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 sarcomere-related 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

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 (QT_C >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 I_K, 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). Drug-induced 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 dangerously increase risk for genetic LQT syndrome.

Catecholaminergic polymorphic ventricular tachycardia

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