Ventricular Arrhythmias in Hypertrophic Cardiomyopathy

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Chapter 28 Ventricular Arrhythmias in Hypertrophic Cardiomyopathy

Pathophysiology

Hypertrophic cardiomyopathy (CMP) is characterized by an otherwise unexplained thickened but nondilated left ventricle (LV) in the absence of any other cardiac or systemic condition capable of producing the magnitude of hypertrophy evident (e.g., aortic valve stenosis, systemic hypertension, some expressions of athlete’s heart, infiltrative or storage disorders), independent of whether obstruction to LV outflow is present.

Hypertrophic CMP is characterized by myocyte disarray. Cardiomyocytes in hypertrophic CMP become hypertrophied, enlarged, and distorted, which leads to disorientation of adjacent cells and arrangement in chaotic disorganized patterns (instead of the normal parallel cellular arrangement), forming circles or whorls around foci of connective tissue. Although the disorganized architecture is evident in the majority (95%) of patients dying of hypertrophic CMP, it is not specific to hypertrophic CMP, and it occurs in other syndromic causes of LV hypertrophy such as Noonan syndrome and Friedreich ataxia, congenital heart disease, hypertension, and aortic stenosis. Nevertheless, myocyte disarray in hypertrophic CMP is typically more extensive, occupying more than 5% of the total myocardium, including substantial portions of hypertrophied as well as nonhypertrophied LV myocardium, 33% of the ventricular septum, and 25% of the free wall.

Changes in myocyte architecture lead to ventricular hypertrophy (Fig. 28-1). The degree and distribution of LV hypertrophy vary markedly. LV hypertrophy can be asymmetrical or symmetrical. The symmetrical form of hypertrophic CMP accounts for more than one-third of cases and is characterized by concentric thickening of the LV with a small ventricular cavity dimension. Asymmetrical septal hypertrophy is the most common variant, which is associated with thickening of the basal anterior septum, which bulges beneath the aortic valve and causes narrowing of the LV outflow region. However, isolated segmental hypertrophy may affect the LV apex (apical hypertrophic CMP) or any portion of the LV. The morphological pattern of LV hypertrophy is not closely predictive of the severity of symptoms or prognosis. Although LV apical aneurysms are observed only rarely (2%), they are associated with a higher rate of adverse disease consequences (10.5% per year) as compared with the general hypertrophic CMP population.¹

FIGURE 28-1 Pathological features of hypertrophic cardiomyopathy (CMP). A, Gross pathology showing markedly increased LV wall thickness associated with hypertrophic CMP (left) as compared with normal cardiac morphology (right). B, Histological sections stained with hematoxylin and eosin demonstrate myocyte disarray, where myocytes are oriented at bizarre and variable angles to each other, and increased myocardial fibrosis (left), the pathognomonic features of hypertrophic CMP. In contrast, normal myocardium demonstrates a very orderly arrangement of myocytes (right). Images are shown at ×10 magnification.

(From Ho CY: Hypertrophic cardiomyopathy, Heart Fail Clin 6:141-159, 2010.)

Hypertrophic CMP is a complex and clinically heterogeneous disease that demonstrates remarkable diversity in disease course, age of onset, severity of symptoms, LV outflow obstruction, and risk for sudden cardiac death (SCD). The characteristic diversity of the hypertrophic CMP phenotype is attributable to the intergenetic heterogeneity (with a variety of mutations encoding protein components of the cardiac sarcomere), the intragenetic heterogeneity (with multiple different mutations identified in each gene), as well as the potential influence of modifier genes and environmental factors.

