Overview 

The tricuspid valve controls the blood flow from the atrium into the heart’s right ventricle. In tricuspid atresia (TA), the valve does not develop correctly in the first 8 weeks of pregnancy. Consequently, blood does not flow into the correct chambers and the oxygenated and deoxygenated blood mix. As a result, the body does not receive enough oxygenated blood.¹ Several symptoms and complications follow this defect. Understanding the genetic factors and syndromes associated with this condition ensures the most effective treatment and how to proceed. This article explores the factors contributing to TA and how to manage it. 

Introduction to Tricuspid Atresia 

Pathophysiology 

To understand what exactly goes wrong in TA, we first have to understand the functions of the heart fully. In the heart, the blood returns to the heart from the body through the vena cava, entering the right atrium. The valves in the heart have the crucial job of controlling the blood flow between chambers which directs blood flow. The tricuspid valve is found on the right side of the heart, between the right atrium and right ventricle. It ensures that the deoxygenated blood from the body reaches the lungs for reoxygenation. Thus ensuring that the body is supplied with sufficient levels of oxygenated blood.² 

TA is a heart defect which originates at birth. During foetal development, there is a genetic complication in the maturing of the tricuspid valve. This can result in the presence of the valve altogether or impair its ability to control blood flow. A sheet of tissue can be found in the tricuspid valve’s place. Because of this, the deoxygenated blood in the atrium cannot flow through to the left ventricle and therefore does not reach the lungs. Instead, the blood flows from the right atrium to the left atrium. This occurs via a small hole between the two chambers. The hole originates from an atrial septal defect (ASD) or through the foramen ovale.³ The foramen ovale is a naturally occurring hole in the heart wall between the two atrial chambers in the foetus, which closes up after birth. Patent foramen ovale is when the hole fails to close.⁴ 

In addition, a hole can be found in the wall between the two ventricles of the foetal heart. This is called ventricular septal defect (VSD). If the VSD is large enough, it provides blood direct access to the main lung artery. This means the heart must work harder to pump blood to the body, thus risking heart failure.⁵ The blood flow between the heart’s chambers causes mixing of oxygenated and deoxygenated. This is detrimental as the cells are not replenished and the body struggles to execute its functions.³

Clinical Representation and Symptoms 

Tricuspid atresia symptoms come into play shortly after birth. This includes:

• Trouble breathing 
• Fast breathing 
• Bluish discolouration of the lips, skin, or nails
• Fast heart rate
• Poor feeding¹

These symptoms can lead to complications further on in life. The lack of oxygen to the body’s tissues results in:

• Irregular heart rhythms 
• Easily out of breath 
• Kidney or liver disease
• Heart failure

Diagnosis and Imaging Studies 

Symptoms exhibited by the baby can be mistaken for other health conditions. Therefore, it is vital to carry out extensive diagnostic tests to ensure the correct condition is identified. A specialised doctor will check for abnormal heart sounds and examine the lungs. Next, a series of procedures are carried out. These tests include:

• Pulse oximetry: a small probe is used to check the oxygen levels in the blood of the baby
• Blood and urine samples
• Chest x-ray which may bring to light any changes often seen with TA 
• An ECG can be used to check for irregular heart rhythms, identify heart murmurs through electrical activity
• An echocardiogram uses sound to create a moving picture of the heart and its valves. Here, TA is identified through abnormal heart structures¹ 

Genetic Basis of Tricuspid Atresia 

In most cases, TA occurs randomly. Familial patterns have been identified in TA. However, they are rare. This makes it difficult to pinpoint the specific genetic abnormalities of TA. The chromosomes found to link to TA were found through several genetic studies.⁶ It was found that the deletion of genes such as:

• 22q11
• 4q31
• Trisomy 13/18 ( genetic condition resulting in an extra chromosome)⁷ 

Additionally, heart-related genes play a part in TA occurrence. These genes are specifically involved in heart development:

• ZFPM2 or Fog-2 
• Gata4
• TBX5
• JAG1
• NOTCH2

The main gene under investigation is the Fog-2 gene.⁶ The Gata4 plays a crucial role in the early development of the heart. It is expressed in combination with the Fog-2 gene. The mutation of Fog-2 and Gata4 resulted in the absence of the tricuspid valve, a pronounced ASD and VSD. The findings presented the importance of Fog-2 in tricuspid valve development, therefore showing a genetic link.⁸ 

Syndromes Associated with Tricuspid Atresia 

The genes listed above are associated with various syndromes linked to TA. By exploring these syndromes, we can deduce common factors between them. As a result, we can clarify the origins of TA and its associated risk factors. 

