Among all known birth defects, congenital heart disease (CHD) is the leading cause of death in infants. Fortunately, advances in surgical techniques and treatments are improving the outlook for these children, and more and more are reaching adulthood. However, because of this increased longevity, it has become increasingly clear that children born with CHD are at risk of developing life-long neurological deficits. Several risk factors for these neurodevelopmental abnormalities have been identified, but direct links between specific factors and neurological defects have yet to be established.
In a recent review article published in Circulation Research, a team from Children’s National Health System summarized what is currently known about how CHD affects brain maturation. Drawing from studies conducted at Children’s National as well as other research institutions, Paul D. Morton, Ph.D., Nobuyuki Ishibashi, M.D., and Richard A. Jonas, M.D., write that clinical findings in patients, improvements in imaging analysis, advances in neuromonitoring techniques and the development of animal models have greatly contributed to our understanding of the neurodevelopmental changes that occur with CHD.
Findings from Children’s National include:
The authors conclude that although there is ample clinical evidence of neurological damage associated with CHD, there is limited knowledge of the cellular events associated with these abnormalities. They offer perspectives about what can be done to improve our understanding of neurological deficits in CHD, and emphasize that ultimately, a multidisciplinary approach combining multiple fields and myriad technology will be essential to improve or prevent adverse neurodevelopmental outcomes in individuals with CHD.
Questions for future research
Q: What are the cellular events associated with each factor involved in neurodevelopmental delays?
Source: Norton, P.D., Ishibashi, N., Jonas, R.A. “Neurodevelopmental Abnormalities and Congenital Heart Disease: Insights Into Altered Brain Maturation,” Circulation Research (2017) 120:960-977.
Cardiology and Heart Surgery
The five-year survival rate for pediatric cancers has climbed to nearly 82 percent, but the damaging, long-term side effects of rigorous treatment are prevalent. Cardiac toxicity, specifically the association of several cancer therapy agents with the development of left ventricular dysfunction, cardiomyopathy, dysrhythmia, valve disease and hypertension, is an issue of growing concern. Cardiac complications are the third leading cause of death for childhood cancer survivors, only after cancer recurrence and secondary malignancy. Cardiac mortality is 10-fold higher among this population as compared with age-matched control subjects.
The American Heart Association released a statement in 2013 pointing to the need for closer monitoring of cardiac affects from cancer treatments. Craig Sable, M.D., Associate Division Chief of Cardiology at Children’s National, co-authored the statement titled “Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions.” The statement concluded that it is crucial to develop an optimal monitoring regimen for this specific subgroup of patients, affirming: “As clinicians continue to learn about the cardiovascular effects of cancer treatment, the importance of primary prevention becomes abundantly clear. The objective of effective monitoring is to identify signs of cardiac disease early enough to potentially prevent, reverse, or slow the deterioration of the structure and function of the heart. We must tailor therapies to decrease the risk of cardiotoxicity while balancing the beneficial effects of the cancer therapy.”
The American College of Cardiology also launched a Cardio-Oncology section dedicated to the subspecialty and noting the need for increased and closer cardiac monitoring for cancer patients. Cardiologists and oncologists at Children’s National came together to address this issue by formalizing a multidisciplinary path of care for patients with malignancies as they enter the care system.
Multidisciplinary care from point of diagnosis
In response to the outstanding need for cardiac observation and follow-up care for cancer patients, Children’s National developed a Cardio-Oncology Program in 2011 to closely follow the heart health of oncology patients to detect and stop progression of heart disease. Led by Niti Dham, M.D., the cardio-oncology program within the Division of Cardiology includes the Cardiology Oncology Blood (COB) Clinic, a special clinic dedicated to pediatric cancer patients. The clinic assesses cancer patients, including bone marrow transplant (BMT) patients, who have been exposed to certain medications or radiation that have shown potential long-term, negative cardiac outcomes. Patients are monitored for any early signs of cardiac changes in hopes to halt or even reverse the disease.
When a child is diagnosed with cancer that requires certain chemotherapies and radiation for treatment, Children’s National oncologists coordinate with Dr. Dham and her team for a cardiac evaluation prior to beginning treatment. Appropriate cardiac screening tests are administered based on the planned cancer treatment regimen. Cardiac health is evaluated regularly throughout the treatment course as well as after completion to continue monitoring for early signs of changes.
“The frequent, close monitoring allows Children’s experts to notice even the slightest differences in the heart, with a goal of preventing progression of cardiac disease,” says Dr. Dham.
The cardiology team works closely with the oncology team through the whole process, alerting them immediately of any changes noted. Together, the subspecialists develop a plan that is safe for each individual patient.
The program also sees patients that have pre-existing cardiac conditions prior to cancer treatments.
“It is tremendously important that we care for the whole child, including each individual health anomaly. Working closely with the oncology team, we try to balance how we treat their cancer at the same time as managing their heart disease,” says Dr. Dham.
New research from Children’s National Health System scientists might help answer this question. In findings presented at the 2017 annual meeting of the Pediatric Academic Societies, the research team shows that exosomes – nanosized chemical messages that cells send to each other to regulate protein production – isolated from very obese teenage patients behave very differently from those derived from lean patients and could be key players in heightening the risk of developing atherosclerosis. This hardening of the arteries can, in turn, increase the risk of heart disease and stroke in adulthood.
A research team led by Robert J. Freishtat, M.D., M.P.H., chief of emergency medicine at Children’s National, is exploring possible links between extra belly fat and obesity-related diseases, such as atherosclerosis, a buildup of plaque in arteries that can harden and restrict blood flow. More precise knowledge of the mechanisms by which obesity ratchets up heart risks holds the promise of helping the next generation of kids avoid experiencing chronic disease.
The working theory is that exosomes derived from belly fat from obese patients have the distinct ability to accelerate biological processes leading to atherosclerosis.
The research team isolated exosomes from five obese teenagers and compared them to five sex-matched lean adolescents. It turns out that exosomes derived from fat pick up their marching orders from microRNA content likely to target cholesterol efflux genes, which help reduce cholesterol buildup in cells.
