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.
Fallot’s tetralogy
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.
