A. Types of Hypertrophic Cardiomyopathy (HCM)

1. Definition
   1. Myocardial hypertrophy in absence of hemodynamic stress which could indue hypertrophy
   2. Characteristic histopathological appearance called myocyte disarray
   3. Histopathological appearance is not specific to HCM but it is required
   4. Genetic characterization is now available but clinically not always helpful
   5. Clinically, HCM is defined as presence of left ventricular hypertrophy without clear cause
   6. Presents with dyspnea, lightheadedness, syncope, chest pain, arrhythmia, sudden death [10]
2. Genetic (Familial)
   1. Formerly idiopathic hypertrophic subaortic stenosis (IHSS)
   2. Also called hypertrophic obstructive cardiomyopathy
   3. Various diseases with autosomal dominant inheritance
   4. Nearly all are due to mutations in sarcomeric protein genes
   5. Global (concentric) hypertrophy occurs
   6. Occurs in 1:500 persons in general population
   7. Overall risk of death is about 1% per year in most persons with FHC
   8. FHC is most common cause of sudden death in young athletes [4]
3. Acquired LVH
   1. Most common type of cardiac hypertrophy
   2. Usually due to hypertension (HTN) and/or aortic stenosis
   3. LVH, rather than global, hypertrophy occurs
   4. This form is not usually considered a true cardiomyopathy
   5. Histologic appearance of muscle cells in this form is relatively normal
4. Yamaguchi's Syndrome - atypical hypertrophy prominant at cardiac apex
5. Other Causes of Myocyte Disarray
   1. Atypical Fabry Disease
   2. Noonan Syndrome - dysmorphic syndrome with variable cardiomyopathy
   3. Friedreich's Ataxia - frataxin mutations, autosomal recessive
6. All of these syndromes are characterized by significant phenotypic heterogeneity

B. Genectics of FHC [5,15]

1. Autosomal dominant pattern (phenotypes are variable within same genotype)
2. Defect in any one of seven genes of the cardiac sarcomere
   1. ß-cardiac myosin H chain gene (MYH7, chromosome 14q11.2-q13)
   2. Cardiac Troponin T (TNNT2, chr 1q32)
   3. Cardiac Troponin I (TNNI3, chr 19p13.2-q13.2)
   4. Alpha-tropomyosin (TPM1, chr 15q22)
   5. Myosin binding protein C (MYBPC3, chr 11p11.2) [4]
   6. Ventricular myosin light chain 1 (MYL3, chr 3p21.2-21.3)
   7. Ventricular myosin light chain 2 (MYL2, chr 12q23-24.3)
   8. Cardiac Actin (ACTC chr 15q14)
   9. AMP-activated protein kinase gamma 2 (chr 7q3)
   10. Titin (TTN)
   11. Alpha-myosin heavy chain
   12. Uncommon presentation of glycogen or lysosomal storage diseases
3. Over 130 individual genetic defects, mainly mis-sense, have been identified
4. Glycogen Storage Diseases [3]
   1. Danon Disease: X-linked lysosome-associated membrane protein 2 (LAMP2) deficiency
   2. AMP-Activated Protein Kinase Gamma2 (PRKAG2) Deficiency - ventricular pre-excitation
5. Children with FHC
   1. Children with with mutations and no symptoms have been identified in family studies
   2. Many have no changes on echocardiography
   3. Some have changes on ECG
   4. Presume that most or all will develop concentric hypertrophy
   5. Genetic causes account for >50% of sporadic cases >65% of familial cases of childhood-onset cardiac hypertrophy [15]
   6. Childhood-onset hypertrophy should prompt genetic analyses of family members [15]

C. Pathology [2]

1. Clinical manifestations of specific sarcomere mutations are not yet clearly understood
2. All cardiac walls show hypertrophy, called "concentric hypertrophy"
   1. Beginnings of hypertrophy are generally observed during adolescence
   2. Left ventricle is usually thickest due to workload (>12mm thick, up to 30-60mm)
   3. LV outflow tract is often most affected, with real physical obstruction present
   4. Muscle fiber arrangements are abnormal in all cases
3. Valvular abnormalities are commonly found, though not usually symptomatic
4. Coronary artery structure, particularly in small vessels, is abonormal
5. Microvascular dysfunction (inadequate myocardial blood flow) is found early in HCM [6]

