Hypertrophic Cardiomyopathy
Anthony Hart
Eiran Z. Gorodeski
I. Introduction.
The generally accepted definition of hypertrophic cardiomyopathy (HCM) is left ventricular (LV) hypertrophy associated with nondilated ventricular chambers in the absence of another cardiac or systemic disease that itself could produce such hypertrophy. There are many causes of LV wall thickening (Table 10.1), including long-standing hypertension, aortic stenosis, and infiltrative cardiomyopathies. However, these diseases can typically be identified by noninvasive markers, such as a history of significant hypertension and severe aortic stenosis. Other diseases will be identified by multisystem organ involvement (e.g., skeletal muscle weakness in Danon disease). HCM can be identified by a constellation of abnormalities, including gene mutations, marked LV thickness (> 25 mm), the presence of left ventricular outflow tract (LVOT) obstruction, and/or the presence of systolic anterior motion (SAM).
While there are many alternative names for HCM, including idiopathic hypertrophic subaortic stenosis, hypertrophic obstructive cardiomyopathy, and muscular subaortic stenosis, the World Health Organization (WHO) recommends that HCM should be used. It is the preferred term because it does not imply that obstruction (present in only approximately 25% of cases) is an invariable component of the disease.
II. Clinical Presentation
A. Natural history
1.The histological features of HCM are disarray of cell-to-cell arrangement, disorganization of cellular architecture, and fibrosis. The most common sites of ventricular involvement are, in decreasing order, the septum, apex, and midventricle. One-third of patients have wall thickening limited to one segment. These morphologic and histological features, which vary in phenotypic and clinical expression, give rise to the characteristically unpredictable natural history of HCM.
2.The prevalence of HCM is approximately 1 in 500, and the condition appears to be familial in origin. This makes HCM one of the most common genetically transmitted cardiovascular diseases. It is found among 0.5% of unselected patients referred for echocardiographic examination and is a leading cause of sudden death among athletes younger than 35 years.
B. Signs and symptoms
1. Heart failure.
Symptoms, which include dyspnea, dyspnea on exertion, paroxysmal nocturnal dyspnea, and fatigue, are largely a consequence of two processes: elevated LV diastolic pressure caused by diastolic dysfunction and dynamic LV outflow obstruction.
a. Events that accelerate heart rate, decrease preload, shorten diastolic filling time, increase LV outflow obstruction (i.e., exercise and tachyarrhythmias), or worsen compliance (i.e., ischemia) exacerbate these symptoms.
Table 10.1 Differential Diagnosis of Left Ventricular Wall Thickening | ||||||||||
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b. Between 5% and 10% of patients with HCM progress to severe LV systolic dysfunction, characterized by progressive LV wall thinning and cavity enlargement.
2. Myocardial ischemia.
Myocardial ischemia occurs in obstructive and nonobstructive HCM.
a.The clinical and electrocardiographic presentation is similar to that of ischemic syndromes in persons without HCM. Ischemia has been demon strated with thallium perfusion studies, elevated myocardial lactate levels during rapid atrial pacing, and positron emission tomography.
b.While epicardial artery obstruction is less common, mismatch of supply and demand due to thickened vessels and small vessel disease from increased collagen deposition in the intima and media are the most likely pathophysiologies of ischemia. Contributing factors include the following:
(1)Small vessel coronary disease with decreased vasodilator capacity
(2)Elevated myocardial wall tension as a consequence of delayed diastolic relaxation time and obstruction to LV outflow
(3)Decreased capillary-to-myocardial fiber ratio
(4)Decreased coronary perfusion pressure
3. Syncope and presyncope
are usually a consequence of diminished cerebral perfusion caused by inadequate cardiac output. These episodes are commonly associated with exertion or cardiac arrhythmia.
4. Sudden death.
The annual mortality rate for HCM is 1%. Most deaths are sudden or unexpected.
a.Not all patients with HCM are at equal risk for sudden death. Twenty-two percent of patients with sudden death have no symptoms. Sudden death appears to be most common among older children and young adults; it is rare in the first decade of life. Approximately 60% of deaths occur dur ing periods of inactivity; the remaining deaths occur after vigorous physical exertion.
b. Arrhythmogenic and ischemic mechanisms can initiate a clinical spiral of hypotension, decreased diastolic filling time, and increased outflow obstruc tion that often culminates in death.
III. Physical examination
A. Inspection
of the jugular venous system may reveal a prominent a wave that indi cates hypertrophy and lack of compliance of the right ventricle. A precordial heave, representing right ventricular (RV) strain, can be found in persons with concomitant pulmonary hypertension.
B. Palpation
1.The apical precordial pulse is usually laterally displaced and diffuse. LV hypertrophy may cause a presystolic apical impulse or palpable fourth heart sound (S4). A three-component apical impulse may occur, with the third impulse resulting from a late systolic bulge of the left ventricle.
