Genetic And Congenital Heart Disease
Hypertrophic obstructive cardiomyopathy Hypertrophic obstructive cardiomyopathy (HOCM) is the most common genetic cardiac disease, with a prevalence of >1 in 500. Although often asymptomatic, it is the leading cause of sudden cardiac death in young athletes, and a significant cause in the general population. HOCM is associated with left ventricular hypertrophy, often asymmetric, caused by disordered myocardial growth. This is frequently coupled to dynamic outflow obstruction as a result of valve dysfunction, conduction defects and arrhythmias. Inheritance is autosomal dominant. Mutations in sarcomererelated genes are present in 60% of cases, the most common being β myosin heavy chain (∼45%) and cardiac myosin binding protein C (∼35%). Clinical features are variable, ranging from asymptomatic through dyspnoea, angina, palpitations and syncope to heart failure, stroke and sudden cardiac death in a minority. Moderate symptoms can be treated with β-blockers and/or verapamil, but in severe cases surgery to relieve the outflow obstruction is required, and high-risk patients benefit from an implantable cardioverter defibrillator (ICD).
Channelopathies are diseases caused by mutations in genes for ion channels, and predispose to arrhythmias, syncope and sudden cardiac death, most commonly in young, otherwise healthy adults with structurally normal hearts.
Long QT (LQT) syndrome is characterized by a prolonged QT interval (QTC >0.44 s; see Chapter 14). This is normally of no consequence and patients are otherwise healthy, but rarely acute emotion or exertion can trigger the polymorphic ventricular tachyarrhythmia known as torsade de pointes (see Chapter 50), causing syncope (most common), seizures or sudden cardiac death. The trigger is increased sympathetic activity (see also CPVT below).
LQT syndrome is inherited in an autosomal dominant fashion, with a prevalence of ∼1 in 6000; ∼4% suffer sudden cardiac death, largely children and young adults, but 30% remain asymptomatic lifelong. In 95% of cases with an identified genetic cause, there are mutations in KCNQ1 or HERG, genes encoding the delayed rectifier K+ channels underlying IK, which is responsible for cardiac action potential repolarization. Most of the rest have mutations in SCN5A, encoding the Na+ channel (see Chapter 12). Treatment with β-blockers to suppress the effects of sympathetic stimulation is effective, but an ICD may be required. Functional LQT syndrome can be acquired in heart failure (see Chapter 46). Druginduced LQT syndrome is common, including class IA and III anti-arrhythmics, but also antimalarial, antihistamine, antibiotic, psychiatric and recreational drugs (e.g. cocaine) because the HERG protein is promiscuous in its interactions. Such drugs dan- gerously increase risk for genetic LQT syndrome.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) has similar symptoms to LQT syndrome, and is also triggered by acute emotion, exercise and increased sympathetic activity; however, the ECG at rest is normal. Symptoms generally become apparent in the first decade of life, and 60% will have had symptoms by the age of 20. Prevalence may be 1 in 10000. Most cases (50–70%) are associated with mutations in RYR2, which encodes the SR al dominant inheritance. A minority (∼8%) have mutations in CASQ2, which encodes calsequestrin and is recessive (see Chapter 12). Treatment is the same as for LQT syndrome.
Brugada syndrome is characterized by ST elevation in precordial leads V1–V3 (see Chapters 11, 14 and 50). Symptoms usually appear after puberty but can occur at any age, and include syncope, cardiac arrest and sudden cardiac death, often during rest or sleep, as a result of ventricular fibrillation. The mean age of sudden death is 40 years. Brugada syndrome is synonymous with sudden unexplained nocturnal death syndrome. Inheritance is autosomal dominant, but symptoms are eight- to 10-fold more common in males. Prevalence worldwide may be as high as 1 in 2000, particularly in South East Asia, where it is the leading cause of death in men under 40 apart from accidents. About 30% of cases have been associated with mutations in SCN5A, encoding cardiac Na+ channels. These lead to shorter action potentials in right ventricle epicardial but not endocardial cells, favouring development of re-entry arrhythmias (see Chapter 50). The only known effective treatment is an ICD.