DiGeorge syndrome involves the 22q11 gene. In this deletion syndrome, chromosome 22 is missing from the genome. The deleted gene impairs heart development and causes problems in the structure of the heart and vessels. TA can arise if the tricuspid valve is not formed properly.⁹

Holt-Oram syndrome is also referred to as the ‘heart-hand’ syndrome. This name comes from the distinctive limb abnormalities it produces. A mutation in the TBX5 gene on chromosome 12 disrupts the expression of a transcription factor, T-box-5. T-box-5 regulates the expression of other genes involved in the development of the heart and the limbs. Tricuspid atresia presents as a symptom of this condition.¹⁰

Alagille syndrome is a rare genetic inherited condition. There is a build-up of bile in the liver due to a lack of bile ducts. This is caused by a mutation in the JAG1 and NOTCH 2 genes. While the liver is the main organ affected, there are cardiovascular manifestations. The JAG1 gene mutation is the main culprit for heart defects. These include VSD and ASD which lead to the development of TA.¹¹

Genetic Testing and Diagnosis

By now, we understand that the genetic basis for this condition is incredibly complicated due to the multiple genes involved. These genes further impact other processes and conditions, making the condition less well-defined. As a result, it is difficult to find a single genetic test for diagnosing TA. This is also true for most heart valve diseases. The current protocol looks at family history and outstanding risk factors that may contribute to TA. Doctors carry out genetic screening and chromosomal microarray testing, which helps to draw attention to potential TA diagnoses.¹³

Treatment and Management 

TA presents itself early which allows for treatment and management to follow promptly. At identification, the child is supplied with oxygen through a ventilator. Additional medicines are prescribed to help the heart and lungs function, such as prostaglandin E1, which keeps arterial ducts open. 

Alternatively, surgeries can be carried out early on if deemed necessary.

• Cardiac catheter - a catheter with a small balloon is inserted into the heart to widen the valve
• Balloon atrial septostomy - a catheter with a balloon is used to widen the hole between the right and left atria. This allows for more blood flow between the two sides of the heart
• In newborns, a Blalock-Taussig shunt allows blood from the aorta to reach the lungs and become oxygenated
• For babies ages 2-6 months, the first shunt is replaced by a new connection (shunt). A major blood vessel from the top of the body is connected to the heart, connecting the superior vena cava to the pulmonary artery
• The Fontan procedure can be performed on children aged 2-3. It involves making a second connection from the lower part of the body to the heart, which allows blood flow to the pulmonary artery¹

Future Direction and Research

Tricuspid atresia is in the early stages of genetic understanding. Researchers are investigating the genetic mutations associated with TA and their respective syndromes. Due to the variability found with this condition, extensive research is required for categorising its features. 

However, there are several pathways for potential gene therapies and novel therapeutic approaches. 

• Stem cell therapy is a promising technique which can be used to regenerate valve tissue. 
• Genetic therapy to correct the defect causing TA

The pre-natal and long-term management can also be further optimised. By improving diagnostic techniques to identify TA in the early stages of pregnancy. It may also be possible to modify the severity of TA before birth. As for long-term management, the focus is on the related syndromes and how they can be treated. Additionally, psychological impacts must also be addressed and tailored to each patient. There is much to explore in the modifications in TA diagnosis, treatment, and management. Further insight into the genetics of TA will improve patient care.¹⁴

Summary 

• Tricuspid Atresia is a congenital heart defect where the tricuspid valve is impaired or missing altogether
• Genes linked to heart defects contribute to TA development such as
  • Fog-2, Gata4, JAG1, NOTCH2
• Several syndromes are associated with TA
  • DiGeorge syndrome - impacts the heart and immune system 
  • Holt-Oram syndrome - TBX5 mutation which causes heart and limb abnormalities 
  • Alagille syndrome -  JAg1 and NOTCH2 mutations impact the heart and liver
• Genetic testing is in the early stages, with chromosomal microarray and family history used for diagnosis
• Surgical interventions depend on the child’s age and other health risks
• Future research aims to refine the genetic therapies for TA to personalise patient treatment and improve outcomes