Gram-positive-bacteria-Streptococcus-pyogenes

Assessing the risk factors in rheumatic heart disease

Gram-positive-bacteria-Streptococcus-pyogenes

Rheumatic heart disease is caused by untreated throat infections from the streptococcal bacterium. The infections progress into acute rheumatic fever and eventually weaken the valves of the heart.

Rheumatic heart disease (RHD) is the most commonly acquired cardiovascular disease in children and young adults. The devastating condition, which was endemic in the United States before 1950, is now relatively rare in the developed world due to social and economic development and the introduction of penicillin. But, in the developing world RHD remains nearly as common as HIV.

Fortunately, RHD is a cumulative disease and opportunities exist for early intervention. To further explore the utility of early diagnosis and intervention, a research team headed by Children’s National Heart Institute cardiologist Andrea Beaton, M.D., conducted a prospective natural history study of children with latent RHD.

RHD is caused by untreated streptococcal throat infections that progress into acute rheumatic fever (ARF) and eventually weaken the valves of the heart. While initial episodes of ARF occur almost exclusively during childhood, RHD most commonly presents in adolescents and young adults. This latent period between ARF and clinically apparent RHD is an ideal opportunity for early intervention, and screening echocardiography (echo) has emerged as a potentially powerful tool for early detection of RHD.

In their study published in the journal Circulation in September 2017, Dr. Beaton and her colleagues examined echocardiograms from children with latent RHD who were enrolled in the Ugandan National RHD registry. The researchers also developed models to search for risk factors and compare progression-free survival between patients who did and did not receive penicillin.

The team reports that children with moderate-to-severe latent RHD discovered by echo screening have poor outcomes. Children with both borderline and mild definite RHD have better outcomes but remain at substantial risk of progression. The researchers also found that children who are diagnosed at a younger age, and the presence of morphological mitral valve features, generally lead to unfavorable outcomes.

The authors conclude that children with moderate to severe RHD at screening should be considered for treatment as clinically diagnosed RHD, and that children with borderline or mild definite RHD at screening should, at a minimum, be maintained in close clinical follow up.

“It is clear that children found to have the earliest forms of RHD, seen only by echo, are at substantial risk for progression of disease. This study urges us forward to see if we can intervene to stop this progression once children are identified,” says Dr. Beaton.  “We are excited that our next project will be to do just that – a randomized clinical trial in Uganda to determine if penicillin can protect the hearts of children found to have latent RHD.”

Catherine Limperopoulous

Brain impairment in newborns with CHD prior to surgery

Catherine Limperopoulous

Children’s National researchers led by Catherine Limperopoulos, Ph.D., demonstrate for the first time that the brains of high-risk infants show signs of functional impairment before they undergo corrective cardiac surgery.

Newborns with congenital heart disease (CHD) requiring open-heart surgery face a higher risk for neurodevelopmental disabilities, yet prior studies had not examined whether functional brain connectivity is altered in these infants before surgery.

Findings from a Children’s National Health System study of this question suggest the presence of brain dysfunction early in the lives of infants with CHD that may be associated with neurodevelopmental impairments years later.

Using a novel imaging technique, Children’s National researchers demonstrated for the first time that the brains of these high-risk infants already show signs of functional impairment even before they undergo corrective open heart surgery. Looking at the newborns’ entire brain topography, the team found intact global organization – efficient and effective small world networks – yet reduced functional connectivity between key brain regions.

“A robust neural network is critical for neurons to travel to their intended destinations and for the body to carry out nerve cells’ instructions. In this study, we found the density of connections among rich club nodes was diminished, and there was reduced connectivity between critical brain hubs,” says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory at Children’s National and senior author of the study published online Sept. 28, 2017 in NeuroImage: Clinical. “CHD disrupts how oxygenated blood flows throughout the body, including to the brain. Despite disturbed hemodynamics, infants with CHD still are able to efficiently transfer neural information among neighboring areas of the brain and across distant regions.”

The research team led by Josepheen De Asis-Cruz, M.D., Ph.D., compared whole brain functional connectivity in 82 healthy, full-term newborns and 30 newborns with CHD prior to corrective heart surgery. Conventional imaging had detected no brain injuries in either group. The team used resting state functional connectivity magnetic resonance imaging (rs-fcMRI), a imaging technique that characterizes fluctuating blood oxygen level dependent signals from different regions of the brain, to map the effect of CHD on newborns’ developing brains.

The newborns with CHD had lower birth weights and lower APGAR scores (a gauge of how well brand-new babies fare outside the womb) at one and five minutes after birth. Before the scan, the infants were fed, wrapped snugly in warm blankets, securely positioned using vacuum pillows, and their ears were protected with ear plugs and ear muffs.

While the infants with CHD had intact global network topology, a close examination of specific brain regions revealed functional disturbances in a subnetwork of nodes in newborns with cardiac disease. The subcortical regions were involved in most of those affected connections. The team also found weaker functional connectivity between right and left thalamus (the region that processes and transmits sensory information) and between the right thalamus and the left supplementary motor area (the section of the cerebral cortex that helps to control movement). The regions with reduced functional connectivity depicted by rs-fcMRI match up with regional brain anomalies described in imaging studies powered by conventional MRI and diffusion tensor imaging.

