CHAPTER 59: HYPERTROPHIC CARDIOMYOPATHIES

Hypertrophic cardiomyopathy (HCM) is defined as left ventricular (LV) hypertrophy in the absence of abnormal loading conditions, such as severe hypertension or valve disease, sufficient to provoke the observed phenotype.¹ It occurs in approximately 1 in every 500 adults,^2,3,4,5,6,7 with a slightly higher prevalence in males, but with no significant differences across ethnicities or geographical locations. Ventricular hypertrophy frequently develops during periods of rapid somatic growth, but can appear de novo at any time from infancy to old age.

The term “hypertrophic cardiomyopathy” embraces a range of disorders that can be grouped into familial/genetic and nonfamilial/nongenetic subtypes^1,8 (Fig. 59–1). The prevalence of individual disorders (phenocopies) varies with age. In 50% to 60% of adolescents and adults, HCM is inherited as an autosomal dominant trait caused by mutations in cardiac sarcomere protein genes. A further 5% of patients have metabolic or storage disorders, neuromuscular disease, chromosome abnormalities, and genetic syndromes such as cardio-facial-cutaneous disorders or phakomatoses. When all these disorders are excluded, 25% to 30% of cases remain unexplained.

Patients with unexplained ventricular hypertrophy have been described for more than 100 years,⁹ but it was not until the publication of Sir Russell Brock’s paper on “functional obstruction of the left ventricle” in 1957¹⁰ and Donald Teare’s¹¹ description of asymmetrical myocardial hypertrophy in 1958 that HCM was established as a distinct disease. From the 1960s onward, diagnostic criteria for the disease evolved with the prevailing technologies used to interrogate the heart. An initial focus on clinical signs and symptoms and cardiac catheterization meant that dynamic LV outflow tract obstruction (LVOTO) was central to the diagnosis of the disease.^{12,13,14,15,16,17,18,19,20} In the 1970s, the asymmetrical distribution of hypertrophy was emphasized by the use of M-mode echocardiography,^{21,22,23,24,25} but with the advent of two-dimensional echocardiographic imaging and, later, cardiac magnetic resonance imaging, the complex spectrum of ventricular involvement is now better appreciated.^26,27

Early clinical reports suggested that HCM is inherited in 30% to 50% of patients.²⁸ This was confirmed in prospective clinical genetic studies using two-dimensional echocardiography that suggested 50% to 60% of cases are inherited as an autosomal dominant trait.^29,30 In 1989, the first genetic mutation for HCM was mapped to chromosome 14^31,32 and then to the β-myosin heavy chain protein, a major component of the cardiac sarcomere.^33,34 Subsequently, hundreds of mutations have been identified, mostly involving the myofilaments of the cardiac sarcomere.^35,36

HCM is the most common genetic cardiovascular disease. In approximately half of adolescents and adults with the disease, it is inherited as an autosomal dominant trait, characterized by a high locus and allelic diversity. More than 1500 mutations have been identified,^{33,37,38,39,40,41,42,43} the majority of which (75%-80%) involve cardiac myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) (Fig. 59–2). Mutations in cardiac troponin T (TNNT2), troponin I (TNNI3), α- tropomyosin (TPM1), myosin light chains (MYL2, MYL3), and cardiac actin (ACTC1) account for 15% to 20% of mutation-positive individuals. Mutations in other sarcomere or related genes, including Z-disc protein genes like muscle LIM protein (CSRP3) or calcium-handling genes such as phospholamban (PLN), account for less than 1% of cases each. A further 5% to 10% of cases are caused by metabolic or storage disorders (eg, Anderson-Fabry disease, mitochondrial disorders, glycogen storage diseases), neuromuscular disorders, chromosome abnormalities, and genetic syndromes such as cardio-facial-cutaneous syndromes, including Noonan and LEOPARD syndromes.⁴⁴ The three most common metabolic causes of HCM, all with a prevalence of approximately 1%, are Anderson-Fabry disease, glycogen storage disease caused by PRKAG2 mutations, and Danon disease.

Two pathogenic mechanisms are thought to account for disease associated with mutations in cardiac sarcomere proteins.⁴³ Missense single nucleotide variants (a nucleotide change that results in an amino acid being substituted by another amino acid in the protein) predominantly lead to a dominant negative effect (described as a “poison peptide” mechanism) in which the mutated protein is not destroyed, but rather integrates into the sarcomere, leading to the disease phenotype; this is thought to be characteristic of MYH7 variants.^41,45,46,47 Alternatively, nonsense single nucleotide variants or small frameshift insertion-deletions can introduce a premature stop codon and cause haploinsufficiency as a result of nonsense mRNA-mediated decay or proteolysis of a truncated (just partially translated) protein.⁴⁸ This mechanism is believed to be typical of the majority of MYBPC3 disease-causing mutations.⁴⁹

HCM is characterized by variable intra- and interfamilial expression and incomplete and age-dependent clinical penetrance.⁴² This genotype-phenotype plasticity is largely unexplained.⁵⁰ Patients are routinely offered genetic testing to provide them with information about the likely impact of disease on their lives and to facilitate lifestyle and medical interventions that improve prognosis.⁵¹ However, for this strategy to succeed, there must be a predictable relation between specific genotypes and disease expression. Meta-analysis of pooled data⁵² shows that a small number of clinical variables are consistently associated with a positive sarcomeric protein genotype, specifically, younger age at presentation, greater hypertrophy, and a positive family history for HCM or sudden cardiac death (SCD). For each of these parameters, the pooled association is significant for the comparison between sarcomere mutation-positive and -negative patients, but not when comparing the two most frequently affected genes, MYBPC3 and MYH7. Although data are limited, patients with more than one sarcomere mutation also seem to present earlier and/or with a more severe phenotype^35,53,54 and a higher likelihood of an evolution to a dilated phenotype.⁵⁵

Gross examination of the heart demonstrates asymmetric septal hypertrophy with a small LV cavity (Fig. 59–3).^56,57,58 The mural endocardium may be thickened by fibrous tissue, and if LVOTO is present, there is often a plaque located on the upper septal area where the mitral valve repeatedly has come in contact with the septum. The mitral valve itself may be abnormal, with elongation of the mitral chordae and anterior displacement of hypertrophied papillary muscles. Abnormal attachments of the mitral valve chordae into the septum, insertion of the papillary muscle head directly into the mitral leaflets, myocardial clefts, and increased ventricular trabeculation are also common.^59,60,61 The left (and sometimes the right) atrium is usually dilated in advanced disease as a result of mitral regurgitation and diastolic dysfunction. Although the epicardial coronary arteries are usually normal, they can follow an intramural course and be compressed during ventricular systole.⁶²

The classical histopathologic appearance of HCM consists of cardiomyocyte hypertrophy and disarray, interstitial and replacement fibrosis, and dysplastic arterioles^62,63 (Fig. 59–4). In patients with some of the rarer phenocopies, other features such as myocyte vacuolation or infiltration may be observed.

