Genetic Cardiomyopathies¶
Chapter 267 | Part 6: Disorders of the Cardiovascular System · Part 6 – Cardiovascular Disorders · Chapter 267
Key Clinical Points¶
- Hypertrophic cardiomyopathy (HCM) prevalence is approximately 1:500 in North America, Africa, and Asia.
- Truncating variants in TTN (titin) are the most common genetic cause of dilated cardiomyopathy (DCM), accounting for up to 25% of familial disease.
- Sudden death risk factors in HCM include history of cardiac arrest or spontaneous sustained ventricular tachycardia (VT), family history of sudden death, LV thickness >30 mm, and LV apical aneurysm.
- Fabry's disease is an X-linked disorder caused by alpha-galactosidase A deficiency, leading to glycosphingolipid accumulation.
- In HCM, outflow tract obstruction is present in ~30% of patients at rest and can be provoked by exercise in another ~30%.
- Genetic testing primarily informs family evaluations but enables detection of specific therapies for metabolic disorders like Fabry's (enzyme replacement) and Danon's disease.
- Athlete's heart hypertrophy regresses with cessation of training, unlike HCM, and is characterized by supernormal exercise capacity (VO2max >50 mL/kg per min).
- LMNA variants in DCM warrant ICD placement before LVEF declines to 0.35 due to high arrhythmia risk.
- Danon disease presents with extreme LV hypertrophy in childhood, often progressing to end-stage heart failure.
- Barth's syndrome (TAZ variants) presents with skeletal myopathy, cognitive impairment, and neutropenia alongside DCM/LVNC.
DEFINITION & OVERVIEW¶
• Genetic Cardiomyopathy: Condition where each morphologic form (hypertrophic, dilated, and restrictive) can be caused or modified by underlying genetic factors. • Clinical Characteristics: ◦ Age-dependent and incomplete penetrance; the phenotype is rarely present at birth and may never manifest in some individuals. ◦ Phenotypic variability: Individuals with the same variant may differ in severity and progression due to genetic, epigenetic, and environmental modifiers. ◦ Inheritance: Most are autosomal dominant (AD), but can be autosomal recessive (AR), mitochondrial, or X-linked. ◦ Genetic Mechanisms: ◦ Missense variants: Amino acid substitutions. ◦ Truncating variants: Nonsense or frameshift mutations leading to haploinsufficiency or dominant negative effects. ◦ Polygenic Risk: Emerging role of multiple less common alleles on penetrance and expression; polygenic risk scores may identify patients without a single high-effect allele. • Genetic Testing Utility: ◦ Primarily used to inform family evaluations. ◦ Identifies specific therapies for metabolic disorders (e.g., enzyme replacements in Fabry's and Gaucher's disease). ◦ Clinical trials are exploring gene therapies for cardiomyopathy.
