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Prescription for a healthy heart: pediatric-driven partnerships

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Dr. Martin and a patient share a smile after a visit at Children’s National Health System.

For pediatric cardiologists, February, National Heart Month, is a special time. We share health tips in the hospital and talk about heart health with those looking for advice, especially with patients and families impacted by congenital heart disease (CHD). It’s also a time to look back at what’s worked well in the field, while accelerating advancements for CHD treatment.

To start, congenital heart disease, a structural abnormality of the heart or of the blood vessels surrounding it, is the most common birth defect and occurs in about one in every 100 live births, affecting 40,000 babies born in the U.S. each year. One million children and 1.4 million adults in the U.S. have CHD. Over the past 15 years, pediatric cardiologists have cut mortality rates for CHD in half. Gratefully, now instead of saving children’s lives, the emphasis is on improving them. The catalyst for this paradigm shift isn’t simply due to a medical breakthrough, but is also the result of collaboration and advocacy.

Pediatric cardiologists worked together with other stakeholders – nurses, neonatologists, parents, state and federal agencies – to implement newborn screening methods in hospitals, with the introduction pulse oximetry screenings for critical congenital heart defects (CCHD). The screening, which measures blood oxygen levels in newborns, focuses on screening babies for CCHD before they leave the hospital. The concept and a national protocol for screening began with a small project in 2002, was endorsed by medical associations by 2012 and required by all states in 2018. The impact of CCHD screening of newborns is remarkable. Data published in JAMA showed a 33 percent reduction in CCHD infant deaths associated with states that required CCHD screening.

The pulse oximetry screening’s impact on the number of lives saved goes beyond identifying newborns with CCHD. Worldwide, though the detection of secondary conditions, such as hypothermia, pneumonia, and sepsis, the pulse oximetry screening is estimated to save roughly 772,000 lives by 2030.

In addition to newborn screening recommendations for CCHD, a group of cardiologists, including myself, worked for the Joint Council on Congenital Heart Disease (JCCHD) to form and support the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC). We developed measures to see how we could improve survival rates between surgeries for infants born with hypoplastic left heart syndrome (HLHS), one of the most common and severe forms of CCHD.

Babies born with HLHS require two heart surgeries within the baby’s first six months. Babies that survived the first operation had a significant mortality rate (15 percent) and frequent growth failure, while waiting for the second operation. Our focused aims were to both decrease the death rate and improve growth in these children. We analyzed data from medical centers, utilized quality improvement principals from the Institute for Health Care Improvement, talked with doctors and families, and invited teams from across the U.S. to partner with us to put quality and safety measures into place.

We emphasized the following points:

  1. Clear communication. Parents leaving the hospital received consistent messages about CHD, the type of surgery their baby had, next steps and how to care for their child at home.
  2. Improved nutrient intake. Parents received clear guidelines about how many calories babies needed to consume, were asked to weigh their baby each day, and taught how to augment feeding.
  3. Warning signs.Parents received a list of typical infant behaviors and HLHS red flags to watch out for, such as if a baby isn’t gaining a certain amount of weight. They received monitors to measure oxygen saturation levels at home. If oxygen saturation dropped significantly or if parents noticed a problem, they called their doctor immediately.

The implementation of these procedures reduced interstage mortality rates and the number of growth failures for HLHS patients. In 2008, six centers participated in the NPC-QIC pilot. By 2018, 65 medical centers in the U.S. and Canada used these methods. Similar to the pulse oximetry screening guidelines, this new method wasn’t the result of a medical breakthrough, but the result of shared learning and shared infrastructure.

Now, we’re referring more adult congenital heart patients to board-certified adult congenital heart disease (ACHD) specialists, a better fit than internists or pediatric cardiologists. Adults with congenital heart defects should have their heart examined at least once by a specialist and those with complex needs should meet with a specialist at least every two years. More than 300 board-certified ACHD specialists practice in the U.S. and the field is growing. The third ACHD board exam takes place this year.

Over the next few decades, I hope we’ll make even more progress with understanding, diagnosing and treating CHD.