The pathophysiology of HCM is complex and consists of multiple interrelated abnormalities, including diastolic dysfunction, LVOTO, and mitral regurgitation.

Left Ventricular Dysfunction

In most patients with HCM, a lifelong process of cardiac remodeling is present, characterized by myocardial fibrosis and wall thinning. In the early stages of this process, patients are often asymptomatic, and conventional noninvasive indices of LV function are within the normal range. As the disease progresses, LV diastolic and systolic function progressively decline, causing either mild-to-moderate LV dilation, decreased LV wall thickness, and a reduction in LV ejection fraction (the so-called “burned-out” or hypokinetic dilated phase) or severe LV diastolic dysfunction characterized by marked atrial dilation with little or no LV dilation (the so-called “restrictive” phenotype). In some patients, moderate-to-severe pulmonary hypertension develops in these advanced stages.⁶⁴

Diastolic dysfunction arises from multiple factors that affect both ventricular relaxation and chamber stiffness (Fig. 59–5).^65,66,67,68 Impairment of ventricular relaxation can result from the high systolic contraction load caused by LVOTO, nonuniformity of ventricular contraction and relaxation, and delayed myosin-actin inactivation caused by abnormal intracellular calcium reuptake.^66,67,68 Diffuse myocardial ischemia caused by supply-demand mismatch also contributes to diastolic dysfunction.^69,70,71,72 Patients with HCM have increased oxygen demand as a result of ventricular hypertrophy and abnormal loading conditions, but also have compromised coronary blood flow to the LV myocardium because of abnormally small and partially obliterated intramural coronary arteries.^{69,70,73,74,75} In addition, myocardial energy metabolism is compromised as a result of inefficient cardiomyocyte contraction, and is an early feature of the disease in carriers of sarcomeric protein mutation.⁷⁶ With exercise, diastolic function is further compromised by a decrease in the diastolic filling period and prolongation of the time to peak filling, which increase pulmonary venous pressure and cause dyspnea.⁶⁸

Severe LV systolic dysfunction has a prevalence of 2% to 5% and an incidence of 0.5 to 1 case per 100 patient-years. It is associated with a poor prognosis as a result of high rates of refractory heart failure and sudden arrhythmic death.⁶⁴ Small observational series suggest that patients with some of the rarer HCM phenocopies are more likely to develop systolic impairment than those with disease caused by sarcomeric protein gene mutations.⁷⁷

During exercise, approximately 25% of HCM patients have an abnormal blood pressure response defined by either a failure of systolic blood pressure to increase > 20 mm Hg or a decrease in systolic blood pressure.^78,79 The response is associated with a poorer prognosis in young adults.^79,80 The mechanism is complex and involves inappropriate systemic vasodilatation during exercise and a reduction in cardiac output reserve caused by small LV stroke volume.⁸¹

Left Ventricular Outflow Tract Obstruction

Dynamic LVOTO caused by contact between the mitral valve leaflets during ventricular systole is present in one-third of patients at rest and a further one-third during exercise or physical maneuvers that reduce ventricular volume or increase contractility.⁸² The mechanism of obstruction was initially thought to be narrowing of the LV outflow tract caused by systolic contraction of the hypertrophied basal ventricular septum and a resultant suction (Venturi) force that pulls the mitral valve leaflets anteriorly.^82,83 The modern concept is that flow against the abnormally positioned mitral valve apparatus in systole causes a drag force on a portion of the mitral valve leaflets that pushes the leaflets into the LV outflow tract.^{84,85,86,87,88} Obstruction to the LV outflow typically varies with loading conditions and contractility of the ventricle (Figs. 59–6, 59–7, and 59–8).^89,82 Obstruction can also be present in the midcavity as a result of hypertrophied papillary muscles abutting against the septum.⁹⁰

Mitral Regurgitation

Mitral regurgitation is common in patients with LVOTO and is an important cause of dyspnea.^1,2,91 Mitral regurgitation is usually caused by the distortion of the mitral valve apparatus from systolic anterior motion secondary to LVOTO. The jet of mitral regurgitation is directed laterally and posteriorly, predominates during mid and late systole (Fig. 59–9), and is proportional to the severity of LVOTO. Changes in ventricular load and contractility that affect the severity of LVOTO will similarly affect the degree of mitral regurgitation (see Fig. 59–8). It is important to identify patients who have additional intrinsic disease of the mitral valve apparatus (eg, prolapse or flail leaflets) because this finding influences subsequent treatment options.^1,92

The majority of patients with HCM are asymptomatic, with the disease being diagnosed based on an abnormal electrocardiogram (ECG), heart murmur, or screening echocardiogram. When symptoms are present, they often vary from day to day and may be exacerbated during hot humid weather, presumably as a result of fluid loss and vasodilation that cause decreases in both preload and afterload. Similarly, symptoms may be more prominent after eating a large meal or after drinking alcohol. Other concomitant problems, such as anemia or fever, may also exacerbate symptoms.

Dyspnea is usually caused by a combination of LVOTO, mitral regurgitation, and LV diastolic dysfunction. Angina, usually in the absence of epicardial coronary disease, is caused by a number of mechanisms, including small-artery narrowing, intramural compression of small arteries from myocardial hypertrophy, abnormal diastolic filling, oxygen supply-demand mismatch, and abnormal coronary flow reserve.^74,93 Transient loss of consciousness occurs in approximately 20% of HCM patients. In most cases, it is a result of syncope caused by LVOTO, activation of LV baroreceptors resulting in reflex vasodilatation, and atrial and ventricular arrhythmia.

