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 Of note, arrhythmogenic events do not necessarily portend other adverse clinical outcomes. Specifically, appropriate ICD discharges do not appear to predict the occurrence of heart failure or the need for other invasive therapies (e.g., surgical myectomy, septal ablation).¹²

Initial Evaluation

Clinical diagnosis is generally made with transthoracic echocardiography, demonstrating LV hypertrophy in a nondilated ventricle (Fig. 28-2). Cardiac magnetic resonance (MR) imaging also can provide very valuable additional information in the diagnosis of hypertrophic CMP and in differentiating it from other disorders. Marked ECG abnormalities are typically present in the majority of patients.

FIGURE 28-2 Echocardiographic appearance of hypertrophic cardiomyopathy. Parasternal long-axis view from a patient with hypertrophic cardiomyopathy demonstrating asymmetrical septal hypertrophy. The interventricular septum (marked by arrow) measures 2.1 cm, the posterior wall measures 0.99 cm. Ao = aorta; IVS = interventricular septum; LA = left atrium; LV = left ventricle; MV = mitral valve; PW = posterior wall; RV = right ventricle.

In addition to clinical history, risk stratification for SCD in hypertrophic CMP patients requires family pedigree analysis (premature sudden death), echocardiogram (hypertrophy, LV outflow gradient), 48-hour ambulatory ECG (nonsustained VT), and a symptom-limited exercise test with careful measurement of blood pressure (abnormal blood pressure response).

Clinical genetic testing for hypertrophic CMP comprising the eight most common disease-causing genes is now commercially available. Overall, the yield of genetic testing in probands with hypertrophic CMP is approximately 60%, but it depends on patient selection, falling to approximately 30% in sporadic disease.^13,¹⁴ Although the knowledge of the underlying gene and mutation has a limited role in risk stratification and management of the individual patient, genetic testing is recommended for patients with an established clinical diagnosis of hypertrophic CMP in whom mutation-specific confirmatory testing would benefit, confirm, or exclude the diagnosis in at-risk family members. Once a pathogenic mutation has been detected, cascade screening of the relatives is indicated. On the other hand, genetic testing is not recommended for diagnosis of hypertrophic CMP in patients with nondiagnostic clinical features because the absence of a sarcomere mutation cannot rule out familial hypertrophic CMP.Furthermore, variants of uncertain significance can pose a problem in subjects with lower clinical pretest probability of a pathogenic sarcomere mutation.⁴

Risk Stratification

The traditionally acknowledged noninvasive risk stratification strategy for primary prevention uses five clinical markers that have been defined in several retrospective and observational studies. These primary prevention risk factors (applicable to hypertrophic CMP patients without prior cardiac arrest) are: (1) premature hypertrophic CMP-related sudden death in one or more relatives; (2) unexplained syncope (especially in the young and related to exertion); (3) multiple, repetitive (or prolonged) nonsustained VT on ambulatory (Holter) monitoring; (4) severe LV hypertrophy (maximal wall thickness of ≥30 mm); and (5) an abnormal blood pressure response during upright exercise (i.e., failure of blood pressure to rise appropriately by more than 20 to 30 mm Hg from baseline).^8,^15,¹⁶

The risk associated with each of these factors is greatest in younger patients; hence, this risk stratification approach is generally employed in patients younger than 50 years. However, it is important to understand that even achieving this measure of longevity does not confer immunity to SCD.

The relative weight that can be assigned to each of the traditional risk markers has not been defined. A consensus document on hypertrophic CMP from the ACC and European Society of Cardiology (ESC) categorized known risk factors for SCD as “major” and “possible in individual patients” (Table 28-1). Although the absence of risk factors identifies a low-risk group, the positive predictive value of any single risk factor is limited. Risk stratification based on incorporation of multiple risk factors would likely improve positive predictive accuracy.⁹

TABLE 28-1 Risk Factors for Sudden Cardiac Death in Hypertrophic Cardiomyopathy

MAJOR RISK FACTORS	POSSIBLE IN INDIVIDUAL PATIENTS
• Cardiac arrest (ventricular fibrillation) • Spontaneous sustained ventricular tachycardia • Family history of premature sudden death • Unexplained syncope • Left ventricular thickness ≥30 mm • Abnormal exercise blood pressure • Nonsustained spontaneous ventricular tachycardia

• Atrial fibrillation

• Myocardial ischemia

• Left ventricular outflow obstruction

• High-risk mutation

• Intense (competitive) physical exertion

From Zipes DP, Camm AJ, Borggrefe M, et al: ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines, J Am Coll Cardiol 48:e247-e346, 2006.