Emerging research examines genetic clues for congenital heart defects, which were once thought to account for 8 percent of cases and may now account for 30 percent of conditions. We’re working with neurologists to examine the timing and pathway of potential oxygen inefficiencies that occur as the brain develops in utero, infancy, and after neonatal surgery. We’ve come a long way, but we continue looking at new frontiers and for innovative solutions.

Fortunately, as cardiologists, we’re good at fixing problems. We work with surgeons and medical teams to repair holes in hearts, or replace them, and reroute blood from an underdeveloped left ventricle to improve circulation. For almost every heart defect, we have evidence-based solutions. However, to continue to help children worldwide, it’s imperative that we don’t forget about what works well: good science, tracking data, sharing best practices, active listening, transparency and constant collaboration.

Gerard Martin, M.D., F.A.A.P., F.A.C.C., F.A.H.A., is a cardiologist and the medical director of global services at Children’s National Health System. Dr. Martin has practiced pediatric cardiology for 34 years and is the Dan G. McNamara keynote speaker at the American College of Cardiology’s 2019 Scientific Sessions. Follow Dr. Martin on Twitter @Gerard_MD.

This article first appeared on KevinMD.com.

Nikki Gillum Posnack

What are the health effects of plastics?

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Nikki Gillum Posnack

Nikki Posnack, Ph.D., assistant professor at the Children’s National Heart Institute, is an early-stage investigator examining the impact plastic chemical exposure has on the developing hearts of newborns and young children.

For newborns or children in the pediatric intensive care unit, plastic tubing is part of daily life. It delivers life-sustaining blood transfusions, liquid nutrition and air to breathe. But small amounts of the chemicals in the plastic of this tubing and other medical devices can leak into the patient’s bloodstream. The potential effects of these chemicals on the developing hearts of newborns and very young children are not well understood.

One researcher, Nikki Posnack, Ph.D., an assistant professor at the Children’s National Heart Institute, aims to change that and shares her early insights, funded by the National Center for Advancing Translation Science (NCATS), in an NCATS news feature.

“While plastics have revolutionized the medical field, we know chemicals in plastics leach into the body and may have unintended effects,” Posnack said. “The heart is sensitive to toxins, so we want to look at the effect of these plastics on the most sensitive patient population: kids who are recovering from heart surgery and already prone to cardiac complications.”

Nobuyuki Ishibashi

Cortical dysmaturation in congenital heart disease

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Nobuyuki Ishibashi

On Jan. 4, 2019, Nobuyuki Ishibashi, M.D., the director of the Cardiac Surgery Research Laboratory and an investigator with the Center for Neuroscience Research at Children’s National Health System, published a review in Trends in Neurosciences about the mechanisms of cortical dysmaturation, or disturbances in cortical development, that can occur in children born with congenital heart disease (CHD). By understanding the early-life impact and relationship between cardiac abnormalities and cortical neuronal development, Dr. Ishibashi and the study authors hope to influence strategies for neonatal neuroprotection, mitigating the risk for developmental delays among CHD patients.

Dr. Ishibashi answers questions about this review and CHD-neurodevelopmental research:

  1. Tell us more about your research. Why did you choose to study these interactions in this patient population?

My research focuses on studying how CHD and neonatal cardiac surgery affect the rapidly-developing brain. Many children with CHD, particularly the most complex anomalies, suffer from important behavioral anomalies and neurodevelopmental delays after cardiac surgery. As a surgeon scientist, I want to optimize treatment strategy and develop a new standard of care that will reduce neurodevelopmental impairment in our patients.

  1. How does this study fit into your larger body of work? What are a few take-home messages from this paper?

Our team and other laboratories have recently identified a persistent perinatal neurogenesis that targets the frontal cortex – the brain area responsible for higher-order cognitive functions. The main message from this article is that further understanding of the cellular and molecular mechanisms underlying cortical development and dysmaturation will likely help to identify novel strategies to treat and improve outcomes in our patients suffering from intellectual and behavioral disabilities.

