Date of Release:  Dec. 14, 2020

SAN FRANCISCO /PRNewswire/ — Over two million babies, children, and adults in the United States are living with congenital heart disease—a range of birth defects affecting the heart’s structure or function. Now, researchers at Gladstone Institutes and UC San Francisco (UCSF) have made inroads into understanding how a broad network of genes and proteins go awry in a subset of congenital heart diseases.

“We now have a better understanding of what genes are improperly deployed in some cases of congenital heart disease,” says Benoit Bruneau, PhD, director of the Gladstone Institute of Cardiovascular Disease and a senior author of the new study. “Eventually, this might help us get a handle on how to modulate genetic networks to prevent or treat the disease.”

Congenital heart disease encompasses a wide variety of heart defects, ranging from mild structural problems that cause no symptoms to severe malformations that disrupt or block the normal flow of blood through the heart. A handful of genetic mutations have been implicated in contributing to congenital heart disease; the first to be identified was in a gene known as TBX5. The TBX5 protein is a transcription factor—it controls the expression of dozens of others genes, giving it far-reaching effects.

Bruneau has spent the last 20 years studying the effect of TBX5 mutations on developing heart cells, mostly conducting research in mice. In the new study published in Developmental Cell, he and his colleagues turned instead to human cells, using novel approaches to follow what happens in individual cells when TBX5 is mutated.

“This is really the first time we’ve been able to study this genetic mutation in a human context,” says Bruneau, who is also a professor in the Department of Pediatrics at UCSF. “The mouse heart is a good proxy for the human heart, but it’s not exactly the same, so it’s important to be able to carry out these experiments in human cells.”

The scientists began with human induced pluripotent stem cells (iPS cells), which have been reprogrammed to an embryonic-like state, giving them—like embryonic stem cells—the ability to become nearly every cell type in the body.

Then, Bruneau’s group used CRISPR-Cas9 gene-editing technology to mutate TBX5 in the cells and began coaxing the iPS cells to become heart cells. As the cells became more like heart cells, the researchers used a method called single-cell RNA sequencing to track how the TBX5 mutation changed which genes were switched on and off in tens of thousands of individual cells.

The experiment revealed many genes that were expressed at higher or lower levels in cells with mutated TBX5. Importantly, not all cells responded to the TBX5 mutation in the same way; some had drastic changes in gene expression while other were less affected. This diversity, the researchers say, reflects the fact that the heart is composed of many different cell types.

“It makes sense that some are more affected than others, but this is the first experimental data in human cells to show that diversity,” says Bruneau.

Bruneau’s team then collaborated with computational researchers to analyze how the impacted genes and proteins were related to each other. The new data let them sketch out a complex and interconnected network of molecules that work together during heart development.

“We’ve not only provided a list of genes that are implicated in congenital heart disease, but we’ve offered context in terms of how those genes are connected,” says Irfan Kathiriya, MD, PhD, a pediatric cardiac anesthesiologist at UCSF Benioff Children’s Hospital, an associate professor in the Department of Anesthesia and Perioperative Care at UCSF, a visiting scientist at Gladstone, and the first author of the study.

Several genes fell into known pathways already associated with heart development or congenital heart disease. Some genes were among those directly regulated by TBX5’s function as a transcription factor, while others were affected in a less direct way, the study revealed. In addition, many of the altered genes were relevant to heart function in patients with congenital heart disease as they control the rhythm and relaxation of the heart, and defects in these genes are often found together with the structural defects.

The new paper doesn’t point toward any individual drug target that can reverse a congenital heart disease after birth, but a better understanding of the network involved in healthy heart formation, as well as congenital heart disease may lead to ways to prevent the defects, the researchers say. In the same way that folate taken by pregnant women is known to help prevent neural tube defects, there may be a compound that can help ensure that the network of genes and proteins related to congenital heart disease stays balanced during embryonic development.

“Our new data reveal that the genes are really all part of one network—complex but singular—which needs to stay balanced during heart development,” says Bruneau. “That means if we can figure out a balancing factor that keeps this network functioning, we might be able to help prevent congenital heart defects.”

About the Study

The paper “Modeling human TBX5 haploinsufficiency predicts regulatory networks for congenital heart disease,” was published by the journal Developmental Cell on December 14, 2020.