The research team looked at differences in cholesterol efflux gene expression in THP-1 macrophages. Uptake of low-density lipoprotein cholesterol, “bad” cholesterol, was 92 percent higher than in those exposed to exosomes from obese patients compared with their lean counterparts. Exposure to obese exosomes also reduced cholesterol efflux.
“Atherogenic properties of fat-cell derived exosomes from obese patients differ markedly from the non-atherogenic profile of exosomes from lean patients. It is especially concerning that we see biological clues of heightened risk in teenagers, and the finding underscores how the seeds for atherosclerosis can be planted very early in life,” Dr. Freishtat says.
The presentation is the latest finding from a research team that, over years of work, is unraveling the mechanisms of cellular signaling by fat cells. By closely examining very obese children – who have the most severe cardiometabolic disease – the team identified strong molecular signals of disease risk that they can search for in leaner patients who may be at risk for disease years from now.
“We know that morbidly obese patients have cardiovascular issues,” explains Dr. Freishtat. “An unanswered question is for patients with no clinical symptoms who are a little overweight. Can we look at them and say whether they are at risk for developing atherosclerosis, insulin resistance or Type 2 diabetes five or 10 years down the line? That’s the whole rationale for doing this work.”
The critical issue is what exosomes are up to. Dr. Freishtat says in lean people, they’re active and are very important in maintaining stable metabolism and homeostatic processes.
“When a person becomes obese, however, exosomes evolve,” he says. “They no longer support insulin signaling, which is helpful, and drive processes in the reverse direction, repressing insulin signaling – which can be harmful,” he adds.
Ultimately, the research team aims to revolutionize how chronic diseases like Type 2 diabetes are diagnosed. For far too long, clinicians have relied on symptoms like high glucose levels and excess urination to diagnose diabetes.
“By the time you have symptoms, it’s too late,” says Dr. Freishtat. “In many cases, damage has been done by relentless exposure to high sugar levels. The biological processes that underlie the Type 2 diabetes process began five, 10, 15 years earlier. If we can detect it earlier, before symptoms arise, intervention is going to have a more significant impact on improving and extending patients’ lives.”
Children’s National Health System is pleased to announce the addition of Can Yerebakan, M.D., and Karthik Ramakrishnan, M.D., to our team of pediatric cardiac surgeons.
Dr. Yerebakan comes to Children’s National from the prestigious Pediatric Heart Center in Giessen, Germany, where he was appointed as an Associate Professor of Cardiac Surgery at the Justus-Liebig-University and performed hybrid treatment of hypoplastic left heart syndrome (HLHS). He was deeply involved in mechanical circulatory support and pediatric heart transplantation in Giessen – a leading center for pediatric heart transplantation in Europe. He also served as Chief of Clinical and Experimental Research in the Department of Congenital Cardiac Surgery at Justus-Liebig-University of Giessen, where he acquired several research grants and contributed to more than 20 abstract presentations at national and international meetings and 20 papers in peer-reviewed journals. . Dr. Yerebakan has published approximately 70 scientific papers with more than 160 impact points in three different languages. He is an active reviewer for journals such as the Journal of Thoracic and Cardiovascular Surgery, European Journal of Cardiothoracic Surgery and serves as assistant editor of the Interactive Cardiovascular and Thoracic Surgery journal and Multimedia Manual Cardiothoracic Surgery journal, both of which are official journals of the European Association of Cardiothoracic Surgery. He has had a distinguished academic career and is internationally recognized for his contributions to the field of congenital cardiac surgery, particularly in the treatment of HLHS and novel surgical treatments for heart failure in the pediatric population. Prior to his tenure at Pediatric Heart Center, Dr. Yerebakan completed his fellowship at Children’s in 2011.
Dr. Ramakrishnan joined Children’s National as a fellow in 2014 after completing his fellowship in congenital cardiac surgery at two major centers in Australia. After his two-year fellowship at Children’s, he joined the faculty. Dr. Ramakrishnan has extensive experience in managing children with congenital heart disease. Apart from routine open heart procedures, he has a special expertise in extracorporeal membrane oxygenation (ECMO) procedures and patent ductus arteriosus (PDA) ligation in extremely premature babies. He also has a keen interest in studying clinical outcomes after pediatric heart surgery. His research projects have included analysis of the United Network of Organ Sharing (UNOS) and the Pediatric Health Information System® (PHIS) databases, and his research has resulted in numerous presentations at national and international meetings. Dr. Ramakrishnan is currently the principal investigator at Children’s National for the Pediatric Heart Transplant Study (PHTS) group and the study coordinator for the Congenital Heart Surgeons’ Society (CHSS) studies. He also is a member of the PHTS working group on the surveillance and diagnosis of cellular rejection, and his clinical studies have resulted in several publications in top peer-reviewed journals.
Drs. Yerebakan and Ramakrishanan join Richard Jonas, M.D., Co-director of Children’s National Heart Institute and Chief of Cardiac Surgery, and Pranava Sinha, M.D., on the Cardiac Surgery attending staff. We look forward to continuing to strengthen our program with the addition of these physicians.
Strokes are common and devastating complications for patients with sickle cell anemia, often leading to severe and lifelong motor and neurocognitive problems for people with this congenital blood disorder. Results of a clinical trial published in 1998 showed that having regular blood transfusions could reduce the risk of having a first stroke by 90 percent in children with sickle cell anemia. Since then, doctors have employed this prophylactic treatment widely. However, blood transfusions can be painful, inconvenient and carry substantial risks themselves — including the potential of blood-borne infections, iron overload and immune-related reactions to blood products. Finding a way to reduce stroke risk without over-relying on blood transfusions could substantially benefit patients with sickle cell anemia.
