From Molecular to Radionuclide and Pharmacological Aspects in Transthyretin Cardiac Amyloidosis

Abstract

Amyloidosis is a rare pathology characterized by protein deposits in various organs and tissues. Cardiac amyloidosis (CA) can be caused by various protein deposits, but transthyretin amyloidosis (ATTR) and immunoglobulin light chain (AL) are the most frequent pathologies. Protein misfolding can be induced by several factors such as oxidative stress, genetic mutations, aging, chronic inflammation, and neoplastic disorders. In ATTR cardiomyopathy (ATTR-CM), the amyloid fibrils can be found in the myocardium interstitial space and are associated with arrhythmias and heart failure. In pathological situations, the transthyretin (TTR) configuration is destroyed by proteolytic action, leading to monomers that further misfold and aggregate to form the amyloid fibrils. ^99mTc-Pyrophosphate (^99m-Tc-PYP), ^99mTc 3,3-diphosphono-1,2-propanodicarboxylic acid (^99m-Tc-DPD) and ^99m-Tc hydroxy-methylene-Dyphosphonate (^99m-Tc-HMDP) are used to detect myocardium amyloid deposits due to their ability to detect calcium ions that are present in the amyloid fibrils through dystrophic calcification. ATTR-CM therapy acts on different stages of the amyloidogenic process, including liver TTR synthesis, TTR tetramer destabilization, and misfolding of the monomers. The main aim of this narrative review is to present ATTR-CM, starting with molecular changes regarding the protein misfolding process and radionuclide aspects and finishing with pharmacological approaches.

Keywords: TTR depleters; TTR knockdown; TTR stabilizers; cardiac amyloidosis; protein misfolding; radionuclide imaging; transthyretin cardiac amyloidosis.

Figure 1

Transthyretin cardiac amyloidosis development. The development of this pathology can be induced by various factors. First of all, genetic mutations and translational errors lead to abnormal transthyretin protein synthesis. Further other factors such as aging, oxidative stress, neoplastic disorders, and acidity can destroy the normal configuration of TTR tetramer proteins with the formation of the misfolded monomers, leading to amyloid fibrils. Currently, several drugs have been developed with different actions, with some blocking hepatic transthyretin (TTR) synthesis (patisiran, revusinan, vutrisiran, inotersen, eplontersen, and NTLA-2001), others acting on TTR stabilization (difluninal, tafamidis, and acoramidis), and some trying to remove the amyloid fibrils (NNC6019, ALXN2220, and AT-02).