Cardiology and Heart Surgery Research

Experimental model study links phthalates and cardiovascular health

February 7, 2018

“Because phthalate chemicals are known to migrate out of plastic products, our study highlights the importance of adopting safer materials, chemical additives and/or surface coatings for use in medical devices to reduce the risk of inadvertent exposure,” explains study senior author Nikki Gillum Posnack, Ph.D.

An experimental model exposed to di-2-ethylhexyl-phthalate (DEHP), a chemical that can leach from plastic-based medical devices, experienced altered autonomic regulation, heart rate variability and cardiovascular reactivity, according to a study published online Nov. 6, 2017 by the American Journal of Physiology. The pre-clinical model study is the first to show such an association between phthalate chemicals used in everyday medical devices like IV tubing and cardiovascular health.

“Plastics have revolutionized medical devices, transformed how we treat blood-based diseases and helped to make innovative cardiology procedures possible,” says Nikki Gillum Posnack, Ph.D., study senior author and assistant professor at the Children’s National Heart Institute within the Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI) at Children’s National Health System. “Because phthalate chemicals are known to migrate out of plastic products, our study highlights the importance of adopting safer materials, chemical additives and/or surface coatings for use in medical devices to reduce the risk of inadvertent exposure.”

According to the Food and Drug Administration, patients who are undergoing IV therapy, blood transfusion, cardiopulmonary bypass or extracorporeal membrane oxygenation or who receive nutrition through feeding support tubes have the potential to be exposed to DEHP.

Patients undergoing extensive interventions to save their lives may be exposed to multiple plastic-based devices that supply oxygen and nutrition or that pump newly oxygenated blood to oxygen-starved organs.

“These interventions keep very fragile kids alive. What’s most important is getting patients the care they need when they need it,” Posnack says. “In the biomaterials field, our ultimate goal is to reduce inadvertent risks to patients that can result from contact with plastic products by identifying replacement materials or safer coatings to lower overall risk.”

In order to assess the safety of phthalate chemicals used in such medical devices, the Children’s-led research team implanted adult experimental models with radiofrequency transmitters that monitored their heart rate variability, blood pressure and autonomic regulation. Then, they exposed the experimental models to DEHP, a softener used in making the plastic polymer, polyvinyl chloride, flexible.

DEHP-treated pre-clinical models had decreased heart rate variability with lower-than-normal variation in the intervals between heart beats. The experimental models also showed an exaggerated mean arterial pressure response to ganglionic blockade. And in response to a stressor, the experimental models in the treatment group displayed enhanced cardiovascular reactivity as well as prolonged blood pressure recovery, according to the study team.

“The autonomic nervous system is a part of the nervous system that automatically regulates such essential functions as blood pressure and breathing rate without any conscious effort by the individual,” Posnack adds. “Because alterations in the autonomic balance provide an early warning sign of trouble – before symptoms of hypertension or atherosclerosis manifest – our findings underscore the importance of additional studies to explore the potential impact of phthalate chemicals on organ function.”

Billie Lou Short, M.D., chief of Children’s Division of Neonatology, called the paper an “important study” that builds on a foundation laid in the late 199os by Children’s researchers who were the first to show that plasticizers migrated from tubing in the extracorporeal membrane oxygenation (ECMO) circuit. Children’s researchers also led a study published in 2004 that evaluated the effect of plasticizers on the human reproductive system. A small number of adolescents who had undergone ECMO as newborns did not experience the complications that had been seen in in experimental models, Dr. Short says.

Posnack’s study co-authors include Rafael Jaimes III, Ph.D., SZI staff scientist; Meredith Sherman, SZI research technician; and Adam Swiercz, Narine Muselimyan and Paul J. Marvar, all of The George Washington University.

Children’s receives NIH grant to study use of stem cells in healing CHD brain damage

February 2, 2018

“Bone marrow stem cells are used widely for stroke patients, for heart attack patients and for those with developmental diseases,” explains Nobuyuki Ishibashi, M.D. “But they’ve never been used to treat the brains of infants with congenital heart disease. That’s why we are trying to understand how well this system might work for our patient population.”

The National Institutes of Health (NIH) awarded researchers at Children’s National Health System $2.6 million to expand their studies into whether human stem cells could someday treat and even reverse neurological damage in infants born with congenital heart disease (CHD).