“Global network organization is preserved, despite CHD, and small world brain networks in newborns show a remarkable ability to withstand brain injury early in life,” Limperopoulos adds. “These intact, efficient small world networks bode well for targeting early therapy and rehabilitative interventions to lower the newborns’ risk of developing long-term neurological deficits that can contribute to problems with executive function, motor function, learning and social behavior.”

Andrea Beaton and Craig Sable

Assessing the global burden of rheumatic heart disease

Andrea Beaton and Craig Sable

A research team that included Children’s National Heart Institute experts Andrea Beaton, M.D., and Craig Sable, M.D., examined data on fatal and nonfatal Rheumatic Heart Disease for a 25 year period from 1990 through 2015 to determine the current global burden of RHD.

Rheumatic Heart Disease (RHD) is the most commonly acquired heart disease in young people under the age of 25. It’s caused by untreated streptococcal throat infections that progress into acute rheumatic fever and eventually weaken the valves of the heart. Fortunately, the devastating condition, which was endemic in the United States before 1950, is now relatively rare in the developed world due to social and economic development and the introduction of penicillin. But, as shown in a recent study published in the New England Journal of Medicine, in the developing world, RHD remains nearly as common as HIV.

As part of the 2015 Global Burden of Disease Study, a research team that included Children’s National Heart Institute experts Andrea Beaton, M.D., and Craig Sable, M.D., examined data on fatal and nonfatal RHD for a 25 year period from 1990 through 2015 to determine the current global burden of RHD. The group employed epidemiologic modeling techniques to estimate the global, regional and national prevalence of RHD, as well as death rates and disability-adjusted life years attributable to the disease.

“This study provides more detail than ever before about the global impact of RHD,” explains Dr. Sable. “It utilizes global burden of disease tools that are updated on an annual basis. These tools are considered highly reputable and allow for ongoing tracking and comparison to other diseases.”

The researchers found that overall, death rates from RHD have declined: there were 347,500 deaths from RHD in 1990 and 319,400 deaths in 2015, a decrease of 8 percent. From 1990 to 2015, the global age-standardized death rate from RHD also decreased from 9.2 to 4.8 per 100,000 — a change of 48 percent.

However, a closer look at the data shows that progress on RHD remains uneven. Although the health-related burden of RHD has declined in most countries over the 25-year period, the condition persists in some of the poorest regions in the world, with the highest estimated death rates in Central African Republic, Federated States of Micronesia, Fiji, India, Kiribati, Lesotho, Marshall Islands, Pakistan, Papua New Guinea, the Solomon Islands and Vanuatu. In several regions, mortality from RHD and the number of individuals living with RHD did not appreciably decline between 1990 and 2015. The researchers estimate that 10 out of every 1,000 people living in South Asia and central sub-Saharan Africa and 15 out of 1,000 people in Oceania were living with RHD in 2015.

“These data are critically important for increasing awareness and funding to reduce the global burden of rheumatic heart disease,” says Dr. Sable. “Dr. Beaton and I are proud to be part of a small team of global investigators leading this effort.”

Children’s National Health System was recently awarded a grant from the American Heart Association to launch a Rheumatic Heart Disease Center, with the goal of developing innovative strategies and economic incentives to improve the prevention and diagnosis of RHD in high-risk, financially disadvantaged countries and low-income communities across the United States. The program will use Children’s robust telemedicine infrastructure to connect co-collaborators around the world, as well as train the next generation of globally minded cardiovascular researchers.

Teens Meditating

Namaste: how mindfulness aids cardiac patients

Teens Meditating

Mindfulness techniques – including yoga, meditation, group support, and other approaches to dealing with stressors – help teens with heart conditions reduce stress levels and better cope with health concerns.

An estimated 30 to 50 percent of teens with congenital heart conditions will experience anxiety and/or depression disorders, but researchers at Children’s National Health System have found that mindfulness techniques such as yoga, meditation and peer support can reduce stress that is often associated with these debilitating conditions.

Published in the journal Pediatric Cardiology, the first-of-its-kind, randomized, two-group study documented the effectiveness of Mindfulness-Based Stress Reduction (MBSR) and online video support groups in lowering illness-related stress for youth with heart conditions. Beyond stress reduction, the study also found that greater use of coping skills predicted lower levels of depression for participants following the interventions. Additionally, patients with higher levels of anxiety and depression pre-intervention recorded the biggest improvements post-study.

“Being a teenager is hard enough, but being the only person you know with a potentially life-threating heart condition can be devastating,” says Vicki Freedenberg, RN, Ph.D., electrophysiology nurse within the Children’s National Heart Institute and the principal investigator for the study. “These results indicate that teaching patients coping skills and connecting them with their peers can not only reduce their stress levels now, but these tools could also dramatically improve their responses to stressors for the rest of their lives.”

MBSR employs psycho-educational tools, including yoga, meditation, group support and other mindful approaches to dealing with stressors – which, for teens with heart conditions, could translate to better coping techniques when anxiety and heart palpitations strike.

