Tag Archive for: congenital heart disease

Nobuyuki Ishibashi

Congenital heart disease and the brain

Nobuyuki Ishibashi

In a recent review article published in Circulation Research, Nobuyuki Ishibashi, M.D., and his colleagues at Children’s National Health System summarized what is currently known about how congenital heart disease affects brain maturation.

What’s known

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.

What’s new

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:

  • An assessment of the intraoperative effects of cardiopulmonary bypass surgery on white matter using neonatal piglets.
  • An arterial spin labeling MRI study that showed newborns with complex CHD have a significant reduction in global cerebral blood flow.
  • A rodent study that modeled diffuse white matter brain injury in premature birth and identified the cellular and molecular mechanisms underlying lineage-specific vulnerabilities of oligodendrocytes and their regenerative response after chronic neonatal hypoxia.

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?
Q: How does the neurodevelopmental status of a patient with CHD change as they age?
Q: How do the genes involved in structural congenital cardiac anomalies affect brain development and function?

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.

International cardiac surgery experts join Children’s National

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.

Can YerebakanDr. 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.

Karthik RamakrishnanDr. 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.

Children’s National experts present at American College of Cardiology 66th Annual Scientific Session

CNHI at ACC

Children’s National Heart Institute Team at American College of Cardiology 66th Annual Scientific Session & Expo.

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:

  • 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.

Congenital heart disease and cortical growth

The cover of  Science Translational Medicine features a new study of the cellular-level changes in the brain induced by congenital heart disease. Reprinted with permission from AAAS. Not for download

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.

This is the consequential malfunction of the brain during congenital heart defects.

Congenital heart disease and white matter injury

This is the consequential malfunction of the brain during congenital heart defects.

Although recent advances have greatly improved the survival of children with congenital heart disease, 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.

What’s known

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.

What’s new

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?
Q: What are the prenatal and neonatal cellular responses to CHD in the developing brain?
Q: What are the molecular mechanisms underlying white matter immaturity and vulnerability to CHD, and how can we intervene?
Q: How can we accurately assess the dynamic neurological outcomes of CHD and/or corrective surgery in animal models?
Q: Prenatal or postnatal insults to the developing brain: which is most devastating in regards to developmental and behavioral disabilities?
Q: How can we best extrapolate from, and integrate, neuroimaging findings/correlations in human patients with cellular/molecular approaches in animal models?

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.

What rare diseases teach us about common ones

Think of the urea cycle as a river. A normal river flows to where it empties, similar to the process the body uses to rid itself of harmful ammonia via the urea cycle.

Think of the urea cycle as a river. A normal river flows to where it empties, similar to the process the body uses to rid itself of harmful ammonia via the urea cycle.

I recently presented at Spotlight Health 2016, the health-focused portion of the Aspen Ideas Festival, about how studying and treating rare diseases can inform innovative treatment approaches for more common medical conditions. Our Division of Genetics and Metabolism sees more than 8,000 patients a year with rare conditions, such as urea cycle disorders and Down syndrome. Through decades of analyzing these diseases and treating children who have them, we have developed therapies that apply not only for the small numbers of patients who have rare diseases but also for more common conditions caused by environmental factors leading to a similar physical response.

For instance, we’ve demonstrated that the stress of cardiopulmonary bypass during surgery to correct congenital heart disease creates conditions similar to a critical blockage in the urea cycle, specifically the biochemical creation of citrulline, a key biochemical.

When that cycle is unable to flow, or continuing the river analogy, becomes dammed up due to a genetic defect, as in urea cycle disorders, or an environmental factor, such as the extreme stress of cardiopulmonary bypass, the body is unable to make enough citrulline which is critical for maintaining normal blood pressure. We’ve shown that replacing that citrulline can correct a lot of these problems whether caused by rare genetics or the cardiac OR.

