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A. Types [6] navigator

  1. Hypertrophic
    1. Acquired - usually with hypertension and/or aortic stenosis
    2. Genetic - 1:500 individuals in general population
  2. Dilated
    1. Acquired
    2. Genetic
  3. Restrictive
    1. Most commonly due to infiltrative diseases
    2. Characterized by impaired ventricular filling, usually with normal systolic function
    3. May be mistaken for constrictive pericarditis
  4. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
  5. Outcomes depend primarily on etiology of cardiomyopathy [1]
    1. Idiopathic cardiomyopathy has ~60% 10 year survival
    2. HIV associated cardiomyopathy has ~10% 10 year survival
    3. Peripartum cardiomyopathy has >90% 12 year survival
    4. Cardiomyopathy due to infiltrative diseases has ~35% 10 year survival
    5. Most cardiomyopathy survival curves reach a plateau at 8-10 years

B. Hypertrophic (HCM) [6,7,8] navigator

  1. Acquired (~50%)
    1. Hypertension
    2. Aortic Stenosis
    3. Left Ventricular Hypertrophy (LVH) is usual adaptive mechanism
    4. Patients typically have hyperfunctioning LV, with ejection fraction usually >60%
    5. The hypertrophied LV carries a high risk of ischemia, MI, CHF (diastolic dysfunction)
    6. Acquired LVH patients typically do NOT have concentric hypertrophy (only LV thickened)
  2. Familial (~50%) [7,8,31,40]
    1. Patients must have Concentric LV hypertrophy to meet criteria
    2. Mutations in sarcomere proteins may induce increased intracellular myocyte calcium
    3. Increased intracellular calcium may predispose to arrhythmias, and sudden death
    4. Familial HCM is strongly associated with ventricular arrhythmias and sudden death [46]
    5. Increasing LV wall thickness is proportional to risk of sudden death in HCM [50]
    6. Increased incidence of sudden death but many patients will do well in long term [40]
    7. In young athletes with sudden death, HCM most common cardiac anomaly on autopsy [18]
    8. Screening for HCM appears to reduce risk of death in athletes [34]
    9. Familial HCM may lead to severe outflow obstruction
    10. Overall risk of death is about 1% per year in most persons with familial HCM [8]
  3. Genetics of HCM [31,40]
    1. Overall, occurs in 1:500 persons in general population
    2. Nine genetic loci, over 130 mutations linked to familial HCM
    3. Most commonly associated with mutations in ß-cardiac myosin H chain gene
    4. Cardiac troponin T, troponin I, alpha-tropomyosin genes mutations also high risk
    5. Myosin binding protein C [32], mylosin light chain -1, and -2 lower risk
    6. AMP-activated protein kinase gamma 2
    7. alpha myosin heavy chain
    8. Single patient with HCM due to titan mutation reported
    9. Distinct mutations in some of these genes cause dilated cardiomyopathy (see below)
  4. Apical Hypertrophic Cardiomyopathy
    1. Yamaguchi's Syndrome - hypertrophy localized to ventricular apex
    2. Deeply inverted T waves in lateral leads on ECG
    3. Natural history includes atypical chest pain symptoms, low risk MI
    4. Diagnosis by catheterization and left ventriculogram
    5. Spade shaped LV with cavity obliteration
    6. Diagnosis with echocardiography difficult as apex is often poorly seen
    7. Symptoms may respond to ß-blocker therapy
  5. Angiotensin II (AT2) and LVH
    1. LVH appears to have another (non-myosin) genetic contribution
    2. Insertion in the ACE gene cluster contributes to LVH
    3. Angiotensin II is a known growth factor for cardiac myocytes
    4. ACE inhibitors (ACE-I) and AT2 receptor blockers (ARB) very effective in HTN+LVH [57]
  6. Atypical Fabry's Disease [11]
    1. Fabry's disease is an X-linked recessive disease with deficiency of alpha-galactosidase
    2. ~3% of men with unexplained LVH have hemizygous Fabry's disease
    3. These patients rarely have any other findings of Fabry's disease
  7. Pathogenesis of Hypertrophy [44]
    1. Physiologic hypertrophy occurs in response to exercise and is eccentric
    2. Muscle fibers become moderately elongated and thickened
    3. Pathologic hypertrophy occurs in response to environment (hypertension), abnormal growth stimuli, genetic mutations
    4. AT2 is an important growth factor for cardiac myocytes
    5. Pathologic hypertrophy is concentric and fibers are thickened, not elongated
    6. Clear differences between pathologic and physiology cardiac hypertrophy
    7. Concentric hypertrophic fibers express embryonic genes
    8. Microvascular dysfunction (inadequate myocardial blood flow) is found early in HCM [4]
  8. Pathophysiological Responses to Hypertrophy [12]
    1. Thickened walls with decreased compliance of ventricles
    2. Elevated filling pressures are required to maintain volume in ventricle
    3. This leads to "diastolic dysfunction" with high left atrial and pulmonary pressures
    4. Thick ventricle often highly susceptible to ischemic damage
    5. Note that cardiac muscle relaxation is an energy (oxygen) dependent process
    6. In addition, epicardial coronary arteries may be compressed during systole [37]
    7. This compression is called myocardial bridging
    8. Myocardial bridging is a risk factor for death in children and possibly adults [38]
    9. LV outflow tract obstruction at rest is a predictor of progression to CHF and death [60]
  9. Treatment [3,7]
    1. Maintain low heart rate to allow time for filling
    2. ARB or ACE-I are preferred agents in most settings
    3. Additional anti-inotropic agents help relax muscle: ß-blockers or verapamil first line
    4. ß-blockers inferior to ACE inhibitors for reduction in LV mass [3] but good antiarrhythmics
    5. Reversal of ischemia, which itself can worsen ability of muscle to relax
    6. Implantable cardioverter-defibrillator (ICD) terminate ventricular arrhythmias and likely have a role in most cases of familial HCM [46]
    7. ICD should be used in essentially all patients with high risk HCM [29]
    8. Wall thickness alone is not a sufficient criteria to dictate aggressive therapy [53]
    9. Wall thickness and additional risk factors should be considered prior to ICD placement [53]
    10. Septal myectomy or myotomy for severe refractory symptoms (marked outflow obstruction)
    11. Alcohol induced septal ablation (necrosis of septum) can be effective for >3 years in severe HCM [58]
    12. Septal ablation may require cardiac pacing but is an alternative to surgery [58]

