Asha Moudgil examines a young patient

Preventing cardiovascular disease after pediatric kidney transplant

Asha Moudgil examines a young patient

Pediatric nephrologist Asha Moudgil, M.D. examines a kidney transplant patient.

As obesity has continued to rise among children in the U.S., so has a condition called metabolic syndrome – a constellation of factors, including high abdominal fat, insulin resistance, high blood pressure, high triglycerides and low amounts of high-density lipoprotein (“good” cholesterol), that increase future risk of cardiovascular disease.

Although metabolic syndrome is dangerous in otherwise healthy children, it’s particularly so for those who’ve received kidney transplants due to chronic kidney disease, says pediatric nephrologist Asha Moudgil, M.D., medical director of transplant at Children’s National Health System. Dr. Moudgil and Children’s National co-authors, Registered Dietitian Kristen Sgambat, Ph.D., RD, and Cardiologist Sarah Clauss, M.D., published a literature review in the February 2018 Clinical Kidney Journal outlining recent research about the cardiovascular effects of metabolic syndrome after kidney transplantation.

“Simply having this transplant multiplies the risk of cardiovascular disease in this vulnerable population,” Dr. Moudgil says. “Combined with lifestyle factors that are driving up metabolic syndrome in general, it’s a ‘one-two punch’ for these patients.”

Dr. Moudgil explains that chronic kidney disease itself leads to poor growth, resulting in shorter stature that’s a risk factor for developing increased waist-to-height ratio upon becoming overweight. When children with this condition undergo long-awaited transplants, it reverses some factors that were suppressing appetite and keeping weight in check: The chronically high levels of urea in their blood decrease after transplant, improving their appetites; and there’s no need to maintain the restrictive diets they had been required to follow for kidney health prior to transplant.

The pharmaceutical regimen that patients follow post-transplant often includes steroids that independently contribute to weight gain and insulin resistance. Combined with the typical American high-fat, high-sugar, and high-sodium diet and low levels of physical activity, the majority of patients with chronic kidney disease gain significant weight after they receive transplants. The prevalence of obesity doubles the first year after transplantation, from about 15 percent to 30 percent, not only driving up cardiovascular disease risk but endangering the longevity of their transplant.

At the same time, says Sgambat, risk factors before and after transplantation drive up prevalence of other parts of metabolic syndrome. These include hypertension, which affects the majority of patients with chronic kidney disease before transplant and typically worsens due to sodium and water retention from immunosuppressive drugs. Dyslipidemia, or abnormal lipid concentrations in the blood, is also common among pediatric kidney transplant patients. One study included in the review showed that 71 percent of patients had high triglycerides three months post-transplant.

Ethnicity also can drive up risk for metabolic syndrome and cardiovascular disease. For example, the literature review says, individuals of African descent have a higher risk of these two conditions potentially due to genetic factors, such as high risk apolipoprotein L1 gene variants.

Together, these factors spur production of inflammatory molecules that trigger the development of early cardiovascular disease. Many kidney transplant recipients die from cardiovascular complications in early adulthood, Sgambat says, driving the need for early detection.

To that end, Dr. Moudgil says pediatric patients don’t typically show overt abnormalities in standard measures of cardiac functioning, such as echocardiography. As an alternative, she and colleagues cover three tools in the literature review that could offer advanced insight into whether patients have initial signs of cardiovascular disease. One of these is carotid intima-media thickness, a measure of the thickness of the carotid artery that can be obtained noninvasively by ultrasound. Another is myocardial strain imaging by speckle tracking echocardiography, a global measure of how the heart changes shape while beating. Cardiac magnetic resonance imaging (MRI), a relatively new technique, is already showing promise in detecting signs of early cardiovascular dysfunction.

A far simpler way to gauge cardiovascular risk, Sgambat adds, is calculating patients’ waist-to-height ratio. This measure doesn’t require sophisticated tools and can be tracked in any clinic over time, alerting patients to health-altering changes before it’s too late.

“It’s even more important to treat cardiovascular risk factors aggressively in this population,” Sgambat says. “Getting a concrete measure that something is trending in the wrong direction may motivate patients to change their diet or lifestyle in ways that a simple recommendation may not.”

Craig Sable

Can a vaccine prevent the earliest forms of rheumatic heart disease?

Craig Sable

Craig Sable, M.D., associate chief of the division of cardiology and director of echocardiography at Children’s National Health System, earned a lifetime achievement award, formally known as the 2018 Cardiovascular Disease in the Young (CVDY) Meritorious Achievement Award, on Nov. 10 at the American Heart Association’s Scientific Sessions 2018.

The CVDY Council bestows the prestigious award to individuals making a significant impact in the field of cardiovascular disease in the young. The CVDY Council supports the mission to improve the health of children and adults with congenital heart disease and acquired heart disease during childhood through research, education, prevention and advocacy.