A team of researchers, including Naomi L.C. Luban, M.D., a Children’s National Health System hematologist and laboratory medicine specialist, tested transfusions against a drug treatment called hydroxycarbamide in a clinical trial to see if the pharmaceutical intervention could reduce strokes at least as well as transfusions. The clinical trial, known as “TCD With Transfusions Changing to Hydroxyurea (TWiTCH),” assigned 60 patients with sickle cell anemia who had abnormally high transcranial Doppler (TCD) flow velocities—a measure of blood flow in the brain that suggests elevated risk of stroke—to receive hydroxycarbamide instead of transfusions. The research team compared the outcomes for these patients with 61 other patients who received standard prophylactic transfusions. Over the 24-month study period, neither group experienced any strokes, although three transient ischemic attacks (a temporary blockage of blood flow in the brain) occurred in each group. These comparable findings suggest that hydroxycarbamide treatment, also known as hydroxyurea, is on par with transfusions for preventing strokes in patients with sickle cell anemia.
Questions for future research
Q: Does hydroxycarbamide offer a long-term way for patients with sickle cell anemia to avoid transfusions?
Source: “Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anemia—TCD With Transfusions Changing to Hydroxyurea (TWiTCH): A multicentre, open-label, phase 3, non-inferiority trial.” Ware, R.E. B. R. Davis, W. H. Schultz, R.C. Brown, B. Aygun, S. Sarnaik, I. Odame, B. Fuh, A. George, W. Owen, L. Luchtman-Jones, Z.R. Rogers, L. Hilliard, C. Gauger, C. Piccone, M.T. Lee, J.L. Kwiatkowski, S. Jackson, S.T. Miller, C. Roberts, M.M. Heeney, T.A. Kalfa, S. Nelson, H. Imran, K. Nottage, O. Alvarez, M. Rhodes, A.A. Thompson, J.A. Rothman, K.J. Helton, D. Roberts, J. Coleman, M.J. Bonner, A. Kutlar, N. Patel, J. Wood, L. Piller, P. Wei, J. Luden, N.A. Mortier, S.E. Stuber, N. L. C. Luban, A.R. Cohen, S. Pressel and R.J. Adams. Published by The Lancet on Feb. 13, 2016.
The world’s leading cardiovascular specialists gathered in Washington, D.C., from March 17-19, 2017, to share the newest discoveries in treatment and prevention at the American College of Cardiology 66th Annual Scientific Session & Expo. Eleven Children’s National pediatric experts presented groundbreaking research and developments from their respective specialties. Gail Pearson, M.D., Sc.D., gave the prestigious Dan G. McNamara Lecture.
In her speech titled “The Future of Congenital Heart Disease Research: Keeping the Patient-Centered Promise,” Dr. Pearson reflected on the progress of congenital heart disease research and shared powerful narratives from patient families, detailing their hopes for the future. She also unveiled what’s on the horizon, including advances in genomics research, a data commons and new approaches for rare diseases. Dr. Pearson is a cardiologist within Children’s National Heart Institute, associate director of the Division of Cardiovascular Sciences, and director of the Office of Clinical Research at the National Heart, Lung, and Blood Institute.
Other highlights from Children’s National presenters include:
- Simple versus Complex CHD: When to Refer to a Specialist?, Ashraf Harahsheh, M.D.
- The Challenge of Anti-coagulation in the Pregnant Patient with Valvular/Congenital Heart Disease and Update on the Management of Adult Congenital Heart Disease, Anitha John, M.D., Ph.D.
- ACC Talk: The IMPACT Registry Can Be Used by Families to Shop for the Best Center, Gerard Martin, M.D.
- Atrial Fibrillation in the Young Athlete: Who is at Risk and How do We Manage This?, Elizabeth Sherwin, M.D.
Pulmonary hypertension (PH), when pressure in the blood vessels leading from the heart to the lungs is too high, is primarily a disease of adults: Patient registries suggest that the mean age of diagnosis is around age 50. However, more and more children are developing this condition, says Chinwe Unegbu, M.D., an assistant professor in the Division of Anesthesiology, Pain and Perioperative Medicine at Children’s National Health System.
Although adults with PH have several different effective treatments, Dr. Unegbu adds, children have few options. One of these is a class of medications known as phosphodiesterase type 5 (PDE-5) inhibitors, which act on molecular pathways that can open up constricted blood vessels. However, some studies have raised questions about the safety of this class of medications, particularly with long-term use of high dosages.
In a new study, Dr. Unegbu and colleagues performed a systematic review of available literature on this class of drugs evaluating their effectiveness and safety for pediatric patients. The review showed that like all medications, PDE-5 inhibitors have some risks. However, Dr. Unegbu says, the review showed that their benefits, including improved echocardiography measurements, cardiac catheterization parameters and oxygenation, far outweigh potential harmful side effects.
“Pediatricians across the nation view the rise in pediatric PH cases with growing concern because the disease can worsen, leading to right ventricular failure and death,” says Dr. Unegbu, lead author of the study. “PH can occur in newborns, infants and children who have a number of health conditions, including congenital heart disease, the most common birth defect among newborns. There are few available treatments for the growing population of children affected by this condition, so it is heartening that the evidence supports PDE-5 inhibitors for patients with PH.”
Patients with PH experience increased pressure in the pulmonary arteries, which carry blood from the heart to the lungs where it picks up oxygen that is ferried throughout the body. According to the National Institutes of Health, this leads patients to suffer from shortness of breath while doing routine tasks, chest pain and a racing heartbeat. Changes to the arteries make it progressively harder for the heart to pump blood to the lungs, which forces the heart to work even harder. Despite the heart muscle compensating by growing larger, less blood ultimately flows from the right to the left side of the heart which can compromise the kidney, liver and other organs, Dr. Unegbu says.
The study team included four researchers from Johns Hopkins University: Corina Noje, M.D., John D. Coulson, M.D., Jodi B. Segal, M.D., M.P.H., and study senior author Lewis Romer, M.D. The researchers scoured Medline, Embase, SCOPUS and the Cochrane Central Register of Controlled Trials, looking for studies that examined PDE-5 inhibitor use by pediatric patients with primary and secondary PH. Their goals included describing the nature and scale of the pediatric PH, assessing available pharmacologic therapies and conducting the systematic review of clinical studies of PDE-5 inhibitors, a mainstay of PH therapy.