EPIDEMIOLOGY¶
• Hypertrophic Cardiomyopathy (HCM): ◦ Prevalence: ~1:500 in North America, Africa, and Asia. ◦ Impact: Leading cause of sudden death in the young; significant cause of heart failure. ◦ Prognosis: Adult diagnosis correlates with decreased survival compared to age-matched peers. • Dilated Cardiomyopathy (DCM): ◦ Familial involvement: >30% of cases. ◦ TTN mutations: Most common cause of DCM; account for up to 25% of familial disease. ◦ Gendered progression: Men with TTN variants develop cardiomyopathy ~10 years before women. • Arrhythmogenic Cardiomyopathy (ACM): ◦ Familial clustering: 30–40% of cases. ◦ Monogenic etiology: Identified in ~25% of cases.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Genetic Heterogeneity: ◦ Locus heterogeneity (many genes) and allelic heterogeneity (multiple variants within a gene). • Sarcomere Gene Variants: ◦ Present in ~40–50% of HCM patients; most common are MYH7 and MYBPC3 (~80% of cases). • Membrane & Structural Proteins: ◦ Dystrophin (DMD): X-linked; leads to Duchenne/Becker muscular dystrophy. ◦ Desmosomal complex (DSP, JUP): Mutations lead to Arrhythmogenic Cardiomyopathy (ACM) and potential for aneurysms. ◦ Nuclear membrane: LMNA (Lamin A/C) and EMD (Emerin) mutations cause conduction disease and high arrhythmia risk. • Channelopathies: ◦ SCN5A (Nav 1.5): Associated with DCM and conduction disease. ◦ RYR2, CASQ2: Associated with ARVC. • Metabolic Disorders: ◦ Danon's Disease (LAMP2): X-linked; skeletal myopathy, cognitive impairment, and HCM phenotype. ◦ Barth's Syndrome (TAZ): X-linked; DCM/LVNC, skeletal myopathy, cognitive impairment, neutropenia. ◦ Fabry's Disease (GLA): X-linked; renal failure, angiokeratomas, painful neuropathy, and HCM phenotype. • Table 267-1: Selected Genetic Defects Associated with Cardiomyopathy ◦ Sarcomere Group: ACTC1, MYH7, MYBPC3, TNNT2, TNNI3, TTN, TPM1, TNNC1, MYL2, MYL3. ◦ Nuclear membrane: LMNA (AD/AR), EMD (X-linked). ◦ Metabolic: LAMP2 (Danon's), TAZ (Barth's), GLA (Fabry's), FXN (Friedreich's ataxia). ◦ Sarcolemmal membrane: DMD, DMPK, DSP, JUP, DSG2, DSC2, PKP2.
CLINICAL FEATURES¶
• Hypertrophic Cardiomyopathy (HCM): ◦ Definition: LV hypertrophy without causative hemodynamic factors. ◦ Morphology: Typically non-uniform; most common in the interventricular septum. ◦ Apical HCM: Less often familial; sarcomere variants present in only ~15%. ◦ Obstruction: Present in ~30% at rest and ~30% during exercise (total ~60%). ◦ Pathophysiology: Enhanced calcium sensitivity, maximal force generation, and impaired relaxation. ◦ Fibrosis/Microvascular Disease: Interstitial fibrosis develops before overt hypertrophy; microvascular ischemia contributes to angina. • Dilated Cardiomyopathy (DCM): ◦ Definition: LVEF ≤ 0.50 and/or LV diastolic dimension >95% predicted for age/sex. ◦ Morphology: Marked dilation, thinned walls, and often increased trabeculation. • Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC): ◦ Pathophysiology: Desmosomal complex defects lead to myocyte death and replacement by fat/fibrous tissue. • Metabolic Cardiomyopathies: ◦ Often present with additional features like skeletal myopathy or renal failure. • Athlete's Heart vs. HCM: ◦ Athlete's Heart: Regresses with training cessation; supernormal exercise capacity (VO2max >50 mL/kg per min); no fibrosis or disarray. ◦ HCM: Persistent hypertrophy; does not regress; associated with fibrosis and potential for arrhythmias.
DIFFERENTIAL DIAGNOSIS¶
• Clinical Mimics of HCM: ◦ Secondary hypertrophy from hypertension, aortic valve disease, or infiltrative/storage diseases. ◦ Pseudohypertrophy: Myocardium thickened by abnormal products in metabolic disorders (often with short PR interval). • Differential for DCM: ◦ Dilated cardiomyopathy vs. Arrhythmogenic Cardiomyopathy (ACM) based on location of fat/fibrosis and genetic markers (e.g., DSP, JUP).
INVESTIGATIONS & DIAGNOSIS¶
- Initial Clinical Evaluation: • History: Identify cardiac/noncardiac disorders; family history of heart failure, skeletal myopathy, conduction issues, and sudden death. • Physical Exam: Assess JVP, edema, orthostatic BP, and perfusion. • Functional Assessment: Changes in ability to perform routine activities.