It is also important to note that the traditional risk stratification strategy in hypertrophic CMP remains imprecise and a few SCDs have been reported in young hypertrophic CMP patients judged to be at low risk without any of the acknowledged risk markers.¹⁷

In addition to the five traditional risk factors, other features of hypertrophic CMP may increase SCD risk for patients in selected subgroups. LV apical aneurysm (which is observed only in 2% of hypertrophic CMP patients) has been associated with a substantial (10%) annual event rate, largely because of the arrhythmogenic substrate created by the fibrotic thin-walled aneurysm.^1,¹⁸ Similarly, patients in the end-stage phase of the disease (characterized by LV systolic dysfunction, wall thinning, and chamber enlargement) awaiting heart transplantation have a substantial arrhythmia-related event rate of 10% per year.¹⁷

Although LV outflow obstruction (subaortic gradient ≥30 mm Hg at rest) is a determinant of progressive heart failure and cardiovascular death (particularly from stroke), the specific relationship to SCD is weak and insufficient to regard LV outflow obstruction as a primary SCD risk marker.¹⁹ Reduction of obstruction by myotomy/myectomy (or alcohol ablation) is not considered a primary strategy for mitigating SCD risk. Similarly, the severity of clinical symptoms such as dyspnea, chest pain, and effort intolerance has not been correlated with increased risk of SCD.⁹

Currently, genetic testing appears to have little clinical application to the assessment of prognosis. Although certain mutations (e.g., some beta-myosin heavy chain and troponin T mutations) responsible for hypertrophic CMP can be associated with a higher risk for SCD compared with other mutations, there is substantial overlap between different disease gene groups, and exceptions are common.⁴ Hence, the prognostic value of disease-causing mutations in hypertrophic CMP for risk stratification is questionable, and the clinical course of individual patients cannot be reliably predicted based solely on particular genetic substrates and disease-causing mutations.¹⁷

Percutaneous alcohol septal ablation appears to augment the risk of SCD in patients with hypertrophic CMP. Alcohol septal ablation typically creates a sizable transmural scar occupying on average 30% of the ventricular septum and 10% of the overall LV chamber. Alcohol-induced infarcts can potentially compound preexisting and underlying myocardial electrical instability resulting in increased arrhythmogenicity and higher risk of malignant ventricular arrhythmias. Several studies have documented the occurrence of sustained ventricular arrhythmias and SCD following septal ablation in approximately 10% to 20% of patients with or without SCD risk factors. Long-term outcome and survival following alcohol ablation is fourfold less favorable compared with myotomy/myectomy (which leaves no intramyocardial septal scar), and the rate of appropriate ICD therapy among alcohol ablation patients with primary prevention ICDs is threefold more frequent than in other patients (10.3% per year versus 3.6% per year).

Invasive EP testing has little predictive value for SCD in hypertrophic CMP, and has proved an impractical and nonspecific prognostic strategy, and without advantage over the traditional noninvasive risk stratification. In addition, it may be difficult to defibrillate hypertrophic CMP patients if rapid VT or VF is initiated.

The role of cardiac MR imaging in risk stratification in patients with hypertrophic CMP is being evaluated. Cardiac MR imaging can help determine the severity and distribution of LV hypertrophy. Detection of myocardial fibrosis by gadolinium cardiac MR imaging (i.e., delayed enhancement) may have a role as a clinical predictor for increased risk of SCD. Up to 80% of patients with hypertrophic CMP have some degree of myocardial gadolinium hyperenhancement (the presumptive imaging correlate of increased myocardial fibrosis or scar) on cardiac MR (Fig. 28-3). However, the extent of hyperenhancement is greater in patients with progressive disease (28.5% versus 8.7%) and in patients with two or more risk factors for SCD (15.7% versus 8.6%).²¹ Additionally, patients with diffuse rather than confluent enhancement had two or more risk factors for SCD (87% versus 33%).¹⁷

FIGURE 28-3 Delayed hyperenhancement magnetic resonance images from a patient with symptomatic hypertrophic obstructive cardiomyopathy, demonstrating areas of extensive scarring in the basal interventricular septum (A, arrow). Notice also the areas of patchy scarring in the posterior wall (B, arrow). The image on the left is a short-axis view, and the image on the right is a three-chamber view. LV = left ventricle.

(From Kwon DH, Smedira NG, Rodriguez ER, et al: Cardiac magnetic resonance detection of myocardial scarring in hypertrophic cardiomyopathy: correlation with histopathology and prevalence of ventricular tachycardia, J Am Coll Cardiol 54:242-249, 2009.)

Electrocardiographic Features

The ECG is abnormal in more than 90% of patients with hypertrophic CMP and in 75% of asymptomatic relatives. An abnormal ECG in the young is a sensitive marker of early disease expression. ECGs show a wide variety of abnormal patterns; however, no particular ECG pattern is characteristic or predictive of future events. Left atrial enlargement, repolarization abnormalities (ST-T changes including marked T wave inversion), and deep and narrow Q waves (most commonly in the inferolateral leads) are the most frequent ECG findings (Fig. 28-4). Voltage criteria for LV hypertrophy alone are nonspecific and are often seen in normal young adults. Giant negative T waves in the midprecordial leads are characteristic of hypertrophy confined to the LV apex.