They identified 1,270 studies. Twenty-one met the criteria to be included in the comprehensive review, including eight randomized controlled trials – the gold standard. The remaining 13 were observational studies in children ranging in age from extremely preterm to adolescence.
“Although there is some risk associated with PDE-5 inhibitor use by pediatric patients with PH, overwhelmingly the data indicate the benefits of using this class of drugs far outweigh the risks. When we looked at specific clinical outcomes, we see definite improvement in a number of measures including oxygenation, hemodynamics and better clinical outcomes: The patients are doing better, feeling better and their exercise capacity rises,” Dr. Unegbu says.
Because of lingering concerns about increased mortality, they also looked at toxicity data associated with this class of drugs. “With the exception of a single trial, the remaining trials included in our review did not demonstrate increased mortality in patients placed on this class of medicines, which was reassuring to us,” she says. Side effects ranged from mild to moderate, such as flushing and headaches. “We can say with a good degree of confidence that providers should feel fairly comfortable prescribing PDE-5 inhibitors.”
Ideally, researchers would like to have access to patient-specific measures that are a good fit for neonates and infants. Unlike adults, infants’ exercise capacity cannot be measured by their ability to climb stairs or use a treadmill. Another limitation, the study authors note, is the dearth of adequately powered clinical trials conducted in kids.
“Most of the studies have been conducted in adults. However, this disease unfolds in a much different fashion in children compared with adults,” Dr. Unegbu says. “We are desperately in need of high-quality studies in the form of randomized controlled trials in pediatric patients and studies that examine the full range of formulations of this class of drugs.”
Over the last several decades, physicians’ improved ability to treat the common comorbidities of Down syndrome, such as congenital heart disease, has dramatically prolonged survival. Today, more than 400,000 people across the country are living with Down syndrome, and life expectancy has increased to 60 years.
New strategies to manage care for patients with Down syndrome must include preventive, evidence-based approaches to address the unique needs of these patients, according to Sheela N. Magge, M.D., M.S.C.E., Director of Research in the Division of Endocrinology and Diabetes at Children’s. She says that these efforts should include looking more closely at the increased risks of obesity and thyroid disease common in this population, and determining how these long term comorbidities relate to cardiovascular and metabolic (cardiometabolic) risk, body image, and quality of life.
An NIH-funded study from Children’s National and the Children’s Hospital of Philadelphia (CHOP), led by Dr. Magge and her colleague from CHOP, Dr. Andrea Kelly, seeks to better understand how the body composition of patients with Down syndrome impacts their likelihood for developing diabetes and obesity-related cardiovascular risks long term.
“We know that individuals with Down syndrome are at increased risk for obesity, but what hasn’t been clear is whether or not they also have the same cardiometabolic risk associated with obesity that we know holds true for other populations,” says Dr. Magge. “In this previously under-studied population, the common assumption based on very limited studies from the 1970’s was that individuals with Down syndrome were protected from the diabetes and cardiovascular risks that can develop in other overweight people. However, more recent epidemiologic studies contradict those early findings.”
The study has enrolled 150 Down syndrome patients and almost 100 controls to date, and the team is currently beginning to analyze the data. Dr. Magge believes that the findings from this study will help to provide new, research-driven evidence to inform the long term clinical management of obesity and cardiometabolic risk in adolescents with Down syndrome.
She concludes, “The goal is for our research to provide the foundation that will advance prevention and treatment strategies for this understudied group, so that individuals with Down syndrome not only have a longer life expectancy, but also a healthier and better quality of life.”
A unique immunotherapeutic approach that expands the pool of donor-derived lymphocytes (T-cells) that react and target three key tumor-associated antigens (TAA) is demonstrating success at reducing or eliminating acute leukemias and lymphomas when these cancers have relapsed following hematopoietic stem cell transplant (HSCT).
“There’s currently a less than 10 percent chance of survival for a child who relapses leukemia or lymphoma after a bone marrow transplant—in part because these patients are in a fragile medical condition and can’t tolerate additional intense therapy,” says Kirsten Williams, M.D., a blood and marrow transplant specialist in the Division of Hematology at Children’s National Health System, and principal investigator of the Research of Expanded multi-antigen Specifically Oriented Lymphocytes for the treatment of VEry High Risk Hematopoietic Malignancies (RESOLVE) clinical trial.
The unique manufactured donor-derived lymphocytes used in this multi-institutional Phase 1 dose-ranging study are receptive to multiple tumor-associated antigens within the cell, including WT1, PRAME, and Survivin, which have been found to be over-expressed in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), B-cell AML/MDS, B-cell acute lymphoblastic leukemia (ALL), and Hodgkins lymphoma. Modifying the lymphocytes for several antigens, rather than a single target, broadens the ability of the T-cells to accurately target and eradicate cancerous cells.
Preliminary results demonstrate a 78 percent response rate to treatment, and a 44 percent rate of total remission for participating patients. To date, nine evaluable patients with refractory and relapsed AML/MDS, B-cell ALL, or Hodgkins lymphoma have received 1-3 infusions of the expanded T-cells, and of those, seven have responded to the treatment, showing reduction in cancer cells after infusion with little or no toxicity. All of these patients had relapse of their cancer after hematopoietic cell transplantation. The study continues to recruit eligible patients, with the goal of publishing the full study results within the next 12 months.
“Our preliminary data also shows that this new approach has few if any side effects for the patient, in part because the infused T-cells target antigens that are found only in cancer cells and not found in healthy tissues,” Dr. Williams notes.
The approach used to expand existing donor-derived TAA-lymphocytes, rather than using unselected T cells or genetically modified T-cells as in other trials, also seems to reduce the incidence of post infusion graft versus host disease and other severe inflammatory side effects. Those side effects typically occur when the infused lymphocytes recognize healthy tissues as foreign and reject them or when the immune system reacts to the modified elements of the lymphocytes, she adds.