[Figure] "Hypertrophic Cardiomyopathy and the Heart Cycle"

C. Dilated Cardiomyopathy (DCM)navigator

  1. Overview of Causes
    1. Post-myocardial infarction (cardiac muscle cell death)
    2. Alcoholic
    3. Infectious
    4. Inflammatory
    5. Autoimmune: ß1-adrenergic autoantibodies [59]
    6. Mitral Regurgitation
    7. Hereditary (see below) [6]
    8. Hemochromatosis
    9. Heavy Metals: Cobalt, Lead, Mercury
    10. Tachycardia Induced - including hyperthyroidism, atrial fibrillation, pacemakers
    11. Drug Induced
    12. Muscular Dystrophies [43]
    13. Deficiency: Thiamine, Selenium, Carnitine
    14. Physiologic dilation in very well conditioned athletes may be normal [39]
    15. Small Vessel: microvascular angina (unclear if this is true cause)
    16. Idiopathic
  2. Ischemic / Infarction
    1. Post-myocardial infarction (loss of functional muscle)
    2. Microvascular coronary artery disease
    3. Extremely common
  3. Alcoholic [2]
    1. Long term, excessive alcohol consumption associated with cardiomyopathy
    2. In men, >80gm alcohol per day is considered abuse
    3. Women appear more susceptible to cardiomyopathy with equal doses of alcohol [9]
    4. In women, >50gm alcohol per day is considered abuse
    5. Patients typically have pancreatitis and/or hepatitis
    6. Also at risk for alcoholic myopathy
    7. Exacerbated by thiamine (and selenium) deficiency
    8. Mild to moderate alcohol consumption (1-2 drinks per day men, 1/2-1 drink per day for women) associated with ~50% reduced risk for developing heart failure [2]
    9. Men with alcoholic cardiomyopathy who reduce alcohol consumption to <60gm/d have no increased risk (versus abstinence) [5]
  4. Infection Associated
    1. Viral: Coxsackie B Virus, CMV, HIV, echovirus, adenovirus, many others
    2. Rickettsial, Fungal
    3. Other: Diphtheria, Mycobacteria
    4. Parasitic: toxoplasmosis, trichinosis, Chagas' Disease (most common worldwide)
    5. PCR evaluation of dilated cardiomyopathic tissue has failed to show coxsackie DNA
  5. Autoimmune / Inflammatory Disease [2]
    1. Collagen Vascular Disease: scleroderma, SLE, dermatomyositis
    2. Sarcoidosis has possible association
    3. Hypersensitivity Myocarditis
    4. Peripartum Cardiomyopathy
    5. Severe myositis probably occurs prior to dilation
    6. ß1-adrenergic autoantibodies [59]
    7. Idiopathic end-stage dilated cardiomyopathy characterized by myocyte apoptosis [48]
  6. Peripartum Cardiomyopathy
    1. Dilatation of all cardiac chambers
    2. Pale appearing myocardium
    3. Ventricular Thrombi
    4. Disintegration of sarcoplasm and heart muscle fibers
    5. Overall better prognosis than other forms of cardiomyopathy [1]
  7. Metabolic Abnormalities
    1. Thiamine, selenium, carnitine deficiency
    2. Endocrine disorders: hypothyroidism, thyrotoxicosis, acromegaly, Cushing's, others
    3. Hypocalcemia, hypophosphatemia
  8. Toxins
    1. Alcohol (see above)
    2. Chemotherapy: adriamycin, bleomycin, isfosfamide, uncommon with cyclophosphamide
    3. Heavy Metals: Cobalt, Lead, Mercury
    4. Anti-retroviral agents: zidovudine, didanosine, zalcitabine
    5. Phenothiazines
    6. Cocaine
    7. Women are more suceptible than men to EtOH [9] and chemotherapy [10] induced cardiomyopathy
  9. Drugs
    1. Anti-retroviral: Zidovudine (AZT), Didanosine (DDI), Zalcitabine (DDC), Interferon alpha
    2. Chemotherapeutic Agents (see below) [16]
    3. Other Drugs: cocaine, phenothiazines
  10. Anthracycline Induced Cardiac Disease [13,35]
    1. Initially causes myocarditis and/or pericarditis
    2. Arrhythmias may ensue
    3. Doxorubicin >500mg/m2 often causes dilated cardiomyopathy
    4. Long term reduction in ejection fraction, very much dose related
    5. Safer as a constant infusion than as a bolus infusion
    6. Idarubicin and epirubicin, and related mitoxantrone, also increase cardiomyopathy risk
    7. Female sex and higher drug doses of doxorubicin (Adriamycin) correlate with development of dilated cardiomyopathy [10]