FIGURE 28-4 Surface ECG in a patient with hypertrophic cardiomyopathy. Note the deep narrow Q waves in the inferolateral leads.

Principles of Management

No treatments to prevent or modify disease progression currently exist. Therefore current treatment focuses on symptom management, assessment for risk of SCD, and family screening. Patients with LV outflow obstructive symptoms or heart failure are treated with beta blockers, verapamil, and disopyramide. Reduced heart rate and decreased contractility resulting from their action can potentially alleviate symptoms related to LV outflow obstruction. In cases that are unresponsive to drugs, septal surgical myotomy/myectomy or percutaneous alcohol septal ablation (Fig. 28-5) should be considered.

FIGURE 28-5 Left coronary angiography in a patient with asymmetrical septal hypertrophic cardiomyopathy. A right lateral oblique view is shown. The septal perforator branch (marked by arrows) of the left anterior descending artery is the target for alcohol septal ablation. A temporary pacing wire is positioned in the right ventricle and a pigtail catheter is positioned in the left ventricle.

For AF the goal is to restore and maintain sinus rhythm. Anticoagulation is also required because of the high risk for thromboembolic complications.

Dual-chamber pacing modifies the LV excitation pattern by changing the depolarization synchrony of the LV contraction, and can potentially be useful in a subset of symptomatic patients who have substantial LV outflow gradients (>30 mm Hg at rest or >50 mm Hg provoked) refractory to medical therapy and are not candidates for surgical myotomy/myectomy or alcohol septal ablation (Fig. 28-6). Although the initial observational studies in patients with hypertrophic CMP showed promising results, subsequent randomized clinical studies failed to show a significant benefit of dual-chamber pacing, and there are currently no data available to support the contention that pacing alters the clinical course of the disease or improves survival or long-term quality of life in hypertrophic CMP. Hence, routine implantation of dual-chamber pacemakers is no longer used, except in rare situations.²²

FIGURE 28-6 Reduction of left ventricular (LV) outflow obstruction by ventricular pacing. The four panels show ECG and hemodynamics (femoral arterial [FA] and LV) under different conditions in a patient with hypertrophic cardiomyopathy and dynamic LV outflow obstruction. Panels from left to right: Baseline sinus rhythm showing a peak LV-FA gradient of almost 40 mm Hg. During atrial pacing at 100/min, the gradient increases to 50 mm Hg. With addition of right ventricular pacing at 100/min and an atrioventricular (AV) interval of 110 milliseconds, the gradient is almost eliminated; finally, when the AV interval is shortened, the gradient increases again to about 30 mm Hg.

Implantable Cardioverter-Defibrillator

ICD therapy is the most effective and reliable approach for reduction of the risk of SCD in patients with hypertrophic CMP, both for secondary prevention and altering the natural history of this disease. Of note, the interval from ICD implantation to first appropriate device intervention is quite variable, and often considerable in length. Even ICD recipients for secondary prevention after a cardiac arrest can survive for many years with or without the aid of ICD discharge.¹⁷ On the other hand, prophylactic pharmacological treatment alone (amiodarone, beta blockers, or verapamil) does not offer hypertrophic CMP patients reliable protection against SCD and is generally not indicated.

ICD implantation is recommended for secondary prevention in patients with prior cardiac arrest or sustained VT, because of the relatively high recurrence rates in this subgroup. ICD implantation is also recommended for primary prevention in patients with multiple risk factors (two or more) for SCD. However, ICD implantation for primary prevention in patients with only one risk factor is controversial. In this subgroup, management decisions should be individualized, taking into consideration other markers of disease severity, other less established risk factors (e.g., prior alcohol septal ablation, LV aneurysm), as well as the desires of the fully informed patient and family.

It is important to note that the number of risk factors in ICD recipients for primary prevention is unrelated to the likelihood of an appropriate therapy; about 35% of patients with appropriate ICD interventions for VT/VF had undergone implantation for only a single risk factor; and the likelihood of appropriate discharge was similar in patients with one, two, or three or more risk markers.¹¹ Therefore, a single marker of high risk may represent sufficient evidence to justify the recommendation for a prophylactic ICD in selected patients with hypertrophic CMP. Indeed, the most recent ACC/AHA/ESC practice guidelines make primary prevention with the ICD a class IIa indication, based on the presence of one or more risk factors.^9,²² Whether hypertrophic CMP patients should have ICDs implanted routinely following alcohol septal ablation is presently unresolved.