“These results are exciting because they may present a truly viable option for the 30 to 40 percent of children who will relapse post-transplant,” Dr. Williams concludes. “Many of the patients who participated were given two options: palliative care or this trial. To see significant success and fewer side effects gives us, and families with children facing relapsing leukemia, some hope for this new treatment.”
Dr. Williams discussed the early outcomes of the RESOLVE trial during an oral presentation at the American Society for Blood and Marrow Transplantation meeting on February 22, 2017.
“The early indicators are very promising for this patient population,” says Catherine Bollard, M.D., M.B.Ch.B., Chief of the Division of Allergy and Immunology, Director of the Program for Cell Enhancement and Technologies for Immunotherapy (CETI) at Children’s National, and senior author of the study. “If we can achieve this, and continue to see good responses with few side effects, it’s possible these methods could become a viable alternative to HSCT for patients with no donor match or who aren’t likely to tolerate transplant.”
This is one of the first immunotherapeutic approaches to successfully capitalize on the natural ability of human T-cells to kill cancer, though previous research has shown significant success for this approach in reducing the deadly impact of several viruses, including Epstein-Barr virus, adenovirus, and cytomegalovirus, post HSCT. These new findings have led to the development of additional clinical trials to investigate applications of this method of TAA-lymphocyte manufacture and infusion for pre-HSCT MDS/AML, B-cell ALL, Hodgkins Lymphoma, and even some solid tumors.
Cardiologists from the Interventional Cardiac Magnetic Resonance (ICMR) Program at Children’s successfully live streamed a right heart catheterization procedure guided by magnetic resonance (MR) imaging during the Member Assembly Session of the Society for Cardiac Magnetic Resonance Scientific Session in early February.
The ICMR program is a first-in-the-nation partnership between Children’s National and the National Heart, Lung, and Blood Institute that features a state-of-the-art dedicated cardiac specific MRI suite for diagnosis, evaluation and intervention for children with heart conditions. The program’s goal is to advance diagnostic and interventional cardiac magnetic resonance imaging techniques in pediatric cardiology and for adults with congenital heart disease. ICMR is cross-disciplinary, connecting researchers, clinicians, engineers and physicists to provide more precise and less invasive diagnostics and treatment options that also reduce radiation exposure for vulnerable patients.
Disruptions in cerebral oxygen supply caused by congenital heart disease have significant impact on cortical growth, according to a research led by Children’s National Health System. The findings of the research team, which include co-authors from the National Institutes of Health, Boston Children’s Hospital and Johns Hopkins School of Medicine, appear on the cover of Science Translational Medicine. The subventricular zone (SVZ) in normal newborns’ brains is home to the largest stockpile of neural stem/progenitor cells, with newly generated neurons migrating from this zone to specific regions of the frontal cortex and differentiating into interneurons. When newborns experience disruptions in cerebral oxygen supply due to congenital heart disease, essential cellular processes go awry and this contributes to reduced cortical growth.
The preliminary findings point to the importance of restoring these cells’ neurogenic potential, possibly through therapeutics, to lessen children’s long-term neurological deficits.
“We know that congenital heart disease (CHD) reduces cerebral oxygen at a time when the developing fetal brain most needs oxygen. Now, we are beginning to understand the mechanisms of CHD-induced brain injuries at a cellular level, and we have identified a robust supply of cells that have the ability to travel directly to the site of injury and potentially provide help by replacing lost or damaged neurons,” says Nobuyuki Ishibashi, M.D., Director of the Cardiac Surgery Research Laboratory at Children’s National, and co-senior study author.
The third trimester of pregnancy is a time of dramatic growth for the fetal brain, which expands in volume and develops complex structures and network connections that growing children rely on throughout adulthood. According to the National Heart, Lung, and Blood Institute, congenital heart defects are the most common major birth defect, affecting 8 in 1,000 newborns. Infants born with CHD can experience myriad neurological deficits, including behavioral, cognitive, social, motor and attention disorders, the research team adds.
Cardiologists have tapped noninvasive imaging to monitor fetal hearts during gestation in high-risk pregnancies and can then perform corrective surgery in the first weeks of life to fix damaged hearts. Long term neurological deficits due to immature cortical development also have emerged as major challenges in pregnancies complicated by CHD.
“I think this is an enormously important paper for surgeons and for children and families who are affected by CHD. Surgeons have been worried for years that the things we do during corrective heart surgery have the potential to affect the development of the brain. And we’ve learned to improve how we do heart surgery so that the procedure causes minimal damage to the brain. But we still see some kids who have behavioral problems and learning delays,” says Richard A. Jonas, M.D., Chief of the Division of Cardiac Surgery at Children’s National, and co-senior study author. “We’re beginning to understand that there are things about CHD that affect the development of the brain before a baby is even born. What this paper shows is that the low oxygen level that sometimes results from a congenital heart problem might contribute to that and can slow down the growth of the brain. The good news is that it should be possible to reverse that problem using the cells that continue to develop in the neonate’s brain after birth.”
Among preclinical models, the spatiotemporal progression of brain growth in this particular model most closely parallels that of humans. Likewise, the SVZ cytoarchitecture of the neonatal preclinical model exposed to hypoxia mimics that of humans in utero and shortly after birth. The research team leveraged CellTracker Green to follow the path traveled by SVZ derived cells and to illuminate their fate, with postnatal SVZ supplying the developing cortex with newly generated neurons. SVZ derived cells were primarily neuroblasts. Superparamagnetic iron oxide nanoparticles supplied answers about long term SVZ migration, with SVZ derived cells making their way to the prefrontal cortex and the somatosensory cortex of the brain.
