mother hugging down who has down syndrome
RESEARCH FEATURE

NHLBI joins trans-NIH effort to boost research on Down syndrome


Studies target heart, lung, and sleep disorders associated with condition

Each year, about 5,300 babies are born in the United States with Down syndrome, a genetic disease that is associated with intellectual and physical challenges. People with the condition have a high risk of heart defects, pulmonary hypertension,  sleep apnea, gastrointestinal defects, Alzheimer’s Disease, and other complications. On the other hand, many appear to be relatively protected against heart attacks, atherosclerosis, and certain types of cancers. Fortunately, many are living longer—the average lifespan has doubled over the past two decades, from 30 years to 60 years. 

Still, for all the good news, research to better understand the unique manifestations of Down syndrome, and to find treatments to boost the quality of life for people with the condition, has been slow to materialize. In addition, the population is often excluded from participation in clinical trials.

Group meeting for Downs Syndrome families
A group meeting for families affected by Down syndrome. Credit: Shutterstock

That may now be changing, thanks to a new trans-NIH research project called INCLUDE, which stands for the Investigation of Co-occurring Conditions Across the Lifespan to Understand Down Syndrome.  The project, which  began in 2018 and involves 18 NIH institutes and centers, is leveraging NIH expertise and resources to study the critical health needs of people with Down syndrome, who are born with an extra copy of chromosome 21, and also find new treatments to help improve their quality of life.

The National Heart, Lung, and Blood Institute (NHLBI) plays a key role in this research effort, particularly in the area of heart disease. About 50% of people with Down syndrome have congenital heart disease, which describes a host of problems with the heart’s structure that are present at birth. They range from holes in the heart to leaky heart valves to failure of the heart’s key components to form properly. The disorders can be life-threatening in some cases.

“Even though we have known the chromosomal abnormality that causes Down syndrome for some time, we still don’t know why so many people with Down syndrome have congenital heart disease,” said Gail Pearson, M.D, Sc.D., Associate Director of the Division of Cardiovascular Sciences at NHLBI, and a co-leader of the NHLBI INCLUDE group. Pearson is also a practicing pediatric cardiologist whose patients include many children with Down syndrome.

“Genes known to be associated with atrioventricular septal defect, the most common complex type of congenital heart defect that individuals with Down syndrome have, are not located on chromosome 21,” she explained. “So, what is it about having three copies of chromosome 21 that drives the behavior of genes on other chromosomes to result in atrioventricular septal defect?  This is an important question that could potentially be answered through INCLUDE research.”  The same questions exist about less complex forms of congenital heart disease that are common in people with Down syndrome, she said.

One group the scientists plan to focus on for answers: adults with Down syndrome. Despite the fact that many have multiple risk factors for coronary artery disease and high rates of obesity, sleep apnea, and type 1 diabetes, they rarely develop atherosclerosis or have heart attacks, Pearson said. Some of the research strategies envisioned for INCLUDE could provide a better understanding of the biological factors behind this apparent resilience in a way that could lead to cardiovascular prevention strategies for people who do not have Down syndrome, she said.

Another area of focus will be obstructive sleep apnea, a common condition in which the upper airway becomes blocked repeatedly during sleep, reducing or completely stopping airflow. In addition to making sleep difficult, studies have linked sleep apnea to serious health problems, including asthma, high blood pressure, heart disease, and even dementia. Sleep apnea occurs in an estimated 30-50% of children with Down syndrome and between 70 and 100% of adults with the syndrome.

According to Aruna Natarajan, M.D., Ph.D., a program director in the NHLBI Division of Lung Diseases, one reason that people with Down syndrome have such a high incidence of sleep apnea could be related to the anatomy of their airways—in particular, floppy airways with low muscle tone that can obstruct breathing. Floppy airways in babies and infants can lead to other problems such as feeding difficulties, which can cause food to accidentally travel down the windpipe and cause choking. This condition can also make it hard to cough, which in turn can make it hard to clear the airways, increasing their risk of severe bacterial and viral respiratory infections.

“If a baby can’t sleep and can’t eat, you can imagine how hard it is on them and their families,” said Natarajan, a practicing intensive care pediatrician who has treated many babies with Down syndrome. To offer relief, one NHLBI study in the INCLUDE portfolio will equip children and adolescents with  Continuous Positive Airway Pressure (CPAP) devices, which deliver mild air pressure through the mouth or nose in order to keep the airways open when worn during sleep. The devices have already been shown to help relieve sleep apnea in the general population and are now the gold standard of sleep apnea care.

Another NHLBI study will explore whether a combination of two drugs, atomoxetine and oxybutynin, can be another effective treatment for sleep apnea in people with Down syndrome. Recently, the experimental drug combo appeared to reduce airway obstruction and improve blood oxygenation in early tests among adults who do not have Down syndrome. Having access to a simple pill could also provide an appealing alternative for those who are unable to use CPAP devices effectively, research suggests.

If heart defects and sleep problems were not challenging enough, people with Down syndrome experience significantly higher rates of pulmonary hypertension than the rest of the population—some 10% of those with the genetic condition have it, and most of them are children. (The problem tends to diminish as they get older, which begs further inquiry.) In pulmonary hypertension, the heart must work harder to pump blood into the lungs because of increased pressure within the arteries of the lungs. This leads to low blood oxygen levels and symptoms such as shortness of breath: left untreated these can lead to life-threatening complications, such as heart failure or heart arrhythmias.

“People once thought pulmonary hypertension was due to congenital heart disease, but we’re finding that it’s independent of that condition,” Natarajan said. “We’re seeing a lot in children with Down syndrome and are exploring this in detail now in a supplement grant to an existing pediatric pulmonary hypertension registry, funded by INCLUDE.”

Generally, NHLBI funding under the INCLUDE project will support research and activities to:

  • Expand the Pediatric Cardiac Genomics Consortium for uncovering causes of congenital heart defects in individuals with and without Down syndrome.
     
  • Explore options for home-based evaluation for obstructive sleep apnea and conduct clinical trials to address sleep apnea outcomes in children with Down syndrome.
     
  • Launch of a new NHLBI training program for young investigators specifically on Down syndrome research as part of the NHLBI’s Pediatric Heart Network.

In short, NHLBI is a key participant in this important trans-NIH program. Researchers hope that the institute’s studies and other NIH studies in the INCLUDE project will go a long way toward addressing health disparities that exist for people with Down syndrome and lead to the development of new therapies to improve health outcomes for those with and without the condition.

 For further information about ongoing projects, please visit the INCLUDE website: https://www.nih.gov/include-project

EDITOR’S NOTE: October is Down Syndrome Awareness Month.

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