Researchers estimate that 1.3 million infants are born each year with CHD, making it the most common major birth defect. Over the past 30 years, advances in medical technology and surgical practices have dramatically decreased the percentage of infants who die from CHD – from a staggering rate of nearly 100 percent just a few decades ago to the current mortality rate of less than 10 percent.

The increased survival rate comes with new challenges: Children with complex CHD are increasingly diagnosed with significant neurodevelopmental delay or impairment. Clinical studies demonstrate that CHD can reduce oxygen delivery to the brain, a condition known as hypoxia, which can severely impair brain development in fetuses and newborns whose brains are developing rapidly.

Nobuyuki Ishibashi, M.D., the study’s lead investigator with the Center for Neuroscience Research and director of the Cardiac Surgery Research Laboratory at Children’s National, proposes transfusing human stem cells in experimental models through the cardio-pulmonary bypass machine used during cardiac surgery.

“These cells can then identify the injury sites,” says Dr. Ishibashi. “Once these cells arrive at the injury site, they communicate with endogenous tissues, taking on the abilities of the damaged neurons or glia cells they are replacing.”

“Bone marrow stem cells are used widely for stroke patients, for heart attack patients and for those with developmental diseases,” adds Dr. Ishibashi. “But they’ve never been used to treat the brains of infants with congenital heart disease. That’s why we are trying to understand how well this system might work for our patient population.”

Dr. Ishibashi says the research team will focus on three areas during their four-year study – whether the stem cells:

Reduce neurological inflammation,
Reverse or halt injury to the brain’s white matter and
Help promote neurogenesis in the subventricular zone, the largest niche in the brain for creating the neural stem/progenitor cells leading to cortical growth in the developing brain.

At the conclusion of the research study, Dr. Ishibashi says the hope is to develop robust data so that someday an effective treatment will be available and lasting neurological damage in infants with congenital heart disease will become a thing of the past.

Dr. Laura Olivieri holding a 3D printed heart

Cardiology and radiology experts to participate in CMR 2018

January 17, 2018

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.

Assessing the risk factors in rheumatic heart disease

December 13, 2017

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.”

The effects of cardiopulmonary bypass on white matter development

December 12, 2017

Nobuyuki Ishibashi, M.D., and a team of researchers looked the effects of cardiopulmonary bypass surgery on the white matter of an animal model.

Mortality rates for infants born with congenital heart disease (CHD) have dramatically decreased over the past two decades, with more and more children reaching adulthood. However, many survivors are at risk for neurodevelopmental abnormalities associated with cardiopulmonary bypass surgery (CPB), including long-term injuries to the brain’s white matter and neural connectivity impairments that can lead to neurological dysfunction.

“Clinical studies have found a connection between abnormal neurological outcomes and surgery, but we don’t know what’s happening at the cellular level,” explains Nobuyuki Ishibashi, M.D., Director of the Cardiac Surgery Research Laboratory at Children’s National. To help shed light on this matter, Ishibashi and a team of researchers looked at the effects of CPB on the white matter of an animal model.

The research team randomly assigned models to receive one of three CPB-induced insults: a sham surgery (control group); full-flow bypass for 60 minutes; and 25°C circulatory arrest for 60 minutes. The team then used fractional anisotropy — a technique that measures the directionality of axon mylenation — to determine white matter organization in the models’ brains. They also used immunohistology techniques to assess the integrity of white matter oligodendrocytes, astrocytes and microglia.

The results, published in the Journal of the American Heart Association, show that white matter experiences region-specific vulnerability to insults associated with CPB, with fibers within the frontal cortex appearing the most susceptible. The team also found that fractional anisotropy changes after CPB were insult dependent and that regions most resilient to CPB-induced fractional anisotropy reduction were those that maintained mature oligodendrocytes.

From these findings, Ishibashi and his co-authors conclude that reducing alterations of oligodendrocyte development in the frontal cortex can be both a metric and a goal to improve neurodevelopmental impairment in the congenital heart disease population. “Because we are seeing cellular damage in these regions, we can target them for future therapies,” explains Ishibashi.

The study also demonstrates the dynamic relationship between fractional anisotropy and cellular events after pediatric cardiac surgery, and indicates that the technique is a clinically relevant biomarker in white matter injury after cardiac surgery.

Children’s National leaders join with Governor Martin O'Malley

Landmark CDC report finds easy, painless test decreases infant cardiac deaths by 33 percent

December 6, 2017

Stakeholders meeting at American College of Cardiology’s Heart House in February 2012 to discuss U.S. implementation and recommendation of pulse ox screening.