The phenotype in many older patients varies from that in younger individuals in that many have a history of hypertension and a sigmoid septal configuration.^{94,95,96,97,98,99} Atrial fibrillation is common in older patients (25%-30%) and may herald systemic embolism and further clinical deterioration.^94,100 Older patients may also have manifestations of other concomitant cardiac disease, such as coronary artery disease, degenerative valvular aortic stenosis, and mitral annular calcification. Amyloidosis (both light chain and transthyretin types) is an important differential diagnosis in elderly patients with HCM.⁷⁷

A systematic clinical approach should be used in all patients to identify specific disorders and guide the selection of further diagnostic tests, including molecular genetic analysis.^1,77,101 Table 59–1 presents some of the most important diagnostic “red flags.”

Cardiac Examination

The classical physical findings of HCM are present in patients who have an LV outflow tract gradient. Patients who do not have LVOTO may have findings of LV hypertrophy on physical examination.

Arterial Pulse

The classic carotid pulsation is brisk with a spike-and-dome pattern, characterized by a rapid rise (percussion wave) followed by a mid-systolic drop that is, in turn, followed by a secondary wave (tidal wave). The mid-systolic fall in amplitude of the carotid pulse contour is caused by premature closure of the aortic valve and coincides with systolic anterior motion of the mitral valve. The late peak results from reduction of the outflow tract gradient as the mitral valve leaflet returns to its original position. In the presence of pronounced obstruction, there is a longer ejection time. The carotid pulsation with dynamic LVOTO differs from that of a fixed obstruction such as valvular or discrete subvalvular aortic stenosis, which is characterized by a decrease in both the rate of rise and the amplitude of the pulsation.

Jugular Venous Pulse

The jugular venous pressure is normal in most patients, but the a wave can be prominent, indicating a decrease in ventricular compliance caused by right ventricular hypertrophy, pulmonary hypertension from left-sided diastolic pressure elevation, or right ventricular outflow obstruction.

Apical Impulse

The apical impulse is almost always abnormal in patients with HCM. Typically, it is a sustained systolic thrust that continues throughout most of systole and can be bifid as a result of a forceful atrial systole. There may be a triple impulse, with a third component occurring near the end of systole if LVOTO is present. A systolic thrill may be palpable at apex from severe mitral regurgitation or at the lower left sternal border from LVOTO.

Cardiac Auscultation

Auscultation usually reveals a normal or loud first heart sound. The second heart sound is usually split physiologically, although some patients have a paradoxical split as a result of either a concomitant left bundle branch block or severe LVOTO. A fourth heart sound is usually present, especially if there is severe hypertrophy. In young patients, an early diastolic filling sound is frequently heard, indicating rapid early filling. In the presence of severe mitral regurgitation, the excess flow across the mitral valve may result in a diastolic flow rumble.

The classic murmur from LVOTO is a crescendo-decrescendo murmur located primarily at the left sternal border. The murmur usually ends before the second heart sound. The murmur can radiate to the base of the heart as well as to the apex, but in contrast to valvular aortic stenosis, there is seldom radiation to the carotid arteries. Mitral regurgitation may be a separate murmur audible at the apex and is more holosystolic in nature. The presence of an aortic diastolic decrescendo murmur should suggest another disease, such as aortic valve disease or a discrete subvalvular stenosis.

Dynamic auscultation should be performed to differentiate the murmur of HCM from that of valvular aortic stenosis and mitral regurgitation. Maneuvers that decrease preload will increase the dynamic gradient and increase the intensity of the murmur (see Fig. 59–8). Although the change in murmur intensity during the strain phase of the Valsalva maneuver has been proposed as a method to diagnose the dynamic murmur of HCM, this classic response may not occur in all patients. A more reliable method for diagnosing a dynamic LVOTO is the response of the murmur to the stand-squat-stand position. From the standing position to a prompt squat, the murmur will markedly decrease in intensity, as a result of increases in afterload and preload. From the squatting to standing position, there will be an increase in intensity of the murmur immediately as afterload is reduced. A progressive increase in intensity of the murmur will continue for the next four to five beats as preload to the left side of the heart is reduced. Simple exercise, such as walking or climbing stairs, can also be used to provoke the murmur. Other maneuvers that are used to change the intensity of the murmur include leg-raising to increase preload (and thereby decrease the intensity of the murmur) and the inhalation of amyl nitrite to decrease afterload, increase heart rate, and increase the intensity of the murmur. There is also an increase in intensity of the systolic murmur after a premature ventricular beat.

Electrocardiography

ECG is abnormal in the majority (~95%) of HCM patients.^1,94 The most frequent ECG alterations are repolarization abnormalities (eg, ST-segment depression and/or T-wave inversion).^102,103 A left-axis deviation is present in up to 30% of patients. Abnormal Q waves, simulating myocardial infarction, are seen in 25% to 30% of patients^102,103 (Fig. 59–10). Varying prevalences of 35% to 70% are reported for increased QRS voltage.^{102,103,104,105} The ECG in patients with predominantly apical LV hypertrophy may show a distinctive pattern of diffuse symmetric and deep T-wave inversions across the precordium or the inferolateral leads (Fig. 59–11).^1,102 Some ECG abnormalities, including pre-excitation and atrioventricular (AV) block, may suggest specific etiologies,⁷⁷ as summarized in Table 59–1.

Abnormalities in the ECG, in particular repolarization changes, can be the only abnormal diagnostic test present in relatives and carriers of mutations in the absence of hypertrophy on cardiac imaging. These patterns have been proposed as part of the diagnostic criteria for relatives and/or part of a “prehypertrophic” phenotype.^94,106

Most patients are in normal sinus rhythm at initial diagnosis, but supraventricular tachycardia (up to 38%-46%), premature ventricular contractions (43%), and nonsustained ventricular tachycardia (25%) are frequent during ambulatory monitoring in adults.^{1,107,108,109} Atrial fibrillation occurs in 25% to 30% of the older population.¹⁰⁰

Chest X-Ray

The chest x-ray usually shows mild-to-moderate enlargement of the cardiac silhouette. The LV contour is rounded, consistent with LV hypertrophy. There is usually enlargement of the left atrium, and the right-sided chambers are usually normal.

Echocardiography

Increased LV wall thickness measured by any imaging technique is the basis for the diagnosis of HCM (Fig. 59–12). In an adult, a wall thickness ≥ 15 mm at end-diastole in one or more myocardial segments and, in children, a wall thickness more than two standard deviations greater than the predicted mean are sufficient to make the diagnosis. In first-degree relatives of patients with unequivocal disease, the diagnosis is based on the presence of an otherwise unexplained LV wall thickness ≥ 13 mm in one or more LV myocardial segments.

