Amyloidosis and Other Restrictive Cardiomyopathies¶
Chapter 270 | Part 6: Disorders of the Cardiovascular System
KEY CLINICAL POINTS¶
- Restrictive cardiomyopathy (RCM) is characterized by impaired ventricular relaxation and diastolic dysfunction, often due to amyloid infiltration, fibrosis, or storage diseases.
- Amyloidosis is the most common cause of RCM, with transthyretin (TTR) and light chain (AL) amyloidosis being the two main subtypes.
- Diagnosis requires integration of clinical findings, imaging (echocardiography, CMR, PYP scan), and tissue biopsy with amyloid typing (mass spectrometry preferred).
- Treatment is disease-specific: TTR amyloidosis uses tafamidis or TTR silencers; AL amyloidosis requires chemotherapy (e.g., daratumumab, bortezomib) and supportive care.
- Prognosis is poor for untreated amyloid cardiomyopathy, with median survival of 4–5 years for wild-type TTR and ~6 months for AL amyloidosis.
1. DEFINITION & OVERVIEW¶
Restrictive cardiomyopathy (RCM) is a clinical syndrome characterized by impaired ventricular relaxation and diastolic dysfunction, often due to infiltration of abnormal substances (e.g., amyloid, fibrosis) or storage diseases. It is distinct from dilated cardiomyopathy and constrictive pericarditis.
Table 270-1 Causes of Restrictive Cardiomyopathies (RCM)¶
| Category | Causes |
|---|---|
| Infiltrative (Between Myocytes) | Amyloidosis, Light chain (AL) amyloid, Familial (variant transthyretin), Wild-type (normal) transthyretin, Inherited metabolic defects |
| Storage (Within Myocytes) | Hemochromatosis (iron), Glycogen storage disease (II, III), Fabry’s disease |
| Fibrotic | Radiation, Scleroderma, Endomyocardial fibrosis, Hypereosinophilic syndrome, Carcinoid syndrome |
| Genetic Variants | Occasional RCM due to genetic variants (DES, sarcomere variants), RCM with desminopathy |
1.1 Subtopic¶
RCM is dominated by abnormal diastolic function within a noncompliant ventricle, often with mildly decreased contractility and ejection fraction (30–50%). Both atria are typically enlarged, and end-diastolic pressures are elevated in both ventricles.
2. EPIDEMIOLOGY¶
RCM is rare, with amyloidosis accounting for ~50% of cases. Wild-type TTR amyloidosis (ATTRwt) is most common in older adults (60–80 years), while AL amyloidosis is more prevalent in middle-aged individuals. Familial TTR amyloidosis (ATTRv) has a genetic basis with incomplete penetrance.
2.1 Risk Factors¶
Age >60 years, family history of TTR amyloidosis, chronic inflammation (AA amyloidosis), and conditions causing proteinuria (e.g., multiple myeloma).
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Amyloidosis is the most common cause of RCM, with two main types: AL (light chain) and TTR (transthyretin). AL amyloidosis results from misfolded light chains from plasma cells, while TTR amyloidosis involves misfolded transthyretin proteins. Both lead to extracellular deposition, causing ventricular stiffness and diastolic dysfunction.
3.1 Molecular Mechanisms¶
TTR amyloidosis involves misfolding of transthyretin into β -sheet fibrils, while AL amyloidosis is driven by uncontrolled production of monoclonal light chains. Both disrupt cardiac structure and function.
4. CLINICAL FEATURES¶
Symptoms include dyspnea, peripheral edema, ascites, and right-sided heart failure. Physical findings include elevated jugular venous pressure, Kussmaul sign, and a paradoxical rise on inspiration. Atrial fibrillation is common, especially in TTR amyloidosis.
4.1 Cardiac Findings¶
Echocardiography shows thickened ventricular walls, small LV cavity, and biatrial enlargement. Amyloid infiltration leads to restrictive physiology with elevated filling pressures.