“We demonstrated that in the postnatal period, newly generated neurons migrate from the SVZ to specific cortices, with the majority migrating to the prefrontal cortex,” says Vittorio Gallo, Ph.D., Director of the Center for Neuroscience Research at Children’s National, and co-senior study author. “Of note, we revealed that the anterior SVZ is a critical source of newborn neurons destined to populate the upper layers of the cortex. We challenged this process through chronic hypoxia exposure, which severely impaired neurogenesis within the SVZ, depleting this critical source of interneurons.”
In the preclinical model of hypoxia as well as in humans, brains were smaller, weighed significantly less and had a significant reduction in cortical gray matter volume. In the prefrontal cortex, there was a significant reduction in white matter neuroblasts. Taken as a whole, according to the study authors, the findings suggest that impaired neurogenesis within the SVZ represents a cellular mechanism underlying hypoxia induced, region specific reduction in immature neurons in the cortex. The prefrontal cortex, the region of the brain that enables such functions as judgment, decision making and problem solving, is most impacted. Impairments in higher order cognitive functions involving the prefrontal cortex are common in patients with CHD.
Physicians treating pediatric patients with complex orthostatic intolerance issues often face a double whammy – the children exhibit symptoms of their cardiovascular condition, but secondary issues relating to gastrointestinal functions are also common. That’s why cardiologists and gastroenterologists at Children’s National Health System have collaborated in recent years to diagnose and find comprehensive treatment solutions for patients with conditions such as neurally mediated hypotension (NMH) and postural orthostatic tachycardia syndrome (POTS).
Their innovative team approach was highlighted in a study of their first 35 patients from age 10-23, published in the Journal of Pediatric Gastroenterology and Nutrition last fall – patients who experienced relief for multiple symptoms thanks to treatment at Children’s National.
The collaboration is possible because of the advancements in gastroenterological diagnostics here – specifically related to the comprehensive GI Motility testing. While patients with POTS can exhibit an abnormal heart rate, low blood pressure, headaches, fatigue or weight loss, their gastroenterological symptoms like nausea and constipation are often under recognized, says Children’s Director of the Comprehensive GI Motility Program Anil Darbari, M.D., MBA, who co-authored the study with a team including Jeffrey Moak, M.D., Director of the Electrophysiology Program at Children’s.
Through antroduodenal manometry of the stomach and upper small intestine, in combination with the cardiovascular tilt table test, the team has been able to more accurately diagnose and treat these patients.
“We have the ability to do them together, thereby making the connection between these two conditions and providing a path for management or treatment,” Dr. Darbari said.
Typically, by the time he sees these patients, those with complex medical issues have often seen several other gastroenterologists at multiple centers, and have been through a lot. The study found that overall, antroduodenal manometry was abnormal in 26 of 35 (74%) patients either at baseline or during tilt table testing in subjects with orthostatic intolerance. Darbari and his colleagues concluded that upper GI motility studies should always be part of the comprehensive evaluation for this population of patients, because treating the autonomic condition improved their gastroenterological symptoms as well.
What does the future look like for this double-whammy approach?
“We have a cohort of over 100 patients with these issues who have been evaluated using this combined diagnostic approach,” Dr. Darbari said. “This gives the team the knowledge and opportunity to help even more kids, which is very rewarding.”
In addition to comprehensive assessment and medical approaches, Children’s National is home to leaders in minimally invasive laparoscopic and endoscopic diagnostic and corrective procedures that have enabled Children’s GI motility specialists and the teams they collaborate with to offer the next level of comprehensive pediatric medical care.
Eight of every 1,000 children born each year have congenital heart disease (CHD). Although recent advances have greatly improved the survival of these children, up to 55 percent will be left with injury to their brain’s white matter – an area that is critical for aiding connection and communication between various regions in the brain. The resulting spectrum of neurological deficits can have significant costs for the individual, their family and society. Although studies have demonstrated that white matter injuries due to CHD have many contributing factors, including abnormal blood flow to the fetal brain, many questions remain about the mechanisms that cause these injuries and the best interventions.
A Children’s National Health System research team combed existing literature, reviewing studies from Children’s as well as other research groups, to develop an article detailing the current state of knowledge on CHD and white matter injury. The scientists write that advances in neuroimaging – including magnetic resonance imaging, magnetic resonance spectroscopy, Doppler ultrasound and diffusion tensor imaging – have provided a wealth of knowledge about brain development in patients who have CHD. Unfortunately, these techniques alone are unable to provide pivotal insights into how CHD affects cells and molecules in the brain. However, by integrating animal models with findings in human subjects and in postmortem human tissue, the scientists believe that it will be possible to find novel therapeutic targets and new standards of care to prevent developmental delay associated with cardiac abnormalities.
For example, using a porcine model, the Children’s team was able to define a strategy for white matter protection in congenital heart surgery through cellular and developmental analysis of different white matter regions. Another study from Children’s combined rodent hypoxia with a brain slice model to replicate the unique brain conditions in neonates with severe and complex congenital heart disease. This innovative animal model provided novel insights into the possible additive effect of preoperative hypoxia on brain insults due to cardiopulmonary bypass and deep hypothermic circulatory arrest.
The Children’s research team also recently published an additional review article describing the key windows of development during which the immature brain is most vulnerable to CHD-related injury.
Questions for future research
Q: Can we create an animal model that recapitulates the morphogenic and developmental aspects of CHD without directly affecting other organs or developmental processes?
Source: Reprinted from Trends in Neurosciences, Vol. 38/Ed. 6, Paul D. Morton, Nobuyuki Ishibashi, Richard A. Jonas and Vittorio Gallo, “Congenital cardiac anomalies and white matter injury,” pp. 353-363, Copyright 2015, with permission from Elsevier.
Rheumatic heart disease (RHD) is caused by repeated infections from the same bacteria that cause strep throat, which progressively lead to worsening inflammation of the heart’s valves with each successive infection. Over time, these valves thicken with scar tissue and prevent the heart from effectively pumping life-sustaining, oxygenated blood. The devastating condition, which was endemic in the United States before 1950, is now so rare that few outside the medical community have even heard of it. But in the developing world, explains Craig Sable, M.D., director of echocardiography and pediatric cardiology fellowship training and medical director of telemedicine at Children’s National Health System, RHD is nearly as common as HIV.
