Cardiac amyloidosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

Overview

The characteristic feature of cardiac amyloidosis is abnormal deposition of abnormally folded light chains of several serum proteins, making them insoluble and accumulate in various organs. This abnormal folding of proteins is most commonly a result of genetic mutations or excessive formation. Involvement of cardiac muscle can lead to heart failure, arrhythmias and advanced conduction disorder .

Pathophysiology

As mentioned above, amyloidosis is characterized by the deposition and extracellular accumulation of fibrillary proteins, leading to the loss of normal tissue architecture. Various proteins are capable of undergoing abnormal beta pleated folding to form amyloid protein. The most common culprit protein responsible for forming amyloid deposits are the light chains of immunoglobulins produced by the plasma cells in bone marrow.

Most frequent types of cardiac amyloidosis are:

• Acquired monoclonal immunoglobulin light-chain amyloidosis
• Familial or hereditary transthyretin (TTR)-related form
• Non-mutant TTR-related amyloidosis (systemic senile amyloidosis)

All these forms frequently involve the myocardium, with the light chain amyloidosis (AL) being the most common.

Acquired monoclonal immunoglobulin light-chain amyloidosis (AL)

• Monoclonal gammopathy of benign type is the most common form associated with AL cardiac amyloidosis. The abnormally folded light chains produced by defective plasma cells deposit in tissues resulting in disruption of tissue architecture by causing free radical damage and organ dysfunction.
• More than 5 - 10% of bone marrow content filled with plasma cells is a poor prognostic indicator. The lambda (λ) chains are more likely to be involved in amyloid deposit formation than the kappa (κ) chains.
• AL cardiac amyloidosis is rarely seen with multiple myeloma, macroglobulinemia and lymphomas.

Hereditary Transthyretin (TTR)-Related Form (ATTR)

• The hereditary or familial form of cardiac amyloidosis is inherited in an autosomal domminant pattern. Mutations leading to substitution of a single amino acid on the protein chain can cause abnormal spacial configuration of the protein, leading to its abnormal deposition in the inter-cellular space.
• The mutations in the genes producing various proteins like transthyretin, fibrinogen, apolipoprotein A1 and A2 are responsible. However, the transthyretin mutation is by far the commonest cause of hereditary cardiac amyloidosis.
• Transthyretin, a protein tetramer synthesized in the liver, is responsible for transport of the thyroid hormone and vitamin A in the body. The extent of myocardial involvement varies with the gene sequence mutated in the transthyretin gene.
• About 90 to 100% patients with "Thr60Ala" mutation, where alanine is substituted for threonine at the 60th position on the transthyretin protein and the "Val122Ile", in which isoleucine is substituted for valine at the 122nd amino acid position, have severe restrictive cardiomyopathy at presentation.
• Whereas the "Val30Met" mutation of transthyretin have cardiac involvement only in the elderly patients, with peripheral and autonomic nervous system being the primary target. The Val30Met mutation is normally present in 3.9% of all African Americans and in about 23% of African Americans with cardiac amyloidosis .
• Cardiac involvement in rare in other variant ATTR like mutations in apolipoprotein A1 and secondary amyloidosis. These more often involve the liver and kidneys.

Senile Systemic Amyloidosis (Non-mutant TTR-related amyloidosis, Wild Type ATTR)

• Also know as systemic senile amyloidosis
• Elderly male prepondrance
• Presence of isolated ventricular amyloid observed in elderly without family history of amyloidosis
• This deposition has shown to be associated with increased mortality

Familial amyloidotic cardiomyopathy

• Defined as presence of TTR mutation that primarily affects the myocardium and without significant neuropathy.

Gross Pathology

The cardiac amyloid deposits are most commonly seen in the myocardium, but can also be seen in atria, pericardium, endocardium and microvasculature.

• On gross examination, the myocardium is thicker, firm and rubbery in consistency. More than half of myocardium involvement is common in the AL type of cardiac amyloidosis.
• The size of ventricular cavity remains unchanged, however filling of the ventricles is restricted (causing restrictive cardiomyopathy) because of the stiffening of ventricular wall as a result of deposition of amyloid material.
• Pericardial effusion and valvular dysfunction is common from pericardial and endocardial involvement. Intracardiac thrombus formation is frequently seen and may result in fatal thromboembolism

Images shown below are courtesy of Professor Peter Anderson and published with permission. © PEIR, University of Alabama at Birmingham, Department of Pathology

Amyloidosis Lesion In Left Atrium: Gross natural color view of a diagnostic lesion

Amyloidosis Lesion In Left Atrium: Gross natural color close-up

Amyloidosis, left atrium, endocardial nodules

Amyloidosis, left atrium, endocardial nodules

Amyloidosis and left ventricular hypertrophy

Microscopic Pathology

• On microscope, the intercellular deposits of hyaline like amyloid material is evident. Resultant myocardial fibrosis restricts the movement of the ventricle, compromising complete filling of the ventricle during diastole.
• Amyloid deposits are also seen in the vasculature, particularly the microvasculature thereby sparing the large epicardial vessels. This leads to myocardial ischemia and tissue infarction.

Heart: Perivascular amyloid, amyloidosis, congo red showing birefringence

Heart: Perivascular amyloid, amyloidosis (Hematoxylin and eosin staining)

Heart: Amyloidosis, aldehyde fuchsin stain

References

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