13th March 2024

Cardiac Involvement in Genetic Disease

Marfan’s syndrome

Pathophysiology

Marfan’s syndrome is a systemic connective tissue disorder which affects around 1 in 3000 to 5000 people. Around 75% of Marfan’s syndrome is inherited from an affected parent in an autosomal dominant pattern, but inheritance can also be autosomal recessive or occur due to a de novo mutation. 

Marfan’s syndrome most commonly results from a genetic mutation in fibrillin-1 (FNB-1), which affects the elastic properties of connective tissues in multiple body systems, including musculoskeletal, ophthalmic, respiratory and cardiovascular. Some cases of Marfan’s syndrome are due to a mutation in TGF-beta receptor 2 (TGFBR2).

Clinical manifestations

Marfan’s syndrome has a range of musculoskeletal features, including arachnodactyly, scoliosis or kyphosis, pectus carinatum or excavatum and dolichostenomelia (long extremities in comparison to the length of an individual’s trunk). The main ophthalmic complication in Marfan’s is lens dislocation, which is usually in an upward and outward (superotemporal) direction. Other clinical features include an increased risk of pneumothorax, high arched palate and joint hypermobility.

Cardiovascular manifestations

Loss of elastic tissue in the aortic wall results in aortic root dilatation in around 60 to 80% of those with Marfan’s. Aortic dilation is associated with complications, including aortic dissection (typically type A) and aortic regurgitation. 

An estimated 40-54% of those with Marfan’s syndrome will have mitral valve prolapse (MVP). This defect is more common in females and older individuals and results in mitral regurgitation. As a result of cardiac valve disease, heart failure may develop in those affected with Marfan’s syndrome. There is also a risk of infective endocarditis after surgical intervention to manage aortic dilation.

Diagnostics

Diagnosis of Marfan’s syndrome can be complicated, and the criteria generally considers family history, aortic dilation or dissection, ocular lens subluxation, genetic testing for FBN-1 and physical examination findings. 

When investigating cardiovascular features of Marfan’s, aortic dilation is initially diagnosed via transthoracic echocardiogram, with at least annual monitoring. CT and MRI are used in conjugation with echocardiogram to confirm aortic dilation. Echocardiogram is also used to diagnose MVP, which will show a mitral valve with elongated leaflets and redundant appearance, affecting one or both leaflets.

Management

The management of aortic dilation in adults is dependent on the aortic diameter. If this is < 4.5cm (or < 4 cm in women of reproductive age), a beta blocker such as metoprolol should be commenced to prevent further dilation and reduce the risk of aortic dissection. Where betablockade is contraindicated, an angiotensin-II receptor antagonist, e.g., losartan, may be used. Calcium channel blockers are not first-line in the treatment of aortic dilation as there is evidence suggesting they may increase the risk of aortic complications.

Monitoring for aortic dilation is typically through the use of echocardiogram and MRI. Should a patient develop symptomatic thoracic aortic dilation or a type A aortic dissection, then urgent surgery is required.

Where the aortic diameter is 4.5cm or more, surgery should be considered, and this is typically valve-sparing aortic root replacement or a composite valve graft. 

Surgery may also be considered in those with aortic diameter <4.5cm if there is a high risk of dissection, such as increase in aortic diameter of at least 3 mm/year; a family history of aortic dissection, if the patient is pregnant or of reproductive age. After surgical intervention, patients will typically require long-term beta blockade. 

Mitral valve repair is indicated for severe mitral regurgitation (grade 4 or more) or with evidence of haemodynamic compromise. Those who have undergone a valve graft with a replacement mechanical valve will need long-term anticoagulation. 

While there is an increased risk of developing infective endocarditis in people with valve replacement, routine antibiotic prophylaxis is not recommended for dental procedures. 

References

• UpToDate – Genetics, clinical features and diagnosis of Marfan syndrome and related disorders
• UpToDate – Management of Marfan syndrome and related disorders
• BMJ Best Practice – Marfan syndrome
• NICE clinical guideline 64 – Prophylaxis against infective endocarditis. Available at: https://www.nice.org.uk/guidance/cg64/evidence/full-guideline-pdf-196759981

Down’s syndrome

Pathophysiology

Down’s syndrome is the most common genetic cause of cognitive disability worldwide and occurs as a result of individuals having an extra copy of chromosome 21 (trisomy 21). It is associated with a range of dysmorphic features and a higher prevalence of medical conditions, including congenital heart defects. Around 95% of those with trisomy 21 are caused by chromosome non-disjunction. Less commonly, trisomy 21 is a result of chromosome translocation or mosaicism.

Diagnosis is most often through prenatal screening, although individuals may be diagnosed after birth through phenotypic features and genetic testing.

Clinical manifestations

Down’s syndrome is associated with a number of characteristic facial features, including up-slanting palpebral fissures and epicanthic folds around the eyes, a flat nasal bridge, low-set ears, brachycephaly, and protruding tongue. Other dysmorphic features include a sandal gap between the first and second toes and transverse palmar crease. 