Participants were randomly assigned to the MBSR group or the video online support group for the six-week study. The study included 46 adolescents, ages 12 to 18, with congenital heart disease, cardiac arrhythmias, cardiac devices or postural orthostatic tachycardia syndrome. Before and after the study period, patients self-reported illness-related stress and coping using the Responses to Stress Questionnaire, as well as anxiety and depression levels using the Hospital Anxiety and Depression Scale.

Participants in the MBSR group met in person for 90 minutes once a week. During the sessions, the study’s lead author led the teens through mindfulness exercises and facilitated group discussions, focusing on fears and stressors related to body image, as well as heart conditions and associated devices.

The online support group used Skype to connect with peers for one hour each week. During the first half of each session, Freedenberg moderated group discussions about cardiac-related health topics requested by the participants, and the last 30 minutes were spent in open discussion on any topic – often ranging from issues at school to sports and entertainment.

“We are encouraged by our initial findings, and they indicate that we need to further study and understand the impact of behavioral and psychosocial interventions in adolescents with cardiac diagnoses,” says Freedenberg. “Adult studies have shown similar interventions can reduce risk for mortality and stroke among cardiac patients, and we are hopeful that further research will show equally positive findings for teens.”

Zhe Han, PhD

Lab led by Zhe Han, Ph.D., receives $1.75 million from NIH

Zhe Han, PhD

A new four-year NIH grant will enable Zhe Han, Ph.D., to carry out the latest stage in the detective work to determine how histone-modifying genes regulate heart development and the molecular mechanisms of congenital heart disease caused by these genetic mutations.

The National Institutes of Health (NIH) has awarded $1.75 million to a research lab led by Zhe Han, Ph.D., principal investigator and associate professor in the Center for Genetic Medicine Research, in order to build models of congenital heart disease (CHD) that are tailored to the unique genetic sequences of individual patients.

Han was the first researcher to create a Drosophila melanogaster model to efficiently study genes involved in CHD, the No.1 birth defect experienced by newborns, based on sequencing data from patients with the heart condition. While surgery can fix more than 90 percent of such heart defects, an ongoing challenge is how to contend with the remaining cases since mutations of a vast array of genes could trigger any individual CHD case.

In a landmark paper published in 2013 in the journal Nature, five different institutions sequenced the genomes of more than 300 patients with CHD and their families, identifying 200 mutated genes of interest.

“Even though mutations of these genes were identified from patients with CHD, these genes cannot be called ‘CHD genes’ since we had no in vivo evidence to demonstrate these genes are involved in heart development,” Han says. “A key question to be answered: How do we efficiently test a large number of candidate disease genes in an experimental model system?”

In early 2017, Han published a paper in Elife providing the answer to that lingering question. By silencing genes in a fly model of human CHD, the research team confirmed which genes play important roles in development. The largest group of genes that were validated in Han’s study were histone-modifying genes. (DNA winds around the histone protein, like thread wrapped around a spool, to become packed into a higher-level structure.)

The new four-year NIH grant will enable Han to carry out the next stage of the detective work to determine precisely how histone-modifying genes regulate heart development. In order to do so, his group will silence the function of histone-modifying genes one by one, to study their function in the fly heart development and to identify the key histone-modifying genes for heart development. And because patients with CHD can have more than one mutated gene, he will silence multiple genes simultaneously to determine how those genes work in partnership to cause heart development to go awry.

By the end of the four-year research project, Han hopes to be able to identify all of the histone-modified genes that play pivotal roles in development of the heart in order to use those genes to tailor make personalized fly models corresponding to individual patient’s genetic makeup.

Parents with mutations linked to CHD are likely to pass heart disease risk to the next generation. One day, those parents could have an opportunity to sequence their genes to learn the degree of CHD risk their offspring face.

“Funding this type of basic research enables us to understand which genes are important for heart development and how. With this knowledge, in the near future we could predict the chances of a baby being born with CHD, and cure it by using gene-editing approaches to prevent passing disease to the next generation,” Han says.

child measuring belly with tape measure

Defining cardiovascular disease and diabetes risks in kids

child measuring belly with tape measure

In the Clinical Report, a study team led by Sheela N. Magge, M.D., M.S.C.E., F.A.A.P., describes the current state of play and offers evidence-based recommendations to guide clinicians on how to approach metabolic syndrome in children and adolescents.

For more than a decade and a half, researchers and clinicians have used the term “metabolic syndrome” (MetS) to describe a set of symptoms that can raise the risk of cardiovascular disease. Although this constellation of factors has proven to be a good predictor of cardiometabolic risk in adults, it has not been as useful for children.

That’s why the American Academy of Pediatrics (AAP) now recommends that pediatricians instead focus on clusters of cardiometabolic risk factors that are associated with obesity, a condition that currently affects one in six U.S. children and adolescents.

