The human heart, the center of the cardiovascular system, is a fist-size organ divided into four chambers: two atria and two ventricles. These are controlled by electrical impulses which cause them to contract and circulate blood around the body, supplying organs and tissues with oxygen and nutrients and removing waste products such as carbon dioxide. The heart is the first organ to become functional during embryogenesis and starts beating in the first few weeks of pregnancy [1].
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Fetal heart development
During the first weeks of embryo development, the placenta provides nutrients to the growing embryo. As the nutritional needs of the embryo increase, the heart and its vascular system are the first to develop, so that the embryo’s needs for nutrients and oxygen supply are met [2].
Fetal heart development starts near the head of the embryo, in a region called the cardiogenic area, with the formation of the primitive heart tube and vascular structures. This is followed by a process known as ‘folding’, which transforms the embryo from a flat disc into a three-dimensional form and shapes the heart tube [3]. It is from this primitive heart tube that the recognizable heart organ forms and eventually creates structures such as the ascending aorta, the right and left ventricle, and the right and left atria. Shortly after, the heart starts to beat through a process known as electrical depolarization, which triggers the muscle of the heart to contract. By the 10th week of pregnancy, the heart and vascular system are developed and can carry out its most essential function, transporting blood throughout the body [4].
Congenital heart defects
Congenital heart defects (CHD) are conditions that develop during embryogenesis and affect the structure and function of the heart. These defects are present at birth and can vary from mild to severe, depending on which structure of the heart is affected [5]. CHD are the most common birth defects: they affect an estimated 1% of newborns and are the leading cause of infant death [6]. There are various types of CHD such as:
- Ventricular septal defect (VSD)
- Atrial septal defect (ASD)
- Heterotaxy
- Alagille syndrome
VSD is the most common CHD.
Causes of congenital heart defects
Even though most CHD have an unknown cause, some of them have been associated with genetic or environmental factors and sometimes with a combination of both.
When a first-degree relative has a CHD, the risk that a child will be born with a CHD increases 3-fold due to genetic changes that run in the family. Some CHD result from genetic changes with an autosomal dominant pattern of inheritance, which increases the risk of inheriting a CHD, whereas other CHD have a different pattern. If one parent has an autosomal dominant CHD, there is a 50% chance of passing it on to their child [7]. Read our modes of inheritance infographic for more information on how genetic diseases are inherited.
Chromosomal abnormalities are another genetic cause of CHD. Chromosomal abnormalities are structural changes of the chromosomes, such as duplication or deletion of a specific part, or the entire chromosome, which result in genetic disorders or syndromes. Syndromes have a variety of symptoms, and are known to affect more than one organ, including the heart. Patients presenting with a syndromic phenotype may have multiple underlying pathologies which need to be identified and treated separately. Infants with chromosomal abnormalities have a 30% possibility of having a CHD. [7]
Other possible causes of CHD are medication taken during pregnancy such as certain acne medication, alcohol, or substance abuse such as opioids, or maternal illness during the early development of the embryo.
Symptoms of congenital heart defects
Symptoms of CHD vary depending on the affected structure or function of the heart and its severity. Some common symptoms include:
- cyanosis, a blueish tone of the skin and lips
- rapid breathing and heart beating
- fatigue
- heart murmurs
- shortness of breath
- poor blood circulation
Depending on the severity of the specific CHD, symptoms might start appearing prenatally as heart rhythm problems or structural defects, or go unnoticed until childhood or adulthood. In severe cases, symptoms can manifest shortly after birth and might need immediate attention. If symptoms are not treated, there is a possibility of various complications, such as developmental and growth problems, heart infections, heart failure and death [8]. Specifically, 1 in 4 deaths in patients with CDH is due to sudden cardiac death [9].
Diagnosis of congenital heart defects
CHD can be diagnosed even before a baby is born, during pregnancy scans and examinations, where the fetus’ heart is checked for structural malformations. Unfortunately though, these tests depend on various factors, such as gestational age and fetal position, and might not identify fetuses with mild or even severe CHD [10].
