Amyloidosis and Other Restrictive Cardiomyopathies¶

Chapter 270 | Part 6: Disorders of the Cardiovascular System · Part 6 – Cardiovascular Disorders · Chapter 270

Key Clinical Points¶

Restrictive cardiomyopathy (RCM) is characterized by a noncompliant ventricle, typically with an ejection fraction (EF) of 30–50%.
Amyloidosis is defined as the extracellular deposition of fibrillar proteinaceous material.
Diagnostic hallmarks include Congo red staining and 'apple-green birefringence' under polarized light microscopy.
Periorbital purpura occurs in 20–30% of cases and is virtually pathognomonic for AL amyloidosis.
The 'bull's-eye' pattern on strain imaging (preserved apical strain, impaired basal strain) is highly suggestive of cardiac amyloidosis.
Tafamidis stabilizes the tetrameric structure of transthyretin and is effective in TTR amyloidosis.
Daratumumab, bortezomib, cyclophosphamide, and dexamethasone are the standard regimen for light chain (AL) amyloidosis.
Kussmaul sign (paradoxical rise in JVP on inspiration) is a classic finding in restrictive cardiomyopathy.
The Val122Ile mutation is the most common TTR variant in the U.S., present in ≈ 3.5% of the population of African descent.
Renal involvement is common in AL amyloidosis but is not a feature of transthyretin (TTR) amyloidosis.

DEFINITION & OVERVIEW¶

• Restrictive Cardiomyopathy (RCM): - Pathophysiology: Dominated by abnormal diastolic function within a noncompliant ventricle. - Ejection Fraction: Typically 30–50%. - Atrial Involvement: Both atria are enlarged, sometimes massively. - Ventricular Dimensions: Mild left ventricular dilation may be present; right ventricular cavity is often normal in size but may dilate in advanced disease. - Clinical Presentation: Often presents with more right-sided symptoms (edema, abdominal discomfort, ascites) due to elevated filling pressures in both ventricles. - Heart Sounds: Fourth heart sound is more common than a third heart sound in sinus rhythm; atrial fibrillation is common. - Jugular Venous Pressure: Often shows rapid Y descents and may show a positive Kussmaul sign (paradoxical rise in JVP on inspiration).

• Amyloidosis Definition: - Definition: A systemic disease characterized by the deposition of fibrillar proteinaceous material primarily in the extracellular space of one or more organs. - Staining Characteristics: Stains with Congo red and exhibits 'apple-green birefringence' under polarized light microscopy. - Electron Microscopy: Deposits consist of nonbranching fibrils ≈ 10 nm in diameter and a few micrometers in length. - Primary Cardiac Precursors: - Transthyretin (TTR): Produced in the liver. - ATTRv: Genetic variant of TTR. - ATTRwt: Wild-type TTR (the most common form of amyloidosis). - Light Chains (AL): Produced by abnormal plasma cells.

EPIDEMIOLOGY¶

• Transthyretin (TTR) Amyloidosis: - Wild-type (ATTRwt): - Most common form of amyloidosis. - Primarily affects men in their 70s and 80s; women present at a later age with a more indolent course. Men are almost 20 times more likely than women to be diagnosed. - Survival: Median survival from the onset of heart failure is approximately 4–5 years, primarily due to progressive congestive heart failure. - Variant (ATTRv): - Val122Ile: Most common TTR variant in the U.S.; present in ≈ 3.5% of the population of African descent. - Presentation: Late-onset restrictive cardiomyopathy, typically from the seventh decade onward. - Survival: Median survival of 2–3 years following the onset of heart failure in untreated patients. - Clinical Features (TTR): - Subclinical Phase: Several years of progression before heart failure occurs. - Atrial Arrhythmias: Common; often atrial fibrillation or atrial flutter, which may be the presenting feature and can worsen heart failure. - Extracardiac Involvement: Heart is the primary clinical organ; lung and gut may show extensive deposits. - Precursor Signs: History of carpal tunnel syndrome (often preceding heart failure by several years), spinal stenosis, or ruptured bicep tendon (occurring 5–8 years before heart failure) in approximately half of patients.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Causes of Restrictive Cardiomyopathies (RCM): - Infiltrative: Amyloidosis (AL, ATTRv, ATTRwt), Inherited metabolic defects. - Storage: Hemochromatosis (iron), Fabry's disease, Glycogen storage disease (II, III). - Fibrotic: Radiation, Scleroderma, Endomyocardial fibrosis, Tropical endomyocardial fibrosis, Hypereosinophilic syndrome (Löffler's endocarditis), Carcinoid syndrome. - Genetic Variants: Desminopathy (due to pathogenic DES variants) or other variants affecting cardiomyocyte function.

