Pathophysiology of Cardiac Amyloidosis

Generally, amyloidosis is characterized by the extracellular accumulation of fibrillar proteinaceous deposits, which are generated through complex kinetics triggered by pro-amyloidogenic factors (gene mutations, proteolysis, and altered environment). Several pathogenetic mechanisms responsible of disease development in CA have been identified, including increased oxidative stress, mitochondrial damage, apoptosis, impaired metabolism, and modifications of intracellular calcium balance which negatively affect both contractility and relaxation of cardiomyocytes. Moreover, additional cytotypes, such as cardiac fibroblasts, seem to be equally involved. Intramyocardial inflammation and cardiac fibrosis have recently emerged as potential contributors to damage and myocardial remodeling. These 2 conditions share common biological pathways, and future studies should investigate the potential beneficial role of antiinflammatory or antifibrotic therapies. CA manifests with a restrictive cardiomyopathy that progressively leads to biventricular thickening, enhanced chamber pressure, diastolic (and systolic) dysfunction, arrhythmias, and valvular disease. As demonstrated by several clinical studies, the enlargement of knowledge about pathophysiology of amyloidosis has led to the development and approval of various therapeutic strategies capable of improving prognosis and quality of life. However, current therapies do not induce amyloid removal or regression, but their action is limited to slow down the disease development. Therefore, the generation of pharmacologic agents capable of selectively targeting the pathogenetic mechanisms of damage (eg, cytotoxic damage) may represent a cutting-edge direction.