Congenital heart disease (CHD) is the most common birth defect, affecting approximately eight out of every 1,000 babies born in the United States. The most severe cases, critical congenital heart disease (CCHD), affect three in every 1,000 babies. Just a few years ago, many of these seemingly healthy infants were discharged from the hospital only to suffer severe complications, brain damage or even death due to their undiagnosed conditions.

In 2009, Children’s National Cardiologist and Medical Director of Global Services Gerard Martin, M.D., and the nursing staff within the Children’s National Heart Institute took on this challenge with peers around the country by urging legislators and educating clinicians that implementing a simple, painless test called pulse oximetry (ox) could identify infants who may suffer from undetected CCHD.

Today, 49 out of 50 states in the United States mandate pulse ox screening, which uses a small, red light, or “probe,” to measure the percent oxygen saturation of hemoglobin in the arterial blood. Use of pulse ox also is included in the Recommended Uniform Screening Panel (RUSP), endorsed by the Secretary of the U.S. Department of Health and Human Services.

This week, the Centers for Disease Control and Prevention released a report presenting definitive evidence that these efforts are saving lives. Published in JAMA, the report shows a 33 percent reduction in pediatric CCHD deaths from 2007 to 2013 in states with mandated pulse ox screening compared to states without screening policies. The study also found a 21 percent drop in infant deaths from other or unspecified cardiac causes in those states. Applying the data to the United States as a whole, this equates to preventing the deaths of 120 newborns each year.

“This is a landmark moment for the countless parents, clinicians, industry partners, legislators and many others who fought tirelessly to have this lifesaving screening added to the routine panel of tests every child receives before they leave the hospital,” says Dr. Martin. “We now have concrete, measurable evidence that their efforts are saving lives.”

Physicians and staff at Children’s National and Holy Cross Hospital in Silver Spring, Md., began their campaign by initiating a research study to examine the feasibility of implementing pulse ox screening for CCHD in a community hospital setting. Their findings not only showed it was possible, but it also only required approximately 3.5 minutes per baby, and it could be integrated into existing workflow without adding additional nursing staff.

Children’s National leaders join with Governor Martin O’Malley and Maryland legislators for the signing of SB 786 and HB 714, mandating pulse oximetry screening across the state on May 19, 2011.

The findings also led to the development of an educational toolkit – now available in English, Spanish, Arabic, French, Chinese and Russian – which Dr. Martin and the Children’s National Heart Institute’s nursing staff have used to teach upwards of 3,000 hospitals, globally, how to implement the screening. Children’s National, in partnership with Baby’s First Test, also released two videos for parents and clinicians respectively, to forward knowledge about pulse ox.

Simultaneously, the Children’s National team worked as national and local advocacy leaders. Dr. Martin served as part of the federal Advisory Committee on Heritable Disorders in Newborns and Children that issued national recommendations to add screening for congenital heart disease to RUSP in 2011. The team also spearheaded efforts that led to the passage of legislative mandates and helped to implement screening for all newborns in Maryland, Virginia and Washington, D.C.

“When we started this work nearly a decade ago, I’d meet so many moms who were crying because they had lost their child to critical congenital heart disease. Now, we meet moms who are crying because their baby’s condition has been found and their life has been saved,” says Dr. Martin. “This report shines a light on so many heroes–the parents who spoke up, the members of the federal advisory committee, the nurses and clinicians who learned and taught others how to implement the screening. Today is a victory for all of us.”

Dr. Martin hopes this announcement will prompt Idaho, the only state that has not adopted universal CCHD screening, to take action. He also says health leaders need to continue to invest in smarter technology and testing capabilities, as well as advance training and education for more thorough prenatal ultrasounds, so that every baby with CCHD is found early and receives lifesaving care.

Research led by Zhe Han featured on cover of JASN, leading kidney disease journal

December 5, 2017

Coenzyme Q10, one of the best-selling nutrient supplements to support heart health also could be beneficial for kidney health, according to research conducted in transgenic fruit flies that was led by Zhe Han, Ph.D., associate professor at Children’s Center for Cancer and Immunology Research.

Nephrocytes, filtration kidney cells in Drosophila, require the Coq2 gene for protein reabsorption, toxin sequestration and critical cell ultrastructure. Silencing the Coq2 gene results in aberrantly localized nephrocyte slit diaphragms and deformed lacunar channels, Han and co-authors found. Nephrocytes closely resemble the podocytes of the human kidney.

