Cardiac Amyloidosis: State-of-the-Art Review in Molecular Pathology

Abstract

Amyloidosis refers to a group of diseases caused by extracellular deposits of misfolded proteins, which alter tissue function and structure, potentially affecting any organ. The term "amyloid" was introduced in the 19th century and later associated with pathological protein deposits. Amyloid fibrils, which are insoluble and resistant to degradation, originate from soluble proteins that undergo misfolding. This process can be triggered by several factors, such as aging, elevated protein concentrations, or pathogenic variants. Amyloid deposits damage organs both by disrupting tissue architecture and through direct cytotoxic effects, leading to conditions such as heart failure. Amyloidosis can be classified into acquired or inherited forms and can be systemic or localized. Diagnosing cardiac amyloidosis is complex and often requires tissue biopsies, which are supported by Congo Red dye staining. In some cases, bisphosphonate bone scans may provide a less invasive diagnostic option. In this state-of-the-art review, we focus on the most common forms of cardiac amyloidosis, from epidemiology to therapy, emphasizing the differences in molecular mechanisms and the importance of pathological diagnosis for appropriate treatment using a multidisciplinary approach.

Keywords: cardiac amyloidosis; cardiomyopathies; cardiovascular diseases; heart diseases; molecular mechanisms; molecular pathology.

Figure 1

Cardiac amyloidosis AL. (A) Macroscopic transverse section of right and left ventricular myocardium with pale and waxy appearance. (B) Macroscopic transverse section of the left atrial myocardium with a pale and waxy appearance. (C) Congo Red staining demonstrates a diffuse perivascular, interstitial, and pericellular amyloid deposition (magnification 4×). (D) At higher magnification (10×), the pericellular and interstitial deposition of congophilic substance (amyloid) becomes more evident, sometimes forming small nodular aggregates. (E) Congo Red staining under polarized light shows a green apple birefringence demonstrating interstitial and perivascular amyloid deposition (magnification 10×). (F) Strong immunohistochemical evidence of kappa light chains in the myocardial interstitium with a pericellular and diffuse pattern (magnification 10×).