Dr. Sable is recognized for his entire body of research, education and advocacy focused on congenital and acquired heart disease, but especially for his rheumatic heart disease (RHD) research in Uganda.

Over the past 15 years, Dr. Sable has brought more than 100 doctors and medical staff to Kampala, the capital and largest city in Uganda, partnering with more than 100 local doctors and clinicians to develop a template for a sustainable infrastructure to diagnose, treat and prevent both RHD and congenital heart disease.

RHD is a result of damage to the heart valves after acute rheumatic fever (ARF). The process starts with a sore throat from streptococcal infection, which many children in the United States treat with antibiotics.

“For patients who develop strep throat, their body’s reaction to the strep throat, in addition to resolving its primary symptoms, can result in attacking the heart,” says Dr. Sable. “The initial damage is called acute rheumatic fever. In many cases this disease is self-limited, but if undetected, over years, it can lead to long-term heart valve damage called rheumatic heart disease. Unfortunately, once severe RHD develops the only treatment is open-heart surgery.”

In 2017, Sable and the researchers published a study in the New England Journal of Medicine about the global burden of RHD, which is often referred to as a disease of poverty.

RHD is observed more frequently in low- and middle-income countries as well as in marginalized communities in high-income countries. RHD has declined on a global scale, but it remains the most significant cause of morbidity and mortality from heart disease in children and young adults throughout the world.

In 2017 there were 39.4 million causes of RHD, which resulted in 285,000 deaths and 9.4 million disability-adjusted life-years.

In 2018 the World Health Organization issued a referendum recognizing rheumatic heart disease as an important disease that member states and ministries of health need to prioritize in their public health efforts.

The common denominator that drives Dr. Sable and the global researchers, many of whom have received grants from the American Heart Association to study RHD, is the impact that creating a scalable solution, such as widespread adoption of vaccines, can have on entire communities.

“The cost of an open-heart surgery in Uganda is $5,000 to $10,000, while treatment for a child with penicillin for one year costs less than $1,” says Dr. Sable. “Investment in prevention strategies holds the best promise on a large scale to eradicate rheumatic heart disease.”

Sable and the team have screened more than 100,000 children and are conducting the first randomized controlled RHD trial, enrolling nearly 1,000 children, to examine the effectiveness of using penicillin to prevent progression of latent or subclinical heart disease, the earliest form of RHD.

During the Thanksgiving holiday weekend, Dr. Sable and a team of surgeons will fly back to Uganda to operate on children affected by RHD, while also advancing their research efforts to produce a scalable solution, exported on a global scale, to prevent RHD in its earliest stages.

Dr. Sable and colleagues from around the world partner on several grant-funded research projects. Over the next few years, the team hopes to answer several important questions, including: Does penicillin prevent the earliest form of RHD and can we develop a vaccine to prevent RHD?

To view the team’s previously-published research, visit Sable’s PubMed profile.

To learn about global health initiatives led by researchers at Children’s National, visit www.GHICN.org.

Charles Berul and Rohan Kumthekar demonstrate tiny pacemaker

A new prototype for tiny pacemakers, faster surgery

Charles Berul and Rohan Kumthekar demonstrate tiny pacemaker

Charles Berul, M.D., chief of cardiology at Children’s National, and Rohan Kumthekar, M.D., a cardiology fellow working in Dr. Berul’s bioengineering lab at the Sheikh Zayed Institute for Pediatric Surgical Innovation, explore ways to make surgical procedures for infants and children less invasive.

Rohan Kumthekar, M.D., a cardiology fellow working in Dr. Charles Berul’s bioengineering lab at the Sheikh Zayed Institute for Pediatric Surgical Innovation, part of Children’s National Health System, presented a prototype for a miniature pacemaker at the American Heart Association’s Scientific Sessions 2018  on Sunday, Nov. 11. The prototype, approximately 1 cc, the size of an almond, is designed to make pacemaker procedures for infants less invasive, less painful and more efficient, measured by shorter surgeries, faster recovery times and reduced medical costs.

Kumthekar, a Cardiovascular Disease in the Young Travel Award recipient, delivered his oral abstract, entitled “Minimally Invasive Percutaneous Epicardial Placement of a Custom Miniature Pacemaker with Leadlet under Direct Visualization,” as part of the Top Translational Science Abstracts in Pediatric Cardiology session.

“As cardiologists and pediatric surgeons, our goal is to put a child’s health and comfort first,” says Kumthekar. “Advancements in surgical fields are tending toward procedures that are less and less invasive. There are many laparoscopic surgeries in adults and children that used to be open surgeries, such as appendix and gall bladder removals. However, placing pacemaker leads on infants’ hearts has always been an open surgery. We are trying to bring those surgical advances into our field of pediatric cardiology to benefit our patients.”