“RHD is the world’s forgotten disease,” Dr. Sable says. An estimated 32.9 million people worldwide have this condition, most of whom reside in low- to middle-income countries — places that often lack the resources to effectively diagnose and treat it.
Dr. Sable, Andrea Z. Beaton, M.D., and international colleagues plan to overturn this paradigm. For the last seven years, the team has worked on developing new technologies that could blunt the severity of RHD, vastly improving patients’ chances of avoiding its most serious complications.
At the heart of their approach is telemedicine — the use of telecommunications and information technology to provide clinical support for doctors and other care providers who often practice a substantial distance away. Telemedicine already has proven extremely useful within resource-rich countries, such as the United States, according to Dr. Sable. He and Children’s National colleagues have taken advantage of it for years to diagnose and treat pediatric disease from a distance, ranging from diabetes to asthma to autism. In the developing world, he says, it could be a game-changer, offering a chance to equalize healthcare between low- and high-resource settings.
In one ongoing project, a team led by Drs. Sable and Beaton is using telemedicine to screen children for RHD, a critical step to making sure that kids whose hearts already have been damaged receive the antibiotics and follow-up necessary to prevent further injury. After five years of working in Africa, the team recently expanded their project to Brazil, a country riddled with the poverty and overcrowding known to contribute to RHD.
Starting in 2014, the researchers began training four non-physicians, including medical technicians and nurses, to use handheld ultrasound machines to gather the precise series of heart images required for RHD diagnosis. They deployed these healthcare workers to schools in Minas Gerais, the second-most populous state in Brazil, to screen children between the ages of 7 and 18, the population most likely to be affected. With each worker scanning up to 30 children per day at 21 area schools, the researchers eventually amassed nearly 6,000 studies in 2014 and 2015.
Each night, the team on the ground transmitted their data to a cloud server, from which Children’s cardiologists, experts in RHD, and a regional hospital, Universidade Federal de Minas Gerais, accessed and interpreted the images.
“There was almost zero downtime,” Dr. Sable remembers. “The studies were transferred efficiently, they were read efficiently, and the cloud server allowed for easy sharing of information if there was concern about any questionable findings.”
In a study published online on November 4, 2016 in the Journal of Telemedicine and Telecare, Dr. Sable and colleagues reported the project’s success. Together, the team diagnosed latent heart disease in 251 children — about 4.2 percent of the subjects screened — allowing these patients to receive the regular antibiotics necessary to prevent further valve damage, and for those with hearts already badly injured to receive corrective surgery.
The researchers continued to collect data after the manuscript was submitted for publication. The team, which includes Drs. Bruno R. Nascimento, Adriana C. Diamantino, Antonio L.P. Ribeiro and Maria do Carmo P. Nunes, has screened a total of roughly 12,000 Brazilian schoolchildren to date.
Dr. Sable notes there is plenty of room for improvement in the model. For example, he says, the research team has not found a low-bandwidth solution to directly transmit the vast amount of data from each screening in real time, which has caused a slight slowdown of information to the hospital teams. The team eventually hopes to incorporate RHD screenings into annual health exams at local health clinics, sidestepping potential drawbacks of school day screenings.
Overall, being able to diagnose RHD using non-physicians and portable ultrasounds could eventually help Minas Gerais and additional low- to middle-income areas of the world where this disease remains endemic reach the same status as the United States and other resource-heavy countries.
“We’re putting ultrasound technology in the hands of people who otherwise wouldn’t have it,” says Dr. Sable, “and it could have a huge impact on their overall health.”
Heart disease is the leading cause of death in the United States, yet for many individuals it is preventable through modifications in diet, physical activity, and sedentary time – all major risk factors. Jacob Hartz, M.D., M.P.H., a cardiology fellow at Children’s National Health System, presented findings from his research on youth cardiovascular health during the American Heart Association (AHA) Scientific Sessions, held November 12-16 in New Orleans. The AHA Scientific Sessions featured the latest developments in science and cardiovascular clinical practice, including all aspects of basic, clinical, population, and translational science. Dr. Hartz spoke on “The Relationship Between Clustering of Cardiovascular Health Behaviors and Physical Fitness Among U.S. Adolescents – Data from the National Health and Nutrition Examination Survey,” and shared how grouping children with risk factors into clusters enabled researchers to pinpoint sedentary time as the leading predictor of heart health.
According to a large international study published in the American Journal of Medical Genetics, physical features vary in patients with Down syndrome across diverse populations. The study, led by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, used an objective digital facial analysis technology developed by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Health System to identify the most relevant facial features characteristic in Down syndrome in diverse populations from 12 countries. This study is the first to compare and contrast Down syndrome across diverse populations. It is the first in a series of studies to be used in the NIH’s Atlas of Human Malformation Syndromes in Diverse Populations, a free resource to help clinicians around the world diagnose birth defects and genetic diseases in people of diverse ancestry, and is the first in a series focused on different genetic syndromes.
Read more here.
Although clinical advances have improved treatments and mortality among patients with cardiovascular disease, heart disease remains the leading cause of death worldwide. Gerard Martin, M.D., cardiologist and medical director of Global Health at Children’s National and Chair of the American College of Cardiology’s Population Health Policy and Promotion Committee shares how cardiologists can improve outcomes by focusing on the link between population health and heart disease in a just-published article in Cardiology.