The arrhythmogenic substrate responsible for ventricular tachycardia (VT) occurrence in hypertrophic CMP has not been completely defined. Myofibrillar disarray as well as diffuse interstitial myocardial fibrosis or extensive scarring (likely caused by abnormalities of intramural coronary arteries and focal ischemia), which potentially predispose to disordered conduction patterns and increased dispersion of electrical depolarization and repolarization, have been suggested as factors contributing to ventricular arrhythmogenesis.²

Molecular Genetics

Hypertrophic CMP is familial in approximately half the cases and sporadic in the other half. The disease is transmitted as a Mendelian trait with an autosomal dominant pattern of inheritance and variable clinical penetrance. There is substantial diversity in the genetic causes of hypertrophic CMP. To date, nearly 900 different mutations have been reported in at least 24 genes encoding eight sarcomere proteins, including cardiac alpha- and beta-myosin heavy chains; cardiac troponins T, I, and C; cardiac myosin-binding protein C; alpha-tropomyosin; actin; titin; and essential and regulatory myosin light chains. Among these genes, mutations in MYH7, encoding beta-myosin heavy chain, and MYBPC3, encoding cardiac myosin binding protein-C, are the most common, each accounting for one-quarter to one-third of all cases.^3,⁴ For each gene, several different mutations have been identified, and specific mutations are associated with different disease severity and prognosis.⁵

In addition, nonsarcomeric protein mutations in genes involved in cardiac metabolism (e.g., the gamma subunit of adenosine monophosphate [AMP]–activated protein kinase, PRKAG2, and lysosome-associated membrane protein 2 [LAMP-2], as in Danon disease), which are responsible for primary cardiac glycogen storage cardiomyopathies in older children and young adults, can be associated with a clinical presentation mimicking or indistinguishable from sarcomeric hypertrophic CMP. A high prevalence of conduction system dysfunction (with the requirement of permanent pacing in 30% of patients) characterizes PRKAG2 mutations. These diseases are often associated with ventricular preexcitation (Wolff-Parkinson-White syndrome). LAMP2 mutations are associated with early-onset LV hypertrophy (often in childhood) with rapid progression of heart failure and poor prognosis. These clinical entities are distinct from hypertrophic CMP caused by sarcomere protein mutations, despite the shared feature of LV hypertrophy. In addition, there can be genetic overlap between hypertrophic CMP and LV noncompaction.⁴

In infants and children, LV hypertrophy mimicking typical hypertrophic CMP caused by sarcomere protein mutations is often associated with congenital malformations and syndromes, inherited disorders of metabolism, and neuromuscular diseases, such as Fabry disease, Pompe disease, amyloidosis, carnitine deficiency, mitochondrial diseases, Friedreich ataxia, Noonan syndrome, and LEOPARD syndrome. Hypertrophic CMP can be distinguished from these disorders by dysmorphological examination, neuromuscular examination, metabolic screening, family information, and genetic testing.^3,⁶

Clinical Considerations

Epidemiology

Hypertrophic CMP is the most common genetic cardiovascular disease, with a prevalence of approximately 0.2% of the general population for the disease phenotype recognized by echocardiography.

Approximately 10% to 20% of individuals with hypertrophic CMP have a lifetime-increased risk for SCD, most likely resulting from VT and ventricular fibrillation (VF). Hypertrophic CMP is the leading single cause of SCD in competitive athletes in the United States, accounting for approximately one-third of such deaths. Although SCD occurs most often in adolescents or young adults, it can occur at any age. However, SCD is uncommon in young children.

SCD can be the first manifestation of disease. Individuals with hypertrophic CMP who are at the highest risk for SCD can have an at least 3% to 5% annual risk for SCD, whereas individuals in the general hypertrophic CMP population have a 1% annual risk for SCD.

Early studies based on tertiary referral-based populations with hypertrophic CMP suggested a poor prognosis with estimated annual mortality rates of 4% to 6%; however, subsequent studies on broader-based populations suggest that prognosis is typically more favorable with estimated annual mortality rates of 1% to 3% and a normal life expectancy of 75 years or more in about 25% of individuals, the majority of whom have little functional disability.