Hypertrophy can be distributed throughout the myocardium, including the right ventricle, but most commonly involves the interventricular septum (Fig. 59–13).^{1,26,110,111,112} Because any segment of the left ventricle can be involved, echocardiographic studies should systematically examine all the segments of the ventricular walls from base to apex. Measurements from the short-axis images are considered more accurate, but it is important not to include right ventricular structures (eg, moderator band or crista supraventricularis) in measurements of wall thickness. When image quality is poor (sometimes an issue with the lateral LV wall or the LV apex), intravenous contrast agents can help to visualize the endocardium.^1,110 The average maximal LV wall thickness in a population of HCM patients is usually 20 to 22 mm; however, 5% to 10% of patients will have maximal wall thickness in excess of 30 mm.

Patterns of hypertrophy may vary with age at presentation.⁹⁵ In the young population, hypertrophy usually involves the entire septum, creating a convex septal contour. In the older population, a “sigmoid” septum, in which the hypertrophy is localized to the basal and mid-septum and associated with increased angulation between the septum and the long axis of the aorta, is more frequent.

The differential diagnosis of LV hypertrophy is considerable. Increased afterload on the left ventricle from either hypertension or valvular aortic stenosis may cause an increase in the LV wall thickness. Infiltrative, metabolic, and neuromuscular diseases such as cardiac amyloidosis, Fabry disease, and Friedreich ataxia are also recognized phenocopies.^{1,77,113,114,115} Echocardiographic characteristics that suggest the presence of particular causes of HCM are listed in Table 59–1. Echocardiographic modalities that assess myocardial deformation can be useful to distinguish between different causes of ventricular hypertrophy.^101,110

It is important to correlate the findings of increased LV wall thickness on echocardiography with the ECG. For example, a relatively small QRS voltage on the 12-lead ECG in the presence of increased wall thickness should raise suspicion of an infiltrative disorder^1,77 (Fig. 59–14). The reverse can occur in glycogen storage disease (eg, Pompe disease) when ECG voltages are dramatically increased, sometimes in association with ventricular pre-excitation.^1,77

In athletes, physiologic adaptation to intense training can rarely cause an increase in LV wall thickness that is difficult to differentiate from HCM.^116,117 Elite athletes who have a dilated ventricular cavity with septal thickness < 14 to 15 mm most likely have “athlete’s heart,” but the combination of these findings may not always be present. A reduction in wall thickness after cessation of training is useful to identify the athletic heart, but may not be practical in all patients.^116,117 Investigations with Doppler tissue imaging, myocardial strain, and cardiac magnetic resonance imaging may assist in differential diagnosis.^118,119,120

Left Ventricular Outflow Tract Obstruction

Two-dimensional echocardiography is the primary tool for defining the presence and severity of LVOTO.^110,121 It is also essential for ruling out other causes of LVOTO, such as a subaortic membrane,^1,110,122 and to identify mitral valve structural abnormalities.

Dynamic LVOTO is characterized by systolic anterior motion (SAM) of the mitral valve apparatus and an open ventricular chamber. Most patients have SAM of the anterior leaflet, but it also occurs with the posterior leaflet.^110,123 Frequently, additional abnormalities of the mitral valve and supporting structures exist.^60,124 These include papillary muscle abnormalities (eg, hypertrophy, anterior and internal displacement, direct insertion into the anterior mitral valve leaflet) and mitral leaflet abnormalities such as elongation or accessory tissue.^1,110 The exact site of the obstruction is determined by visualizing the region of the SAM-septal contact.^110,125 In the classical form of obstructive HCM, obstruction occurs at the most basal portion of the septum as it projects into the LV outflow tract. In some patients, obstruction extends into the left ventricle from SAM of the chordal apparatus or mid-ventricular obstruction caused by hypertrophied papillary muscles.^90,110

Dynamic LVOTO is characterized by a high-velocity, “dagger-shaped” signal on continuous wave Doppler (Fig. 59–15).^110,126 LVOTO is defined as an instantaneous peak Doppler LV outflow tract pressure gradient ≥ 30 mm Hg at rest or during physiologic provocation such as Valsalva maneuver, standing, or exercise. A gradient of ≥ 50 mm Hg is usually considered to be the threshold at which LVOTO becomes hemodynamically important.^1,110 Latent LVOTO (ie, present only during physiologic provocation) is present in approximately one-third of patients. In patients with outflow tract gradients < 50 mm Hg, provocation with the Valsalva maneuver (including on standing if no gradient is provoked at the lateral decubitus or sitting position) is recommended as part of the routine echocardiographic examination. In symptomatic patients without LVOTO, exercise stress echocardiography should be performed.¹

Doppler color flow imaging can be used to determine the presence and severity of mitral regurgitation (see Fig. 59–9).^110,127 If the mitral regurgitation is secondary to distortion of the mitral valve apparatus from the SAM, the color jet will be directed laterally and posteriorly. In addition, the regurgitation will predominate in mid to late systole. If there is a holosystolic signal of mitral regurgitation that is directed centrally or anteriorly, then a primary abnormality of the mitral valve apparatus should be suspected.^1,110 The mitral regurgitation signal by continuous wave Doppler may contaminate the outflow tract velocity signal, and care must be taken to differentiate the true outflow tract velocity from the mitral regurgitation jet (Fig. 59–16).¹¹⁰

Diastolic Dysfunction

Left atrial dimensions, pulmonary vein flows, pulmonary artery systolic pressure estimation, and Doppler tissue imaging together with the transmitral flow velocity curves provide estimates of LV filling pressures.^1,110 The left atrial size (measured as anteroposterior diameter, area, or volume) is also an important prognostic marker.¹¹⁰

Systolic Dysfunction

LV ejection fraction and fractional shortening can overestimate LV systolic function because radial contractile function is typically preserved or increased in HCM.¹¹⁰ Doppler tissue imaging of mitral annular motion is useful to evaluate longitudinal contraction of the ventricle and is usually abnormal in patients with HCM, despite normal or supranormal ejection fraction. Abnormally low annular velocities are useful in detecting subclinical disease (ie, patients who carry an HCM-associated genetic abnormality but have not yet developed increased LV wall thickness).^{110,128,129,130} Tissue Doppler imaging may also be useful in distinguishing HCM from the physiologic increase in wall thickness observed in some athletes, who generally have preserved or increased annular velocities.¹²⁰