    8. Best evaluation is with radioventriculogram (RVG), not echocardiography
    9. Free radical formation and damage to myocytes is most likely
    10. Dexrazoxane (Zinecard®) is an iron chelating agent approved to reduce this toxicity [36]
    11. However, dexrazoxane increases risk of severe myelosuppression
  11. Cardiac Disease from Other Chemotherapeutic Agents [13]
    1. Mitoxantrone (adriamycin analog) also causes cardiomyopathy
    2. High risk in patients with heart disease, radiation therapy, hypertension
    3. Previous chemotherapy is also a major risk factor
    4. Ifosfamide can also cause an acute dilated cardiomyopathy
    5. Trastuzumab (Herceptin®, anti-HER2 antibody) increases risk of dilated cardiomyopathy
    6. Sunitinib, a multitargeted tyrosine kinase inhibitor, associated with hypertension, LV dysfunction, CHF (usually reversible) [63]
  12. Neuromuscular Disease
    1. Duchenne's and Becker's muscular dystrophy [43]
    2. Myotonic Dystrophy
    3. Friedrich's Ataxia
  13. Familial [6]
    1. Up to 35% of idiopathic dilated cardiomyopathy
    2. Autosomal and X Linked Forms
    3. X Linked - mutant cardiac dystrophin [49] or tafazzin
    4. Dystrophin anomalies related to Duchenne's and Becker's Muscular Dystrophy [43]
    5. Multiple autosomal gene mutations associated with DCM
    6. Lamin A/C gene mutations (conduction system disease also present) [45]
    7. Desmin myopathy - skeletal myopathy with dilated cardiomyopathy [47]
    8. Delta sarcoglycan mutations
    9. Cardiac ß-myosin heavy gene mutations (chr 14q11.2-13) [52]
    10. Cardiac troponin T mutations (chr 14q11.2-13) [52]
    11. Actin mutations
    12. Other autosomal genes not yet specifically identified (chromosomal location known)
    13. Mitochondrial DNA: tRNA-Lysine gene mutations [6]
    14. Treatable asymptomatic dilated cardiomyopathy found in ~5% of relatives of patients with clinical dilated cardiomyopathy [28]
  14. Valvular Disease (chronic)
    1. Volume overloaded left ventricle, usually with normal outflow pressures
    2. Aortic Regurgitation
    3. Mitral Regurgitation
  15. Symptoms
    1. Usually present with chest pain and/or dyspnea on exertion
    2. Symptoms of frank congestive heart failure with systolic dysfunction
    3. Systemic Emoblization due to formation and escape of intracardiac thrombi
    4. Pulmonary emboli in R heart failure, foramen ovale, or septal defects
    5. Ambulatory ECG monitoring with telephonic continuous loop monitors very helpful [42]
    6. Evaluation for presence of systemic muscular dystrophy should be done
  16. Pathogenesis of Dilation
    1. Overworked cardiac muscle eventually becomes weakened
    2. Fibers become eccentrically hypertrophied, or long and thin fibers
    3. Long, thin fibers cannot generate necessary contractile force
    4. Apoptosis and disordered fiber bundles arise
    5. Dystrophin remodelling (disruption of amino terminus) found in severe disease [55]
    6. Result is worsening contractile function and eventual failure
    7. Failing heart associated with increased TNF alpha levels
    8. TNF alpha contributes to myocyte apoptosis and CHF progression
  17. Pathophysiologic Response to Dilation
    1. Weak muscle, decreased contractility, increased or normal compliance
    2. Preload increase required to maintain cardiac output
    3. Ongoing cardiac myocyte apoptosis in idiopathic dilated cardiomyopathy [48]
    4. Apoptosis is not typically seen in non-infarct areas in ischemic cardiomyopathy
    5. As heart fails, cardiac tissue down-regulates ß-adrenergic receptors
    6. Thus, failing heart has less sensitivity to adrenergic stimulation
    7. Thyroid hormone administration may increase ß-receptor expression [21]
    8. Level of remodelled dystrophin is an indicator of LV dysfunction [55]
    9. Dystrophin remodelling is reversible in some patients on LV assist devices [55]
    10. Physiology of "normal" LV dilation in elite athletes is under investigation [39]

