Transthyretin Amyloid Cardiomyopathy-2025 Update: Current Diagnostic Approaches and Emerging Therapeutic Options

Abstract

Transthyretin-related (ATTR) amyloidosis is a progressive, multisystem disease caused by the extracellular deposition of misfolded transthyretin (TTR) monomers as insoluble amyloid fibrils. Clinical manifestations vary widely and may include cardiomyopathy (ATTR-CM), polyneuropathy (ATTR-PN), or mixed phenotypes. The condition is increasingly recognized as an underdiagnosed contributor to heart failure, particularly in elderly patients. ATTR amyloidosis exists in two major forms: hereditary (ATTRv), resulting from mutations in the TTR gene, and wild-type (ATTRwt), typically affecting men over 70 years of age. Advances in disease understanding have led to a paradigm shift in management, with the introduction of targeted therapies that slow disease progression and improve prognosis. First-generation therapies such as tafamidis have demonstrated survival benefits in ATTR-CM. More recently, second-generation agents-such as the TTR stabilizer acoramidis and RNA silencers including vutrisiran and eplontersen-have shown promising efficacy in clinical trials. Additional strategies under investigation include gene editing and monoclonal antibodies targeting TTR amyloid deposits. This review outlines current diagnostic strategies and therapeutic options for ATTR amyloidosis, emphasizing the need for early detection and individualized treatment approaches. The expanding therapeutic landscape highlights the importance of accurate phenotyping and timely intervention to optimize clinical outcomes.

Keywords: ATTR cardiomyopathy; ATTR polyneuropathy; amyloidosis; antisense oligonucleotide; cardiac amyloidosis; clinical development; gene editing; siRNA; transthyretin.

Figure 1

Pathogenesis and specific therapeutic strategies in transthyretin (ATTR) amyloidosis. The figure illustrates the production of TTR protein in the liver, its dissociation from tetramers into monomers, misfolding, and aggregation into amyloid fibrils that deposit in the heart, peripheral nervous system (PNS), kidneys, and eyes. Three therapeutic strategies are shown: (1) Gene silencing, using antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs); (2) TTR stabilization, with small-molecule drugs that prevent tetramer dissociation; and (3) ATTR removal, with monoclonal antibodies targeting misfolded TTR or amyloid deposits. → indicates biological progression; ⇌ indicates reversible molecular equilibrium; ⊥ indicates pharmacological inhibition at the respective stage. Abbreviations: ASO, antisense oligonucleotide; CRISPR, clustered regularly interspaced short palindromic repeats; GalNAc, N-acetylgalactosamine; IgG, immunoglobulin G; i.v., intravenous; PNS, peripheral nervous system; s.c., subcutaneous; siRNA, small interfering RNA.

Figure 2

Possible diagnostic algorithm for ATTR-CM and ATTR-PN [17,18,19,30]. The figure illustrates a stepwise diagnostic pathway for suspected transthyretin amyloidosis (ATTR) presenting with either cardiac (ATTR-CM) and/or neurological (ATTR-PN) symptoms. Evaluation includes laboratory screening for monoclonal proteins, bone scintigraphy (graded 0–3), histological confirmation, and genetic testing for hereditary ATTR variants. Cardiac magnetic resonance (CMR) may support the diagnosis in patients with polyneuropathy and suggest cardiac involvement. Abbreviations: AL, light-chain (amyloid) amyloidosis; ATTR, transthyretin amyloidosis; CM, cardiomyopathy; PN, polyneuropathy.

Figure 3

Approved and emerging therapeutic options for transthyretin (ATTR) amyloidosis with predominant cardiomyopathy (ATTR-CM), polyneuropathy (ATTR-PN), or mixed phenotype.Patients with ATTRv-CM and concurrent polyneuropathy (PN stage 1 or 2) should be managed in close collaboration with neurologists. Treatment selection should be guided by the extent of cardiac and neurological involvement and according to approved indications by local regulatory authorities. For predominant ATTR-CM (ATTRwt-CM or ATTRv-CM): • Tafamidis is approved by both FDA and EMA. • Acoramidis is approved for ATTR-CM in both the US and EU. • Vutrisiran is approved for ATTR-CM in both the US and EU. • Eplontersen is currently under evaluation for ATTR-CM in an ongoing phase III clinical trial (“CARDIO-TTRansform”). For predominant ATTRv-PN (stage 1 or 2): • Tafamidis is approved in the EU for stage 1 ATTRv-PN. • Patisiran, Inotersen, Eplontersen, Vutrisiran are approved in both the US and EU for ATTRv-PN (stage 1/2).