The research team’s paper, published online April 2017, this fall was featured on the cover of Journal of the American Society of Nephrology, the No. 1 kidney disease journal.

“I am honored that the JASN editors chose to feature my lab’s work on the cover of this prestigious journal,” Han says. “This underscores the utility of our gene-replacement approach, which silenced the fly homolog in the tissue of interest – here, the kidney cells – and provided a human gene to supply the silenced function.”

AusculTech DX wins Washington Business Journal 2017 Innovation Award

October 23, 2017

StethAid is a low-cost mobile device-based digital stethoscope that lets pediatric healthcare providers know instantly if a heart murmur is innocent or a signal of a more pathological heart problem.

AusculTech DX, a start-up company that formed within the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Health System, was selected as a Washington Business Journal 2017 Innovation Award honoree for their device, StethAid.

StethAid is a low-cost mobile device-based digital stethoscope that lets pediatric healthcare providers know instantly if a heart murmur is innocent or a signal of a more pathological heart problem. The device was developed by Robin Doroshow, M.D., a pediatric cardiologist at Children’s National, and Raj Shekhar, Ph.D., a principal investigator with the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National to help eliminate unnecessary referrals of patients with Still’s murmurs to pediatric cardiologists.

In studying her extensive library of recorded heartbeats, Dr. Doroshow noticed that the Still’s murmur had the same distinct musical tone, regardless of the patient’s age, size and heart rate. When she realized that there was likely a way to teach a computer to recognize the tone, she approached Shekhar with her idea. He developed a highly accurate computer algorithm, based on AI (artificial intelligence) principles, to recognize the consistent Still’s tone and worked to develop the digital device. In early 2015, the team formed AusculTech DX. In early 2016, a clinical prototype was developed and they began testing the device.

The Washington Business Journal’s annual Innovation Awards honor Greater Washington companies, agencies and teams working to keep the metro on the cutting edge in tech, health care, cybersecurity and more. AusculTech DX was one of the 15 honorees selected for the 2017 Innovation Awards.

Brain impairment in newborns with CHD prior to surgery

October 18, 2017

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.”

$250K awarded to six winners presenting innovative pediatric medical devices

September 26, 2017

SZI Symposium Winners

Six companies presenting innovative medical device solutions that address significant unmet needs in pediatric health were awarded a total of $250,000 in grant money yesterday in San Jose, Calif. at the Fifth Annual Pediatric Device Innovation Symposium, organized by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Health System.

The “Make Your Medical Device Pitch for Kids!” competition is sponsored by the National Capital Consortium for Pediatric Device Innovation (NCC-PDI), an FDA-funded consortium led by Children’s National and the A. James Clark School of Engineering at the University of Maryland. Four companies were awarded $50,000 each and two were awarded $25,000. The six winners were selected from a field of twelve finalists. A record 98 total submissions from five countries were received for the competition this year.

“To improve care for children, it is imperative that we recognize and encourage relevant new solutions in pediatric medical devices, especially in light of the challenges innovators face in addressing this specialized market,” said Kurt Newman, M.D., president and CEO of Children’s National. “Children’s National is committed to fostering collaboration among innovators, clinicians, policy makers and investors to advance pediatric device development for the benefit of children everywhere.”

This year’s winning innovations receiving $50,000 awards are:

CorInnova, Houston, Texas – soft robotic, non-blood-contacting biventricular cardiac assist device for the treatment of heart failure in children
Green Sun Medical, Fort Collins, Colo. – novel device that provides necessary pressure for the correction of spinal deformity while providing real-time feedback to clinicians
Hub Hygiene and Georgia Institute of Technology, Atlanta, Ga. – low-cost, single-use cleaning technology to prevent central line-associated blood stream infections (CLABSI), a hospital-acquired infection by pediatric ICU patients
NAVi Medical Technologies, Houston, Texas – device to provide accurate information about the localization of an umbilical venous catheter (UVC) used in critically-ill newborns to reduce the risk of catheter malposition

Winning innovations receiving $25,000 awards are:

Prapela, LLC, Boston, Mass. – novel “baby box” that will allow for a non-pharmacological approach to help drug-exposed infants relax and sleep during withdrawal and post-withdrawal care
X-Biomedical, Inc., Philadelphia, Pa. – portable surgical microscope for use in surgeries for treatable causes of blindness in low-income countries and under-resourced setting

“We are honored to recognize these outstanding innovations with this funding,” said Kolaleh Eskandanian, Ph.D., executive director of the Sheikh Zayed Institute and NCC-PDI. “We are even more excited about welcoming this new cohort of companies to our family of pediatric device startups and entrepreneurs. Together we can move the needle a bit faster and safer to bring pediatric products to market.”