The absence of risk factors for SCD accurately identifies a cohort of patients with a low risk of SCD. Nevertheless, regular periodic reassessment of low-risk adults with Holter monitoring, exercise testing, and echocardiography is recommended. Changes in symptoms, particularly sustained palpitations or syncope, warrant urgent reevaluation at any age.

Catheter Ablation

In patients with apical aneurysms and SMVT, recurrence is quite high and antiarrhythmic drug therapy or catheter ablation should be considered. Antiarrhythmic medications have limited efficacy. When catheter ablation is undertaken, it should be appreciated that an epicardial approach may be warranted in a significant number of patients; in a recent report, an electrophysiologically identifiable epicardial scar was present in 80% of patients compared with 60% with an endocardial scar.^1,^2,^18,^23,²⁴

Participation in Sports

Participation in intense competitive sports can represent a potential risk factor in athletes with hypertrophic CMP, even when conventional markers are absent, and exclusion from most participation in contact and most organized competitive sports is recommended (even in patients with ICDs), with the exception of low-intensity, class 1A sports (e.g., golf, bowling, billiards).

Family Screening

As expected in an autosomal dominant disease, every offspring has a 50% chance of inheriting the mutation and therefore of developing hypertrophic CMP. However, because of age dependence of penetrance, many mutation carriers may not exhibit phenotypic expression early in life, and many others may express the phenotype, but remain asymptomatic and, hence, remain undiagnosed unless screened. Therefore, it is generally considered that all first- and second-degree genetically related family members of patients with hypertrophic CMP should undergo screening with detailed history and physical examination, 12-lead ECG, and echocardiogram.

Because penetrance is age dependent, many family members may not express the phenotype at the time of examination and may be falsely considered “unaffected.” Thus, periodic evaluation of the “unaffected” family members is necessary, as some may develop hypertrophic CMP later in life. Annual screening should be considered in adolescents and young adults (ages 12 to 25 years), in athletes, and in those with a family history of early-onset disease. Screening every 3 to 5 years in other individuals may be adequate (Table 28-2).¹³

TABLE 28-2 Clinical Screening Strategies with Echocardiography and 12-Lead ECG for Detection of Hypertrophic Cardiomyopathy in Families

AGE OF FAMILY MEMBER	SCREENING STRATEGY
<12 yr old	Optional unless: • Family history of premature hypertrophic CMP death or other adverse complications • Competitive athlete in an intense training program • Onset of symptoms • Other clinical suspicion of early left ventricular hypertrophy

12 to ~18–21 yr old Every 12–18 mo >18–21 yr old Probably about every 5 yr, or more frequent intervals with a family history of late-onset hypertrophic CMP and/or malignant clinical course

CMP = cardiomyopathy.

When the causative mutation in the index patient is identified, genetic testing is recommended for all first-degree relatives and can have particular advantages over clinical screening, as ECG or echocardiographic abnormalities may be absent or subtle, or develop late in life. Furthermore, genetic testing affords permanent reassurance to those family members who test gene-negative, obviating the need for clinical investigations or long-term follow-up and screening of their offspring.^4,¹⁴

Athletes with a family history of hypertrophic CMP should probably undergo annual ECG, echocardiography, 24-hour Holter monitoring, exercise testing, and genetic testing before being allowed to participate in competitive sports.

Asymptomatic individuals found to carry a hypertrophic CMP mutation on genetic screening should undergo a comprehensive cardiac evaluation and risk stratification similar to patients with known hypertrophic CMP. Additionally, genotype-positive athletes should be excluded from most competitive sports, even when they are asymptomatic and have no abnormalities on echocardiogram and ECG.

Prophylactic pharmacological therapy in asymptomatic carriers of hypertrophic CMP genes is ineffective and not recommended.

References

1. Furushima H., Chinushi M., Iijima K., et al. Ventricular tachyarrhythmia associated with hypertrophic cardiomyopathy: incidence, prognosis, and relation to type of hypertrophy. J Cardiovasc Electrophysiol. 2010;21:991-999.

2. Santangeli P., Di Biase L., Lakkireddy D., et al. Radiofrequency catheter ablation of ventricular arrhythmias in patients with hypertrophic cardiomyopathy: safety and feasibility. Heart Rhythm. 2010;7:1036-1042.

3. Morita H., Rehm H.L., Menesses A., et al. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med. 2008;358:1899-1908.

4. Ackerman M.J., Priori S.G., Willems S., et al. HRS/EHRA Expert Consensus Statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm. 2011;8:1308-1339.

5. Boussy T., Paparella G., de Asmundis C., et al. Genetic basis of ventricular arrhythmias. Heart Fail Clin. 2010;6:249-266.

6. Pinto J.R., Parvatiyar M.S., Jones M.A., et al. A functional and structural study of troponin C mutations related to hypertrophic cardiomyopathy,. J Biol Chem. 2009;284:19090-19100.