Two-dimensional speckle tracking strain imaging often shows a decreased global longitudinal strain when LV ejection fraction is in the normal range.¹¹⁰ Circumferential strain is either increased or decreased depending on the stage of the disease. Impaired regional or global longitudinal function has been suggested as a marker of mutation carriage in the absence of hypertrophy.¹¹⁰

Transesophageal Echocardiography

In most patients, anatomic and hemodynamic information can be obtained by transthoracic echocardiography alone, but transesophageal echocardiography may be useful in patients in whom discrete subvalvular stenosis or a primary abnormality of the mitral valve is suspected.¹¹⁰ It is also mandatory for the peri- and intraoperative monitoring of septal myectomy to confirm of the mechanism of LVOTO, guide the surgical strategy, and detect postsurgical complications such as ventricular septal defects and residual LVOTO.^1,110

Cardiac Magnetic Resonance Imaging

Cardiac magnetic resonance imaging (CMRI) provides high-resolution images of the myocardium and accurately determines the site and extent of hypertrophy.^110,131 These properties are particularly important in patients with equivocal hypertrophy and/or difficult echocardiographic images.¹³¹ CMRI is particularly useful in patients with hypertrophy affecting the LV apex and anterolateral wall.^27,131 Apical aneurysms are often only recognized with CMRI, and right ventricular hypertrophy is more easily appreciated with CMRI compared to echocardiography¹³¹ (Fig. 59–17).

SAM of the mitral valve, elongation of the leaflets, papillary muscle abnormalities, accessory bundles, crypts, LV outflow tract flow turbulence, mitral regurgitation, perfusion abnormalities, and intramyocardial fibrosis or scarring can be visualized with CMRI.^131,132 Some of these features may occur in the absence of LV hypertrophy, as a part of a constellation of symptoms described as a “prehypertrophic” phenotype, in sarcomere gene mutation carriers.^110,131,133

Nuclear Imaging

Single-photon emission computed tomography myocardial perfusion imaging frequently shows reversible and fixed defects in HCM in the absence of epicardial coronary artery disease.¹¹⁰ Positron emission tomography allows quantification of myocardial blood flow, which typically shows a blunted response to vasodilators.^71,110 In the most recent guidelines, no specific recommendation has been made for the use of nuclear imaging for ischemia assessment.¹ However, technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy is useful in detecting cardiac amyloidosis of the transthyretin (TTR) type (either inherited or wild-type/senile) (see Fig. 59–14C).^1,110

Cardiac Catheterization

Cardiac catheterization to assess LV function and dynamic LVOTO is not required in most HCM patients unless there is a discrepancy between the echocardiogram and the clinical presentation.¹ LVOTO can be assessed by placing an end-hole catheter at the LV apex and pulling it back to the base of the heart and then into the aorta. However, because the small LV cavity can cause catheter “entrapment,” resulting in a falsely increased LV systolic pressure, the gradient is ideally assessed by a simultaneous LV inflow and LV outflow (or aortic) pressure,^65,134 but this requires a trans-septal approach.

When there is little resting obstruction, provocation using the Valsalva maneuver or infusion of isoproterenol can be performed in the catheterization laboratory. The Brockenbrough phenomenon—the hallmark of latent obstruction—refers to the phenomenon after a premature contraction, in which an increase in the contractility of the ventricle results in a marked increase in the degree of dynamic obstruction (Fig. 59–18). This is seen as an increase in the outflow gradient and a decrease in the aortic pulse pressure after the pause. This is in contradistinction to a fixed obstruction in which there is an increase in gradient from the increase in stroke volume, but also an increase in aortic pulse pressure.

Left ventriculography usually reveals a small LV cavity size with hypertrophied papillary muscles further impinging into the cavity. Hyperdynamic radial systolic function causes complete obliteration of the mid and apical cavity in systole (Fig. 59–19). In the apical variant of HCM, there is obliteration of the apex by the hypertrophied muscle, causing a “spade-like” configuration. There may be an apical akinetic or dyskinetic pouch with “aneurysm” formation with mid-ventricular obstruction.

Coronary angiography is indicated when patients complain of angina out of proportion to the degree of obstruction.¹ Myocardial bridging is frequent (prevalence up to 15%-25%), particularly in younger patients with severe hypertrophy; however, the impact of bridging on outcomes is unclear.^62,135,136

Endomyocardial biopsy is only recommended when the noninvasive workup suggests inflammatory, infiltrative, or metabolic disease that cannot be confirmed by other means (eg, biopsy of another tissue/organ).¹

Cardiac Computed Tomography

Aside from the visualization and diagnosis of epicardial coronary disease, cardiac computed tomography can also be used in HCM for morphologic and even functional evaluation of the cardiac chamber dimensions, wall thickness, and systolic function in cases of poor echocardiographic acoustic window and contraindications or intolerance to CMRI.¹

Stress Testing

Exercise stress testing is of limited value for the diagnosis of epicardial coronary disease in patients with HCM, but is helpful in assessing prognosis and the mechanism of symptoms.^78,137,138 Cardiopulmonary exercise testing provides an objective measurement of exercise tolerance, and parameters such as ventilatory efficiency, anaerobic threshold, and peak oxygen consumption are predictors of death from heart failure.¹³⁹

Laboratory Testing

General laboratory tests are useful in the assessment of comorbidities and symptoms and in the diagnosis of phenocopies (see Table 59–1 for some examples). N-terminal pro–B-type natriuretic peptide is a strong predictor of all-cause death and cardiac transplantation in HCM.¹⁴⁰ Measurement of plasma and leukocyte α-galactosidase A is used to screen for Fabry disease in male patients, and serum and urine immunofixation and measurement of free light chains should be measured when amyloid disease is suspected.^1,77 A raised creatine kinase is seen in younger patients with inborn errors of metabolism and muscular dystrophies.