• Pathophysiology of Amyloid Deposition: - Structural Changes: Extracellular deposits increase heart mass and wall thickness; decreased compliance leads to restrictive pathophysiology. - Ventricular Impact: Both LV and RV walls show increased thickness. - Valve Involvement: Tricuspid regurgitation may be present; association between aortic valve stenosis and TTR amyloidosis exists (mechanism of causality is unclear). - Systemic Findings: - Liver: An unusually hard liver suggests AL amyloid infiltration (not seen in TTR). - Autonomic Neuropathy: Causes postural hypotension; a feature of AL and some ATTRv, but not ATTRwt. - Specific Signs: Macroglossia or periorbital bruising strongly suggest AL; carpal tunnel syndrome or ruptured bicep tendon point toward TTR.

CLINICAL FEATURES¶

• General Cardiac Features: - Presentation: Congestive heart failure with prominent right-sided symptoms (edema, ascites). - Arrhythmia: Atrial fibrillation is common and may be the presenting feature. - Physical Exam: - Heart Sounds: Fourth heart sound more common than third in sinus rhythm. - Murmurs: Tricuspid regurgitation or aortic stenosis (associated with TTR).

• AL Amyloidosis Specifics: - Pathophysiology: Associated with plasma cell dyscrasia. - Systemic Signs: Periorbital purpura (20–30%), macroglossia, and hard liver. - Autonomic Involvement: Often presents with postural hypotension.

• TTR Amyloidosis Specifics: - Clinical Course: Often more indolent than AL; heart is the primary organ involved. - Neuropathy: Can be mild or severe; if autonomic neuropathy is present, postural hypotension is common. - Precursor Signs: Carpal tunnel syndrome and ruptured bicep tendon are key indicators.

DIFFERENTIAL DIAGNOSIS¶

• Primary Differentials: - Constrictive Pericardial Disease: Both present with dominant right-sided heart failure. - Hypertensive Heart Disease: Typically shows LVH on ECG; amyloid rarely presents with such high-pressure history. - Hypertrophic Cardiomyopathy (HCM): Distinct from amyloid as it rarely presents with peripheral edema and usually has LVH on ECG. - Fabry Disease: May have similar echocardiographic appearance but features specific skin manifestations. - Mitochondrial Cardiomyopathies: Similar echo to amyloid but associated with maternally inherited diabetes, deafness, and strokes. - Diabetes: Advanced cases may present with heavy proteinuria.

DIAGNOSTIC APPROACH¶

Initial Screening: Suspect cardiac amyloidosis (CA) based on echocardiogram, CMR, or strongly suggestive clinical scenario.
Laboratory Assessment: Assess for plasma cell dyscrasia via serum/urine PEP, IFE, and serum free light chains.
Branching Logic Based on Plasma Cell Dyscrasia:
If ABNORMAL → Proceed to cardiac or other organ biopsy → If POSITIVE for light chain → AL (LIGHT CHAIN) AMYLOIDOSIS.
If NORMAL → Perform Technetium imaging (PYP, DPD, or M11F).
Technetium Imaging Results:
If uptake is ≥ 10% → TTR AMYLOIDOSIS.
If No cardiac uptake → Proceed to cardiac biopsy.
Biopsy and Genetic Testing (for cases with no/low uptake):
If Biopsy is POSITIVE → Perform genetic testing for variant TTR gene.
If POSITIVE → VARIANT TTR (ATTRv) AMYLOIDOSIS.
If NEGATIVE → WILD-TYPE TTR (ATTRwt) AMYLOIDOSIS.
If Biopsy is NEGATIVE → AMYLOIDOSIS EXCLUDED.

