Description
Cardiac Amyloidosis is a clinical condition characterised by extracellular deposition of pathological insoluble fibrillar proteins, known as amyloid, in the heart. This deposition disrupts the normal architecture and function of the heart, causing diastolic dysfunction which progresses to restrictive cardiomyopathy and rhythm disturbances.
Pathogenesis
Amyloidosis is caused by the misfolding of certain proteins that leads to their accumulation in tissues. In the heart, this accumulation interferes with the normal heart muscle function. The most common types of amyloid deposition in the heart include light chain (AL) and transthyretin (ATTR) amyloidosis. AL is associated with plasma cell dyscrasias, while ATTR can be hereditary (ATTRm) or wild-type (ATTRwt, non-hereditary).
Amyloidosis is a systemic process, hence involvement of all four chambers is common.
Subtypes
Cardiac involvement is seen in most subtypes of amyloidosis. The most common are:
- AL (light chain) Amyloidosis: Involves the deposition of fragments of immunoglobulin light chains, and is associated with plasma cell dyscrasias.
- ATTR Amyloidosis: Transthyretin (TTR) amyloidosis, which can be further classified into hereditary/familial (ATTRm) and wild-type (non-hereditary, ATTRwt).
Epidemiology, Risk Factors & Associations
- The prevalence of cardiac amyloidosis is not fully known due to underdiagnosis but it is estimated to occur in 5-13% of people over the age of 80 (for ATTRwt type).
- Risk factors for AL amyloidosis include older age, male gender, and having monoclonal gammopathy of undetermined significance (MGUS).
- Familial ATTRm is associated with specific gene mutations (most commonly in the TTR gene). Associations with other systemic conditions will be covered in respective articles.
Clinical Features
- May present with symptoms and signs of heart failure: dysponoea, fatigue, and peripheral oedema.
- Other clinical features may include arrhythmias and signs of increased filling pressures such as elevated jugular venous pressure and a third heart sound.
- Importantly, symptoms may not align with the degree of cardiac infiltration and organ dysfunction seen on imaging and diagnostic studies.
Complications
- Progressive heart failure: Amyloid deposition in the myocardium causes increased stiffness and thickening of the heart walls, leading to diastolic dysfunction and ultimately systolic failure.
- Arrhythmias (atrial fibrillation, heart block): Amyloid infiltrates the conduction system of the heart leading to abnormal heart rhythms such as atrial fibrillation or heart block.
- Sudden cardiac death: This can be caused by severe rhythm disturbances or profound heart failure induced by amyloid deposition.
Pathological Features
Morphology
Grossly, the heart is typically enlarged and firm with a rubbery consistency. There may be ventricular wall thickening, predominantly involving the left ventricle.
Histopathology
Deposition of amyloid material in the interstitium, resulting in expansion of the interstitium and separation of myocytes.
Biochemistry
The amyloid deposits are composed of insoluble fibrillar proteins. These can be light chains (AL) or transthyretin (ATTR).
Genetics
Genetic mutations are seen in ATTRm type, most commonly in the TTR gene.
Immunohistochemistry
Amyloid deposits stain with Congo red dye and show apple-green birefringence under polarised light.
Radiological Features
General Imaging Features
Amyloid deposits are generally seen in the myocardium, more pronounced in the ventricles. The deposition can lead to myocardial thickening and restrictive physiology, reflected in imaging findings.
An increase in the thickness of the interatrial septum and right atrial free wall by more than 6 mm is specific.
Echocardiography
- Concentric left ventricular wall thickening
- Hyperechoic Granular sparkling appearance of the myocardium
- Impaired diastolic function
- Advanced cases can show systolic dysfunction
- Bi-atrial enlargement
Cardiac MRI
- Global subendocardial late gadolinium enhancement (highly specific and sensitive)
- Diffuse myocardial T1 elevation
- Extracellular volume expansion
- Abnormal T2 signal can be seen
Cardiac PET
- Focal or diffuse uptake of radiotracer
CT
- Pericardial thickening or effusion may be seen
- Coronary artery calcification is typically absent
Grading and Staging
Staging systems for cardiac amyloidosis include the Mayo Clinic staging system which uses NT-proBNP and troponin levels, as well as the presence of free light chains, for risk stratification.
Differential Diagnosis
- Restrictive Cardiomyopathy: Similar to amyloidosis, it presents with signs of heart failure, but echocardiography might show biatrial enlargement with less ventricular wall thickening. Endomyocardial biopsy may be needed to confirm the diagnosis.
- Sarcoidosis: This systemic disease can involve the heart and mimic amyloidosis. However, it often presents with other systemic symptoms, and cardiac imaging may show patchy myocardial involvement, aneurysms, or ventricular thinning.
- Endomyocardial Fibrosis: This condition is characterised by fibrous tissue changes in the endomyocardium leading to restrictive physiology, but the fibrosis typically spares the myocardium which distinguishes it from amyloidosis.
- Hypertensive Heart Disease: Presents with left ventricular hypertrophy, but typically without the ‘sparkling’ texture seen in amyloidosis on echocardiography. Also, hypertension is a predominant feature in these patients.
- Hypertrophic Cardiomyopathy: This genetic disorder also results in left ventricular hypertrophy but typically shows a non-dilated, hyperdynamic left ventricle with asymmetric septal hypertrophy. Family history and genetic testing can also help in differentiation.
Management
- Cardiologists manage heart failure symptoms and arrhythmias.
- Haematologists are involved when AL amyloidosis is diagnosed, due to the underlying plasma cell dyscrasia.
- In cases of suspected or confirmed amyloidosis, the usual next diagnostic step is tissue biopsy for confirmation and subtyping of amyloid.
- Genetic testing may be needed in cases of suspected ATTRm amyloidosis.
- Novel therapies targeting amyloid deposition are under investigation.