Transthyretin (TTR) Cardiac Amyloidosis

Abstract

The systemic amyloidoses are a family of diseases induced by misfolded or misassembled proteins. Extracellular deposition of these proteins as soluble or insoluble cross β-sheets disrupts vital organ function.1 More than 27 different precursor proteins have the propensity to form amyloid fibrils.2 The particular precursor protein that misfolds to form amyloid fibrils defines the amyloid type and predicts the patient's clinical course. Several types of amyloid can infiltrate the heart, resulting in progressive diastolic and systolic dysfunction, congestive heart failure, and death. Treatment of cardiac amyloidosis is dictated by the amyloid type and degree of involvement. Consequently, early recognition and accurate classification are essential.3 The diagnosis of amyloidosis requires histological identification of amyloid deposits. Congo Red staining renders amyloid deposits salmon pink by light microscopy, with a characteristic apple green birefringence under polarized light conditions (Figure 1). Additional immunohistochemical staining for precursor proteins identifies the type of amyloidosis (Figure 2).4 Ultimately, immunogold electron microscopy and mass spectrometry confer the greatest sensitivity and specificity for amyloid typing.5,6 Figure 1. Congo Red staining of myocardial tissue from a patient with amyloid cardiomyopathy. A , Light microscopy; B , polarized light microscopy, 400× magnification. Figure 2. Transthyretin amyloid cardiomyopathy by immunohistochemical staining. Endomyocardial biopsy samples were stained with antibodies to ( A ) kappa light chain, ( B ) lambda light-chain, ( C ) serum amyloid A, and ( D ) transthyretin amyloid. Bright-light micrographs at 400× magnification. Two types of amyloid commonly infiltrate the heart: (1) Immunoglobulin light-chain (AL or primary systemic) amyloid and (2) transthyretin (TTR) amyloid. Transthyretin-related amyloidoses, in turn, encompass 2 forms of disease: Familial disease arising from misfolding of a mutated or variant TTR (familial amyloid cardiomyopathy or familial amyloidotic polyneuropathy [FAP]) and a sporadic, nongenetic disease caused by misaggregation of wild-type transthyretin (senile systemic amyloidosis [SSA]). Cardiac amyloidosis can also be …