  1. What do you want pediatricians and researchers to know about this study? Why is it important right now?

Although the hospital mortality risk is greatly reduced, children with complex CHD frequently display subsequent neurological disabilities affecting intellectual function, memory, executive function, speech and language, gross and fine motor skills and visuospatial functions. In addition to the impact of the neurological morbidity on the patients themselves, the toll on families and society is immense. Therefore it is crucial to determine the causes of altered brain maturation in CHD.

  1. How do you envision this research influencing future studies and pediatric health outcomes? As a researcher, how will you proceed?

In this article we placed special emphasis on the need for well-designed preclinical studies to define disturbances in cortical neurogenesis due to perinatal brain injury. I believe that further study of the impact of hypoxemia on brain development is of broad relevance — not just for children with congenital heart disease, but for other populations where intellectual and behavioral dysfunctions are a source of chronic morbidity, such as survivors of premature birth.

  1. What discoveries do you envision being at the forefront of this field?

One of the important questions is: During which developmental period, prenatal or postnatal, is the brain most sensitive to developmental and behavioral disabilities associated with hypoxemia? Future experimental models will help us study key effects of congenital cortical development anomalies on brain development in children with CHD.

  1. What impact could this research make? What’s the most striking finding and how do you think it will influence the field?

Although cortical neurogenesis at fetal and adult stages has been widely studied, the development of the human frontal cortex during the perinatal period has only recently received greater attention as a result of new identification of ongoing postnatal neurogenesis in the region responsible for important intellectual and behavioral functions. Children’s National is very excited with the discoveries because it has opened new opportunities that may lead to regeneration and repair of the dysmature cortex. If researchers identify ways to restore endogenous neurogenic abilities after birth, the risk of neurodevelopment disabilities and limitations could be greatly reduced.

  1. Is there anything else you would like to add that we didn’t ask you about? What excites you about this research?

In this article we highlight an urgent need to create a truly translational area of research in CHD-induced brain injury through further exploration and integration of preclinical models. I’m very excited about the highly productive partnerships we developed within the Center for Neuroscience Research at Children’s National, led by an internationally-renowned developmental neuroscientist, Vittorio Gallo, Ph.D., who is a co-senior author of this article. Because of our collaboration, my team has successfully utilized sophisticated and cutting-edge neuroscience techniques to study brain development in children born with CHD. To determine the causes of altered brain maturation in congenital heart disease and ultimately improve neurological function, we believe that a strong unity between cardiovascular and neuroscience research must be established.

Additional study authors include Camille Leonetti, Ph.D., a postdoctoral research fellow with the Center for Neuroscience Research and Children’s National Heart Institute, and Stephen Back, M.D., Ph.D., a professor of pediatrics at Oregon Health and Science University.

The research was supported by multiple grants and awards from the National Institutes of Health, inclusive of the National Heart Lung and Blood Institute (RO1HL139712), the National Institute of Neurological Disorders and Stroke (1RO1NS054044, R37NS045737, R37NS109478), the National Institute on Aging (1RO1AG031892-01) and the National Institute of Child Health and Human Development (U54HD090257).

Additional support for this review was awarded by the American Heart Association (17GRNT33370058) and the District of Columbia Intellectual and Developmental Disabilities Research Center, which is supported through the Eunice Kennedy Shriver National Institute of Child Health and Human Development program grant 1U54HD090257.

Photo of nurses in the cardiac intensive care unit at Children's National

Can pyruvate support metabolic function following heart surgery?

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Photo of nurses in the cardiac intensive care unit at Children's National

Nurses rush a child to the cardiac intensive care unit at Children’s National Health System.

Can pyruvate, the end product of glycolysis, help improve cardiovascular function in children who have cardiopulmonary bypass surgery and suffer from low cardiac output syndrome (LCOS)? This question is one that Rafael Jaimes, Ph.D., a staff scientist at Children’s National Heart Institute, a division of Children’s National Health System, is studying, thanks to a two-year grant from the American Heart Association.

The competitive grant awards Dr. Jaimes with $110,000 to study how pyruvate may help improve cardiac output among pediatric patients with LCOS. The compound aims to stimulate metabolic function, now treated by inotropic agents, such as dobutamine and milrinone. These agents ensure optimal delivery of oxygen from the heart to the brain, as well as to other organs in the body, following heart surgery. While these agents help patients with cardiac dysfunction, there is still a critical need for safe and effective therapies.