Instead of using open-chest surgery, the current standard for implanting pacemakers in children, doctors could implant the tiny pacemakers by making a relatively tiny 1-cm incision just below the ribcage.

“The advantage is that the entire surgery is contained within a tiny 1-cm incision, which is what we find groundbreaking,” says Kumthekar.

With the help of a patented two-channel, self-anchoring access port previously developed by Berul’ s research group, the operator can insert a camera into the chest to directly visualize the entire procedure. They can then insert a sheath (narrow tube) through the second channel to access the pericardial sac, the plastic-like cover around the heart. The leadlet, the short extension of the miniature pacemaker, can be affixed onto the surface of the heart under direct visualization. The final step is to insert the pacemaker into the incision and close the skin, leaving a tiny scar instead of two large suture lines.

The median time from incision to implantation in this thoracoscopic surgery study was 21 minutes, and the entire procedure took less than an hour on average. In contrast, pediatric open-heart surgery could take up to several hours, depending on the child’s medical complexities.

“Placing a pacemaker in a small child is different than operating on an adult, due to their small chest cavity and narrow blood vessels,” says Kumthekar. “By eliminating the need to cut through the sternum or the ribs and fully open the chest to implant a pacemaker, the current model, we can cut down on surgical time and help alleviate pain.”

The miniature pacemakers and surgical approach may also work well for adult patients with limited vascular access, such as those born with congenital heart disease, or for patients who have had open-heart surgery or multiple previous cardiovascular procedures.

The miniature pacemakers passed a proof-of-concept simulation and the experimental model is now ready for a second phase of testing, which will analyze how the tailored devices hold up over time, prior to clinical testing and availability for infants.

“The concept of inserting a pacemaker with a 1-cm incision in less than an hour demonstrates the power of working with multidisciplinary research teams to quickly solve complex clinical challenges,” says Charles Berul, M.D., a guiding study author, electrophysiologist and the chief of cardiology at Children’s National.

Berul’s team from Children’s National collaborated with Medtronic PLC, developers of the first implantable pacemakers, to develop the prototype and provide resources and technical support to test the minimally-invasive surgery.

The National Institutes of Health provided a grant to Berul’s research team to develop the PeriPath, the all-in-one 1-cm access port, which cut down on the number of incisions by enabling the camera, needle, leadlet and pacemaker to be inserted into one port, through one tiny incision.

Other study authors listed on the abstract presented at Scientific Sessions 2018 include Justin Opfermann, M.S., Paige Mass, B.S., Jeffrey P. Moak, M.D., and Elizabeth Sherwin, M.D., from Children’s National, and Mark Marshall, M.S., and Teri Whitman, Ph.D., from Medtronic PLC.

Marva Moxey-Mims in her office at Children's National.

Making the case for a comprehensive national registry for pediatric CKD

Marva Moxey-Mims in her office at Children's National.

“It’s of utmost importance that we develop more sensitive ways to identify children who are at heightened risk for developing CKD.,” says Marva Moxey-Mims, M.D. “A growing body of evidence suggests that this includes children treated in pediatric intensive care units who sustained acute kidney injury, infants born preterm and low birth weight, and obese children.”

Even though chronic kidney disease (CKD) is a global epidemic that imperils cardiovascular health, impairs quality of life and heightens mortality, very little is known about how CKD uniquely impacts children and how kids may be spared from its more devastating effects.

That makes a study published in the November 2018 issue of the American Journal of Kidney Diseases all the more notable because it represents the largest population-based study of CKD prevalence in a nationally representative cohort of adolescents aged 12 to 18, Sun-Young Ahn, M.D., and Marva Moxey-Mims, M.D., of Children’s National Health System, write in a companion editorial published online Oct. 18, 2018.

In their invited commentary, “Chronic kidney disease in children: the importance of a national epidemiological study,” Drs. Ahn and Moxey-Mims point out that pediatric CKD can contribute to growth failure, developmental and neurocognitive defects and impaired cardiovascular health.

“Children who require renal-replacement therapy suffer mortality rates that are 30 times higher than children who don’t have end-stage renal disease,” adds Dr. Moxey-Mims, chief of the Division of Nephrology at Children’s National. “It’s of utmost importance that we develop more sensitive ways to identify children who are at heightened risk for developing CKD. A growing body of evidence suggests that this includes children treated in pediatric intensive care units who sustained acute kidney injury, infants born preterm and low birth weight, and obese children.”

At its early stages, pediatric CKD usually has few symptoms, and clinicians around the world lack validated biomarkers to spot the disease early, before it may become irreversible.

While national mass urine screening programs in Japan, Taiwan and Korea have demonstrated success in early detection of CKD, which enabled successful interventions, such an approach is not cost-effective for the U.S., Drs. Ahn and Moxey-Mims write.

