General
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• Hypertrophic cardiomyopathy (HCM) was first described by a pathologist, Teare, at St. George's Hospital in London in 1958 (Br Heart J 1958;20:1), when he demonstrated left ventricular hypertrophy of unknown cause

Epidemiology
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• Prevalence of HCM in the general population is about 1/500

Pathophysiology
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• About 25% of individuals with HCM demonstrate an obstruction to the outflow of blood from the left ventricle during rest and in 70% of patients, obstruction can be provoked under certain conditions
  • This is known as dynamic outflow obstruction, because the degree of obstruction is variable and is dependent on the loading conditions (ventricular filling and arterial blood pressure) and the contractility state of the left ventricle
  • Myocardial hypertrophy and extracellular fibrosis predispose to increased left ventricular stiffness which in concert with compromised cellular energetics and abnormal calcium handling lead to diastolic dysfunction manifested as dyspnea and exercise intolerance
  • The altered structure of the coronary vessels and increased diastolic pressure (reduced blood supply), with the hypertrophy and outflow tract obstruction (increased demand), may cause myocardial ischemia manifested as angina, and may trigger ventricular arrhythmias

Clinical features
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• Symptoms include arrhythmias and systemic embolism
• Clinical course varies markedly: some patients remain asymptomatic throughout life, some have severe symptoms of heart failure, and others die suddenly, often in the absence of previous symptoms (JPMA 2003;53:1)

Diagnosis
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• Diagnosis is based upon a number of features of the disease, including findings in echocardiography, cardiac catheterization and cardiac MRI
• A family history of HCM or unexplained sudden death in otherwise healthy individuals may also help

Prognostic factors
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• Annual mortality rates of up to 6% have been reported based largely from tertiary referral centres
• The following clinical factors are important independent predictors of HCM mortality:
  1. Occurrence of atrial fibrillation, stroke etc.
  2. Presence of basal outflow obstruction of at least 30 mm Hg
  3. Marked left ventricular wall thickness of more than 25 mm
• Genetic factors:
  • Mutations in the b-MHC gene associated with a high incidence of sudden death and a poor prognosis: Arg453Cys, Arg403Gln, Arg453Cys and Arg719Trp
  • Mutations with good prognosis and near normal survival: Gly256Glu, Val606Met, Leu908Val and Phe513Cys

Treatment
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• Pharmacological therapy to improve diastolic filling and reduce myocardial ischaemia is the primary means of relieving symptoms in HCM
• Ventricular septal myotomy / myectomy (Morrow procedure) is the standard surgical option for severely symptomatic patients with HCM and marked basal obstruction to left ventricular outflow due to mitral valve systolic anterior motion
• Alcohol induced septal ablation can also be used as a means of reducing both septal thickness and the outflow gradient in patients with HCM

Clinical images
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Echocardiogram

Gross description
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• Recommended to sample 15-20 blocks, especially from the interventricular septum (IVS), in apparently normal looking heart
• Massive hypertrophy (defined as a maximal wall thickness of 35 mm or more in adults and the equivalent in children) is the characteristic feature of HCM
• There is marked variation in macroscopic involvement:
  1. The interventricular septum is most commonly affected, with or without involvement of either the anterior wall or posterior left ventricular free wall
     • Note that symmetrical involvement of the left ventricle (concentric hypertrophy), indistinguishable from hypertensive cardiomyopathy, is common in the elderly
  2. Patients less than 30 years old show asymmetric septal hypertrophy
  3. Patients over 85 years have relatively mild left ventricular wall thickening confined to the septum, with more basal septal bulging
  4. Elderly patients with mild hypertension show a predominantly basal septal bulging and anterior septal hypertrophy of the left ventricle
  5. In 25% of all HCM in Japan and in Brazilian women, there is involvement of the apex, with sparing of the upper portion of the septum
     • Mid-ventricular HCM with apical energy affects 1.5% of Japanese

Gross images
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Cardiomyopathy asymmetrical septal hypertrophy

Mitral valve atrial surface thickening

Between hypertrophic and dilated

Concentric

Micro description
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• The earliest histological changes are myocyte disorganization / disarray which is widespread throughout the left and, to a lesser extent, in the right ventricle
• The interventricular septum demonstrates myocyte disarray, the hallmark of HCM
• Low power shows the abnormal arrangement of large hypertrophied muscle bundles crossing each other
• The most sensitive and specific change is circular arrays of myocytes around central foci of connective tissue

Micro images
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Myofiber disarray

Interstitial fibrosis with
many fibroblastic cells

Electron microscopy description
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• In normal myocytes, cross sections of the sarcomere show a highly organized orthohexagonal array, with six thin actin filaments surrounding one thick myosin filament
• In HCM, the myocyte has abnormal myofibrillary arrangements, with loss of the usual parallel arrays and the presence of irregular side to side branch connections
• Type IV collagen is seen as thick homogenous patches around the myocyte membrane
• This change, although very sensitive for the diagnosis, is of low specificity
• The abnormal myosin interferes with the normal spatial arrangement of the myofibril, leading to bizarre misshapen myocytes with an abnormal cell to cell arrangement
• Marked disorganization of intercalated discs is also observed in areas featuring myofiber disarray

Molecular / cytogenetics description
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• Familial HCM is an autosomal dominant genetically heterogeneous disease characterised by partial penetrance and variable expression
• So far, seven genes have been shown to be associated with the disease
• B-myosin heavy chain (MYH7) and the cardiac myosin binding protein C (MYBPC3) genes are the most frequently involved
• Others include both regulatory and essential myosin light chains, myosin binding protein-C, cardiac troponin T, cardiac troponin I and a-tropomyosin
• Some mutations in the b-MHC gene are associated with a high incidence of sudden death and a poor prognosis
• The Arg453Cys mutation is associated with a malignant clinical course in HCM due not only to sudden death but also to end-stage heart failure
• Arg403Gln, Arg453Cys and Arg719Trp are linked with a high incidence of sudden death and significantly shorter survival than other mutations
• Three mutations have been reported to have a particularly good prognosis with near normal survival: Gly256Glu, Val606Met, Leu908Val and Phe513Cys

Additional references
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• Current Diagnostic Pathology 2000;6:251, WikiDocs - Hypertrophic cardiomyopathy, WebPath

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