Over the past few years, massive parallel sequencing platforms have replaced conventional Sanger sequencing in diagnostic genetic testing, allowing for a larger panel of genes (or even the entire exome/genome) to be evaluated.¹⁴¹ However, the yield of definite pathogenic mutations in HCM is probably similar to that reported with conventional sequencing.^142,143

Genetic evaluation of probands should be complemented by careful genetic counseling in all probands.^1,51 This includes the construction of a family pedigree, which can be valuable in assessing patterns of inheritance and in detecting etiologic clues.^1,77 When genetic testing is performed and a clear pathogenic mutation is identified in an affected patient, then their first-degree relatives may be screened using targeted DNA analysis for the same mutation. Relatives who carry a pathogenic mutation are kept under regular follow-up, and those who do not carry the mutation can be discharged because their risk of developing the disease is considered similar to that of the general population.^1,51 When no mutation or a DNA variant of unknown significance is detected, family screening will need to be performed using clinical assessment alone.^1,52 Economic modeling studies have suggested that genetic screening strategies are more effective than clinical screening alone.^1,144 Clinical screening of first-degree relatives should be performed every 12 to 18 months in adolescents and every 2 to 5 years in adults.^1,51

The natural history of individual patients with HCM is highly variable.^2,64,94 The early literature described a poor prognosis with high incidence of sudden death (4%-6% per year), but this was influenced by significant referral biases toward small cohorts of selected younger patients who had been referred because they were judged to be at high risk or had severe symptoms requiring specialized care.^{2,94,145,146,147,148,149} Contemporary studies report much lower overall sudden death rates (0.5%-1% per year) as a result of the inclusion of patients with milder disease^2,94,148,149 and also because of the effect of modern treatment.^148,149 Nonetheless, there are clearly patient subgroups that are at high risk for death.^2,94

Sudden Cardiac Death

Sudden and unexpected death may be the first manifestation of HCM (incidence 0.8% per year).^{1,2,4,5,94,150} SCD is most frequent in young adults less than 30 years of age,^{1,2,4,5,94,150,151} but is rare in infants and very young children.

Pathophysiologic mechanisms involved in SCD include re-entry ventricular arrhythmia promoted by myocyte disarray, hypertrophy, and fibrosis. Abnormalities in intracellular calcium dynamics cause delayed afterdepolarizations and triggered ventricular arrhythmia.¹⁵² Other mechanisms for SCD including asystole, rapid supraventricular arrhythmias, pulseless electrical activity, and AV block.¹⁵²

Several clinical features are associated with a high risk for SCD in patients with HCM (Table 59–2).^{1,4,94,152,153,154,155,156} Patients who have had a prior cardiac arrest or spontaneous sustained ventricular tachycardia are at highest risk. A family history of premature SCD in a first-degree relative with HCM portends a high risk, particularly if there are multiple occurrences. Other risk markers include recent unexplained syncope, nonsustained ventricular tachycardia, abnormal blood pressure response to exercise, and extreme LV hypertrophy (> 30 mm). The presence of replacement scar in the myocardium on contrast-enhanced cardiovascular magnetic resonance may identify higher risk patients, although most data suggest that it is a better predictor of heart failure death than sudden death.^{1,4,94,157,158} It has been proposed that genotype analysis might be used as a stratifying marker for prognosis because specific mutations have been shown to convey either favorable or adverse prognosis.¹⁵⁹ However, these studies are based on a relatively small number of genotyped families, and further work is required to establish the role of genetic testing in risk stratification.^1,159

Atrial Fibrillation and Stroke

The overall prevalence of paroxysmal and permanent atrial fibrillation (AF) is 22%, and the annual incidence is 3%.¹⁰⁰ This corresponds to a fourfold increase in prevalence in comparison with the general population. AF usually indicates advanced disease and is often associated with clinical deterioration. The onset of AF can result in hemodynamic deterioration.¹ Systemic embolism occurs in 6% of patients and is usually associated with AF.¹⁰⁰ Left atrial size and volume are associated with the development of AF and thromboembolism. Other risk factors for AF include severe wall thickness, vascular disease, higher New York Heart Association class, and older age.¹⁶⁰

Heart Failure

Approximately 5% of patients progress to an end-stage phase (also called burned-out phase),^{161,162,163,164} defined by an LV ejection fraction < 50%. This is associated with progressive congestive heart failure symptoms, exercise intolerance, and atrial arrhythmias.^64,150 The LV cavity enlarges, and the dynamic outflow tract gradient (if present at diagnosis) usually disappears. Eventually, the morphologic appearance of the ventricle resembles a dilated cardiomyopathy (hypokinetic-dilated subtype) or restrictive cardiomyopathy (hypokinetic-restrictive subtype).⁶⁴ These patients have a poor outlook with a high risk of death resulting from heart failure or SCD.^64,150,163

Infective Endocarditis

Infective endocarditis occurs in 4% to 5% of patients with HCM.¹⁶⁴ The lesions are usually located on the interventricular septum, the ventricular surface of the mitral valve, or, less often, the aortic valve.

Left Ventricular Outflow Tract Obstruction

Medical Therapy

Patients with LVOTO should maintain hydration at all times, avoid excessive alcohol consumption, and maintain a healthy weight. Arterial and venous vasodilators should be avoided. Rapid AF is often poorly tolerated in patients with LVOTO and should be promptly managed with cardioversion. Digoxin is contraindicated because of the positive inotropic effects.¹

Medical therapy should be considered the first-line therapy for the relief of symptoms in patients with obstructive HCM. β-Adrenergic blocking agents are usually the drugs of choice.^{1,4,94,165,166,167,168,169,170} Theoretic actions of β-blockers include decreased heart rate response to exercise, relief of angina by a decrease in myocardial oxygen demand, and improvement in diastolic filling time. Acute hemodynamic studies have shown that β-blocking agents blunt the increase in gradient that occurs with exercise (or isoproterenol), but have little effect on the resting gradient. Clinical studies suggest an improvement in angina, exercise tolerance, and syncope in 60% to 80% of patients. However, only approximately 40% of patients continue to have sustained symptomatic improvement.^165,166,171 The dosage of β-blocker should be titrated to symptom relief or to obtain a resting heart rate of < 60 bpm.

Nondihydropyrine calcium channel blockers—specifically, verapamil and diltiazem—are also of value in the treatment of HCM,^{66,172,173,174,175,176} particularly if β-blockers are contraindicated or ineffective.¹ By preventing calcium influx, they not only decrease inotropy and chronotropy, but also improve abnormal diastolic relaxation.^{66,175,176,177} Verapamil is used most frequently because of its minimal effect on afterload. Clinical studies have shown a decrease in both basal and provoked gradients during acute drug intervention with verapamil. Verapamil has been shown to improve exercise tolerance by 20% to 30% in short-term follow-up. Calcium channel blockers may improve angina to a greater degree than β-blockers, but sustained symptomatic improvement is seen in < 50% of patients. The dose of verapamil should be titrated up to 480 mg/d to obtain a resting heart rate of 60 bpm.