- Laboratory & Imaging: • ECG: Standard 12-lead. • CXR: Basic imaging. • Echocardiogram: 2D and Doppler for structure/function. • MRI: Assess myocardial inflammation and fibrosis. • Chemistry: Electrolytes, Glucose, Renal function (Cr, BUN), Liver function, Lipid profile, TSH, Iron studies, Troponin. • Hematology: CBC with differential, ESR.
- Specialized Investigations: • Infectious Panel: Respiratory pathogens, HIV, Chagas, Lyme, Toxoplasmosis, Trichinosis. • Genetics: Multigene cardiomyopathy panel. • Serologies: For active rheumatologic disease. • Biopsy: Endomyocardial biopsy with EM for specific diagnoses (e.g., metabolic).
- Risk Stratification for Sudden Death in HCM (Table 267-2): • Major Risk Factors: ◦ History of cardiac arrest or spontaneous sustained VT (non-vagal, often post-exertion). ◦ Syncope. ◦ Family history of sudden cardiac death. ◦ LV apical aneurysm. ◦ LV thickness >30 mm (present in <10% of patients). • Modifying Risk Factors: ◦ Spontaneous non-sustained VT (>3 beats at rate >120) on exercise or 24–48h ambulatory recording.
MANAGEMENT & TREATMENT¶
- General Management Principles: • Treatment is based on phenotype rather than specific genetic variant. • All patients must be evaluated for atrial fibrillation and risk of sudden death regardless of symptoms.
- Hypertrophic Cardiomyopathy (HCM) Algorithm (Flowchart 1): • Step 1: Assess Fluid Retention. ◦ If Yes → Titrate beta blocker and/or calcium channel blocker. ◦ If No → Use diuretics with caution to avoid hypovolemia (especially if outflow gradient is present). • Step 2: Manage Persistent Symptoms. ◦ If symptoms are persistent → Proceed to Outflow Gradient assessment. • Step 3: Address Outflow Gradient. ◦ If Outflow Gradient is Present → Try mavacamten or disopyramide. ◦ If Refractory Symptoms with Outflow Gradient → Consider procedure (Septal ablation OR Septal myectomy). ◦ If Outflow Gradient is Absent → Proceed to Step 4. • Step 4: Manage LV Dysfunction. ◦ If Evidence of severe progressive LV dysfunction → Rarely, consider cardiac transplantation. ◦ If No progression → Reevaluate cause of symptoms.
- Specific Management by Condition: • Dilated Cardiomyopathy (DCM): Standard management for heart failure; specific consideration for LMNA variants: early ICD placement before LVEF falls below 0.35. • Metabolic Cardiomyopathies: Specific therapies for metabolic defects (e.g., enzyme replacements in Fabry's or Gaucher's). • Arrhythmogenic Cardiomyopathy (ACM): Management of arrhythmias and potential for aneurysms.
PROGNOSIS & COMPLICATIONS¶
• HCM Prognosis: ◦ Pediatric presentation → increased early morbidity/mortality. ◦ Adult diagnosis → lower survival compared to age-matched peers without HCM. • Arrhythmia Risk: ◦ High in patients with fibrosis, myocyte disarray, and specific mutations (LMNA, SCN5A). • Heart Failure: ◦ Progression to heart failure is more common in families with a history of sudden death.
SPECIAL CONSIDERATIONS¶
• Athletes: ◦ Must distinguish Athlete's Heart from HCM. ◦ Athlete's Heart: No fibrosis, no disarray, supernormal exercise capacity (VO2max >50 mL/kg per min), regression of hypertrophy with training cessation.
KEY PEARLS & CLINICAL TRAPS¶
• HCM Prevalence: ~1:500; primary cause of sudden death in young people. • DCM Genetics: TTN mutations are the most common (25% of familial cases). • Risk Stratification: LV thickness >30 mm and history of syncope/sudden death are critical markers for ICD consideration. • Metabolic Markers: Fabry's (X-linked) and Danon's (X-linked) have distinct extra-cardiac features (e.g., renal failure, skeletal myopathy). • LMNA Mutation: High risk of arrhythmia; requires early intervention before LVEF drops to 0.35. • Outflow Obstruction: Present in ~60% of HCM patients (30% at rest, 30% during exercise).