Could yoga, meditation, group support, or online video chats improve outcomes for adolescents with cardiac diagnoses? Vicki Freedenberg, Ph.D., R.N., electrophysiology nurse scientist at Children’s National Health System, shared insights from her research using these interventions at the American Heart Association (AHA) Scientific Sessions, held November 12-16 in New Orleans. The AHA Scientific Sessions featured the latest developments in science and cardiovascular clinical practice, including all aspects of basic, clinical, population, and translational science. In her presentation titled “Mindfulness Based Stress Reduction and Group Support Decrease Stress, Anxiety, and Depression in Adolescents with Cardiac Diagnoses: A Randomized Two-Group Study,” Freedenberg presented findings from her study comparing outcomes between cardiac patients who participated in a Mindfulness Based Stress Reduction program, which used meditation, yoga, and group support, and a second group that participated in a clinician-led online video support group with peers. Early results suggest that stress significantly decreased in both groups, and higher baseline anxiety and depression scores predicted lower levels of post-intervention anxiety and depression.
The emerging field of 3-D printing and 3-D digital displays has the potential to change the way surgeons and cardiologists make decisions. Laura Olivieri, M.D., a cardiologist at Children’s National Health System, shared insights on this topic during the American Heart Association (AHA) Scientific Sessions, held November 12-16 in New Orleans. The AHA Scientific Sessions featured the latest developments in science and cardiovascular clinical practice, including all aspects of basic, clinical, population, and translational science. In her presentation “Cardiovascular Imaging for 3-D,” Dr. Olivieri explained how cardiovascular imaging physicians can “image gently” to create 3-D models while reducing patients’ exposure to radiation and sedation. She also shared best practices for producing 3-D models from magnetic resonance imaging and echocardiograms, which are often underutilized for this purpose.
Read more about Children’s National AHA Scientific Sessions speakers.
Over the 22 years that Mary T. Donofrio, M.D., has been practicing fetal cardiology, the field has changed radically. The goal once had been simply to offer parents an accurate diagnosis and prepare them for sometimes devastating outcomes. Now, Dr. Donofrio, who directs the Fetal Heart Program and Critical Care Delivery Program at Children’s National Health System, says specialists can follow fetuses throughout the pregnancy and manage many conditions in the womb, greatly improving their chances of living long and productive lives.
Case in point: Transposition of the great arteries, a congenital defect characterized by reversal of the heart’s two main arteries—the aorta, which distributes oxygenated blood throughout the body, and the pulmonary artery, which carries deoxygenated blood from the heart to the lungs. The single abnormality means that the oxygenated “red” blood flows back to the lungs while deoxygenated “blue” blood flows out to the body.
After birth, when the cord is clamped and the connection to the placenta severed, the baby’s cardiovascular system must adjust. If the fetal connections between the two sides of the heart no longer remain, the brain and other organs in infants with this defect are severely deprived of oxygen. The condition may be fatal if something is not done immediately to reopen the fetal connections to stabilize the circulation before surgery can be done. But if the fetal cardiologist can keep tabs on what’s happening to the heart over time and prepare a specialty team of cardiologists to treat the problem immediately after birth, chances of survival are significantly improved.
More than a decade ago, as a young attending physician, Dr. Donofrio witnessed a case that has stuck with her to this day. The baby’s diagnosis of transposition of the great arteries was not made until shortly before birth. In addition, the two fetal blood flow connections that allow blood to circulate had closed, causing severe heart failure. Although the care team performed an emergency delivery and immediate cardiac procedure, including initiation of a heart-lung machine in the delivery room to try to stabilize the circulation, the baby ultimately died due to complications from a very low oxygen level. “I always wonder what happened,” Dr. Donofrio says. “Was the baby’s heart always that bad and nobody noticed it, or did it change over time?”
In a paper published recently in the Journal of Neonatal-Perinatal Medicine, she and colleagues illustrate the dramatic transformation in care that has taken place in the 14 years since this unforgettable case. The new publication describes the case of a different fetus diagnosed at 22 weeks gestation with transposition of the great arteries in 2015 at Children’s National. Unlike many congenital heart disorders, the heart’s four chambers appear misleadingly normal at the typical mid-pregnancy ultrasound. Despite the challenging diagnosis for many obstetricians, this fetus’ heart condition was recognized early by looking at the arteries leaving the heart in addition to the chambers.
While such a defect is fatal if left untreated, Dr. Donofrio explains there are two pathways that can allow the blood to get to where it needs to go such that the circulation is stabilized and the damage mitigated. One is the fetal blood vessel known as the ductus arteriosus that typically stays open for a day or two after birth. The second is an opening between the heart’s two upper chambers, known as the foramen ovale, which usually closes upon delivery. By keeping those two pathways open, blood can cross from one side of the heart to the other, buying time in the delivery room so that babies can be stabilized before they receive surgery to permanently move the arteries back to their normal position.
In the 2015 case, Dr. Donofrio and colleagues had the chance to monitor the fetus and the fetal heart at follow-up appointments every four weeks after diagnosis. What they saw completely changed the course of their treatment plan and likely saved the baby’s life. With each ultrasound, they saw that the ductus arteriosus and the foramen ovale—the critical connections needed for survival—were gradually closing.
Dr. Donofrio noted at the fetal evaluation at 38 weeks that the structures had closed, and the heart was showing signs that it was not functioning well. She and her team realized that the only way to save this baby was to deliver earlier than planned and to have cardiac specialists standing by ready to perform a life-saving procedure to open the connections right after the baby was separated from the placenta. The baby was delivered by Cesarean section in the cardiac operating room at Children’s. The cardiac intervention team immediately created a hole where the foramen ovale should have been by using a balloon to open the tissue that had closed. The care team also administered a prostaglandin infusion, a drug that can keep the ductus arteriosis open. This time, however, the medicine did not work. The baby was stabilized with several cardiac medications and, with little time to spare, the cardiac surgeons operated on the one-day-old baby to switch his great arteries back to the normal position, saving his life.
The baby is now 1-year-old, Dr. Donofrio says, and is healthy—a scenario that likely wouldn’t have happened had the fetal team not made the diagnosis and continually monitored the condition in the womb.
“I remember back to that first case when we were really scrambling to do everything we could at the last minute because we didn’t have the information we needed until the very end,” Dr. Donofrio says. “Now, we can spot problems early and do something about it. For me, that’s amazing. We’re making a difference, and that’s a really great thing.”