She added that in addition to the financial support and consultation services through NCC-PDI, the awardees can leverage the validation received through this highly competitive process to raise the additional capital needed for commercialization. Since inception in 2013, NCC-PDI has supported 67 pediatric devices and the companies and research labs owning these devices have collectively raised $55 million in additional funding.

The twelve finalists each made five-minute presentations to the symposium audience and then responded to judges’ questions. Finalists also included Anecare, LLC, Salt Lake City, Utah; ApnoSystems, Buenos Aires, Argentina; Deton Corp., Pasadena, Calif.; Kite Medical, Dublin, Ireland; Moyarta 2, LLC, The Plains, Va.; and Oculogica, Inc., New York, N.Y.

Serving on the distinguished panel of judges were Susan Alpert, M.D., of SFA Consulting, a former director of the FDA Office of Device Evaluation and former senior vice president and chief regulatory officer of Medtronic; Charles Berul, M.D., co-director, Children’s National Heart Institute; Andrew Elbardissi, M.D., of Deerfield Management; Rick Greenwald, Ph.D., of the New England Pediatric Device Consortium (NEPDC); James Love, J.D., of Oblon; Josh Makower, M.D., of NEA; Jennifer McCaney, Ph.D., of MedTech Innovator; Jackie Phillips, M.D., of Johnson & Johnson; and Tracy Warren of Astarte Ventures.

The pitch competition is a highlight of the annual symposium organized by the Sheikh Zayed Institute at Children’s National, designed to foster innovation that will advance pediatric healthcare and address the unmet surgical and medical device needs for children. New this year, the symposium co-located in a joint effort with The MedTech Conference powered by AdvaMed, the premier gathering of medtech professionals in North America.

Keynote speakers at the event included Daniel Kraft, M.D., faculty chair of Medicine & Neuroscience, Singularity University and executive director, Exponential Medicine; Vasum Peiris, M.D., chief medical officer, Pediatrics and Special Populations, FDA; and Alan Flake, M.D., director of Center for Fetal Research, Children’s Hospital of Philadelphia.

Panel discussions focused on gap funding for pediatric innovation, the journey from ideation to commercialization, and the pediatric device needs assessment in the future regulatory environment.

Assessing the global burden of rheumatic heart disease

September 13, 2017

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.

Namaste: how mindfulness aids cardiac patients

September 13, 2017

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.”

European workgroup creates recommendations for CCHD pulse oximetry screening

September 5, 2017

Several experts, including Gerard R. Martin, M.D., recently published recommendations for the use and standardization of pulse oximetry screening for critical congenital heart defects in newborns.

The European Pulse Oximetry Screening Workgroup recently published recommendations for the use and standardization of pulse oximetry screening for critical congenital heart defects in newborns. Children’s National Medical Director of Global Services Gerard R. Martin, M.D., was among the experts that compiled the recommendations.

Approximately 1 in 500 babies is born with a critical congenital heart defect (CCHD). Because these conditions can cause serious, life-threatening symptoms, early detection and intervention is essential. Pulse oximetry screening (POS) – a method that measures oxygen saturation – is regarded as a simple, quick and reliable tool for early detection of CCHD, and was recommended for use in screening by the American Academy of Pediatrics and the American Heart Association in 2011.

In Europe, although POS is being used by an increasing number of hospitals, few countries have issued national guidelines recommending universal POS. To remedy this situation, neonatologists, experts in CCHD screening, and representatives from major scientific pediatric societies across Europe came together to create recommendations for the use and standardization of POS for early detection of CCHD across Europe.

Their recommendations, which were published in The Lancet, are as follows:

POS for critical congenital heart defects should be recommended for all European countries
POS should be done with new-generation equipment that is motion tolerant
Screening should occur after 6 hours of life or before discharge from the birthing centre (preferably within 24 hours after birth)
Screening should be done in two extremities: the right hand and either foot
Each country should consider the advantages and disadvantages of the two available protocols and use that which best suits their population

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

July 31, 2017

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.

Defining cardiovascular disease and diabetes risks in kids

July 25, 2017

In the Clinical Report, a study team 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 a new collaborative report, a study team from Children’s National Health System’s Division of Endocrinology and Diabetes, Harvard Medical School and Duke Children’s Hospital and Health Center 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.

