Key Information
Source
Year
2025
summary/abstract
Abstract
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an infiltrative cardiomyopathy that results from myocardial deposition of misfolded transthyretin (TTR) protein. The biology of amyloid formation has been elucidated resulting in several effective therapeutic strategies. Accordingly, the therapeutic landscape for ATTR-CM is rapidly evolving, with multiple disease-modifying therapies (DMTs) approved and others anticipated to be imminently available. Currently, DMT strategies involve either stabilization of TTR, thereby inhibiting misfolding, or reduction of hepatic TTR production, and antibodies (“depleters”) that facilitate amyloid fibril removal are under development. In this review, available evidence is synthesized and expert experience provided to assist clinicians in the complex navigation of treatment selection and the role of advanced therapies (heart transplantation and left ventricular assist device), as well as to identify key areas for future research.
Transthyretin Stabilizers for ATTR-CM: Is One Better Than the Other?
The rate-limiting step in TTR amyloid pathogenesis is dissociation of the TTR tetramer. Small-molecule binding of the 2 equivalent thyroxine-binding sites within the TTR tetramer increases the activation energy associated with tetramer dissociation, thereby stabilizing the tetramer and slowing TTR amyloid fibril formation.3 Two such drugs are approved by the U.S. Food and Drug Administration (FDA) for the treatment of ATTR-CM: tafamidis and acoramidis.
Tafamidis is a benzoxazole derivative that
Silencing TTR With Drugs or CRISPR: Benefits and Risks
Knocking down TTR production at the hepatocyte level to reduce the amyloidogenic precursor protein has also been an effective treatment strategy. Initial clinical trials enrolled patients with ATTRv polyneuropathy. Vutrisiran, a second-generation small interfering RNA molecule administered every 3 months by subcutaneous injection, results in a reduction of circulating TTR by 80%-90% and, based on favorable results in HELIOS-A (A Study of Vutrisiran [ALN-TTRSC02] in Patients With Hereditary
ATTR Fibril Depleters
Approved therapies slow or stop amyloid fibril formation and ongoing deposition, but there are currently no approved therapies that directly reduce the amyloid load in organs or improve organ function. Proof of principle supporting this approach was reported by the National Amyloidosis Center, where 3 patients with ATTR-CM had evidence of a spontaneous regression of cardiac amyloidosis in the setting of high titers of idiopathically developed polyclonal antibodies against TTR amyloid.18 The
Emerging Questions in the Face of Multiple Effective Therapies
With several DMTs for ATTR-CM, there are emerging questions, including but not limited to: 1) the choice of an initial therapy; 2) whether to switch, combine, or de-prescribe therapies; 3) how to monitor the safety and efficacy of therapies; and 4) whether to treat presymptomatic individuals (Central Illustration). Unfortunately, there is currently little evidence to guide decision making.23
As noted, 2 classes of therapy for ATTR-CM are effective, including TTR stabilizers (tafamidis5 and
Is There Still a Role for Inotropes, LVADs, and HT in ATTR-CM?
Despite earlier diagnosis and more treatment options, patients with ATTR-CM may still present with or progress to end-stage HF. In these instances, inotropes, mechanical circulatory support, and HT may be considered in select cases.
Data on the use of inotropes in cardiac amyloidosis is limited. However, a retrospective single-center analysis of 40 patients (22 with ATTRv and 11 with ATTRwt) with a mean ejection fraction of 30% and cardiac index of 1.9 L/min/m2 treated with chronic intravenous