Applying rare disease treatment approaches to more common diseases is not limited to urea cycle disorders. Work by my colleague Carlos Ferreira, MD, demonstrates how a rare genetic calcifying arterial disease (generalized arterial calcification in infancy, GACI) causes the same calcium buildup and blockages as chronic kidney disease. Dr. Ferreira hypothesizes that life-saving drugs developed for use in GACI could help patients with long-term kidney disease by averting organ damage and eventual failure caused by the buildup of calcium crystals.

The more we learn about these rare diseases, the more we come to appreciate the tremendous implications our findings have for patients with the rare disorders and potentially hundreds of thousands of others.

About the Author

Marshall Summar, MD
Research interests: The interactions between common genetic variations and the environment.

Some functional brain connectivity altered in fetuses with CHD

chd_fetus

What’s Known
Congenital heart disease (CHD), a structural problem with the heart at birth, is the most common birth defect and impacts 8 of every 1,000 newborns.

While many infants with mild disease require no intervention, others have complex CHD that necessitates specialized treatment shortly after birth. Complex defects change how blood flows through the heart and to other organs—including the brain.

What’s New
Newborns with this diagnosis are at an elevated risk for neurodevelopmental disabilities, underscoring the importance of monitoring fetal brain development and function to identify which newborns need additional surveillance and medical intervention. Neuroimaging research in recent years has shown that resting-state functional magnetic resonance imaging (rs-fMRI) can provide critical insights into how the brain functions, at rest. The research team in the Developing Brain Research Laboratory at Children’s National Health System successfully measured brain function in 90 different brain regions in healthy resting fetuses and pregnancies complicated by CHD. The team reports for the first time that there was robust functional connectivity between hemispheres in both fetuses diagnosed with CHD and controls matched by gestational age. The Children’s researchers and clinicians, however, found that some functional connections were weakened in the association and paralimbic regions of the brain that are involved in attention, emotions, and behaviors.

Questions for Future Research
Q: Does decreased regional connectivity in these association and paralimbic brain regions in CHD-complicated pregnancies influence infants’ neurodevelopment after birth?
Q: Can rs-fMRI be used to identify early disturbances in brain development in CHD-complicated pregnancies, and can the imaging technique lead to improved surveillance and more timely therapeutic intervention?

Source: “Functional Brain Connectivity Is Altered in Fetuses With Congenital Heart Disease.” J. De Asis-Cruz, A. Yarish, M. Donofrio, G. Vezina, A. du Plessis, and C. Limperopoulos. Presented during the 2016 American Society of Neuroradiology Annual Meeting, Washington, DC. May 25 2016.

Cardiology and heart surgery update: fetal magnetic resonance imaging, chest pain

July 20, 2016 – Utility of fetal magnetic resonance imaging in assessing the fetus with cardiac malposition
Abnormal cardiac axis and/or malposition can trigger an evaluation of fetuses for congenital heart disease. A research team led by Mary T. Donofrio, MD, director of the Fetal Heart Program at Children’s National Health System, sought to examine how fetal magnetic resonance imaging (fMRI) – might complement obstetrical ultrasound or fetal echocardiography (echo) – in defining etiology. The team reviewed 42 fetuses identified as having abnormal cardiac axis and/or malposition by fetal ultrasound and echo. While 55 percent of cases (23) had extracardiac anomalies, 29 percent (12) were reassigned by fMRI. fMRI findings were confirmed in 8 of these 12 cases postnatally.

June 13, 2016 – Targeted echocardiographic screening for latent rheumatic heart disease in Northern Uganda
Echocardiographic screening to detect latent rheumatic heart disease (RHD) has the potential to reduce the burden of disease, however additional research is needed to develop sustainable public health strategies. Some 33 million people, many living in low-resource environments, have RHD. What’s more, relatives of children with latent RHD may be at risk for developing the chronic heart condition. The research team found that siblings of children who were RHD-positive were more likely to have RHD, underscoring the importance of screening brothers and sisters of a child with confirmed RHD.