It affects a range of body systems, with individuals being more likely to experience gastrointestinal conditions, including duodenal atresia and coeliac disease, endocrine conditions, typically thyroid disease or type 1 diabetes mellitus.

The majority of individuals with Down’s syndrome will have some level of cognitive impairment and have a higher risk of developing dementia. 

Others with Down’s syndrome may experience haematological conditions such as polycythaemia and leukaemia and respiratory conditions, including obstructive sleep apnoea.

Cardiovascular manifestations

Around half of those with Down’s syndrome will have congenital heart disease. The most common congenital heart defect is atrioventricular septal defect. Other anomalies include ventricular septal defect, atrial septal defect, tetralogy of Fallot and patent ductus arteriosus. 

Individuals with Down’s syndrome can develop cardiac valve problems, most commonly mitral valve prolapse or aortic regurgitation.

Atrioventricular septal defect

In normal development, there is a canal connecting the atria and ventricles known as the AV canal. Typically, at 4 weeks gestation, the endocardial cushions which form the canal fuse and create the atrioventricular (AV) valves and septum. Incorrect fusion of the endocardial cushions results in an AV septal defect (AVSD) and left to right shunt. 

AVSD can be divided into complete and partial. A complete AVSD results in an ostium primum atrial septal defect (ASD), a ventricular septal defect (VSD) and a single AV valve due to complete failure of the endocardial cushions to fuse. Complete AVSD is more common than partial AVSD in Down’s syndrome. A partial AVSD is a result of incomplete fusion of the endocardial cushions and leads to an ostium primum ASD and a VSD but with separate AV valves with a cleft mitral valve. ASVD may present with the following: 

• Tachypnoea
• Tachycardia
• Pallor
• Poor feeding and weight gain

Diagnostics

Down’s syndrome can be diagnosed before birth through antenatal screening followed by amniocentesis or chorionic villus sampling. It may also be diagnosed postnatally based on physical characteristics and confirmed by genetic testing in the form of chromosomal karyotype.

A paediatric cardiologist should review all newborn babies diagnosed with Down’s syndrome and have an echocardiogram to assess for congenital heart defects.

Management

Children with complete AVSD will require surgical repair, typically performed between ages 3-6 months. Life-long follow-up is required due to the risk of AV valve regurgitation or LVOT obstruction.

Continued clinical monitoring in adolescence and adulthood is required to monitor for mitral valve prolapse and aortic regurgitation.

References

• UpToDate – Down syndrome: Clinical features, diagnosis and management
• BMJ Best Practice – Down’s syndrome
• BMJ Best Practice – Congenital heart disease
• StatPearls – Atrioventricular Septal Defect – https://www.ncbi.nlm.nih.gov/books/NBK562194/

Long QT syndrome

Pathophysiology

Long QT syndrome (LQTS) can be congenital or acquired and is characterised by a prolonged QT interval on electrocardiogram (ECG) as a result of prolonged ventricular repolarisation. 

The QT interval on an ECG can be adjusted to estimate the QT interval at a heart rate of 60 beats per minute; this is known as the corrected QT (QTc) and is used to measure QT length. QTc is prolonged if > 440 ms in men or > 460ms in women.

Acquired LQTS can be due to medications or electrolyte abnormalities as well as due to forms of bradyarrhythmia. However, the focus of this section is on congenital LQTS.

Congenital LQTS occurs in around 1 in 2000 people worldwide and results from genetic mutations coding for ion channels responsible for prolonging myocardial repolarisation, which in turn prolongs QT interval. A prolonged QT interval or corrected QT (QTc) can result in arrhythmias, most commonly a form of polymorphic ventricular tachycardia called torsades de pointes. Although multiple genes have been identified in congenital LQTS, three genes account for as many as 80-95% of cases, which are shown below.

Clinical features

Congenital LQTS can be split syndromes based on the phenotype:

Typically, LQTS presents by the time someone is 30 years old. Presentation may be with syncope or syncope followed by seizures. Symptoms, including chest pain, breathlessness or palpitations, will usually precede syncopal episodes. There may be distinct triggers (see above), such as swimming or being startled. Sudden cardiac arrest is an uncommon but possible presentation of LQTS. All of these cardiac events are the result of arrhythmias caused by a prolonged QT interval.

Some people with congenital LQTS are asymptomatic and remain so throughout their lives. Diagnosis may occur through screening of an affected family member.