A small subset of patients can deteriorate hemodynamically with verapamil, presumably because of a lowering of afterload.¹⁷⁸ This deterioration occurs particularly in the presence of severe outflow tract gradients (≥ 100 mm Hg), high diastolic filling pressures, and elevated pulmonary artery systolic pressures.¹ Diltiazem has greater vasodilating properties and should be considered when there is intolerance or contraindications for β-blockers or verapamil.¹ Dihydropyridine calcium channel blockers should be avoided in patients with LVOTO because these pure vasodilators can increase the severity of the outflow tract by reducing afterload.

Disopyramide is used to treat patients with obstructive HCM^{1,4,168,169,170,179,180} by reason of its negative inotropic effect. Concomitant β-blockade may be important to prevent rapid AV node conduction, particularly during exercise or with coexistent AF.^1,179 It can also be used together with verapamil. The dose of disopyramide required to produce symptomatic benefit is between 300 to 600 mg/d. The corrected QT interval needs to be monitored at the initiation of disopyramide and dose reduced if > 480 ms.¹ The anticholinergic adverse effects of the drug can limit its usefulness in older patients. Contraindications to its use include glaucoma, prostatism, and concomitant medication with QT-prolonging drugs.¹

Septal Reduction Therapy

For patients who have an LVOTO gradient ≥ 50 mm Hg, moderate-to-severe symptoms (New York Heart Association functional class III-IV), or recurrent exertional syncope despite maximally tolerated drug therapy, other treatment options such as septal myectomy, septal ablation, or dual-chamber pacing should be considered.^1,4

Surgical septal myectomy is the gold standard therapy for patients with obstruction and severe drug-refractory symptoms when performed in experienced surgical centers.^{1,4,181,182,183,184,185,186,187,188} The procedure consists of a transaortic resection of a small amount of muscle from the proximal to mid-septal region (Morrow procedure). This enlarges the LV outflow tract and significantly decreases or totally abolishes LVOTO in 90% of patients. In patients with concomitant mitral regurgitation secondary to SAM of the mitral valve, mitral regurgitation usually diminishes as a result of the myectomy.^1,4,189,190

A more extensive myectomy procedure is sometimes performed^191,192 when there is mid-cavity obstruction. However, follow-up data are more scarce for this more extensive procedure.¹ In patients with abnormalities of the papillary muscle, dissection and reduction of the anomalous papillary muscle apparatus may also be performed, as well as mobilization or realignment.^193,194

Mitral valvuloplasty or plication in combination with myectomy is used in some patients with elongated mitral valve leaflets.^195,196,197 Mitral valve replacement is generally performed only when there is severe and unrepairable disease of the mitral valve.¹ Simultaneous mitral valve surgery is necessary in 11% to 20% of patients.¹ Another proposed surgical technique consists of cutting the thickened secondary mitral valve chordae combined with a shallow septal muscular resection.¹⁹⁸

In large-volume centers, the operative mortality for septal myectomy is < 1%,^199,200 but the risk is higher (3%-4%) in elderly patients who require other procedures, such as aortic valve replacement, mitral valve repair, or coronary artery bypass grafting. Complications (AV nodal block, ventricular septal defect, and aortic regurgitation) of surgery are uncommon.^{1,110,201,202,203}

Alcohol septal ablation (ASA) is a procedure in which alcohol is infused in the septal perforator arteries in order to cause necrosis and scarring of the proximal interventricular septum.^{1,4,204,205,206} The subsequent wall thinning and remodeling of the basal septum results in reduction of the LVOTO (Figs. 59–20 and 59–21).

Several centers have reported successful short-term outcomes following septal ablation.^{205,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222} The major complication of ASA is complete heart block, which, with small doses of alcohol and guidance with myocardial contrast echocardiography, occurs in 7% to 20% of patients.^{1,4,221,222,223,224} Patients are more likely to experience complete heart block if left bundle branch block is present prior to the ablation procedure.^{1,4,221,222,225,226} Other complications of septal ablation include coronary artery dissection, excessive myocardial infarction from leakage of the alcohol into other coronary arteries, ventricular septal defects, and myocardial perforation. A maximum LV wall thickness < 16 mm at the point of leaflet-septal contact is a risk factor for ventriculoseptal defects in both ASA or myectomy.¹ The periprocedural mortality is comparable to myectomy.^1,221,222

Current guidelines^1,4 recommend a thorough anatomic and functional evaluation of the septum, mitral valve leaflets, and subvalvular apparatus to guide the choice of invasive septal reduction therapy. ASA may be less effective if extensive septal fibrosis is demonstrated on CMRI and in cases of massive septal hypertrophy. Septal myectomy is preferred in the presence of other abnormalities requiring surgical intervention.

Dual-Chamber Pacing for Left Ventricular Outflow Obstruction

Dual-chamber pacing from the right ventricular apex can decrease the outflow tract gradient as a result of alteration of ventricular contraction and a decrease in systolic projection of the basal septum into the LV outflow tract. It may also induce a chronic remodeling effect during continuous pacing with enlargement of the LV cavity and a further decrease in LVOTO.^1,2,4,94,227

Several randomized trials have shown a decrease in outflow tract gradient of 25% to 40% of baseline values, but this was not associated with any improvement in quality of life scores or exercise capacity.²²⁸ Nevertheless, dual-chamber pacing may be useful in selected patients with resting or provocable LVOTO ≥ 50 mm Hg, sinus rhythm, and drug-refractory symptoms who have contraindications for ASA or septal myectomy or are at high risk of developing heart block following ASA or septal myectomy.¹ Candidates for dual-chamber pacing also include patients who have significant bradycardia so as to facilitate an increased dosage of medication and patients who need an automatic defibrillator as a primary treatment.¹

There are some technical considerations when using pacemaker therapy for treatment of patients with HCM.^229,230 Pacing or sensing the atrium, in addition to pacing the ventricle, is necessary to maintain the hemodynamic contribution of atrial contraction. There is an optimal AV delay for maximizing hemodynamic performance (Fig. 59–22).^231,232 If the paced AV interval is too short, it may increase left atrial pressure and reduce preload, whereas an overly long AV delay can result in incomplete pre-excitation of the right ventricle with suboptimal reduction in gradient. It is necessary to have the pacemaker tip placed in the apex of the right ventricle to achieve the maximum reduction in gradient, and pacing parameters need to be optimized to achieve maximum pre-excitation of the right ventricular apex with minimal compromise of LV filling.