D. Pathophysiology [7]
[Figure] "The Heart Cycle in HCM"

1. Hypertrophy appears mainly to be compensatory mechanism for weak systolic function
2. Abnormal sarcomeres are likely central problem
   1. Weak sarcomeres lead to compensatory changes
   2. First, intracellular myocyte calcium increases in order to improve inotropy
   3. Increased calcium stimulates calcium-dependent transcription factors
   4. Gene expression is altered, and myocyte hypertrophy occurs
   5. In addition, increased calcium predisposes to arrhythmia generation
   6. Result is thick cardiac walls, relative ischemia, and predisposition to arrhythmia
3. Thickened walls with decreased compliance of ventricles
   1. Stroke volume may decrease, particularly with severe thickening
   2. Compensatory tachycardia may occur to maintain cardiac output
4. Elevated filling pressures (preload) are required to maintain volume in ventricle
5. Preload pressures increase leading to increased atrial and pulmonary pressures
6. This is called "diastolic dysfunction"
7. Thick ventricles are often highly susceptible to ischemic damage
   1. Cardiac muscle relaxation as well as contraction depends on energy (oxygen)
   2. Therefore, relative ischemia can worsen diastolic dysfunction
   3. Coronary arterial abnormalities are often found in FHC and may add to ischemia
   4. In addition, epicardial coronary arteries may be compressed during systole
   5. This compression is called myocardial bridging
   6. Myocardial bridging is a risk factor for death in children and possibly adults
8. LV outflow tract obstruction at rest is a predictor of progression to CHF and death [8]

E. Diagnosis

1. Screening for HCM in athletes appears to reduce risk of sudden death [9]
2. Whether high school athletes should be screened prior to intense activity is unclear
3. High suspicion in family members of persons with diagnosed FHC
4. ECG screening once a year after age 10 or so is probably reasonable
5. Consider longer term ambulatory ECG monitoring (such as 24-48 hour or loop recordings)
6. Echocardiography is only positive later in life
7. Cardiac biopsy showing typical histopathological myocyte disarray [2]
   1. Individual cardiomyocytes vary in size and shape
   2. Form abnormal intercellular connections
   3. Usually with expansion of interstitial compartment and areas of replacement fibrosis
8. Key issue is risk stratification for chances of sudden death
9. Increased Risk for Sudden Death [3,14]
   1. Previous Cardiac Arrest or Sustained Ventricular Tachycardia (VT)
   2. Adverse Genotype
   3. Family history of sudden death or cardiac arrests
   4. Multiple-repetitive or prolonged bursts of non-sustained VT
   5. Recurrent Syncope
   6. Massive LVH
   7. Increasing LV wall thickness is proportional to risk of sudden death in HCM [11]

F. Treatment [1,2,3]

1. No disease modifying therapy yet identified
2. Overall risk of death is about 1% per year in most persons with familial HCM
3. Treatment Focused on Symptoms
   1. Prophylaxis with ß-blockers or verapamil for low risk HCM patients is not supported
   2. Angina, palpitations or dyspnea, high dose ß-blockers or verapamil are used
   3. With LV outflow tract obstruction, ß-blockers or disopyramide recommended
   4. Disopyramide may be effective in some patients resistant to other therapies
   5. Diuretics added in patients with refractory dyspnea with heart failure component
   6. Surgical, alcohol or other ablation therapy for refractory patients
4. High Risk for Sudden Death
   1. Electrophysiology study should be considered for clear evaluation of risk
   2. Implantable cardioverter-defibrillator (ICD) is strongly preferred, clearly effective [14]
   3. Long term amiodarone therapy may be considered, generally in addition to ICD
5. Congestive Heart Failure (CHF)
   1. Maintain low heart rate to allow time for filling,
   2. Reduce inotropy to improve ventricular relaxation
   3. ß-blockers or verapamil are generally preferred (combination may be needed)
   4. Disopyramide is sometimes used instead, particularly with outflow obstruction
   5. Diuretics may be added cautiously to other agents
   6. Nitrates may improve ischemia, which itself can worsen ability of muscle to relax
   7. Caution must be used when reducing preload in these patients
6. Severe Refractory Disease
   1. Septal myotomy/myectomy or heart transplantation may be required
   2. Alcohol septal ablation (necrosis of septum) can be effective for >3 years in severe HCM [12]
   3. Septal ablation may require cardiac pacing but is an alternative to surgery [12]
   4. Dual chamber pacing may improve LV outflow gradient

References

1. Nishimura RA and Holmes DR Jr. 2004. NEJM. 350(13):1320
2. Elliott P and McKenna WJ. 2004. Lancet. 363(9424):1881
3. Maron BJ. 2002. JAMA. 287(10):1309
4. Maron BJ. 2003. NEJM. 349(11):1064
5. Franz WM, Muller OJ, Katus HA. 2001. Lancet. 358(9293):1627
6. Cecchi F, Olivotto I, Gistri R, et al. 2003. NEJM. 349(11):1027
7. Hill JA and Olson EN. 2008. NEJM. 358(13):1370
8. Maron MS, Olivotto I, Betocchi S, et al. 2003. NEJM. 348(4):295
9. Corrado D, Basso C, Schiavon M, Thiene G. 1998. NEJM. 339(6):364
10. Binder WD, Fifer MA, King ME, Stone JR. 2005. NEJM. 353(8):824 (Case Record)
11. Spirito P, Bellone P, Harris KM, et al. 2000. NEJM. 342(24):1778
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13. Arab M, Maron BJ, Gorham JM, et al. 2005. NEJM. 352(4):362
14. Maron BJ, Spirito P, Shen WK, et al. 2007. JAMA. 298(4):405
15. Morita H, Rehm HL, Menesses A, et al. 2008. NEJM. 358(18):1899