2.The carotid pulse has been classically described as bifid. This rapid carotid upstroke followed by a second peak is caused by a hyperdynamic left ventricle. This is in contrast to the parvus et tardus pulse of fixed aortic or subvalvular aortic stenosis, which is a carotid pulse characterized by a delayed amplitude and upstroke.
C. Auscultation
1. S1 (first heart sound) is usually normal and is preceded by S4.
2.S2 (second heart sound) can be normal or paradoxically split as the result of the prolonged ejection time of patients with severe outflow obstruction.
3.The harsh, crescendo-decrescendo systolic murmur associated with HCM is best heard at the left sternal border. It radiates to the lower sternal border but not to the neck vessels or axilla.
a.An important aspect of the murmur is its variation in intensity and duration with ventricular loading conditions. During periods of increased venous return, the murmur is of shorter duration and is less intense. In the underfilled ventricle and during periods of increased contractility, the mur mur is harsh and of a longer duration.
(1)The concomitant murmur of mitral insufficiency can be differentiated because of its holosystolic, blowing quality that radiates to the axilla.
(2)A soft, early, decrescendo, diastolic murmur of aortic insufficiency is found in approximately 10% of patients with HCM.
b. Maneuvers that affect preload and afterload can be helpful in diagnosing HCM and differentiating it from other systolic murmurs (Table 10.2).
Table 10.2 Effects of Maneuvers or Pharmacologic Intervention to Differentiate Murmur of Hypertrophic Cardiomyopathy from Aortic Stenosis | ||||||||||||||||||||||||||||||||||||||||||
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TABLE 10.3 Molecular Genetics of Hypertrophic Cardiomyopathy | ||||||||||||||||||||||||||||||
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IV. Genetic aspects of HCM.
Familial HCM is caused by mutation in one of the genes currently known to encode different components of sarcomere proteins or sarcomere associated proteins that are inherited in an autosomal dominant manner (see Chapter 42). To date, familial HCM is known to be caused by over 1,400 different mutations in at least 8 genes (Table 10.3). Multiple analyses suggest that these common genetic subtypes are essentially phenotypically indistinguishable.
HCM genotype does not necessarily imply that subjects will have the phenotypic traits of HCM as variable penetrance exists, and environmental factors as well as modifier genes affect whether a particular subject will manifest HCM phenotypically
Patients with an identified pathogenic mutation are at an increased risk for cardiovascular death, nonfatal stroke, or progression to NYHA functional class III or IV compared with patients with no identified mutations.
V. Diagnostic testing
A. Electrocardiogram (ECG).
Although most patients have electrocardiographic evidence of disease, no changes are pathognomonic for HCM. Common electro cardiographic findings in HCM are listed in Table 10.4. These abnormalities do not correlate with disease severity or pattern of hypertrophy.
B. Echocardiography
is the preferred diagnostic method because of its high sensitivity and low risk profile. It also allows characterization of the site of obstruction. Careful
assessment for conditions that can also cause secondary hypertrophy (aortic or subaortic stenosis, hypertension, infiltrative diseases, etc.) should also be done.
assessment for conditions that can also cause secondary hypertrophy (aortic or subaortic stenosis, hypertension, infiltrative diseases, etc.) should also be done.
TABLE 10.4 Electrocardiographic Findings in Hypertrophic Cardiomyopathy | |||||
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TABLE 10.5 Two-Dimensional, M-Mode, and Doppler Echocardiographic Findings in Hypertrophic Cardiomyopathy | |||||||||||
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1. M-mode and two-dimensional
echocardiographic findings in HCM are listed in Table 10.5. Close evaluation of the extent of hypertrophy should be done given the role of septal thickness in risk stratification for sudden cardiac death (SCD).
2. Doppler echocardiography
enables recognition and quantification of dynamic LVOT obstruction as well as the response to various maneuvers.
a.Approximately one-fourth of patients with HCM have a resting pressure gra dient between the body and LVOT; others have only provocable gradients.
b.The diagnosis of HCM with obstruction is based on resting peak instanta neous gradient > 30 mm Hg. These gradients correlate directly with the time of onset and duration of contact between the mitral leaflet and the septum, as occurs during SAM of the mitral leaflet. The earlier and longer the contact occurs, the higher the pressure gradient.
(1)Inducing obstruction and, therefore, gradients, in patients believed to have latent obstruction, can be accomplished with substances (e.g., amyl nitrite, isoproterenol, and dobutamine) or maneuvers (e.g., Valsalva maneuver and exercise) that decrease LV preload or increase contractility.
(2)Although the clinical relevance of outflow obstruction has been debated, relief by means of surgical or pharmacologic technique is associated with clinical improvement among many patients. Echocar-diographic recognition of HCM and of HCM with outflow obstruction is, therefore, important.
c. Recognition of mitral regurgitation (MR). Echocardiographic evaluation of MR and the detection of valve anomalies may have a considerable effect on medical and surgical strategies in the care of patients with HCM.
(1) Approximately 60% of patients with HCM have structural abnormalities of the mitral valve, including increased leaflet area, elongation of leaflets, and anomalous insertion of papillary muscles directly into the anterior mitral leaflet.