Diagnostics

Diagnosis of congenital LQTS involves the following:

• ECG to look at the corrected QT (QTc) and T wave morphology
• Ruling out secondary causes of QT prolongation
• 24 ambulatory ECG monitoring
• Exercise stress test for exercise-associated arrhythmias

If congenital LQTS is suspected, then the Schwartz score is calculated to look at the likelihood of a congenital LQTS diagnosis. This looks at ECG findings and factors, including the patient’s clinical history and family history. A score of 3.5 points and above is classed as high risk, and the likelihood of the patient having congenital LQTS is 80%. Intermediate risk is classed as 1.5 to 3 points, and these individuals require genetic testing to evaluate if this is congenital. If the patient scores 0-1 points, then they are classed as low risk, and genetic testing should not be performed.

Management

All patients should be advised on avoiding medications that may prolong the QT interval, such as tricyclic antidepressants. Patients should replace electrolytes if experiencing vomiting or diarrhoea, as hypokalaemia and hypomagnesemia can increase the risk of a prolonged QT interval. Patients should also avoid competitive sports.

Regardless of whether patients are symptomatic or not, a beta blocker, usually propranolol or nadolol, should be started to prevent ventricular tachyarrhythmias. 

In addition, those with congenital LQTS who have not had a cardiac event but are at high risk (QTc >500ms in those with LQT1 or 2, or men with LQT3 with a QTc >550 ms) or in any patient with congenital LQTS who has experienced a previous cardiac event, should be considered for the following treatments:

1st line treatments in conjunction with beta-blockers:

• Implantable cardioverter-defibrillator (ICD) if they have had a previous cardiac event, recurrent syncope on beta blockers or Jervell and Lange-Nielsen syndrome
• Mexiletine can be considered in individuals with LQT3

2nd line treatment in conjunction with beta-blockers:

• Left cervicothoracic sympathectomy (resection of lower half of left stellate ganglion as well as other thoracic ganglia to partially denervate the heart) can be considered in those unable to tolerate beta blockers; those receiving multiple ICD shocks, recurrent syncope despite beta blockers or Jervell and Lange-Nielsen syndrome.

3rd line treatment in conjunction with beta-blockers:

• Permanent pacemaker can be considered alongside beta blockers if a patient has ongoing symptoms despite cervicothoracic sympathectomy.

Patients should have minimum annual ECG monitoring as well as an ECG check after starting or dose adjustment of beta blockers. Exercise testing or Holter monitoring can be used to assess adequate beta-blockade after starting beta blockers.

References

• UpToDate – Congenital long QT syndrome 
• BMJ Best Practice – Long QT syndrome
• Life in the Fastlane – https://litfl.com/qt-interval-ecg-library/

Brugada syndrome

Pathophysiology

Brugada syndrome is an autosomal dominant condition, more common in men, presenting in adulthood. It is defined by ECG abnormalities with associated ventricular tachyarrhythmias or sudden cardiac arrest. Individuals with ECG findings who are asymptomatic have Brugada pattern, not syndrome.

Brugada syndrome results from mutations in SCN genes, which code for cardiac sodium channels. These sodium channels result in short cardiac action potentials, predisposing to arrhythmias.

Clinical manifestations

Individuals with Brugada syndrome experience ventricular tachyarrhythmias such as ventricular fibrillation or polymorphic ventricular tachycardia, which can result in syncope or sudden cardiac arrest; the latter is the first presentation in one-third of patients. Affected individuals may also experience nocturnal agonal respiration or palpitations related to atrial fibrillation, which is associated with Brugada syndrome.

ECG abnormalities and cardiac arrest in those with Brugada syndrome are associated with triggering factors, including:

• Fever
• Drugs including sodium channel blockers such as flecainide, beta-blockers, calcium channel blockers, tricyclic antidepressants, alcohol, cocaine
• Electrolyte abnormalities such as hyperkalaemia and hypokalaemia

Diagnostics

For a diagnosis of Brugada syndrome to be made, a patient requires a Brugada pattern on ECG and either symptoms or a family history in keeping with Brugada syndrome. The diagnostic ECG changes are coved ST-segment elevation in one or more of the right precordial leads (V1-3) followed by a negative T wave.

In individuals where Brugada syndrome is suspected but the basal ECG is not diagnostic, ECG abnormalities can be elicited by a drug challenge with a sodium channel blocker such as flecainide.

It is important to exclude other causes for V1-3 ST elevation on ECG, such as ischaemia or pericarditis.

The diagnosis commonly occurs after a patient has a cardiac event and then is found to have ECG abnormalities. Those with Brugada syndrome will require genetic testing.

Management

The first line treatment option for Brugada syndrome is insertion of an implantable cardioverter-defibrillator to stop arrhythmias and prevent cardiac arrest. If someone experiences recurrent ICD shocks due to arrhythmias, then they may require antiarrhythmic medications. 

Those with Brugada syndrome should avoid medications previously mentioned that may result in ECG changes, and should individuals develop a fever, this should be promptly investigated and treated.

Those with the Brugada pattern typically do not require specific treatment.

References

• UpToDate – Brugada syndrome
• European Society of Cardiology – Management of patients with a Brugada ECG pattern – https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-7/Management-of-patients-with-a-Brugada-ECG-pattern