5. DIFFERENTIAL DIAGNOSIS¶
RCM must be differentiated from constrictive pericarditis, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Key features include the absence of pericardial thickening in RCM and the presence of amyloid-related systemic manifestations (e.g., neuropathy, organ involvement).
5.1 Key Differentiators¶
Constrictive pericarditis shows pericardial thickening on imaging, while RCM has no such findings. AL amyloidosis presents with systemic features like macroglossia and carpal tunnel syndrome.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnosis combines clinical suspicion, imaging (echocardiography, CMR, PYP scan), and tissue biopsy. Amyloid typing is critical for treatment decisions.
Table 270-2 Rare Forms of Amyloidosis¶
| Amyloid Type | Precursor Protein | Frequency of Cardiac Involvement | Other Organ Involvement | Comment |
|---|---|---|---|---|
| AA | Serum amyloid A (inflammatory protein) | <5% | Kidney, liver | Usually associated with chronic inflammation |
| ApoA1 | Apolipoprotein 1 | 25–30% | Kidney, liver, spleen, nervous system, larynx | Rare, with family history |
| ApoA4 | Apolipoprotein 4 | 65–70% | Kidney | Renal involvement without proteinuria is common |
| Afib | Fibrinogen A-alpha (gene mutation) | Not described | Kidney, spleen | Rare, with glomerular amyloidosis |
| ALECT2 | Leukocyte cell-derived chemotaxin 2 | Not described | Kidney | Liver involvement common in Hispanics |
| Gelsolin | Gelsolin | Unknown prevalence | Corneal lattice dystrophy, skin, neurologic | Predominantly Finnish patients |
6.1 Diagnostic Algorithm¶
- Suspect RCM based on echocardiogram, CMR, or clinical features.
- Assess for plasma cell dyscrasia (serum/urine PEP, IFE, free light chains).
- Perform technetium PYP scan for TTR amyloidosis.
- Confirm with tissue biopsy and mass spectrometry for amyloid typing.
7. MANAGEMENT & TREATMENT¶
Treatment is disease-specific. TTR amyloidosis uses tafamidis or TTR silencers; AL amyloidosis requires chemotherapy (e.g., daratumumab, bortezomib). Supportive care includes diuretics, beta-blockers, and management of arrhythmias.
7.1 Pharmacologic Therapies¶
TTR amyloidosis: Tafamidis, eplontersen, vutrisiran. AL amyloidosis: Daratumumab, bortezomib, cyclophosphamide, dexamethasone. Supportive: Diuretics, spironolactone, SGLT2 inhibitors.
8. PROGNOSIS & COMPLICATIONS¶
Untreated wild-type TTR amyloidosis has a median survival of 4–5 years, while AL amyloidosis has a median survival of ~6 months. Complications include progressive heart failure, arrhythmias, and systemic amyloid deposition in organs like the liver and kidneys.
8.1 Prognostic Factors¶
Early diagnosis, absence of severe renal impairment, and effective amyloid typing improve outcomes. Cardiac transplantation may be considered in select cases.
9. SPECIAL CONSIDERATIONS¶
Pregnancy and elderly patients require careful management due to autonomic neuropathy and comorbidities. AL amyloidosis may present with carpal tunnel syndrome, while TTR amyloidosis is associated with macroglossia and neuropathy.
9.1 Pediatric Considerations¶
Desminopathy and sarcomere variants may present with restrictive cardiomyopathy in children, requiring genetic testing and multidisciplinary care.
10. KEY POINTS & CLINICAL PEARLS¶
- Amyloidosis is the most common cause of RCM, with TTR and AL being the main subtypes.
- Diagnosis requires integration of imaging, biopsy, and amyloid typing.
- TTR amyloidosis is treated with stabilizers (tafamidis) or silencers (eplontersen);
- AL amyloidosis requires chemotherapy and supportive care.
- Prognosis is poor without early intervention, emphasizing the need for rapid diagnosis.