According to the Centers for Disease Control and Prevention, 1 in 10 U.S. infants in 2016 was born preterm, prior to 37 weeks gestation. Because of that trend, the commentators advocate for “a concerted national effort” to track preterm and low birth weight newborns. (These infants are presumed to have lower nephron endowment, which increases their risk for developing end-stage kidney disease.)

“We need a comprehensive, national registry just for pediatric CKD, a database that represents the entire U.S. population that we could query to glean new insights about what improves kids’ lifespan and quality of life. With a large database of anonymized pediatric patient records we could, for example, assess the effectiveness of specific therapeutic interventions, such as angiotensin-converting enzyme inhibitors, in improving care and slowing CKD progression in kids,” Dr. Moxey-Mims adds.

Nikki Gillum Posnack

Do plastic chemicals contribute to the sudden death of patients on dialysis?

Nikki Gillum Posnack

Nikki Posnack, Ph.D., assistant professor with the Children’s National Heart Institute, continues to explore how repeat chemical exposure from medical devices influences cardiovascular function.

In a review published in HeartRhythmNikki Posnack, Ph.D., an assistant professor at the Children’s National Heart Institute, and Larisa Tereshchenko, M.D., Ph.D., FHRS, a researcher with the Knight Cardiovascular Institute at Oregon Health and Science University, establish a strong foundation for a running hypothesis: Replacing BPA- and DEHP- leaching plastics for alternative materials used to create medical devices may help patients on dialysis, and others with impaired immune function, live longer.

While Drs. Tereshchenko and Posnack note clinical studies and randomized controlled trials are needed to test this theory, they gather a compelling argument by examining the impact exposure to chemicals from plastics used in dialysis have on a patient’s short- and long-term health outcomes, including sudden cardiac death (SCD).

“As our society modifies our exposure to plastics to mitigate health risks, we should think about overexposure to plastics in a medical setting,” says Posnack. “The purpose of the review in HeartRhythm is to gather data about the impact chemical compounds, leached from plastic devices, have on cardiovascular outcomes for patients spending prolonged periods of time in the hospital.”

In this review, the authors explore chemical risk exposures in a medical setting, starting with factors that influence sudden cardiac death (SCD) among dialysis patients.

Why study dialysis patients?

SCD in dialysis patients accounts for one-third of deaths in this population. This prompts a need to develop prevention strategies, especially among patients with end-stage renal disease (ESRD).

The highest mortality rate observed among dialysis patients is during the first year of hemodialysis, a dialysis process that requires a machine to take the place of the kidneys and remove waste from the bloodstream and replenish it with minerals, such as potassium, sodium and calcium. During this year, mortality during hemodialysis is observed more frequently during the first three months of treatment, especially among older patients.

Possible reasons for an increased risk of an earlier death include chemical exposure, which is casually associated with altered cardiac function, as well as genetic risks for irregular heart rhythms and heart failure. In the HeartRhythm review, Drs. Tereshchenko and Posnack analyze factors that influence mortality:

Hemodialysis treatment, dialysis, is associated with plastic chemical exposure

Drs. Tereshchenko and Posnack note that dialysis tubing and catheters are commonly manufactured using polyvinyl chloride (PVC) polymers. The phthalate plastics used to soften PVC can easily leech if exposed to lipid-like substances, like blood. Research shows phthalate chemical concentrations increase during a four-hour dialysis.

Di(2-ethylhexyl) phthalate (DEHP) is a common plastic used to manufacture dialysis tubes, thanks to its structure and economy.

Bisphenol-A (BPA) is another common material used in medical device manufacturing. From the membranes of medical tools to resins, or external coatings and adhesives, BPA leaves behind a chemical residue on PVC medical devices.

In reviewing the research, the authors find dialysis patients are often exposed to high levels of DEHP and BPA. The amount of exposure to these chemicals varies in regards to room temperature, time of contact, other circuit coatings and the flow rate of dialysis. A faster flow rate correlates with reductions in chemical leaching and lower mortality rates.

Plastic chemical exposure is casually associated with altered cardiac function

Drs. Tereshchenko and Posnack note a causal relationship already exists between chemicals absorbed from plastics and cardiovascular outcomes.

Dr. Posnack’s previous research found BPA concentrations impaired electrical conduction in neonatal cardiomyocytes – young, developing heart cells – potentially altering the heart’s normal rhythm and function.

To the best of their knowledge, no clinical research has been conducted on DEHP exposure and SCD. However, proof-of-concept models find in vivo phthalate exposure alters autonomic regulation, which can slow down natural heart-rate rhythm and create a lag in recovery time to stressful stimuli. For humans, this type of stressful stimulation would be equivalent to recovering from a bike ride, car accident, or in this case, ongoing dialysis treatment with impaired immune function.

In other models, BPA exposure has been shown to cause bradycardia, or a delayed heart rate. In excised whole heart models, BPA has also been shown to alter cardiac electrical activity.