“In so many areas of medicine, we find that strategies designed for adults simply do not meet the unique needs of children and adolescents,” says Sheela N. Magge, M.D., M.S.C.E., F.A.A.P., director of research in Children’s National Health System’s Division of Endocrinology and Diabetes, and lead author of the study published July 24 in Pediatrics. “Rather than focusing on specific cut-off levels of risk factors or whether a child’s condition fits a particular definition of metabolic syndrome, we propose that pediatricians look for youth with multiple component risk factors, such as high blood sugar, hypertension, obesity and abnormal lipid levels. These children should be targeted for more intensive intervention efforts.”

Since the National Cholesterol Education Program Adult Treatment Panel III coined the term “metabolic syndrome” in 2001 to describe a cluster of factors that leave adults at higher risk for developing diabetes and cardiovascular disease, research has exploded. The topic remains controversial within pediatrics, however, with dozens of competing definitions of pediatric MetS offered.

In the AAP Clinical Report, the study team describes the current state of play and offers evidence-based recommendations to guide clinicians on how to approach MetS in children and adolescents.

Adults with MetS have at least three of the following five individual risk factors:

  • High blood sugar (hyperglycemia)
  • Increased waist circumference (central adiposity)
  • Elevated triglycerides
  • Decreased high-density lipoprotein cholesterol (HDL-C), so-called “good” cholesterol and
  • Elevated blood pressure (hypertension).

This toxic combination ups adults’ odds of developing diabetes or heart disease. The process is set in motion by insulin resistance. Think Mousetrap, with each new development facilitating the next worrisome step. As fat expands, the cells become enlarged and become more resistant to insulin – a hormone that normally helps cells absorb glucose, an energy source. However, insulin retains the ability to stimulate fatty acids, which promotes even more fat cell expansion. Ectopic fat ends up stored in unexpected places, such as the liver. To top it off, the increased fat deposits end up causing increased inflammation in the system.

Sheela Magge

“Given the absence of a consensus on the definition of MetS, the unstable nature of MetS and the lack of clarity about the predictive value of MetS for future health in pediatric populations, pediatricians are rightly confused about MetS,” Dr. Magge and co-authors write.

At least five health entities, including the World Health Organization, introduced clinical criteria to define MetS among adults, Dr. Magge and colleagues write. Although more than 40 varying definitions have been used for kids, there is no clear consensus whether to use a MetS definition for children at all, especially as adolescents mature into adulthood. Depending on the study, at least 50 percent of kids no longer meet the diagnostic criteria weeks or years after diagnosis.

“Given the absence of a consensus on the definition of MetS, the unstable nature of MetS and the lack of clarity about the predictive value of MetS for future health in pediatric populations, pediatricians are rightly confused about MetS,” Dr. Magge and co-authors write.

As a first step to lowering their patients’ cardiometabolic risks, pediatricians should prevent and treat obesity among children and adolescents, the study authors write. Each year, clinicians should perform annual obesity screening using body mass index (BMI) as a measure, and also should screen children once a year for elevated blood pressure. Nonfasting non-HDL-C or fasting lipid screening should be done for children aged 9 to 11 to identify kids whose cholesterol levels are out of line. The team also recommends screening for abnormal glucose tolerance and Type 2 diabetes in youth with BMI greater than or equal to the 85th percentile, 10 years or older (or pubertal), with two additional risk factors, such as family history, high-risk race/ethnicity, hypertension or a mother with gestational diabetes.

Pediatricians do not need to use cut points based on MetS definitions since, for many risk factors, the growing child’s risk lies along a continuum.

Treatments can include lifestyle modifications – such as adopting a negative energy balance diet, drinking water instead of sugar-sweetened beverages, participating in a moderate- to high-intensity weight-loss program, increasing physical activity and behavioral counseling.

“Identifying children with multiple cardiometabolic risk factors will enable pediatricians to target the most intensive interventions to patients who have the greatest need for risk reduction and who have the greatest potential to experience benefits from such personalized medicine,” Dr. Magge and colleagues conclude.

Spectral data shine light on placenta

preemie baby

A research project led by Subechhya Pradhan, Ph.D., aims to shed light on metabolism of the placenta, a poorly understood organ, and characterize early biomarkers of fetal congenital heart disease.

The placenta serves as an essential intermediary between a pregnant mother and her developing fetus, transporting in life-sustaining oxygen and nutrients, ferrying out waste and serving as interim lungs, kidneys and liver as those vital organs develop in utero.

While the placenta plays a vital role in supporting normal pregnancies, it remains largely a black box to science. A research project led by Subechhya Pradhan, Ph.D., and partially funded by a Clinical and Translational Science Institute Research Award aims to shed light on placenta metabolism and characterize possible early biomarkers of impaired placental function in fetal congenital heart disease (CHD), the most common type of birth defect.

“There is a huge information void,” says Pradhan, a research faculty member of the Developing Brain Research Laboratory at Children’s National Health System. “Right now, we do not have very much information about placenta metabolism in vivo. This would be one of the first steps to understand what is actually going on in the placenta at a biochemical level as pregnancies progress.”

The project Pradhan leads will look at the placentas of 30 women in the second and third trimesters of healthy, uncomplicated pregnancies and will compare them with placentas of 30 pregnant women whose fetuses have been diagnosed with CHD. As volunteers for a different study, the women are already undergoing magnetic resonance imaging, which takes detailed images of the placenta’s structure and architecture. The magnetic resonance spectroscopy scans that Pradhan will review show the unique chemical fingerprints of key metabolites: Choline, lipids and lactate.

