Luke Cunningham, MD and Kumudha Ramasubbu, MD, FACC

1. What is hypertrophic cardiomyopathy?

    Hypertrophic cardiomyopathy (HCM) is a primary disorder of the cardiac muscle characterized by inappropriate myocardial hypertrophy of a nondilated left ventricle (LV) in the absence of a cardiovascular or systemic disease (i.e., aortic stenosis or systemic hypertension). Historically, HCM has been known by a confusing array of names, such as idiopathic hypertrophic subaortic stenosis (IHSS), muscular subaortic stenosis, and hypertrophic obstructive cardiomyopathy (HOCM). Currently, hypertrophic cardiomyopathy is the preferred term.

2. What is the prevalence of HCM?

    The reported prevalence of HCM from epidemiologic studies is about 1:500 in the general population (0.2%). HCM affects men and women equally and occurs in many races and countries.

3. What are the genetic mutations that cause HCM, and how are they transmitted?

    Thus far, more than 400 mutations in 11 genes have been identified that can cause HCM. These genes encode for cardiac sarcomere proteins that serve contractile, structural, and regulatory functions. They are cardiac troponin T, cardiac troponin I, myosin regulatory light chain, myosin essential light chain, cardiac myosin-binding protein C, α- and β-cardiac myosin heavy chain, cardiac α actin, α tropomyosin, titin, and muscle LIM protein (MLP). Mutations in cardiac myosin-binding protein C and β-cardiac myosin heavy chain are the most common and account for 82% of all mutations. HCM is inherited as an autosomal dominant trait; therefore, patients with HCM have a 50% chance of transmitting the disease to each of their offspring.

4. Who should be screened for HCM?

    Patients with known HCM mutations, but without evidence of disease, and first-degree relatives of patients with HCM should be screened. Screening is performed primarily with history, physical examination, 12-lead electrocardiogram (ECG), and two-dimensional echocardiography. Traditionally, screening was performed on a 12- to 18-month basis, usually beginning by age 12 until age 18 to 21. However, it is now recognized that development of the HCM phenotype uncommonly can occur later in adulthood. Therefore, the current recommendation is to extend clinical surveillance into adulthood at about 5-year intervals or to undergo genetic testing (Table 27-1).

5. Who should undergo genetic testing?

    Genetic testing, which is not commercially available, has become recognized as an important aspect in the evaluation of HCM. It is strongly recommended that patients diagnosed with HCM be evaluated by a genetics specialist. In an index patient, genetic testing is also recommended in order to identify the risk in first-degree family members of developing HCM. First-degree relatives of patients with HCM should undergo the previously discussed clinical screening, with or without genetic testing based on genetic counseling. However, genetic testing is not helpful in first-degree family members of an HCM patient without identifiable pathologic mutation.

6. What are the histologic characteristics of HCM?

    The histology of HCM is characterized by hypertrophy of cardiac myocytes and myocardial fiber disarray. The abnormal myocytes contain bizarrely shaped nuclei and are arranged in disorganized patterns. The volume of the interstitial collagen matrix is greatly increased, and the arrangement of the matrix components is also disorganized. Myocardial disarray is seen in substantial portions of hypertrophied and nonhypertrophied LV myocardium. Almost all HCM patients have some degree of disarray, and in the majority, at least 5% of the myocardium is involved.

7. What are the common types of HCM?

    The distribution and severity of LV hypertrophy in patients with HCM can vary greatly. Even first-degree relatives, with the same genetic mutation, usually show different patterns of hypertrophy. Various patterns of LV hypertrophy have been reported. The most common site of hypertrophy is the anterior interventricular septum (Fig. 27-1), which is seen in more than 80% of HCM patients and is known as asymmetrical septal hypertrophy (ASH). Concentric LV hypertrophy, with maximal thickening at the level of the papillary muscles, is seen in 8% to 10% of patients with HCM. A variant with primary involvement of the apex (apical HCM) is common in Japan and rare in the U.S. (less than 2%) and is characterized by spadelike deformity of the LV.

8. What are the most common symptoms in patients with HCM?

    Most patients with HCM have no or only minor symptoms and often are diagnosed during family screening. The most common symptoms are as follows:

9. How is HCM differentiated from athlete’s heart?

    Long-term athletic training can lead to cardiac hypertrophy, known as athlete’s heart. This clinically benign physiologic condition must be differentiated from HCM, because HCM is the most common cause of sudden death in competitive athletes. Clinical parameters that support the diagnosis of HCM instead of athlete’s heart are asymmetric hypertrophy greater than 16 mm, LV end-diastolic dimension less than 45 mm, enlarged left atrium, impaired LV relaxation on Doppler mitral valve inflow parameters and tissue Doppler echocardiography, absent response to deconditioning (e.g., hypertrophy does not regress with absence of exercise), family history of HCM, and sarcomeric protein mutation identified by genetic testing. These parameters are summarized in Table 27-2.

10. Describe the classic murmur of obstructive HCM and bedside maneuvers that differentiate it from other cardiac abnormalities

    The classic murmur of obstructive HCM is a harsh crescendo–decrescendo systolic murmur and is heard best between the left sternal border and apex. It often radiates to the axilla and base but not into the neck vessels. A variety of provocative maneuvers can augment or suppress the murmur to help differentiate it from other systolic murmurs.

    Maneuvers that increase intracardiac blood volume or decrease contractility typically lead to a decrease in murmur intensity, and maneuvers that decrease intracardiac blood volume or increase contractility lead to an increase in murmur intensity (Table 27-3).