Abnormal electrophysiological substrate in end-stage renal disease

Since the heart and kidneys work in tandem to transport blood throughout the body, and manage vital functions, such as our heart rate, blood flow and breathing, the authors cite additional factors that lead to ongoing heart and kidney problems, with a look at end-stage renal disease (ESRD).

General heart-function kidney risks include abnormal electrophysiological (EP) substrate, the underlying electrical activity of the cardiac tissue, and genetic risk factors, including the TBX3 gene, a gene associated with a unique positioning of the heart and SCD.

“We don’t want to cite alarm about having a medical procedure or about relying on external help, such as dialysis, for proper kidney function,” says Posnack. “Especially since dialysis is a life-saving medical intervention for patients with inadequate kidney function.”

Pre-existing abnormal EP substrate interacts with plastic chemical exposure in incident dialysis, which increases risk of SCD in genetically predisposed ESRD patients

To summarize their findings, Drs. Tereshchenko and Posnack list a handful of support areas, starting with observations about reductions in cardiovascular mortality and SCD following kidney transplants. They note hemodialysis catheters are associated with larger DEHP exposure and a higher risk of SCD, compared to arteriovenous fistulas, highways surgically created to connect blood from the artery to the vein.

Drs. Posnack and Tereshchenko also note a correlative observation about higher SCD rates observed six hours after hemodialysis, when peak levels of DEHP and BPA are circulating in the bloodstream.

To compare and control for these factors among dialysis patients, the researchers cite different mortality patterns with hemodialysis and peritoneal dialysis. Patients on hemodialysis experience higher mortality during the first year of treatment, compared to peritoneal dialysis, who have higher mortality rates after the second year of treatment. Hemodialysis relies on a machine to take the place of kidney function, while peritoneal dialysis relies on a catheter, a small tube surgically inserted into the stomach.

“Our goal is to build on our previous research findings by analyzing variables that have yet to be studied before, and to update the field of medicine in the process,” says Dr. Posnack. “This includes investigating the cardiovascular risks of using BPA- and DEHP-materials to construct medical devices. Ultimately, we hope to determine whether plastic materials contribute to cardiovascular risks, and investigate whether patients might benefit from the use of alternative materials for medical devices.

Drs. Tereshchenko and Posnack note that despite the associations between chemical exposure from medical devices and increased cardiovascular risks, there are no restrictions in the United States on the use of phthalates and BPA chemicals used to manufacture medical devices.

Their future research will explore how replacing BPA- and DEHP-leaching plastics influence mortality and morbidity rates of ESRD patients on dialysis, as well as other patients exposed to repeat chemical exposure, such as patients having cardiac surgery.

“We want to make sure we identify and then work to minimize any potential risks of plastic exposure in a medical setting,” adds Dr. Posnack. “Our goal is to put the health and safety of patients first.”

Dr. Posnack’s research is funded by two grants (R01HL139472, R00ES023477) from the National Institutes of Health.

Pregnant-Mom

Safeguarding fetal brain health in pregnancies complicated by CHD

Pregnant-Mom

During the last few weeks of pregnancy, certain regions of the fetal brain experience exponential growth but also are more vulnerable to injury during that high-growth period.

Yao Wu, Ph.D., a research postdoctoral fellow in the Developing Brain Research Laboratory at Children’s National Health System, has received a Thrasher Research Fund early career award to expand knowledge about regions of the fetal brain that are vulnerable to injury from congenital heart disease (CHD) during pregnancy.

CHD, the most common birth defect, can have lasting effects, including overall health issues; difficulty achieving milestones such as crawling, walking or running; and missed days at daycare or school, according to the Centers for Disease Control and Prevention. Brain injury is a major complication for infants born with CHD. Catherine Limperopoulos, Ph.D., director of Children’s brain imaging lab, was the first to provide in vivo evidence that fetal brain growth and metabolism in the third trimester of pregnancy is impaired within the womb.

“It remains unclear which specific regions of the fetal brain are more vulnerable to these insults in utero,” Limperopoulos says. “We first need to identify early brain abnormalities attributed to CHD and understand their impact on infants’ later behavioral and cognitive development in order to better counsel parents and effectively intervene during the prenatal period to safeguard brain health.”

During the last few weeks of pregnancy, certain regions of the fetal brain experience exponential growth but also are more vulnerable to injury during that high-growth period. The grant, $26,749 over two years, will underwrite “Brain Development in Fetuses With Congenital Heart Disease,” research that enables Wu to utilize quantitative, non-invasive magnetic resonance imaging (MRI) to compare fetal brain development in pregnancies complicated by CHD with brain development in healthy fetuses of the same gestational age.Wu will leverage quantitative, in vivo 3-D volumetric MRI to compare overall fetal and neonatal brain growth as well as growth in key regions including cortical grey matter, white matter, deep grey matter, lateral ventricles, external cerebrospinal fluid, cerebellum, brain stem, amygdala and the hippocampus.