Treatment of Nonobstructive Cardiomyopathy

β-Blockers and calcium channel blockers can been used to improve diastolic filling in symptomatic patients with normal LV ejection fraction and no resting or provoked LVOTO.^1,4,94 Diuretics can decrease elevated filling pressures.

For patients with reduced ejection fraction (< 50%), general guidelines for chronic heart failure apply, including the use of renin-angiotensin-aldosterone system inhibitors and diuretics.^1,4 Cardiac transplantation is the only therapy for patients who have severe symptoms and are unresponsive to conventional treatments. Post-transplantation survival is similar or better than for other disease (75% at 5 years; 60% at 10 years).⁹⁴

Both β-blockers and calcium channel antagonists are the recommended pharmacologic options for angina, after excluding LVOTO or obstructive epicardial coronary artery disease.^1,4

Prevention of Sudden Cardiac Death

Individuals with HCM are advised against participation in competitive sports and intense physical activity to reduce their risk of sudden ventricular arrhythmia.^{1,233,234,235,236} Low-to-moderate levels of aerobic exercise are permitted as part of a healthy lifestyle after careful risk assessment.

Amiodarone has been shown in retrospective nonrandomized trials to be associated with improved survival in young HCM patients with nonsustained ventricular tachycardia, but there are no randomized trial data to suggest that antiarrhythmic agents in general improve survival in patients with HCM.^{1,4,152,155,237,238} For this reason, implantation of an implantable cardioverter-defibrillator (ICD) is the most effective and reliable treatment option for protecting patients against SCD.

Estimation of SCD risk should be a routine part of clinical management. In adolescents and adults, the risk assessment should comprise clinical and family history, 48-hour ambulatory ECG, transthoracic echocardiogram (or CMRI in the case of poor echo windows), and a symptom-limited exercise test. The decision to recommend an ICD to patients is complex and requires individualized discussion of the long-term risks and benefits of the device.^1,4

ICDs are generally indicated in patients with prior cardiac arrest or sustained spontaneous ventricular tachycardia.^1,4 Implantation of ICDs for primary prophylaxis is guided by the presence of a small number of clinical characteristics (see Table 59–2).¹⁵² One approach is to consider an ICD in patients with more than one risk factor or when an individual risk factor is deemed sufficient by itself to warrant therapy (eg, multiple sudden deaths in a family or frequent unexplained syncope).^4,155 Contemporary evidence suggests that this approach is modestly successful in identifying high-risk patients,²³⁹ but it also has some limitations; specifically, it estimates relative and not absolute risk; it does not account for the different effect size of individual risk factors; and some risk factors, such as LV wall thickness, are treated as binary variables when they are associated with a continuous increase in risk.^152,154 One proposed solution is to consider other clinical features, such as myocardial fibrosis (determined by contrast-enhanced CMRI), LV apical aneurysms, and the inheritance of multiple sarcomere protein gene mutations, as arbiters that can be used to guide ICD therapy in individuals who are at an intermediate risk.^4,155 An alternative is to estimate risk using a multivariate prediction tool analogous to that used in other scenarios such as coronary artery disease prevention.^1,153 In all cases, decisions on ICDs must balance the likely benefit against the lifelong risk of complications and the impact of an ICD on lifestyle, socioeconomic status, and psychological health.¹

Stroke Prevention

Anticoagulation is recommended for patients with AF and HCM.^1,4 Despite the absence of randomized controlled trials, a recent exploratory retrospective analysis showed a reduction in thromboembolic events with vitamin K antagonists.¹⁶⁰ The CHA₂DS₂-VASc score (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or thromboembolism, vascular disease, age 65-74 years, sex category [ie, female sex]) does not correlate well with clinical outcome in patients with HCM and is not recommended to assess thromboembolic risk.^1,160 A recent systematic review and meta-analysis showed the feasibility of AF ablation in HCM, but more repeat procedures and antiarrhythmic drugs were needed to prevent recurrence.²⁴⁰

New Drug Targets and Disease-Modifying Drugs

The growing number of preclinical carriers identified through genetic testing and family screening has led to increased interest in the development of new therapeutics that can inhibit or attenuate the development of the HCM phenotype.^241,242 Potential strategies that are under evaluation include small molecules that interfere with cross-bridge kinetics, manipulation of myofilament calcium sensitivity, modification of calcium cycling/homeostasis (eg, through late-sodium current inhibition), inhibition of fibrosis-promoting pathways and mediators, modification of cardiomyocyte energy metabolism, and genetic therapies such as exon skipping and RNA interference to reduce expression of mutant missense transcripts.^43,241,243

Pregnancy

All HCM patients who wish to become pregnant should be given prenatal counseling about the risk of transmission of disease to their offspring (autosomal dominant inheritance pattern with 50% risk for transmission to each child) and the risks associated with pregnancy.¹ Patients with HCM usually tolerate pregnancy well if they are not severely symptomatic prior to conception, but should be managed by expert teams throughout.¹ Echocardiography is recommended each trimester or in the presence of new symptoms.

If patients have been on treatment with β-blockers or calcium channel blockers, these drugs should be continued throughout the pregnancy. β-Blockers are also indicated in the presence of new symptoms related to LVOTO,¹ with close monitoring of fetal growth. Verapamil, diltiazem, and disopyramide can be used when benefits are judged to outweigh potential risks.¹ Low-dose diuretics may be required if pulmonary congestion occurs. Birth should be planned and take place in a high-risk center. Epidural and spinal anesthesia should be used cautiously given the risks of vasodilation and hypotension in the presence of significant LVOTO, but are not contraindicated in current guidelines.¹ Cesarean section should be considered in cases of severe LVOTO, preterm labor in patients receiving oral anticoagulant drugs, and severe heart failure symptoms.¹

We thank Dr. Steve R. Ommen, Dr. Rick A. Nishimura, and Dr. A. Jamil Tajik, who contributed to the previous version of this chapter in the 13th edition.