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 ^[1].

Pathophysiology

As mentioned above, amyloidosis is characterized by the deposition and extracellular accumulation of fibrillary proteins, leading to the loss of normal tissue architecture^[2]. 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. 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.

Most frequent types of cardiac amyloidosis are:

Acquired monoclonal immunoglobulin light-chain amyloidosis
Hereditary transthyretin (TTR)-related form
Non-mutant TTR-related amyloidosis
Senile amyloidosis

All three forms frequently involve the myocardium, with the light chain amyloidosis (AL) being the most common^[3]^[4].

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.
AL cardiac amyloidosis is rarely seen with multiple myeloma, macroglobulinemia and lymphomas.

Hereditary transthyretin (TTR)-related form (ATTRm)

Caused by greater than 100 mutations of TTR
The protein is synthesized by the liver

Non-mutant TTR-related amyloidosis (ATTRwt)

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^[5]^[6]

Familial amyloidotic cardiomyopathy

Defined as presence of TTR mutation that primarily affects the myocardium and without significant neuropathy.^[7]

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 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 seen in ^[8]^[9]^[10]

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