The research is an offshoot of a prospective study funded by the National Institutes of Health that uses advanced imaging techniques to record brain growth in 50 fetuses in pregnancies complicated by CHD who need open heart surgery and 50 healthy fetuses. MRI studies are conducted during the second trimester (24 to 28 weeks gestational age), third trimester (33 to 37 weeks gestational age) and shortly after birth but before surgery. In addition, fetal and neonatal MRI measurements will be correlated with validated scales that measure infants’ and toddlers’ overall development, behavior and social/emotional maturity.

“I am humbled to be selected for this prestigious award,” Wu says. “The findings from our ongoing work could be instrumental in identifying strategies for clinicians and care teams managing high-risk pregnancies to optimize fetal brain development and infants’ overall quality of life.”

Graph showing magnesium reduces arrhythmia risk

Magnesium helps prevent postsurgical arrhythmias in pediatric patients

Graph showing magnesium reduces arrhythmia risk

Magnesium (Mg) helps reduce arrhythmias, irregular heart rhythms, in adults. It also helps alleviate the symptoms of postoperative atrial fibrillation, or AFib, which can lead to blood clots, stroke and heart failure. Can it help prevent postsurgical arrhythmias in pediatric patients with congenital heart disease?

New research from Children’s National Health System finds a 25- or 50-mg dose of Mg used during congenital heart surgery (CHS) helps prevent arrhythmias, especially junctional ectopic tachycardia (JET) and atrial tachycardia (AT), common arrhythmias following CHS, according to a study published in the August 2018 edition of The Journal of Thoracic and Cardiovascular Surgery.

To reach this conclusion, the researchers separated 1,871 CHS patients from Children’s National into three groups: a control group of 750 patients who had surgery without Mg, a group of 338 patients receiving a 25-mg /kg dose of Mg during surgery and a group of 783 patients receiving a 50-mg/kg dose of Mg during surgery. The data looked at CHS cases over eight years, from 2005 to 2013, to determine if Mg administration during surgery alleviates postoperative arrhythmias and if the amount, measured by a 25- or 50-mg/kg dose, makes a difference.

“This study, the first conducted in pediatric patients, finds administering magnesium during congenital heart surgery reduces the likelihood of postsurgical arrhythmias,” says Charles Berul, M.D., a study author and the chief of cardiology at Children’s National. “We don’t detect a dose-dependent relationship, which means a small or larger amount of magnesium is equally effective at preventing arrhythmias following surgery.”

The researchers found that up to one-third of CHS patients experience postoperative arrhythmias, with JET and AT accounting for more than two-thirds of arrhythmias following CHS. They note that despite the administration of Mg during surgery, there continues to be a high incidence of postoperative arrhythmias – affecting 18 percent or about one in five CHS patients.

“We hope this study guides future research to see if adding new or additional agents to magnesium eliminates, or further reduces, postoperative arrhythmias,” notes Dr. Berul. “For now, we’re happy to find an algorithm to put into practice and to share with other medical centers, as a way to help pediatric patients recover from congenital heart surgery—stronger, faster and with a reduced risk of complications.”

The researchers note that postoperative arrhythmias impact the recovery period of CHS, increase the duration of intubation and CICU stay and prolong hospital stay.

Making the grade: Children’s National is nation’s Top 5 children’s hospital

Children’s National rose in rankings to become the nation’s Top 5 children’s hospital according to the 2018-19 Best Children’s Hospitals Honor Roll released June 26, 2018, by U.S. News & World Report. Additionally, for the second straight year, Children’s Neonatology division led by Billie Lou Short, M.D., ranked No. 1 among 50 neonatal intensive care units ranked across the nation.

Children’s National also ranked in the Top 10 in six additional services:

For the eighth year running, Children’s National ranked in all 10 specialty services, which underscores its unwavering commitment to excellence, continuous quality improvement and unmatched pediatric expertise throughout the organization.

“It’s a distinct honor for Children’s physicians, nurses and employees to be recognized as the nation’s Top 5 pediatric hospital. Children’s National provides the nation’s best care for kids and our dedicated physicians, neonatologists, surgeons, neuroscientists and other specialists, nurses and other clinical support teams are the reason why,” says Kurt Newman, M.D., Children’s President and CEO. “All of the Children’s staff is committed to ensuring that our kids and families enjoy the very best health outcomes today and for the rest of their lives.”

The excellence of Children’s care is made possible by our research insights and clinical innovations. In addition to being named to the U.S. News Honor Roll, a distinction awarded to just 10 children’s centers around the nation, Children’s National is a two-time Magnet® designated hospital for excellence in nursing and is a Leapfrog Group Top Hospital. Children’s ranks seventh among pediatric hospitals in funding from the National Institutes of Health, with a combined $40 million in direct and indirect funding, and transfers the latest research insights from the bench to patients’ bedsides.