“If there’s any detriment in cardiac output, the heart’s function begins to degrade,” explains Dr. Jaimes. “You see a downward spiral effect with reduced cardiac output because the heart is dependent on its own perfusion. It needs to pump blood throughout the body to survive.”

This is where the pyruvate study, and the grant, will be applied: Can pyruvate target the essential muscle of the heart and reverse this cardiac destabilization – and as soon as possible?

“By increasing the metabolic output of the heart’s local muscle, cardiac output increases,” Dr. Jaimes explains. “That’s going to lead to better recovery.”

Better recovery could be measured by how fast a child recovers from heart surgery as well as how much time they spend in the hospital, clinically referred to as throughput. A faster recovery could also influence a child’s quality of life and reduce overall health care costs.

Based on preliminary data that shows pyruvate improves cardiac function in experimental models after ischemic insult, which is what happens when pediatric patients undergo cardiac surgery, Dr. Jaimes believes the results will likely replicate themselves in his preclinical models.

To start, he’ll test pyruvate using 100 blood samples and discarded tissue from patients. The blood samples will be tested for metabolic markers, including measured pyruvate levels.

Part of what encouraged Dr. Jaimes to study how this compound could complement or replace standard therapies was the encouragement he received from his mentors in the field.

“Nobody has looked into using pyruvate for almost 30 years,” says Dr. Jaimes. “It’s not commercially favorable, there’s no patent on it, it doesn’t have a lot of marketability and there are no financial incentives, so it’s been put aside.”

As part of a discussion with cardiologists at a medical conference in Washington, Dr. Jaimes brought up the idea of using pyruvate for pediatric heart surgeries and received positive feedback.

“Once everyone’s eyes lit up, I knew I was on to something,” says Dr. Jaimes about the encouragement he received to pursue this study.

“You put lactate and glucose in your IV solutions,” adds Dr. Jaimes. “Pyruvate is an essential nutrient. It’s almost an essential sugar so there’s no reason not to put it in. If these cardiologists are intrigued by the project, maybe the American Heart Association will be, too.”

In addition to funding the study, which could support future research about how metabolic makers in the blood can be stimulated to fast-track recovery following heart surgery, the American Heart Association grant is specific to pediatric health outcomes.

“The current state of pharmaceutical treatment for patients recovering from cardiac surgery is designed and created for adults,” says Dr. Jaimes. “From our research in pediatrics, we know that children aren’t small adults.”

Dr. Jaimes explains that children are different on an anatomical and physiological level. Their cells even look and function different, compared to adult cells, because they haven’t matured yet.

While congenital heart defects are rare, they affect 1 percent, or 40,000 births worldwide, they often require multiple surgeries throughout a child’s lifespan. LCOS impacts 25 percent of patients following cardiopulmonary bypass and the timing of treatment is important. In severe cases, insufficient cardiac output following surgery could impact a child’s long-term development, ranging from reasoning, learning, attention and executive function, to developing age-appropriate language and social skills.

“The metabolic insufficiencies I’m looking at, which may help improve the muscle function of the heart, are just one piece of a bigger puzzle in pediatric cardiology,” notes Dr. Jaimes about ongoing research at Children’s National Heart Institute. “We already know pyruvate is safe. We just have to see if it’s effective in supporting a patient’s recovery in the intensive care unit.”

Dr. Jaimes will work with his research mentor Nikki Posnack, Ph.D., assistant professor at the Children’s National Heart Institute, on this preclinical study throughout the grant’s lifecycle, which starts in early January 2019 and ends in late December 2020.

Nikki Gillum Posnack

Examining BPA’s impact on developing heart cells

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Nikki Gillum Posnack

“We know that once this chemical enters the body, it can be bioactive and therefore can influence how heart cells function,” says Nikki Gillum Posnack, Ph.D. “This is the first study to look at the impact BPA exposure can have on heart cells that are still developing.”