Other authors include Kavitha Rao, Patrick Devine, Andrew Blair, Swetansu Hota, Michael Lai, Bayardo Garay, Reuben Thomas, Piyush Goyal, Tatyana Sukonnik, Kevin Hu, Gunes Akgun, and Laure Bernard of Gladstone; Giovanni Iacono and Holger Heyn of Barcelona Institute of Science and Technology; Henry Gong, Matthew Speir, Maximilian Haeussler, and Joshua Stuart of the University of California, Santa Cruz; Lauren Wasson, Christine Seidman, and J. G. Seidman of Harvard Medical School; and Brynn Akerberg, Fei Gu, Kai Li, and William Pu of Boston Children’s Hospital.

The work was supported by grants from the National Institutes of Health (UM1HL098179, UM1HL098166, R01HL114948, USCF CVRI 2T32HL007731-27), the California Institute for Regenerative Medicine (RB4-05901), the Office of the Assistant Secretary of Defense for Health Affairs (W81XWH-17-1-0191), the Foundation for Anesthesia Education and Research, the Society for Pediatric Anesthesia, the Hellman Family Fund, the UCSF REAC Grant, and the UCSF Department of Anesthesia and Perioperative Care.

About Gladstone Institutes

To ensure our work does the greatest good, Gladstone Institutes focuses on conditions with profound medical, economic, and social impact—unsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. It has an academic affiliation with UC San Francisco.

Media Contact: Julie Langelier | Assistant Director, Communications | julie.langelier@gladstone.org | 415.734.5000
1650 Owens Street, San Francisco, CA 94158 | gladstone.org | @GladstoneInst

SOURCE Gladstone Institutes

Related Links

https://gladstone.org

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There are many types of congenital heart defects. The most common defects involve the inside walls of the heart, the valves of the heart, or the large blood vessels that carry blood to and from the heart. Some defects require no treatment, but some require treatment soon after birth. Because diagnosis and treatment of congenital heart defects has improved, more babies are surviving and now many adults are living with congenital heart defects.

Types of Congenital Heart Defects

There are many types of congenital heart defects. They range from simple to complex and critical. Simple defects, such as atrial septal defect and ventricular septal defects, may have no symptoms and may not require surgery. Complex or critical defects such as hypoplastic left heart syndrome may have severe, life-threatening symptoms. Babies born with a critical congenital heart defect typically have low levels of oxygen soon after birth and need surgery within the first year of life.

Atrial septal defect

An atrial septal defect is a hole in the wall between the atria, which are the two upper chambers of the heart. The hole causes blood to flow from the left atrium and mix with the right atrium, instead of going to the rest of the body. Atrial septal defect is considered a simple congenital heart defect because the hole may close on its own as the heart grows during childhood, and repair may not be necessary.

Patent ductus arteriosus

This common type of simple congenital heart defect occurs when a connection between the heart’s two major arteries does not close properly after birth. This leaves an opening through which blood can flow when it should not. Small openings may close on their own.

Pulmonary stenosis

Pulmonary stenosis is a narrowing of the valve through which blood leaves the heart on its way to the lungs.

Ventricular septal defect

A ventricular septal defect is a hole in the wall between the ventricles, which are the two lower chambers of the heart. Blood may flow from the left ventricle and mix with blood in the right ventricle, instead of going to the rest of the body. If the hole is large, this may make the heart and lungs work harder and may cause fluid to build up in the lungs.

Tetralogy of Fallot

This is the most common complex congenital heart defect. Tetralogy of Fallot is a combination of four defects:

• Pulmonary stenosis.
• A large ventricular septal defect.
• An overriding aorta. With this defect, the aorta is located between the left and right ventricles, directly over the ventricular septal defect. As a result, oxygen-poor blood from the right ventricle can flow directly into the aorta instead of into the pulmonary artery.
• Right ventricular hypertrophy. In this case, the muscle of the right ventricle is thicker than usual because it has to work harder than normal.

Other critical congenital heart defects

Common congenital heart defects include:

• Coarctation of the aorta
• Double-outlet right ventricle
• D-transposition of the great arteries
• Ebstein’s anomaly
• Hypoplastic left heart syndrome
• Interrupted aortic arch
• Pulmonary atresia with intact ventricular septum
• Single ventricle
• Total anomalous pulmonary venous return
• Tricuspid atresia
• Truncus arteriosus

Causes of Congenital Heart Defects

Congenital heart defects happen because the heart does not develop normally while the baby is growing in the womb. Doctors often do not know why congenital heart defects occur. Researchers do know that genetics can sometimes play a role.