Choline, a nutrient the body needs to preserve cellular structural integrity, is a marker of cell membrane turnover. Fetuses with CHD have higher concentrations of lactate in the brain, a telltale sign of a shortage of oxygen. Pradhan’s working hypothesis is that there may be differing lipid profiles and lactate levels in the placenta in pregnancies complicated by CHD.  The research team will extract those metabolite concentrations from the spectral scans to describe how they evolve in both groups of pregnant women.

“While babies born with CHD can undergo surgery as early as the first few days (or sometimes hours) of life to correct their hearts, unfortunately, we still see a high prevalence of neurodevelopmental impairments in infants with CHD. This suggests that neurological dysfunctional may have its origin in fetal life,” Pradhan says.

Having an earlier idea of which fetuses with CHD are most vulnerable has the potential to pinpoint which pregnancies need more oversight and earlier intervention.

Placenta spectral data traditionally have been difficult to acquire because the pregnant mother moves as does the fetus, she adds. During the three-minute scans, the research team will try to limit excess movement using a technique called respiratory gating, which tells the machine to synchronize image acquisition so it occurs in rhythm with the women’s breathing.

Angioletta Rheumatic Heart Disease

Rheumatic Heart Disease Center Launches with $3.7 Million AHA Grant

Angioletta Rheumatic Heart Disease

Ten-year-old Angioletta was clinically diagnosed with rheumatic heart disease in 2014 (severe leakage of her mitral valve). She’s been medically managed at the clinic Children’s helps support and conducts research at in Gulu, and she is a very active participant in the support group led by Children’s National research assistant, Amy Scheel. Angioletta hasn’t had any major complications, but her only hope for long-term survival is to undergo open heart surgery to replace her abnormal valve. Experts are looking towards the research from the new Center to help prevent future generations of children like Angioletta from developing RHD.

Known as the ‘world’s forgotten disease,’ Rheumatic Heart Disease (RHD) is caused by untreated streptococcal throat infections that progress into acute rheumatic fever (ARF) and eventually weaken the valves of the heart. It is the most common cardiovascular disease in children and young adults globally – affecting nearly 33 million people and causing 345,000 deaths annually – yet, it is preventable with early detection and access to penicillin.

To help end the epidemic, Children’s National Health System has been awarded a $3.7 million grant from the American Heart Association (AHA) to launch a Rheumatic Heart Disease Center, with the goal of developing innovative strategies and economic incentives to improve the prevention and diagnosis of RHD in high-risk, financially disadvantaged countries and low-income communities across the United States.

Children’s National is one of four centers in the AHA’s Strategically Focused Children’s Research Network, which is dedicated to improving children’s heart health and reducing the global burden of cardiovascular disease and stroke. AHA selected Children’s for the grant based on its proven record of global collaboration to solve complex health issues and the potential impact of this research. The program will use Children’s robust telemedicine infrastructure to connect co-collaborators around the world, as well as train the next generation of globally minded cardiovascular researchers.

“While it’s often thought that we’ve already beaten rheumatic heart disease, data shows there’s nearly no decrease in mortality rates in low-income countries. The disease is endemic in Sub-Saharan Africa, and some poverty-stricken communities in the U.S. are hit nearly as hard,” said Craig Sable, M.D., associate division chief of cardiology. “We are thrilled to receive this funding from the AHA, which will help us close the research gap for this neglected disease and change the plight of millions of children around the world.”

About the center and research focus areas

Over the next four years, the Rheumatic Heart Disease Center, led by Children’s National Heart Institute experts Dr. Sable and Andrea Beaton, M.D., cardiologist, along with RHD leaders around the globe, will develop evidence-based strategies to strengthen the health system’s response to RHD through synergistic basic, clinical and population science research along the entire spectrum of the disease.

Andrea Beaton and Craig Sable

The Rheumatic Heart Disease Center, led by Children’s National Heart Institute experts Andrea Beaton, M.D., and Craig Sable, M.D., along with RHD leaders around the globe, will develop evidence-based strategies to strengthen the health system’s response to RHD.

The basic research project, led by James Dale, M.D., chief of the division of infectious disease at the University of Tennessee in Memphis, will work to better define the immune system response to Group A Streptococcal (GAS) infection, or strep throat, paving the way for vaccine development. In collaboration with a partner site in Cape Town, South Africa, experts will recruit 300 children ages 5-15 to participate for 24 months in a study capturing and classifying various strains of the GAS bacteria. Similar to the common flu, the strains of GAS bacteria vary from region to region and year to year. By identifying immune system targets, or how our bodies fight GAS, the research can inform the creation of effective and long-lasting vaccines.