Reference Tables¶
TABLE 266-2 Initial Evaluation of Cardiomyopathy Clinical Evaluation Thorough history and physical examination to…¶
Harrison's 22e, p.2003
| Clinical Evaluation | |
|---|---|
| Thorough history and physical examination to identify cardiac and noncardiac disorders |
|
| Detailed family history of heart failure, cardiomyopathy, skeletal myopathy, conduction disorders, tachyarrhythmias, and sudden death |
|
| History of alcohol, illicit drugs, chemotherapy or radiation therapy | |
| Assessment of changing ability to perform routine and desired activities | |
| Assessment of jugular venous pressure, edema, orthostatic blood pressure, adequacy of perfusion |
|
| Laboratory Evaluation | |
| Electrocardiogram | |
| Chest radiograph | |
| Two-dimensional and Doppler echocardiogram | |
| Magnetic resonance imaging for evidence of myocardial inflammation and fibrosis |
|
| Chemistry: | |
| Serum sodium, potassium, calcium, magnesium | |
| Fasting glucose (glycohemoglobin in diabetes mellitus) | |
| Creatinine, blood urea nitrogen | |
| Albumin, total protein, liver function tests | |
| Lipid profile | |
| Thyroid-stimulating hormone | |
| Serum iron, transferrin saturation | |
| Urinalysis | |
| Creatine kinase isoforms | |
| Cardiac troponin level | |
| Hematology: | |
| Hemoglobin/hematocrit | |
| White blood cell count with differential Total eosinophil count if abnormal % on differential |
|
| Erythrocyte sedimentation rate | |
| Evaluation When Specific Diagnoses Are Suspected | |
| Respiratory pathogen panel during acute respiratory syndromes | |
| Diagnosis of other specific infections such as: Human immunodeficiency virus |
|
| Chagas’ disease (Trypanosoma cruzi) Lyme disease (Borrelia burgdorferi) and other tick-borne diseases Toxoplasmosis Trichinosis |
|
| Genetic counseling and testing with multigene cardiomyopathy panel | |
| Serologies for active rheumatologic disease | |
| Endomyocardial biopsy including sample for electron microscopy when suspecting specific diagnosis with therapeutic implications |
|
| Catheterization with coronary angiography in patients who have evidence of ischemia/infarction and are candidates for intervention |
|
| 267 | Genetic Cardiomyopathies Neal K. Lakdawala, Lynne Warner Stevenson, Joseph Loscalzo |
TABLE 267-1 Selected Genetic Defects Associated with Cardiomyopathy Sarcomere¶
Harrison's 22e, p.2004
| GENE PRODUCT | INHERITANCE | CARDIAC PHENOTYPE | ISOLATED CARDIAC PHENOTYPEa |
EXTRACARDIAC MANIFESTATIONS | |
|---|---|---|---|---|---|
| Sarcomere | ACTC1 (cardiac actin) | AD | HCM, DCM | Yes | |
| MYH7 (β myosin heavy chain) | AD | HCM, DCM, LVNC | Yes | Skeletal myopathy | |
| MYBPC3 (myosin binding protein C) | AD | HCM | Yes | ||
| TNNT2 (cardiac troponin T) | AD | HCM, DCM, LVNC | Yes | ||
| TNNI3 (cardiac troponin I) | AD, AR | HCM, DCM, RCM | Yes | ||
| TTN (Titin) | AD | DCM | Yes | ||
| TPM1 (α-tropomyosin) | AD | HCM, DCM | Yes | ||
| TNNC1 (cardiac troponin C) | AD | DCM | Yes | ||