Genetics

It is common for congenital heart defects to occur because of changes in the child’s DNA. The changes in the DNA may or may not have come from the parents.

Rarely, congenital heart defects are caused by particular genes that are inherited from the parents. That means a parent who has a congenital heart defect may have an increased risk of having a child with the defect.

Risk Factors for Congenital Heart Defects

Congenital heart defects are the most common type of birth defect, occurring in about one percent of live births in the United States. If your child has a congenital heart defect, you may think you did something wrong during your pregnancy to cause the problem.

However, doctors often do not know why congenital heart defects occur. Researchers do know that the risk of having a baby with a congenital heart defect is influenced by family history and genetics, the mother’s health, sex, and exposure during pregnancy to environmental factors, such as smoke or certain medicines. Other medical conditions can also raise your risk for having a baby with a congenital heart defect.

Family history and genetics

Congenital heart disease is not usually passed along to your children, but there is some risk. The risk is increased if your baby’s other parent or another of your children has a congenital heart defect.

Environmental factors

Exposure to certain substances during pregnancy may increase your risk of having a baby with a congenital heart defect.

• Smoking during pregnancy or exposure to secondhand smoke.
• Taking some medicines—such as angiotensin-converting enzyme (ACE) inhibitors for high blood pressure and retinoic acids for acne treatment—in the first trimester.

Other medical conditions

Some medical conditions increase the risk of having a baby with a congenital heart defect, such as:

• Diabetes. Your risk is higher if you have diabetes before pregnancy, or if you are diagnosed with diabetes while you are in your first trimester. However, a diagnosis of gestational diabetes, which occurs later in the pregnancy, is not a major risk factor.
• Phenylketonuria. This rare, inherited disorder affects how your body processes a protein called phenylalanine, which is found in many foods. Getting phenylketonuria under control before getting pregnant can reduce your risk of having a baby with a congenital heart defect.
• Rubella. Infection with the rubella virus, also known as German measles, during pregnancy increases your risk.

Sex

Congenital heart defects can occur in either sex. Congenital heart defects are slightly more common at birth in boys than girls. Some congenital heart defects are a characteristic of conditions such as Turner syndrome that more commonly affect females.

Signs, Symptoms, and Complications

Some congenital heart defects cause few or no signs and symptoms. Since more children with congenital heart defects are living longer, we now know that complications can develop later in life. Signs, symptoms, and complications will vary based on the type of congenital heart defect that you or your child have.

Signs and symptoms

Signs and symptoms may be different for newborns and adults. They also depend on the number, type, and severity of the heart defect. Some common signs and symptoms include:

• Cyanosis
• Fatigue
• Heart murmurs
• Poor blood circulation
• Rapid breathing

Congenital heart defects do not cause chest pain or other painful symptoms. Older children or adults may get tired easily or short of breath during physical activity.

Complications

Complications depend on the type of congenital heart defect you have. Some of the possible complications include:

• Arrhythmia 
• Blood clots  
• Developmental disorders and delays. Children with congenital heart defects are more likely to have problems with behavior. They are also more likely to have speech and attention-deficit/hyperactivity disorders.
• Emotional health issues. Depression, anxiety, and post-traumatic stress disorder are common among people with congenital heart defects.
• Endocarditis, a type of heart inflammation
• Endocrine disorders, including thyroid problems, bone health issues, and diabetes. Problems with the hormones that deal with calcium can cause bone problems.
• Heart failure. Heart failure is the leading cause of death in adults with congenital heart defects. Some children with congenital heart defects develop heart failure.
• Kidney disease
• Liver disease
• Pneumonia. Pneumonia is a leading cause of death in adults with congenital heart disease.
• Pregnancy complications. Women with congenital heart defects have an increased risk of complications during pregnancy and childbirth.
• Pulmonary hypertension
• Stroke

Diagnosing Congenital Heart Defects

Some congenital heart defects are diagnosed during pregnancy or soon after birth. Others may not be diagnosed until adulthood. Your or your child’s doctor will perform a physical exam and order diagnostic tests and procedures based on what he or she finds in the physical exam.