“The 10 pediatric centers on this year’s Best Children’s Hospitals Honor Roll deliver exceptional care across a range of specialties and deserve to be highlighted,” says Ben Harder, chief of health analysis at U.S. News. “Day after day, these hospitals provide state-of-the-art medical expertise to children with complex conditions. Their U.S. News’ rankings reflect their commitment to providing high-quality care.”

The 12th annual rankings recognize the top 50 pediatric facilities across the U.S. in 10 pediatric specialties: cancer, cardiology and heart surgery, diabetes and endocrinology, gastroenterology and gastrointestinal surgery, neonatology, nephrology, neurology and neurosurgery, orthopedics, pulmonology and urology. Hospitals received points for being ranked in a specialty, and higher-ranking hospitals receive more points. The Best Children’s Hospitals Honor Roll recognizes the 10 hospitals that received the most points overall.

This year’s rankings will be published in the U.S. News & World Report’s “Best Hospitals 2019” guidebook, available for purchase in late September.

Baby in the NICU

Getting to the heart of cardiac output

Baby in the NICU

To keep infants in the neonatal intensive care unit (NICU) as healthy as possible, it’s important to keep close tabs on their vital signs. During their NICU stay, most babies have continuous monitoring of their blood pressure, respiratory rate and blood oxygen saturation. And although continuous monitoring of heart rate is also typically standard, other information about heart function – such as cardiac output, a measure of how well the heart is pumping blood – remains a challenge to obtain in these vulnerable babies.

Clinical markers like blood pressure, heart rate and urine output are available, but they are indirect measures of cardiac output, how much blood the heart pumps per minute. Less invasive techniques, such as Doppler ultrasound, can be imprecise. Respiratory mass spectrometry or catherization would provide more precision by directly calcuating cardiac output but carry risks or are not feasible for neonates.

Clinicians at Children’s National Health System hypothesized that COstatus monitors could offer a way to directly measure cardiac output among neonates. The COstatus monitor – a minimally invasive way to measure hemodynamics – captures cardiac output, total end diastolic volume, active circulation volume and central blood volume.

The research team tested the approach by leveraging ultrasound dilution: Injecting saline, which has an ultrasound velocity of 1533m/second, slows the ultrasound velocity of blood from its normal rate of 1580m/second and produces a dilution curve.

“It is feasible to directly measure neonatal cardiac output by ultrasound dilution via the COstatus monitor in the first two weeks of life with no adverse events,” says Khodayar Rais-Bahrami, M.D., a Children’s neonatologist and senior author for the research presented during the Pediatric Academic Societies 2018 annual meeting. “When we took consecutive measurements, we saw very little variance in the parameters.”

The COstatus monitor uses an extracorporeal loop that is connected to arterial and venous catheters. The 12 neonates included in the study already had umbilical venous catheters as well as either a peripheral arterial line or umbilical arterial catheter. The infants ranged in weight from 0.72 to 3.74 kg and were born at 24 to 41.3 gestational weeks.

The infants’ cardiac output was measured 54 times from 1 to 13 days of life. Up to two measurement sessions occurred daily for a maximum of four days. The mean cardiac output was 0.43 L/minute with a mean cardiac index of 197mL/kg/minute.

Future research will describe normal cardiac output ranges for neonates as well as how these measurements evolve during the first week of life.

In addition to Dr. Rais-Bahrami, study co-authors include Simranjeet S. Sran, M.D., and Mariam Said, M.D., a Children’s neonatologist.

Nikki Gillum Posnack

Examining BPA’s impact on developing heart cells

Nikki Gillum Posnack

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

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

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

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

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

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

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

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

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

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2017: A banner year for innovation at Children’s National

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In 2017, clinicians and research faculty working at Children’s National Health System published more than 850 research articles about a wide array of topics. A multidisciplinary Children’s Research Institute review group selected the top 10 articles for the calendar year considering, among other factors, work published in high-impact academic journals.

“This year’s honorees showcase how our multidisciplinary institutes serve as vehicles to bring together Children’s specialists in cross-cutting research and clinical collaborations,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “We’re honored that the National Institutes of Health and other funders have provided millions in awards that help to ensure that these important research projects continue.”

The published papers explain research that includes using imaging to describe the topography of the developing brains of infants with congenital heart disease, how high levels of iron may contribute to neural tube defects and using an incisionless surgery method to successfully treat osteoid osteoma. The top 10 Children’s papers:

Read the complete list.

Dr. Batshaw’s announcement comes on the eve of Research and Education Week 2018 at Children’s National, a weeklong event that begins April 16, 2018. This year’s theme, “Diversity powers innovation,” underscores the cross-cutting nature of Children’s research that aims to transform pediatric care.