April 3, 2016 – Chest pain in children – the charge implications of unnecessary referral
While pediatricians are responsible for triaging chest pain complaints, questions linger about the best approach to reassure patients whose conditions are benign as well as how to best identify patients whose chest pain warrants further evaluation and testing. The study sought to assess how many patients with chest pain were inappropriately referred and found that chest pain due to cardiac disease is very rare in children. Thus, children whose chest pain is not accompanied by cardiac red flags can be managed safely by their pediatrician.

April 2, 2016 – Hemodynamic consequences of a restrictive ductus arteriosus and foramen ovale in fetal transposition of TGA
Dextro-transposition of the great arteries (d-TGA) occurs when the position of the main pulmonary artery and the aorta – the two main arteries that carry blood out of the heart – are switched. Newborns with d-TGA are at risk for compromise due to foramen ovale (FO) closure and pulmonary vascular abnormalities. One such fetus seen at 22 weeks of gestational age had a hypermobile, unrestrictive FO and small ductus arteriosus (DA) with bidirectional flow. By the 32 week, however, the DA was small with restrictive bidirectional flow. Doppler imaging showed reversed flow in the left pulmonary artery. By the 38th gestational week, the FO was closed, the left atrium/ventricle were dilated, and the DA was tiny. Within 30 minutes after birth, a balloon atrial septostomy was performed, and the infant later underwent surgical repair.

Catherine Limperopoulos

Connection between abnormal placenta and impaired growth of fetuses discovered

CLimperopoulous

A team of researchers used 3-D volumetric magnetic resonance imaging (MRI) in an innovative study that reported that when the placenta fails to grow adequately in a fetus with congenital heart disease (CHD), it contributes to impaired fetal growth and premature birth. Fetal CHD involves an abnormality of the heart and is associated with increased risk for neurodevelopmental morbidity.Until now, CHD in the fetus and its relationship to placental function has been unknown. But the advanced fetal imaging study has shown for the first time that abnormal growth in the fetus with CHD relates to impaired placental growth over the third trimester of pregnancy. Catherine Limperopoulos, PhD, Director of Children’s National Developing Brain Research Laboratory in the Division of Diagnostic Imaging and Radiology, is the senior author of the study published in the September 2015 issue of the journal Placenta, “3-D Volumetric MRI Evaluation of the Placenta in Fetuses With Complex Heart Disease.”

Specifically, the decreased 3-D volumetric MRI measurements of pregnant women reported in this study suggest placental insufficiency related to CHD. The placenta nourishes and maintains the fetus, through the delivery of food and oxygen. Its volume and weight can determine fetal growth and birth weight.

Abnormality in placental development may contribute to significant morbidity in this high risk-population. This study shows impaired placental growth in CHD fetuses is associated with the length of the pregnancy and weight at birth. Nearly 1 in every 100 babies is born in the United States with a congenital heart defect.

Developing the capacity to examine the placenta non-invasively using advanced MRI is needed to identify early markers of impaired placental structure and function in the high-risk pregnancy. This is a critical first step towards developing strategies for improved fetal monitoring and management, Dr. Limperopoulos says.

“We are trying to develop the earliest and most reliable indicators of placental health and disease in high-risk pregnancies. Our goal is to bring these early biomarkers into clinical practice and improve our ability to identify placental dysfunction,” Dr. Limperopoulos says. “If we can develop the capacity to reliably identify when things begin to veer off course, we then have a window of opportunity to develop therapies to restore function.”

The study used in-vivo 3-D MRI studies and explored placental development and its relationship to neonatal outcomes by comparing placental volumetric growth in healthy pregnancies and pregnancies complicated by CHD.

While mortality rates continue to decrease steadily in newborns diagnosed with complex CHD, long-term neurodevelopmental impairments are recognized with increasing frequency in surviving infants, Dr. Limperopoulos says.

“Our goal is to better support the developing fetus with CHD. We can best accomplish this if we develop technology that can allow us to safely and effectively monitor the fetal-placental unit as a whole throughout pregnancy,” Dr. Limperopoulos says.

“This is the new frontier, not only to ensure survival but to safeguard the fetus and to ensure the best possible quality of life,” she says.