Clinical Presentation

The clinical presentation of hypertrophic CMP is characterized by extreme variability in disease course, age of onset, severity of symptoms, and risk for SCD. Many patients are either asymptomatic or mildly symptomatic. The majority of patients present during adolescence or young adulthood, but symptoms can develop at any age. Symptomatic patients typically present with dyspnea, chest pain, palpitations, fatigue, orthostatic lightheadedness, presyncope, and syncope. Other complications include atrial and ventricular arrhythmias, infective endocarditis, and congestive heart failure. As noted, SCD can be the first manifestation of the disease.⁷

Shortness of breath, particularly exertional, is the most common symptom of hypertrophic CMP, occurring in up to 90% of patients, typically secondary to diastolic LV dysfunction. Syncope occurs in approximately 15% to 25% of patients, typically secondary to abnormal hemodynamic function (i.e., dynamic LV outflow obstruction) or, infrequently, secondary to cardiac arrhythmias.^7,⁸ Atrial fibrillation (AF) is the most common arrhythmia observed in hypertrophic CMP, occurring in approximately 20% to 25% of patients, and is associated with an increased risk of stroke and thromboembolic complications.

LV outflow obstruction, when present, can produce a characteristic dynamic systolic ejection murmur and bifid pulse. About 25% of individuals with hypertrophic CMP demonstrate LV outflow obstruction at rest, but in many patients the obstruction is variable, occurring in response to exercise or maneuvers that decrease LV preload or afterload or increase contractility or heart rate (dynamic outflow obstruction).

Although LV ejection fraction (LVEF) is typically preserved or even hyperdynamic, up to 5% to 10% of patients may progress to the “burned-out” or end-stage phase of hypertrophic CMP, marked by LV systolic dysfunction, and occasionally progressive LV dilatation and wall thinning. These patients may develop refractory symptoms or end-stage heart failure requiring cardiac transplantation.

Ventricular Arrhythmias

The predominant arrhythmia syndrome associated with hypertrophic CMP is sudden cardiac arrest, presumably due to polymorphic VT or VF. SCD occurs with an annual mortality rate of approximately 6% in referral-based populations and 1% in community-based studies. However, certain patient subgroups can have much higher rates, surpassing the American College of Cardiology/American Heart Association (ACC/AHA) guideline document definition of high risk for SCD (≥2% annual risk).⁹

Hypertrophic CMP is the most common cause of SCD in young people, including competitive athletes, in the United States. SCD occurs throughout life, with a peak in adolescence and young adulthood (<30 to 35 years of age), and can be the initial disease presentation. SCD occurs most commonly during mild exertion or sedentary activities; nonetheless, an important proportion of such events is associated with vigorous exertion.

Ambulatory electrocardiogram (ECG) monitoring frequently reveals premature ventricular complexes (in 88% of patients), nonsustained VT (25% to 30%), and supraventricular tachyarrhythmias such as AF and atrial flutter (30% to 40%). The frequency of all arrhythmias during 48-hour ambulatory ECG monitoring is age related. Nonsustained VT is associated with severity of hypertrophy and symptom class; supraventricular arrhythmias are more common in patients with LV outflow obstruction.

Stable sustained monomorphic VT (SMVT) is rare, but can occur in patients with midventricular obstruction or apical LV aneurysms. The recurrence rate of VT is relatively high (56%) in hypertrophic CMP patients, and electrical storm can occur. During electrophysiological (EP) testing, induction of SMVT has a low reproducibility, and polymorphic VT and VF are often induced. The VT is commonly associated with a superior axis on the frontal plane, suggesting LV apical origins. An arrhythmic substrate, such as an aneurysm, can be important for the occurrence of stable SMVT.^1,¹⁰

Appropriate implantable cardioverter-defibrillator (ICD) discharges in hypertrophic CMP patients occur annually in 10.6% of ICD recipients for secondary prevention after cardiac arrest (5-year cumulative probability, 39%), and in 3.6% of ICD recipients for primary prevention (5-year probability, 17%).¹¹

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