D. Treatment of Dilated Cardiomyopathy [6] navigator

  1. Similar to that for systolic dysfunction / congestive heart failure
  2. Intake Modifications
    [Figure] "Dilated Cardiomyopathy and the Heart Cycle"
    1. Dietary modification with sodium intake <2gm / day
    2. Free water restriction 1.5-5L / day - especially when serum [Na] is <130mM
  3. Agents Blocking Remodeling
    1. These agents may induce reverse remodeling (see below)
    2. ACE-I or ARB - high doses are probably most beneficial as tolerated
    3. ACE-I combined with ARB may be more effective than either alone
    4. Hydralazine + Nitrates in patients intolerant of ACE-I
    5. Aldosterone blockade with spironolactone (Aldactone®) or eplerinone ()
    6. Carvedilol, a vasodilatory (alpha and beta) adrenergic blocker, improves mortality [25]
    7. ß-blockers induce measurable changes in gene expression in dilated cardiac tissue [56]
    8. Low dose ß-blockers, particular vasodilatory types, improve symptoms, mortality [24]
  4. Other Agents
    1. Nitrates may be added to ACE inhibitors for additional benefits
    2. Diuretics - for acute treatment; chronically for symptomatic improvement
    3. Digoxin generally recommended in patients symptomatic with EF< ~25%
    4. Amlodipine (Norvasc®) may improve survival in dilated cardiomyopathy / CHF [19]
    5. L-thyroxine (Synthroid®, others) 100µg/day improves symptoms [21]
    6. Anti-coagulation with warfarin for EF <20% or history of thrombi, INR 2-3
    7. In controlled trial, growth hormone improved LV mass, but not clinical symptoms [15,33]
    8. Pentoxifylline 400mg po tid showed marked clinical improvement dilated CHF [30]
    9. Specific removal of ß1-adrenergic autoantibodies improves function [59]
  5. Devices
    1. Cardiac pacing (resynchronization therapy) may also be beneficial [54]
    2. Prophylactic implantable cardioverter defibrillator (ICD) in dilated cardiomyopathy with LVEF <35% reduced risk of sudden death from arrhythmia [61]
    3. Left ventricular assist device (LVAD) - improves cardiac output in severe LV dysfunction
    4. LVAD with aggressive drug therapy lead to reversal of idiopathic dilated cardiomyopathy, explanation of LVAD, and return to normal function in 11 of 15 severe patients [62]
    5. Total artificial heart as bridge to cardiac transplant [41]
  6. Heart Transplantation