As pediatric use of iNO increased, mortality rates dropped

Smiling-baby-boy

iNO, a colorless odorless gas, is used to treat hypoxic respiratory failure in infants born full-term and near term.

Use of inhaled nitric oxide (iNO) among pediatric patients has increased since 2005 and, during a 10-year time period, mortality rates dropped modestly as the therapeutic approach was applied to a broader range of health ailments, according to an observational analysis presented Feb. 26, 2018, during the 47th Critical Care Congress.

iNO, a colorless odorless gas, is used to treat hypoxic respiratory failure in infants born full-term and near term and also has become an important therapy for acute respiratory distress syndrome and pulmonary hypertension in newborns.

Jonathan Chan, M.D., a Children’s National Health System critical care fellow, analyzed de-identified data from patient visits from January 2005 to December 2015 at 47 children’s hospitals around the nation. Dr. Chan included 18,343 patients in the analysis. Among the findings:

  • As a group, the children had an overall mortality rate of 22.7 percent. The mortality rate dropped from 29.1 percent in 2005 to 21.2 percent in 2015.
  • The median adjusted cost per admission was an estimated $158,740 ($5,846 per patient day).

“This large observational study indicates that the use of iNO grew from 2005 to 2015,” Dr. Chan says. “While hospital stays grew longer during the study period, we saw a decrease in mortality of 0.01 percent per year.”

The highest number of admissions with iNO use included:

Dr. Chan notes that because this is a retrospective observational analysis, the study’s findings should be interpreted as exploratory.

“Off-label use of iNO continues to increase among pediatric patients. And an increasing proportion of admissions are for specialty areas other than neonatal care,” he adds. “Increasing off-label use of iNO is associated with decreased mortality. But it also is associated with an increased length of stay, higher hospital costs and more units of iNO administered.”

47th Critical Care Congress presentation

Monday, Feb. 26, 2018

Murfad Peer

Mechanically-assisted circulation for the failing Fontan

Murfad Peer

“Right now, the only way to really fix a failing Fontan is with a heart transplant, but the number of donor hearts is fixed and the number of people needing transplants has been increasing over time,” explains Murfad Peer, M.D. “So we are in a really tight spot. We need to do something, and we need to do it quickly.”

The only treatment currently available for patients born with single ventricle heart defects is the Fontan operation. And, while the operation provides excellent long-term palliation and survival, Fontan hearts eventually fail, and there are limited treatment options to help these patients make it to a heart transplant. A team led by  Murfad Peer, M.D., a cardiac surgeon at Children’s National, is trying to increase the survivorship of these patients with a heart pump.

“Right now, the only way to really fix a failing Fontan is with a heart transplant, but the number of donor hearts is fixed and the number of people needing transplants has been increasing over time,” explains Dr. Peer. “Most of these Fontan patients are so sick they are not even candidates for a transplant. So we are in a really tight spot. We need to do something, and we need to do it quickly.”

Currently in the United States, more than 800 Fontan procedures are done every year. The operation involves connecting the superior and inferior vena cava directly to the pulmonary artery so that deoxygenated blood flows straight to the lungs.

“When you do a Fontan, you do a series of surgeries that basically bypass the right heart, so that blood flow to the lungs is passive — it’s going to the lungs because of venous pressure,” says Dr. Peer. “There’s no ventricle actually pumping blood directly to the lungs.”

So, while the Fontan operation has facilitated the survival of a generation of children born with congenital heart disease, it does not recreate normal circulation. And, after about 15 to 20 years, the pressure on the right side of the heart becomes so high in some patients that blood starts backing up into the veins, resulting in organ failure.

One way to keep blood flowing is by adding a pump. Dr. Peer and his team hypothesized this could be accomplished by returning circulation to the way it was before the Fontan operation, and then supporting the ventricle with a standard commercially available continuous flow ventricular assist device (VAD) that pumps blood into the lungs and the aorta.

“We took a commercially available left-ventricle assist device and split the outflow graft so that it could flow both into the systemic circulation and into the lungs,” says Dr. Peer.

The team tested their mechanically assisted single ventricle circulation (MASVC) in an animal model of functionally univentricular circulation, and they were able to sustain the animal for two hours. The results were published in January 2018, in the World Journal for Pediatric and Congenital Heart Surgery.

Going forward, the team plans on testing MASVC for longer periods of time to determine its long-term durability. Dr. Peer is also working on computer modeling MASVC in a patient using an MRI.

Nikki Gillum Posnack

Experimental model study links phthalates and cardiovascular health

Nikki Gillum Posnack

“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.

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.”

effects of cardiopulmonary bypass surgery on the white matter of piglets.

The effects of cardiopulmonary bypass on white matter development

 cardiopulmonary bypass

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.

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.