children and families who choose to participate in research. Without them, we would not be able to learn the best ways to take care of kids with congenital or acquired heart disease.