Transthyretin cardiac amyloidosis: pathogenesis, treatments, and emerging role in heart failure with preserved ejection fraction

Abstract

Transthyretin (TTR) amyloidosis causes heart failure from cardiac deposition of TTR amyloid fibrils, the by-product of TTR homotetramer disassembly. Wild-type (WT) TTR deposition leads to senile amyloidosis, predominantly manifesting with cardiomyopathy. Missense mutations in the TTR gene result in familial TTR amyloidosis. Certain mutations are more likely to affect the heart, while others cause more neurologic involvement. Extracellular fibril deposition triggers intracellular stress response, upregulation of the inflammatory cascades, apoptosis, and organ dysfunction. Recent studies suggest that TTR cardiac amyloid may be a significant contributor to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Summarized in this review are the molecular pathways underlying the cellular toxicity of TTR amyloid fibrils and the emerging therapies aimed at TTR tetramer stabilization, abrogation of TTR synthesis in the liver, or inhibition of amyloidogenesis.

Keywords: cardiac amyloidosis; heart failure with preserved ejection fraction (HFpEF); transthyretin (TTR).

Figure 1

A crystal structure of TTR homotetramer (reproduced with permission from Dr. Isabella Graef). The natural ligand T4 provides kinetic stability to the TTR homotetramer, as does T119M if found in the presence of a thermodynamically destabilizing mutation such as Val30Met. V122I is one of the most common TTR mutations found worldwide.

Figure 2

A proposed mechanism for the pathogenesis of TTR amyloidosis. Stable WT or mutant TTR tetramers are synthesized in the liver and must pass through the protein folding quality control machinery in the ER (ERAD) prior to being secreted. Highly unstable mutant tetramers such as Asp18Gly (D18G) are degraded via the ubiquitin–proteasome system, while WT TTR and stabilized mutants such as Val122Ile (V122I) are efficiently secreted into the serum. With aging-related oxidation, coupled with thermodynamic instability caused by certain mutations, TTR tetramers disassociate, forming amyloid fibrils that deposit extracellularly in target organs, such as the heart. Amyloid fibrils bind RAGE, triggering intracellular inflammatory cascades that result in apoptosis, organ dysfunction, and death. Novel treatments include antisense oligonucleotides and siRNA aimed at inhibiting TTR synthesis. Tafamidis and diflunisal are small molecule stabilizers. The lysine-rich molecular tweezers inhibit amyloidogenesis, while anakinra suppresses the downstream inflammatory cascade.