MANAGEMENT & TREATMENT¶

AL Amyloidosis Treatment:
Standard Regimen: Daratumumab, bortezomib, cyclophosphamide, and dexamethasone.
TTR Amyloidosis Treatment:
Tafamidis: Used to stabilize the tetrameric structure of transthyretin.
General Management:
Diuretics: Used for management of heart failure symptoms.
Beta Blockers & Vasodilators: Not recommended for routine use in RCM as they may not be well tolerated due to reduced contractility and functional reserve.

PROGNOSIS & COMPLICATIONS¶

• AL Amyloidosis: - High mortality; rapid progression of multi-organ involvement (heart, kidney). • TTR Amyloidosis: - ATTRwt: Median survival from heart failure: 4–5 years. - ATTRv: Median survival from heart failure: 2–3 years. - Current Therapies: Tafamidis has slowed disease progression and improved survival.

SPECIAL CONSIDERATIONS¶

• African Americans: - Higher prevalence of Val122Ile mutation (≈ 3.5% of population). - Presents as late-onset restrictive cardiomyopathy (7th decade+). • Women with TTR: - Less common than in men; typically presents at a later age and has a more indolent course.

KEY PEARLS & CLINICAL TRAPS¶

• Diagnostic Rule of Thumb: If PYP scan ≥ 10% uptake → TTR; if plasma cell dyscrasia is abnormal → AL. • Pathognomonic Signs: Periorbital purpura (AL); Carpal tunnel/Bicep rupture (TTR). • Imaging Markers: 'Bull's-eye' pattern on strain imaging (preserved apical, impaired basal) suggests cardiac amyloid. • Clinical Distinction: T1/T2 mapping and Gadolinium MRI can help differentiate infiltration from true hypertrophy; "delayed nulling" of the myocardium is a hallmark of amyloid.

Reference Tables¶

TABLE 270-1 Causes of Restrictive Cardiomyopathies (RCM) Infiltrative (Between Myocytes) Amyloidosis¶

Harrison's 22e, p.2020

Infiltrative (Between Myocytes)
Amyloidosis
Light chain (AL) amyloid
Familial (variant transthyretin)a
Wild-type (normal) transthyretin
Inherited metabolic defectsa
Storage (Within Myocytes)
Hemochromatosis (iron),a also with dilated cardiomyopathy phenotype when advanced
Inherited metabolic defectsa
Fabry’s disease
Glycogen storage disease (II, III)
Fibrotic
Radiation
Scleroderma
Endomyocardial
Possibly related fibrotic diseases
Tropical endomyocardial fibrosis
Hypereosinophilic syndrome (Löffler’s endocarditis)
Carcinoid syndrome
Radiation
Drugs: e.g., serotonin, ergotamine
Genetic Variants Affecting Cardiomyocyte Function
Occasional RCM due to genetic variants more commonly associated with dilated or hypertrophic cardiomyopathy RCM and skeletal muscle involvement with desminopathy due to pathogenic DES variants
270	Amyloidosis and Other Restrictive Cardiomyopathies Rodney H. Falk, Neal K. Lakdawala, Lynne Warner Stevenson, Joseph Loscalzo

TABLE 270-2 Rare Forms of Amyloidosis¶

Harrison's 22e, p.2027

AMYLOID TYPE	PRECURSOR PROTEIN	FREQUENCY OF CARDIAC DISEASE	OTHER ORGAN INVOLVEMENT	COMMENT
AA	Serum amyloid A (an inflammatory protein)	<5%	Kidney, liver	Usually associated with longstanding chronic inflammation. Uncommon in developed countries, and cardiac involvement rarely the predominant factor.
	Apolipoprotein 1	25–30%	Kidney, liver, spleen, nervous system, larynx
AapoA4	Apolipoprotein 4	65–70%	Kidney	Family history often not present. Renal involvement without proteinuria is common, and cardiac involvement is usually present but often relatively mild.
	Fibrinogen A-alpha (gene mutation)	Not described	Kidney, spleen
ALECT2	Leukocyte cell-derived chemotaxin 2	Not described	Kidney	Liver involvement common. ALECT2 predominantly found in Hispanics.
	Gelsolin	Unknown prevalence. Usually mild, and manifesting as conduction disease	Corneal lattice dystrophy Skin and neurologic features