Dr. Beaton will lead the clinical project that will work to improve understanding and detection of ARF, the precursor to RHD. According to Dr. Beaton, the current, outdated paradigm is that patients with RHD at one point experienced a full-blown episode of ARF – including fever, severe joint pains and rash. These symptoms should be unmistakable and prompt treatment, but in truth the disease remains vastly underdiagnosed in high-risk regions. Through an on-the-ground partnership with experts at Mulago National Referral Hospital in Uganda, the clinical project will work to enroll over 1,000 children ages 3-18 with more subtle symptoms, potentially suggestive of ARF, in order to paint a more accurate picture of the disease in Africa today.

“The gap between the low number of children diagnosed with ARF and the high number of young adults with advanced RHD remains one of the most challenging mysteries and barriers to improved RHD prevention,” said Dr. Beaton. “For the first time, we will systematically characterize the clinical, laboratory and echocardiographic features of ARF in low-resource settings, with the goal of developing a biological signature for ARF that can be translated into a diagnostic test and improve detection.”

Dr. Beaton expects that this research could benefit other related diseases too, such as kidney disease or serious skin infections.

The population research project, led by David Watkins, M.D., M.P.H., an expert in epidemiological and economic modeling at the University of Washington in Seattle, will work to build an economic case for prevention around the world, using the data from the basic and clinical work. The goal is to identify local gaps in delivery of health services for disease prevention and treatment and to measure the cost-effectiveness of RHD interventions, as well as the cost of inaction – especially as patients suffering from advanced RHD are often in the prime of their productive, adult lives. Researchers anticipate the findings will provide effective tools for addressing RHD in other endemic countries too.

zika virus

Will the Zika epidemic re-emerge in 2017?

Anthony Fauci

Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, discussed the possibility of a reemergence of Zika virus at Children’s National Research and Education Week.

Temperatures are rising, swelling the population of Aedes mosquitoes that transmit the Zika virus and prompting an anxious question: Will the Zika epidemic re-emerge in 2017?

Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH), sketched out contrasting scenarios. Last year in Puerto Rico, at least 13 percent of residents were infected with Zika, “a huge percentage of the population to get infected in any one outbreak,” Dr. Fauci says. But he quickly adds: “That means that 87 percent of the population” did not get infected. When the chikungunya virus swept through the Caribbean during an earlier outbreak, it did so in multiple waves. “We are bracing for a return of Zika, but we shall see what happens.” Dr. Fauci says.

When it comes to the continental United States, however, previous dengue and chikungunya outbreaks were limited to southern Florida and Texas towns straddling the Mexican border. Domestic Zika transmission last year behaved in much the same fashion.

“Do we think we’re going to get an outbreak [of Zika] that is disseminated throughout the country? The answer is no,” Dr. Fauci adds. “We’re not going to see a major Puerto Rico-type outbreak in the continental United States.”

Dr. Fauci’s remarks were delivered April 24 to a standing-room-only auditorium as part of Research and Education Week, an annual celebration of the cutting-edge research and innovation happening every day at Children’s National. He offered a sweeping, fact-filled summary of Zika’s march across the globe: The virus was first isolated from a primate placed in a treehouse within Uganda’s Zika forest to intentionally become infected; Zika lurked under the radar for the first few decades, causing non-descript febrile illness; it bounced from country to country, causing isolated outbreaks; then, it transformed into an infectious disease of international concern when congenital Zika infection was linked to severe neural consequences for babies born in Brazil.

zika virus

Zika virus lurked under the radar for several decades, causing non-descript febrile illness; it bounced from country to country, resulting in isolated outbreaks; then, it transformed into an infectious disease of international concern.

“I refer to Brazil and Zika as the perfect storm,” Dr. Fauci told attendees. “You have a country that is a large country with a lot of people, some pockets of poverty and economic depression –  such as in the northeastern states –  without good health care there, plenty of Aedes aegypti mosquitoes and, importantly, a totally immunologically naive population. They had never seen Zika before. The right mosquitoes. The right climate. The right people. The right immunological status. And then, you have the explosion in Brazil.”

In Brazil, 139 to 175 babies were born each year with microcephaly – a condition characterized by a smaller than normal skull – from 2010 to 2014. From 2015 through 2016, that sobering statistic soared to 5,549 microcephaly cases, 2,366 of them lab-confirmed as caused by Zika.

Microcephaly “was the showstopper that changed everything,” says Dr. Fauci. “All of a sudden, [Zika] went from a relatively trivial disease to a disease that had dire consequences if a mother was infected, particularly during the first trimester.”

As Zika infections soared, ultimately affecting more than 60 countries, the virus surprised researchers and clinicians a number of times, by:

  • Being spread via sex
  • Being transmitted via blood transfusion, a finding from Brazil that prompted the Food and Drug Administration to recommend testing for all U.S. donated blood and blood products
  • Decimating developing babies’ neural stem cells and causing a constellation of congenital abnormalities, including vision problems and contractions to surviving infants’ arms and legs
  • Causing Guillain-Barré syndrome
  • Triggering transient hearing loss
  • Causing myocarditis, heart failure and arrhythmias

When it comes to the U.S. national response, Dr. Fauci says one of the most crucial variables is how quickly a vaccine becomes available to respond to the emerging outbreak. For Zika, the research community was able to sequence the virus and launch a Phase I trial in about three months, “the quickest time frame from identification to trial in the history of all vaccinology,” he adds.