At least five health entities, including the World Health Organization, introduced clinical criteria to define MetS among adults, the study authors 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,” the study 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,” the study authors conclude.

Spectral data shine light on placenta

July 19, 2017

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.

Rheumatic Heart Disease Center Launches with $3.7 Million AHA Grant

July 3, 2017

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.

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.

Children’s National Heart Institute experts partner with FDA and nation’s leading cardiology organizations to advance pediatric drug development

June 29, 2017

New joint health policy statement offers roadmap for immediate changes in clinical trial design to save children’s lives

Families with children suffering from rare and difficult-to-treat cardiovascular diseases may soon have better access to drugs to treat their often life-threatening conditions. For the first time, experts from the U.S. Food and Drug Administration (FDA), the American College of Cardiology, the American Heart Association and the American Academy of Pediatrics are working together to describe the challenges and opportunities to improve pediatric drug research as shared in a joint statement published online June 29 in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.

“Children should have access to the latest advances in treatment and the best care. By challenging the status quo and designing new, safe and effective alternative study designs, we can give them the best opportunity to grow up stronger,” notes David Wessel, M.D., executive vice president and chief medical officer, Hospital and Specialty Services at Children’s National Health System. Dr. Wessel is internationally recognized for his pioneering work in caring for children with heart disease. As the senior author of the new joint statement and principal investigator of the STARTS-1 trial, which is the catalyst for this collaboration, he says he is “optimistic about this forward progress.”

According to the statement, less than 50 percent of drugs approved for use in the United States have sufficient data to support labeling for dosing, safety and efficacy in children. Additionally, a 2008 report by Pasquali et al, which reviewed more than 30,000 records of hospitalized children with cardiovascular disease, found that 78 percent received at least one off-label medication and 31 percent received more than three.

There are numerous challenges in the development and approval of medications for children – especially those with rare diseases – but the paper’s lead author, Craig Sable, M.D., associate division chief of cardiology at Children’s National, says we can and need to do better.

“While randomized clinical drug trials remain the gold standard in advancing care for adults with cardiovascular disease, relying solely on these types of trials for children unnecessarily limits the drugs approved for use in children,” says Dr. Sable. “Through this unique collaboration that unifies the voice of leaders in pediatric cardiology and the FDA, our goal is to provide a framework to better define which drugs are needed and how we can create novel study designs to overcome the current trial barriers.”

To read more about the barriers and ideas presented, please find the full statement here.

Will the Zika epidemic re-emerge in 2017?

June 5, 2017

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 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.”

Congenital heart disease and the brain

June 2, 2017

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

What’s known

Among all known birth defects, congenital heart disease (CHD) is the leading cause of death in infants. Fortunately, advances in surgical techniques and treatments are improving the outlook for these children, and more and more are reaching adulthood. However, because of this increased longevity, it has become increasingly clear that children born with CHD are at risk of developing life-long neurological deficits. Several risk factors for these neurodevelopmental abnormalities have been identified, but direct links between specific factors and neurological defects have yet to be established.

What’s new

In a recent review article published in Circulation Research, a team from Children’s National Health System summarized what is currently known about how CHD affects brain maturation. Drawing from studies conducted at Children’s National as well as other research institutions, Paul D. Morton, Ph.D., Nobuyuki Ishibashi, M.D., and Richard A. Jonas, M.D., write that clinical findings in patients, improvements in imaging analysis, advances in neuromonitoring techniques and the development of animal models have greatly contributed to our understanding of the neurodevelopmental changes that occur with CHD.

Findings from Children’s National include:

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

The authors conclude that although there is ample clinical evidence of neurological damage associated with CHD, there is limited knowledge of the cellular events associated with these abnormalities. They offer perspectives about what can be done to improve our understanding of neurological deficits in CHD, and emphasize that ultimately, a multidisciplinary approach combining multiple fields and myriad technology will be essential to improve or prevent adverse neurodevelopmental outcomes in individuals with CHD.

Questions for future research

Q: What are the cellular events associated with each factor involved in neurodevelopmental delays?
Q: How does the neurodevelopmental status of a patient with CHD change as they age?
Q: How do the genes involved in structural congenital cardiac anomalies affect brain development and function?

Source: Norton, P.D., Ishibashi, N., Jonas, R.A. “Neurodevelopmental Abnormalities and Congenital Heart Disease: Insights Into Altered Brain Maturation,” Circulation Research (2017) 120:960-977.