Congenital heart diseases (CHDs) are abnormalities of cardiac structure that are present from birth, caused by abnormal development between 3 and 8 weeks’ gestation. The incidence of CHD is ∼1% of live births, not including valve disorders such as mitral prolapse or bicuspid aortic valve. Many spontaneously aborted or stillborn fetuses have cardiac malformations, or chromosomal abnormalities associated with structural heart defects. Maternal rubella infection, alcohol abuse and some medications are associ- ated with CHD. CHDs normally present in infancy with either congestive heart failure or central cyanosis. Congestive heart failure in an infant is usually caused by a left to right shunt, such as a ventricular septal defect (VSD) or a patent ductus arteriosus (PDA), or as a result of aortic obstruction. Central cyanosis may be caused by severe pulmonary disease or right to left shunt. It is characteristic of transposition of the great vessels and tetralogy of Fallot.
VSDs are the most common CHD (0.2% of births), and may occur with other abnormalities. In utero, pulmonary vascular resistance (PVR) exceeds systemic vascular resistance (SVR), so most blood exits the left ventricle via the aorta. However, after birth PVR < SVR, and blood is shunted from the left to right ventricle via the VSD, and into the pulmonary artery (Figure 55a). The magnitude of shunt is related to the size of defect and relative size of PVR and SVR. In young children, moderate VSD may limit exercise or cause fatigue, an enlarged heart and hypertrophy. Shunting of blood into the pulmonary circulation leads to pulmonary hypertension, and if persistent irreversible pulmonary vascular remodelling. PVR may then exceed SVR, reversing the shunt and causing cyanosis (Figure 55b; Eisenmenger’s syndrome). Surgical correction is then not possible, so infants with significant VSD benefit from early surgery. Half of smaller VSDs close spontane- ously within ∼4 years.
Patent (or persistent) ductus arteriosus
PDA may arise because the duct does not close properly due to malformations, possibly related to maternal rubella. It is more common in females. The duct may not close in premature babies due to immaturity. Frequently, PDA is not diagnosed at birth, but only after development of heart failure or infective endocarditis. Treatment is initiated as soon as possible to prevent development of full heart failure. Ligation of the ductus arteriosus must be performed within 5 years of birth. A cyclooxygenase inhibitor to reduce PGE1 is sometimes sufficient to promote closure.
Transposition of the great arteries
This occurs when the left ventricle empties into the pulmonary artery and the right ventricle into the aorta. It may be associated with VSD, atrial septal defect (ASD) or PDA. The transposition results in two parallel circulations, where deoxygenated systemic venous blood is returned to the body and oxygenated pulmonary venous blood returns to the lungs, causing severe central cyanosis. Unless corrected, it is fatal within 2 weeks for ∼30% of cases and within a year for 90%. Surgical correction involves transection of the great vessels and reconnection to their appropriate ventricles. Prior to surgery infants can be stabilized by creation of an artificial ASD, allowing mixing of blood in the atria and oxygenation of systemic blood. Administration of PGE1 delays closure of the ductus arteriosus and so further access of oxygenated blood to the systemic circulation.
The most common cyanotic CHD in children surviving to 1 year (Figure 55c). It consists of a VSD, pulmonary stenosis, an over- riding aorta (positioning of aorta over the VSD) and right ventricular hypertrophy. There is a high right ventricular pressure and right to left shunt. The degree of cyanosis depends on the pulmonary stenosis, generally due to misalignment of the infundibulum. Infants with Fallot’s tetralogy develop slowly, and may present with dyspnoea, fatigue and hypoxic episodes (Fallot’s or tetralogy spells), characterized by rapidly worsening cyanosis, progressing to limpness, stroke and loss of consciousness. Surgical correction of the VSD and ventricular obstruction is performed in infancy and has <5% mortality.
Atrial septal defects
ASDs usually go unrecognized until adulthood. They generally involve the midseptum in the ostium secundum and are distinct from a patent foramen ovale. The left to right shunt increases pulmonary blood flow, which if sustained into adulthood leads to pulmonary vascular remodelling and pulmonary hypertension. Adults with ASDs may also have atrial arrhythmias or left ventricular failure. Severe pulmonary hypertension can reverse the left to right shunt and cause right to left shunt and cyanosis. ASDs with significant left to right shunts should be repaired before development of irreversible pulmonary hypertension. Once a right to left shunt has developed, surgical repair is not performed.