Zika is a single-stranded, enveloped RNA virus that is closely related to dengue, West Nile, Japanese encephalitis and Yellow fever viruses, which gives the NIH and others racing to produce a Zika vaccine a leg up. The Yellow fever vaccine, at 99 percent effectiveness, is one of the world’s most effective vaccines.

“I think we will wind up with an effective vaccine. I don’t want to be over confident,” Dr. Fauci  says. “The reason I say I believe that we will is because [Zika is] a flavivirus, and we have been able to develop effective flavivirus vaccines. Remember, Yellow fever is not too different from Zika.”

EKG monitor

Protecting the hearts of pediatric cancer patients

EKG monitor

Children’s National has developed a cardio-oncology program to closely follow the heart health of oncology patients to detect and stop progression of heart disease.

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

Niti Dham

“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 Niti Dham, M.D.

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.

Fat Cells

Cellular signals may increase atherosclerosis risk

Fat Cells

Fat cells from obese patients have the ability to send signals that can accelerate biological processes leading to atherosclerosis.

Obesity has been linked to a variety of adverse health conditions, including Type 2 diabetes, cancer, heart attack and stroke – conditions that may begin as early as childhood in patients whose obesity also begins early. While this much is known, it has been unclear how extra fat mass might lead to these chronic health conditions.

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.”

Chinwe Unegbu

PDE-5 inhibitors for pediatric hypertension

Chinwe Unegbu

A study led by Chinwe Unegbu, M.D., indicates the benefits of PDE-5 inhibitors to treat pediatric pulmonary hypertension far outweigh potential harmful side effects.

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.”

Teen Girl drawing a heart on an iPad

Illuminating cardiometabolic risk in Down syndrome

Teen Girl drawing a heart on an iPad

A leading researcher at Children’s National says researchers should look closely at the increased risks of obesity and thyroid disease common in patients with Down Syndrome, and determine how these long term comorbidities relate to cardiovascular and metabolic (cardiometabolic) risk, body image, and quality of life.

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.”

Photo of patient walking through the hallways

Cardiovascular and GI symptom relief

Photo of patient walking through the hallways

By adding antroduodenal manometry to the cardiovascular tilt table test, doctors in the GI Motility Program are able to collaborate with cardiologists to treat both cardiovascular and gastroenterological symptoms in children with complex orthostatic intolerance.

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.

Taking telemedicine to heart

For seven years, a Children’s National team has worked on new technologies to blunt the severity of rheumatic heart disease around the world, vastly improving patients’ chances of avoiding serious complications.

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.”

This work was supported by a grant from the Verizon Foundation and in-kind donations from General Electric and ViTelNet.

Fetal Cardiac Health

Managing transposition of the great arteries in the womb

Fetal Cardiac Health

Monitoring and managing fetuses’ heart health in the womb can greatly improve their chances of living long and productive lives

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.”

Newborn pulse oximetry screening: which algorithm is best?

Gerard Martin

There’s a consensus that Pulse oximetry screening (POS) is a proven way to find critical congenital heart defects. But, screenings, specifically the algorithm used, vary. Gerard R. Martin, M.D., Medical Director of Global Health at Children’s National Health System, and Andrew K. Ewer, MD, explore which algorithm is best in their just-published article in Pediatrics. Read more.

Mary Donofrio

Getting to the heart of cardiac malposition with fetal MRI

Mary T. Donofrio, MD, Director of the Fetal Heart Program and Critical Care Delivery Program at Children's National Health System

Mary T. Donofrio, M.D., Director of the Fetal Heart Program and Critical Care Delivery Program at Children’s National Health System

In a small percentage of pregnancies, the fetuses’ hearts develop in the wrong place. In the congenital anomaly known as heterotaxy syndrome that often includes a severe heart defect, the heart is often displaced from its usual position in the left chest. In other instances, the heart starts out in a normal position; however, it is pushed out of its normal position by a mass that grows in the chest cavity, by abnormal development of the lungs, or due to other causes. Although rare, babies born with cardiac malpositions associated with other congenital defects can be the most serious of all possible birth defects.

Sometimes, fetuses with these congenital problems die in the womb. Others do not survive long after birth. In some pregnancies, surgery is performed shortly after childbirth to stabilize the circulation so newborns even have a chance at life.

Correctly diagnosing these cardiac conditions during pregnancy can help doctors and parents alike make the most informed decisions and plan ahead.

However, the tools now used most often to reveal the overall anatomic details of cardiac malpositions — obstetrical ultrasound and fetal echocardiography — often don’t give a full picture. A clear view of the fetus can be obscured by the position of the fetus, insufficient amniotic fluid, or even a mother’s body habitus. Imaging techniques sometimes also have a hard time distinguishing between liver, bowel, and lung because the echogenicity of these tissues — the signature that sound waves make as they bounce back from their targets — is so similar.