E. Restrictive Cardiomyopathy [22]navigator

  1. Overview of Causes
    1. Infiltrative
    2. Non-Infiltrative: Idiopathic, Familial, Scleroderma, Hypertrophic
    3. Storage Disease
    4. Idiopathic
  2. Infiltrative
    1. Amyloidosis - multiple types of amyloid can cause cardiac disease [17,23,26]
    2. Sarcoidosis
    3. Gaucher's Disease
    4. Mucopolysaccharidoses
  3. Cell Storage Disease
    1. Hemochromatosis
    2. Fabry's Disease
    3. Glycolipid Accumulation
    4. Glycogen Storage Diseases
  4. Pathophysiology
    1. May result in CHF with "normal" LV contraction [14]
    2. Problem is heart muscle relaxation, also called diastolic dysfunction
    3. Often accompanied by conduction system disease
  5. Presentation
    1. Generally similar to CHF
    2. Dyspnea, orthopnea, peripheral edema, ascites
    3. Angina generally does not occur, except with amyloidosis
    4. Thromboembolic complications may occur, particularly in idiopathic disease
    5. Conduction disturbances common in amyloidosis and sarcoidosis
    6. Atrial fibrillation common in idiopathic disease and amyloidosis
  6. Evaluation and Treatment
    1. Attempt to discern and treat underlying cause (rarely reverses damage to heart)
    2. Echocardiography, ECG, Doppler studies
    3. Cardiac catheterization and endomyocardial biopsy often indicated to clarify diagnosis
    4. Symptomatic treatment as in CHF - diuretics are mainstay
    5. Important to maintain sinus rhythm - amiodarone is often useful
    6. Anticoagulation with warfarin recommended to reduce thromboembolic complications
    7. Heart transplantation may be required (original disease may recur)

F. Arrhythmogenic Right Ventricular Cardiomyopathy [6,20]navigator

  1. Also called arrhythmogenic right ventricular dysplasia (ARVD)
  2. Massive fibrofatty infiltration of mainly the right ventrical
    1. Abnormalities in signalling and/or cell adhesion proteins have been found
    2. Leads to malfunction of myocytes and likely myocyte death
    3. Replacement of normal myocytes with "scar" fibrofatty tissue
  3. Genetics
    1. Familial disease in ~30% of patients
    2. Autosomal dominant (AD) forms are most common
    3. AD forms linked to loci on chromosomes 1, 2, 10, 14
    4. Ryanodine receptor (chr 1q42) mutations AD forms
    5. Plakoglobin and desmoglobin mutations in autosomal recessive form
    6. Desmoplakin mutations also found
    7. Plakoglobin, desmoplakin, and desmoglobin found in adherens and desmosomal junctions
  4. AR Naxos Syndrome
    1. Due to deletion in plakoglobin gene on chromosome 17q21
    2. ARVC
    3. Non-epidermolytic palmoplantar keraoderma
    4. Wooly hair
  5. Symptoms
    1. Sudden death is often presentation in proband
    2. Ventricular arrhythmias leading to syncope, light-headedness
    3. CHF
  6. Diagnosis
    1. Structural and histological features
    2. Electrocardiographic features fairly unique
    3. Genetic factors
    4. Possible that magnetic resonance imaging of ventricular wall is helpful
    5. Standardized clinical criteria have been developed
  7. Treatment
    1. ß-adrenergic blockers are first line unless severe CHF is present
    2. Class III agents such as amiodarone or sotalol in patients with persistent arrhythmias
    3. Catheter ablation in patients with arrhythmogenic foci
    4. Implantable cardioverter defibrillator (ICD) in patients with high risk of sudden death
    5. Standard treatments for CHF if it arises

G. Summary of CharacteristicsnavigatorSummary Properties of Cardiomyopathies
PropertiesDilatedHypertrophicRestrictive
1. Inflow Obstruction+++++++
2. Outflow Obstruction--+++--
3. Low Output++++++
4. Chest Pain++--
5. Arrhythmia++++++

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