Cardiac Amyloidosis Etiology
Cardiac amyloidosis is caused by the extracellular deposition of misfolded proteins that form insoluble amyloid fibrils in the myocardium, with the two most common etiologies being AL (immunoglobulin light chain) amyloidosis and ATTR (transthyretin) amyloidosis 1, 2.
Primary Etiologic Categories
AL Amyloidosis (Immunoglobulin Light Chain)
- Mechanism: Misfolded clonal immunoglobulin light chains produced by plasma cells in the bone marrow aggregate to form amyloid deposits 1
- Associated conditions: Multiple myeloma (10-15% of cases) or Waldenström's macroglobulinemia 1, 3
- Light chain type: Lambda isotype in 75-80% of cases, kappa in remaining cases 3
- Cardiac involvement: Present in >50% of AL amyloidosis patients 2
- Demographics: Median age >60 years, slight male predominance 2
ATTR Amyloidosis (Transthyretin)
ATTR has two distinct etiologic subtypes 1:
1. Hereditary ATTR (hATTR)
- Mechanism: Genetic mutations in the TTR gene cause production of abnormal, amyloidogenic "variant" TTR protein 1
- Inheritance: Autosomal dominant with variable penetrance 4
- Common mutations in North America 2:
- Val122Ile (West African descent)
- Thr60Ala (Northern Ireland descent)
- Val30Met (Swedish, Portuguese, Japanese descent)
- Manifestations: Familial amyloid polyneuropathy (nerve-predominant) or familial amyloid cardiomyopathy (heart-predominant) 1
2. Wild-Type ATTR (wtATTR)
- Mechanism: Normal "wild-type" TTR protein misfolds to form amyloid deposits, typically due to aging 1
- Previously known as: Senile amyloidosis 1
- Demographics: Median age >70 years, strong male predominance 2
- Prevalence: Autopsy studies show myocardial ATTR deposits in up to 25% of individuals >80 years old 2
Less Common Etiologies
AA Amyloidosis (Amyloid A Protein)
- Mechanism: Deposition of amyloid type A protein resulting from chronic infectious or inflammatory diseases 1
- Associated conditions: Rheumatoid arthritis, Crohn's disease, ulcerative colitis 1
- Cardiac involvement: <10% of cases 5
- Previously known as: Secondary amyloidosis 1
Other Rare Forms
- Hemodialysis-associated amyloidosis: β-microglobulin 2 deposition 5
- Isolated atrial amyloidosis: Atrial natriuretic factor, limited to heart 5
- Organ-specific forms: Familial visceral amyloidosis, familial corneal amyloidosis 1
- Apolipoprotein A-I amyloidosis (AApoA-I) 6
Key Pathophysiologic Distinctions
AL amyloidosis involves both direct light chain toxicity (causing lysosomal dysfunction and reactive oxygen species formation) and fibril deposition 2. This dual mechanism explains the particularly poor prognosis when cardiac involvement is present.
ATTR amyloidosis pathophysiology is more heterogeneous and depends on whether a mutation is present 2. The disease primarily involves progressive extracellular fibril accumulation causing myocardial stiffening 7.
Clinical Recognition Points
Red flags for underlying etiology 2:
- ATTR: Musculoskeletal manifestations (biceps tendon rupture, spinal stenosis, carpal tunnel syndrome)
- AL: Macroglossia, periorbital purpura, acquired factor X deficiency, significant proteinuria
- Both: Heart failure with preserved ejection fraction, atrial arrhythmias, aortic stenosis
Critical caveat: In 10-40% of patients with ATTR-CM, there may be concomitant monoclonal gammopathy of uncertain significance (MGUS), which can confound diagnosis and requires hematology collaboration to distinguish from true AL amyloidosis 3.