| MYL2 (myosin regulatory light chain) | AD | HCM | Yes | Skeletal myopathy | |
| MYL3 (myosin essential light chain) | AD | HCM | Yes | ||
| DES (desmin) | AD | RCM, DCM | Yes | ||
| FLNC (filamin C) | AD | DCM | Yes | ||
| NEXN (nexilin) | AD | DCM | Yes | ||
| VCL (vinculin) | AD | DCM | Yes | ||
| Nuclear membrane |
LMNA (lamin A/C) | AD, AR | CDDC | Yes | Skeletal myopathy |
| EMD (emerin) | X-linked | CDDC | No | Skeletal myopathy, contractures | |
| PLN (phospholamban) | AD | DCM, ARVC | Yes | ||
| SCN5A (NAV 1.5) | AD | CDDC | Yes | ||
| RYR2 (cardiac ryanodine receptor) | AD | ARVC | Yes | ||
| CASQ2 (calsequestrin 2) | AR | ARVC | Yes | ||
| Cellular metabolism |
PRKAG2 (γ-subunit of AMP kinase) | AD | HCM+ | Yes | |
| LAMP2 (lysosomal associated membrane protein) |
X-linked | HCM+ | Nob | Danon’s disease: skeletal myopathy, cognitive impairment |
|
| TAZ (tafazzin) | X-linked | DCM, LVNC | No | Barth’s syndrome: skeletal myopathy, cognitive impairment, neutropenia |
|
| FXN (frataxin) | AR | HCM | No | Friedreich’s ataxia: ataxia, diabetes mellitus type 2 |
|
| TMEM43 (transmembrane protein 43) | AD | ARVC | Yes | ||
| GLA (α-galactosidase-A) | X-linked | HCM+ | No | Fabry’s disease: renal failure, angiokeratomas and painful neuropathy |
|
| Mitochondrial DNA | Maternal transmission |
DCM, HCM | No | ||
| Sarcolemmal membrane |
DMD (dystrophin) | X-linked | DCM | Nob | Duchenne’s and Becker’s muscular dystrophy |
| DMPK (dystrophica myotonica protein kinase) |
AD | DCM | No | Myotonic dystrophy type 1 | |
| DSP (desmoplakin), JUP (plakoglobin) | AD, AR | ARVC, DCM | Yes | ||
| DSG2 (desmoglein 2), DSC2 (desmocollin 2), PKP2 (plakophilin 2) |
AD | ARVC | Yes | ||
| Other examples | RBM20 (RNA binding motif 20) | AD | DCM | Yes | |
| BAG3 (BCL2-associated athanogene 3) | AD | DCM | Yes | ||
| ALPK3 (α-kinase 3) | AR | HCM | Yes |
TABLE 267-2 Risk Stratification for Sudden Death in Hypertrophic Cardiomyopathy¶
Harrison's 22e, p.2008
| MAJOR RISK FACTOR | SCREENING TECHNIQUE | |
|---|---|---|
| History of cardiac arrest or spontaneous sustained ventricular tachycardiaa |
History | |
| Nonvagal, often with or after exertion |
||
| Family history of sudden cardiac death |
Family history | |
| Generally applicable to patients with apical hypertrophy |
||
| LV thickness >30 mm | Present in <10% of patients |
Echocardiography or cardiac magnetic resonance imaging |
| Present in <10% of patients |
||
| Variables Utilized in the European Society of Calculator for Estimated Risk of Sudden Death |
||
| LV outflow tract gradient |
Peak gradient measured at rest or with the Valsalva maneuver, mmHg |
Echocardiography |
| Diameter measured in the parasternal long axis, mm |
||
| LV thickness | Maximal wall thickness, mm |
Echocardiography |
| Syncope, family history, nonsustained ventricular tachycardia |
As above | As above |
| Modifying Risk Factors | ||
| As a percentage of myocardial mass |
||
| Spontaneous nonsustained ventricular tachycardia |
>3 beats at rate >120 | Exercise or 24-h to 48-h ambulatory recording |