“To be able to offer parents the best and most comprehensive counseling, and to begin planning for the type of intensive and multidisciplinary care that many of these babies will require, we need to have access to as much information as we can about each baby, not only relating to the heart but all the other organs as well,” says Mary T. Donofrio, M.D., a pediatric cardiologist who directs the Children’s National Health System Fetal Heart Program and Critical Care Delivery Program. “Unfortunately in some instances, obstetrical ultrasound and fetal echocardiography, the two diagnostic tools used most often in these cases, can be limited in what they tell us.”

What fetal MRI can show

An underutilized technique that gathers more details about the associated abnormalities that often accompany cardiac malposition during pregnancy is fetal magnetic resonance imaging, or fetal MRI, says Dr. Donofrio. Even though this technique is widely used to diagnose other fetal conditions, such as brain anomalies, it’s rarely used to better define the overall anatomy in cardiac malposition.

To determine whether fetal MRI is effective in complementing obstetrical ultrasound and fetal echocardiography, the current standard of care for this condition, Dr. Donofrio and colleagues took a retrospective look at all cases of cardiac malposition in which fetuses were evaluated using MRI between 2008 to 2013 at Children’s National. Their search turned up 42 cases.

Twenty-three cases had been diagnosed with obstetrical ultrasound and fetal echocardiography as having additional abnormalities beyond the heart’s changed position, and 19 had been given the diagnosis of heterotaxy syndrome. Each patient had been assigned to various known subtypes of these conditions, with some classified as having an unknown etiology for the findings.

After fetal MRI, the diagnoses of nearly one-third changed or were better delineated. Seven of the 23 cases of cardiac malposition attributed to an extra cardiac anomaly were reassigned to a cause different from the original diagnosis based on the new, more detailed information provided by fetal MRI, including three in which a complete diagnosis could not be made due to poor visualization by ultrasound. Five of the 19 cases attributed of heterotaxy were reassigned to different subgroups within this disorder or were given a different diagnosis completely after fetal MRI.

In eight of these 12 diagnoses that changed after fetal MRI, doctors were able to confirm these findings postnatally. Other cases were either lost to follow-up, pregnancy termination, or fetal demise.

The research team led by Dr. Donofrio published these results in the August 2016 issue of Prenatal Diagnosis.

Overall, she says the findings demonstrated the benefits of using fetal MRI as an adjunct to obstetrical ultrasound and fetal echocardiography. MRI offers advantages over ultrasound, she explains, including better spatial resolution, a wider field of view, and a way to see through or around maternal body fat, overlying fetal bone, or a fetus whose position is not optimal.

“Determining the etiology of cardiac malposition remains a challenging diagnosis, and the value of accurate prenatal diagnosis has been long recognized,” Donofrio and colleagues write in the study. “Ultimately, fetal MRI can assist with identifying the etiology of cardiac malposition for informative prenatal counseling and multidisciplinary planning.”

Elena Grant

Interventional cardiac magnetic resonance team welcomes new specialist

elena-grant-photo

The Interventional Cardiac Magnetic Resonance (ICMR) Program at Children’s National is actively developing newer and safer ways to perform cardiac procedures on young patients, with some of the world’s leading experts in cardiac catheterization and imaging. Elena Grant, M.D., a former pediatric cardiology fellow at Children’s National, is the newest member to join the team that pioneered real-time MRI-guided radiation-free cardiac catheterization for children.

In addition to clinical work as a Children’s National Interventional Cardiologist, Dr. Grant will perform preclinical research at the National Institutes of Health to develop new procedures, techniques, and devices that can be translated to clinical practice to treat children and adults with congenital heart disease.

Dr. Grant specializes in interventional cardiology. She received her medical degree from the University of Dundee Medical School in Dundee, Scotland, followed by Foundation Training in Edinburgh, Scotland. She completed her pediatric residency at Massachusetts General Hospital, her Pediatric Cardiology fellowship at Children’s National, and she recently finished an advanced fellowship in interventional pediatric cardiology at Children’s Healthcare of Atlanta and Emory University.

Advances in interventional cardiovascular MRI

Children’s National is at the forefront of this exciting new field and is currently the only institution in the United States to perform radiation-free MRI-guided cardiac catheterization procedures in children.

ICMR is a partnership with the National Institutes of Health that brings together researchers, clinicians, engineers, and physicists to provide radiation-free, less invasive, and more precise diagnostics and treatment options for pediatric patients and adults with congenital heart disease.

The ICMR approach to heart catheterization uses real-time MRI, instead of X-ray, in pediatric research subjects undergoing medically necessary heart catheterization. This research study is intended as a step toward routine MRI-guided catheterization in children, which attempts to avoid the hazards of ionizing radiation (X-ray).

In 2015, after working with NIH to explore how interventional cardiovascular MRI could be integrated into pediatric practices, the ICMR team, including Dr. Grant, Russell Cross, M.D., Joshua Kanter, M.D., and Laura Olivieri, M.D., performed the first  radiation-free MRI-guided right heart catheterization on a 14-year-old girl at Children’s National. Since then, nearly 50 such procedures have been successfully completed, and the team is working to broaden the age range and cardiac disease complexity of patients who can undergo the procedure.

About 1 percent of newborns are born with a heart condition, and the team at Children’s performs more than 450 X-ray guided cardiac catheterizations and over 500 cardiac MRI scans per year.