Newborns who have not been diagnosed prenatally can still be diagnosed early after birth as part of standard newborn care available in some countries. Use of a pulse oximeter to measure the pulse rate and the percentage of hemoglobin that is saturated with oxygen in the blood has been recommended as a standard newborn screening care by associations such as the American Academy of Pediatrics, the American College of Cardiology, and the American Heart Association [11].
In less serious cases, CHD are diagnosed later in life. When a healthcare provider suspects CHD due to symptoms, they will start with a physical examination and then proceed to certain heart tests to image the heart’s structure and monitor its function.
Genetic testing for congenital heart defects
Genetic changes on a person’s DNA can cause CHD. For example, changes in the GATA4 gene have been associated with atrial septal defects, ventricular septal defects, and pulmonary stenosis, and changes in the MYH6 gene have been associated with defects of the valve, such as bicuspid aortic valve [12].
Due to the complexity of the phenotypes and the heterogeneity of cardiovascular disorders, genetic testing can lead to an accurate diagnosis and effective clinical management. Additionally, specific genetic changes identified via genetic testing can provide a more accurate prognosis on post-surgical interventions and long-term outcomes. For example, a genetic change on the EDN1 gene has been associated with improved post-transplant survival in patients with specific cardiac anatomy, whereas a genetic change on the SOD2 gene has been associated with worse post-transplant survival in patients with no syndromic characteristics [12]. Genetic testing could also be considered when a family member is already diagnosed with CHD, to identify any pre-symptomatic carriers.
Genetic testing for inherited cardiovascular diseases is recommended by professional societies such as the American Heart Association (AHA) based on an individual’s family and clinical history. The recommendations include disease-specific considerations, testing for specified genes and applicable clinical care depending on the genetic testing results [13].
Treatment of congenital heart defects
Even though the management of people with CHD has been improved greatly over the years, the understanding behind what causes these defects remains limited. Untreated or unmonitored CHD can lead to disability of varying degrees, or even death. Of all infants born with a CHD, about half of them will need medical assistance during infancy. A further 25% will need surgical intervention within the first decade of their lives. Prognosis without surgical intervention is very poor, as only 10% of affected children survive to adolescence [14].
Treatment is based on the specific heart defect and symptoms present. For mild cases of CHD, treatment might not be needed, but regular check-ups and monitoring are advised. For more severe cases of CHD that affect everyday life, symptoms could be minimized or stabilized with certain medications. Examples are diuretics to remove excess fluid and improve breathing difficulties, and medication to alter heartbeat and improve the heart’s ability to pump blood. Medication for the most severe cases acts only to minimize symptoms, as patients eventually require surgical intervention and ongoing monitoring throughout their life [15]. Surgical intervention includes procedures such as cardiac catheterization to repair a simple CHD, or more invasive surgeries to repair defects such as a hole in the heart, valve replacement or vascular reforming.
For extreme cases of CHD, that are noticeable from birth and have a great impact on the health of the infant, such as unrepairable birth defects, heart transplant could be considered. If the heart transplant is successful, the patient will have normal cardiovascular function and blood flow, but they will have to take lifelong immunosuppressive medication to control transplant side effects, such as infections, and prevent the new heart being rejected by the body as a foreign object. In cases of heart transplant in infants and children, the heart grows along with the child and regular monitoring continues as they grow and throughout adulthood. Although the average lifespan of a heart transplanted during infancy or childhood used to be over 20 years, the combination of the immunosuppressive medication, furthered research, and better surveillance protocols have expanded the lifespan of the organ to over 30 years [16].
Gene therapy, which works by altering the mutated gene rather than relying on medication or surgery, is a promising intervention for the prevention and treatment of various genetic diseases, including CHD, and has become the focus of numerous cardiovascular research projects, with some of them reaching pre-clinical stages.
Conclusion
CHD are the most common type of birth defect and have a broad severity of symptoms. A better understanding of the reasons behind the development of CHD could lead to greater advancements in preventing and managing CHD, providing a better prognosis and outcome for patients. Genetic testing of CHD can be key for targeted curative treatment, accurate prognosis and effective interventions.
References
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