More than 8 million pounds of bisphenol A (BPA), a common chemical used in manufacturing plastics, is produced each year for consumer goods and medical products. This endocrine disruptor reaches 90 percent of the population, and excessive exposure to BPA, e.g., plastic bottles, cash register receipts, and even deodorant, is associated with adverse cardiovascular events that range from heart arrhythmias and angina to atherosclerosis, the leading cause of death in the U.S.

To examine the impact BPA could have in children, researchers with Children’s National Heart Institute and the Sheikh Zayed Institute for Pediatric Surgical Innovation evaluated the short-term risks of BPA exposure in a preclinical setting. This experimental research finds developing heart cells respond to short-term BPA exposure with slowed heart rates, irregular heart rhythms and calcium instabilities.

While more research is needed to provide clinical recommendations, this preclinical model paves the way for future study designs to see if young patients exposed to BPA from medical devices or surgical procedures have adverse cardiac events and altered cardiac function.

“Existing research explores the impact endocrine disruptors, specifically BPA, have on adults and their cardiovascular and kidney function,” notes Nikki Gillum Posnack, Ph.D., a study author and assistant professor at Children’s National and The George Washington University. “We know that once this chemical enters the body, it can be bioactive and therefore can influence how heart cells function. This is the first study to look at the impact BPA exposure can have on heart cells that are still developing.”

The significance of this research is that plastics have revolutionized the way clinicians and surgeons treat young patients, especially patients with compromised immune or cardiac function.

Implications of Dr. Posnack’s future research may incentivize the development of alternative products used by medical device manufacturers and encourage the research community to study the impact of plastics on sensitive patient populations.

“It’s too early to tell how this research will impact the development of medical devices and equipment used in intensive care settings,” notes Dr. Posnack. “We do not want to interfere with clinical treatments, but, as scientists, we are curious about how medical products and materials can be improved. We are extending this research right now by examining the impact of short-term BPA exposure on human heart cells, which are developed from stem cells.”

This research, which appears as an online advance in Nature’s Scientific Reports, was supported by the National Institutes of Health under awards R00ES023477, RO1HL139472 and UL1TR000075, Children’s Research Institute and the Children’s National Heart Institute. NVIDIA Corporation provided GPUs, computational devices, for this study.

Dr. Laura Olivieri holding a 3D printed heart

Cardiology and radiology experts to participate in CMR 2018

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Later this month, the international cardiovascular magnetic resonance (CMR) community will gather in Barcelona, Spain, for CMR 2018, a joint meeting organized by the European Association of Cardiovascular Imaging (EACVI) and the Society for Cardiovascular Magnetic Resonance (SCMR). Among the many attendees will be several cardiology and radiology experts from Children’s National Heart Institute:

  • Pediatric cardiology fellow Ashish Doshi, M.D., will be giving a talk titled, “Subendocardial resting perfusion defect in a case of acute fulminant myocarditis,” and will also present a poster titled, “Native T1 measurements in pediatric heart transplant patients correlate with history of prior rejection episodes.”
  • Pediatric cardiology fellow Rohan Kumthekar, M.D., will present a poster titled, “Native T1 values can identify pediatric patients with myocarditis.”
  • Cardiologist Laura Olivieri, M.D., will present two posters: “Native T1 measurements from CMR identify severity of myocardial disease over time in patients with Duchenne muscular dystrophy on therapy,” and “Feasibility of noncontrast T1 and T2 parametric mapping in assessment of acute ventricular ablation lesions in children.”
  • Pediatric cardiology fellow Neeta Sethi, M.D., will present a poster titled, “Cardiac magnetic resonance T2 mapping in the surveillance of acute allograft rejection in pediatric cardiac transplant patients.”

Additionally, Drs. Doshi and Sethi and Ileen Cronin, FNP-BC, a nurse practitioner in the Cardiac Catheterization Laboratory/Interventional Cardiac Magnetic Resonance (ICMR) Program, received travel awards to attend the conference.

CMR 2018 will be held January 31-February 3, 2018 and will focus on the theme of “Improving Clinical Value by Technical Advances.” The meeting’s emphasis will be on the common goal of improving clinical outcomes in cardiovascular disease through innovation in basic MR development and medical engineering.