Physical exam

During a physical exam, your doctor will do the following:

• Listen to your or your child’s heart and lungs with a stethoscope.
• Look at your baby’s general appearance. Some children with certain heart defects also have genetic syndromes that make them look a certain way.
• Look for signs of a heart defect, such as shortness of breath, rapid breathing, delayed growth, signs of heart failure, or cyanosis.

Diagnostic tests and procedures

To diagnose a congenital heart defect, your doctor may have you or your baby undergo some of the following tests and procedures:

• Echocardiography to diagnose a heart defect or follow your or your child’s progress over time. Fetal echocardiography can sometimes diagnose a congenital heart defect before a baby is born.
• Electrocardiogram (EKG or ECG)to evaluate the rhythm of the heartbeat.
• Cardiac catheterization to measure the pressure and oxygen level inside the heart chambers and blood vessels. This can help the doctor figure out whether blood is flowing from the left side of the heart into the right side of the heart, instead of going to the rest of the body.
• Chest X-ray to show whether the heart is enlarged. It can also show whether the lungs have extra blood flow or extra fluid, a sign of heart failure.
• Genetic testing to determine if particular genes or genetic syndromes such as Down syndrome are causing the congenital heart defect. Your doctor may refer you or your child to a specialist in genetic testing.
• Cardiac MRI to diagnose a heart defect or follow your or your child’s progress over time.
• Pulse oximetry to estimate how much oxygen is in the blood. A small sensor is attached to an infant’s hand or foot or an older person’s finger or toe.

Treating Congenital Heart Defects

Treatment will depend on which type of congenital heart defect you have. Treatments for congenital heart defects include medicines, surgery, and cardiac catheterization procedures. Many congenital heart defects do not require treatment at all. However, children with critical congenital heart defects will need surgery in the first year of life. Some people with congenital heart defects may need treatment, including repeated surgery, throughout their lives. All people with congenital heart defects should be followed by a cardiologist, a doctor who specializes in the heart, throughout their whole life.

Medicines

Your child’s doctor may prescribe medicines to help close patent ductus arteriosus in premature infants.

• Indomethacin or ibuprofen triggers the patent ductus arteriosus to constrict or tighten, which closes the opening.
• Acetaminophen is sometimes used to close patent ductus arteriosus.

Procedures

Cardiac catheterization is a common procedure that is sometimes used to repair simple heart defects, such as atrial septal defect and patent ductus arteriosus, if they do not repair themselves. It may also be used to open up valves or blood vessels that are narrowed or have stenosis.

In this procedure, a thin, flexible tube called a catheter is put into a vein in the groin or neck. The tube is threaded to the heart. Possible complications include bleeding, infection, and pain at the catheter insertion site and damage to blood vessels.

Surgery

In heart surgery, a cardiac surgeon opens the chest to work directly on the heart.

Surgery may be done for these reasons:

• To repair a hole in the heart, such as a ventricular septal defect or an atrial septal defect.
• To repair a patent ductus arteriosus.
• To repair complex defects, such as problems with the location of blood vessels near the heart or how they are formed.
• To repair or replace a valve.
• To widen narrowed blood vessels.

Surgeries that are sometimes needed to treat congenital heart defects include:

• Heart transplant. Children may receive a heart transplant if they have a complex congenital heart defect that cannot be repaired surgically or if the heart fails after surgery. Children may also receive a heart transplant if they are dependent on a ventilator or have severe symptoms of heart failure. Some adults with congenital heart defects may eventually need a heart transplant.
• Palliative surgery. Some babies with only one ventricle are too weak or too small to have heart surgery. They must have palliative surgery, or temporary surgery, first to improve oxygen levels in the blood. In this surgery, the surgeon installs a shunt, a tube that creates an additional pathway for blood to travel to the lungs to get oxygen. The surgeon removes the shunt when the baby’s heart defects are fixed during the full repair.
• Ventricular assist device. For people with heart failure from a congenital heart defect, this device supports the heart until a transplant occurs. These devices can be difficult to use in people who have congenital heart defects because of the heart’s abnormal structure.
• Total artificial heart. For some people with complex congenital heart defects, a total artificial heart may be needed instead of a ventricular assist device.

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