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Chapter Summary

This chapter discusses prevalence, pathophysiology, contemporary invasive and noninvasive diagnosis, and emerging management strategies for cardiac amyloidosis, including both wildtype and variant transthyretin disease as well as light-chain disease (see Fuster and Hurst's Central Illustration). Novel therapies can alter the natural history of cardiac amyloidosis and thus the condition should be considered as a differential diagnosis in any individual with heart failure with preserved ejection fraction, increased left ventricular wall thickness beyond 1.2 cm, and other concerning comorbid conditions including but not limited to atrial fibrillation, carpal tunnel syndrome, and autonomic dysfunction. In variant transthyretin amyloidosis, particularly the V142I pathogenic variant affecting 3% to 4% of Black Americans, facilitating genetic cascade testing in first-degree family members, and subsequent earlier recognition of phenotypic disease and treatment with transthyretin stabilizers, may result in slower disease progression and greater mortality benefit. Ongoing clinical trials using transthyretin silencers may dramatically alter the field if they also show morality benefit and less disease progression for both wildtype and/or variant disease. Additionally, if left untreated, light-chain cardiac amyloidosis is a very fatal disease; however, achieving hematologic response in patients with the condition, either with chemotherapy with bortezomib-based regimens or the anti-CD-38 monoclonal antibody daratumumab, can substantially alter prognosis.

HISTORY

Rudolf Virchow described the reaction of amyloid deposits with iodine and sulfuric acid in 1853. Because this reaction was positive, he assumed that these deposits were starch-like and coined the term amyloid (derived from amylum, the Latin word for “starch”)1 (Fig. 43–1). However, they were later found to be devoid of cellulose by Carl Freidreich and in fact were more albuminoid.2 In ensuing decades after the introduction of Congo red staining, they were found to have apple-green birefringence under polarized light with a beta pleat structure composing the amyloid fibers.

Figure 43–1.

(A) and (B) Cardiac amyloid, note the marked thickening of the right and left ventricular walls. The white deposits of amyloid resulted in the incorrect labeling as "lardaceous degeneration" by Rokitansky in 1842 as "resembling bacon".

PATHOPHYSIOLOGY

Today, amyloidosis reflects a localized or systemic process as a result of at least 30 precursor proteins that destabilize, rearranging into such beta-pleated sheets that make up the fibers that can deposit in various organs. Amyloid deposits are all extracellular and appear hyaline-like and amorphous when stained with hematoxylin and eosin (Fig. 43–2). As mentioned, under polarized light, amyloid deposits exhibit apple-green birefringence with Congo red staining (Fig. 43–2). This finding in any tissue is the gold standard for diagnosis of amyloidosis. Alternatively, some pathology labs will perform staining with sodium sulphate-Alcian Blue in preference to Congo red.

Figure 43–2.

Endomyocardial biopsy demonstrating interstitial deposits of amyloid on ...

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