11. How does the carotid pulse in obstructive HCM differ from that in valvular aortic stenosis?

    In patients with obstructive HCM, the carotid pulse has an initial brisk rise, followed by midsystolic decline as a result of LVOT obstruction, then a second rise (pulsus bisferiens). In contrast, as a result of the fixed obstruction in aortic stenosis, the carotid upstroke is diminished in amplitude and delayed (pulsus parvus and tardus).

12. What noninvasive studies are helpful in making the diagnosis of HCM?

    The ECG is abnormal in the majority of patients with HCM; however, no changes are pathognomonic for HCM. The common abnormalities are ST-segment and T-wave changes, voltage criteria for left ventricular hypertrophy (LVH), prominent Q waves in the inferior (II, III, aVF) or precordial (V2 to V6) leads, left axis deviation, and left atrial enlargement. Apical HCM, seen predominantly in Japanese patients, is characterized by giant negative T waves in the precordial leads.

    Echocardiography is the primary and preferred diagnostic modality for HCM. The cardinal feature is LVH with diastolic wall thickness 15 mm or greater. Other findings include a septal-to-posterior wall ratio 1.3 or more (seen in patients with ASH), small LV cavity, reduced septal motion and thickening, normal or increased motion of the posterior wall, systolic anterior motion of the mitral leaflets, mitral regurgitation (mid- to late systolic), partial midsystolic closure of aortic valve with coarse fluttering of the leaflets in late systole, and diastolic dysfunction. In the setting of dynamic LVOT obstruction, a resting LVOT gradient may or may not be detected. A significant gradient is defined as a resting gradient more than 30 mm Hg and a provocable gradient more than 50 mm Hg. The LVOT Doppler signal in HCM is typically late peaking and is referred to as dagger shaped.

    Magnetic resonance imaging (MRI) is becoming a valuable tool to complement echocardiographic findings. It offers high-resolution images, three-dimensional imaging, and tissue characterization. MRI is especially useful to detect LVH in areas that may be difficult to assess by echocardiography, or if the technical quality of echocardiographic images is inadequate.

13. What is systolic anterior motion and what causes it?

    Systolic anterior motion (SAM) is the abnormal anterior displacement of the anterior mitral leaflet toward the septum during midsystole. Several mechanisms have been proposed for SAM:

This typically results in eccentric mitral regurgitation directed posteriorly. Because SAM worsens during the course of systole, the mitral regurgitation also becomes more prominent during mid- to late systole.

14. Describe the mechanism of LVOT obstruction in HCM

    LVOT obstruction in HCM is produced by SAM of the anterior mitral leaflet and midsystolic contact with the hypertrophic ventricular septum. The magnitude of the subaortic gradient is directly related to the duration of contact between the mitral leaflet and the septum. The subaortic gradient is often dynamic and responds to provocative maneuvers in the same manner as the systolic murmur (see Question 9 and Table 27-3).

15. What are the characteristic hemodynamic findings during cardiac catheterization in obstructive HCM?

    Cardiac catheterization is not required for the diagnosis of HCM, and the diagnosis is usually made using noninvasive tests. Cardiac catheterization is generally reserved for assessment of coronary artery disease and evaluation before surgical procedures, such as myectomy. The typical findings during cardiac catheterization are subaortic or midventricular outflow gradient on catheter pullback, spike-and-dome pattern of aortic pressure tracing, elevated left atrial and LV end-diastolic pressures, elevated pulmonary capillary wedge pressure, increased V wave on wedge tracing (as a result of mitral regurgitation), and elevated pulmonary arterial pressure.

16. What is the Brockenbrough-Braunwald sign?

    Normally, following a premature ventricular contraction (PVC), with the subsequent sinus beat there is increased contractility and stroke volume, leading to an increase in the systolic blood pressure and thus an increase in the pulse pressure (the difference between systolic and diastolic pressure). However, in patients with HCM, the increased contractility after a PVC results in increased LVOT obstruction, leading to a decrease in stroke volume and systolic pressure, and thus a decrease in pulse pressure. This phenomenon is known as the Brockenbrough-Braunwald sign.

17. What are the risk factors for sudden cardiac death in patients with HCM?

    Sudden cardiac death (SCD) is the most devastating consequence of HCM and is often the initial clinical manifestation in asymptomatic individuals. The most common cause of SCD in HCM patients is ventricular tachyarrhythmias. Seven major risk factors for SCD have been identified:

18. What medications should generally be avoided in patients with obstructive HCM?

    Medications that decrease preload and afterload and increase contractility will worsen LVOT obstruction and therefore should be avoided.

19. What are the pharmacologic therapies for patients with HCM?

    Pharmacologic therapy is primarily used to alleviate symptoms of heart failure, angina, and syncope in HCM patients. Routine pharmacologic therapy is not recommended in asymptomatic patients.

20. What nonpharmacologic treatments are available to patients with HCM?

21. What are the indications for an implantable cardioverter-defibrillator (ICD) in HCM?

    An ICD is the preferred therapy for prevention of SCD in HCM patients. The recommended indications are as follows:

22. What is the natural history of HCM?

    The clinical course of patients with HCM is variable. Clinical manifestation can present at any age, from birth to age 90 or older. Many patients remain asymptomatic or mildly symptomatic for many years and achieve normal life expectancy. Others develop progressive symptoms of heart failure with exertional dyspnea and functional limitation despite medical therapy. Increase in LVH is predominately seen in adolescents and young adults. In older adults, LV wall thickness generally remains stable. Approximately 10% to 15% of patients will progress to end-stage HCM as described earlier. Atrial fibrillation occurs in 10% to 20% of HCM patients and may lead to clinical deterioration. The annual mortality rate in patients with HCM is about 1% in adults and 2% in children.

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