Mazen Hanna

Purpose of Review: The management of end-stage heart failure in cardiac amyloidosis due to both light chain (AL-CA) and transthyretin (ATTR-CA) with heart transplantation has historically been limited by concerns about systemic progression after transplant. As a result, heart transplantation as a strategy was often restrictive and many patients were excluded. This review synthesizes contemporary evidence and outlines a practical framework to guide heart transplant evaluation and decision making in advanced disease. We emphasize evolving multidisciplinary selection principles. Recent Findings: In the recent era (since the 2010s), multicenter experience has demonstrated that carefully selected patients with advanced AL-CA and ATTR-CA can achieve favorable outcomes after heart transplantation. Specifically, selected individuals with wild type transthyretin cardiac amyloidosis (ATTRwt-CA) may be appropriate candidates. For hereditary transthyretin cardiac amyloidosis (ATTRv-CA), isolated heart or combined heart liver transplantation (CHLT) can been considered, although modern transthyretin targeted therapies increasingly influence this decision. Patients with AL-CA may undergo transplantation alongside timely plasma cell directed treatment. Summary: Historically, outcomes for heart transplantation in patients with cardiac amyloidosis were poor. Improved patient selection as well as advances in plasma cell targeted therapy for AL-CA and transthyretin stabilizing or gene silencing treatments for ATTR-CA have reshaped expectations. The improved outcomes seen in more contemporary cohorts support heart transplantation as a viable option for selected patients with advanced disease.

Given the multi-organ involvement of transthyretin (ATTR) amyloidosis, associated symptoms such as peripheral neuropathy, biceps tendon rupture, lumbar stenosis, and bilateral carpal tunnel syndrome can develop concurrently with cardiac disease or even precede the cardiac diagnosis by up to a decade. Screening of tissue obtained opportunistically during an otherwise indicated procedure or diagnostic test has shown promise for the early identification of nascent cardiac amyloidosis (CA) in patients who might otherwise remain undiagnosed for years. This review aims to: (1) briefly summarize the cardiac and non-cardiac manifestations of transthyretin cardiomyopathy (ATTR-CM) that may raise clinical suspicion for the disease; (2) discuss tissue-based screening within contemporary ATTR-CM diagnostic pathways; (3) describe the diagnostic yield and management challenges of tissue screening, with a focus on early detection; (4) examine the treatment and surveillance implications of tissue screening in both symptomatic and asymptomatic individuals. Multidisciplinary collaboration (e.g., partnerships between hand surgery centers and amyloid centers) and criteria-based screening of specimens obtained during noncardiac and cardiac surgery may offer an effective strategy for identifying patients earlier in the associated disease course. However, given the variable diagnostic yield, the significant anxiety associated with comprehensive evaluation for ATTR-CM, and the potentially high cost of treating CA with one of the three therapies approved by the Food and Drug Administration (FDA), further refinement of screening criteria and additional investigation into the impact of early treatment on disease trajectory and outcomes are needed.

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy is a progressive, fatal disease characterized by deposition of extracellular misfolded transthyretin (TTR) in the myocardium. Eplontersen is an N-acetylgalactosamine ligand–conjugated antisense oligonucleotide targeting hepatocyte TTR messenger RNA to reduce the production of circulating TTR. METHODS: CARDIO-TTRansform is a Phase 3, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of eplontersen in transthyretin amyloidosis with cardiomyopathy. Key inclusion criteria include histological evidence of amyloid deposits or grade 2 to 3 cardiac uptake on cardiac scintigraphy in the absence of plasma cell dyscrasia, New York Heart Association class I–III, and end-diastolic interventricular septum thickness >12 millimeters. Participants were randomized 1:1 to receive eplontersen 45 mg or placebo, administered subcutaneously every 4 weeks for up to 140 weeks, followed by a 20-week post-treatment evaluation period or open-label extension. Participants received locally available standard of care, including unrestricted use of TTR stabilizers. The primary end point is a composite of cardiovascular mortality and recurrent clinical cardiovascular events through 140 weeks. Secondary end points, in order of testing hierarchy, include changes from baseline in 6-minute walk distance and Kansas City Cardiomyopathy Questionnaire overall summary score, recurrent cardiovascular events, all-cause mortality, the primary end point in the patient subgroup receiving stabilizers at baseline, and cardiovascular mortality. Echocardiography was performed in all participants, with cardiovascular magnetic resonance imaging and technetium scintigraphy in a subset. CONCLUSIONS: CARDIO-TTRansform is fully enrolled, with 1432 randomized participants who were dosed with study drug or placebo. As the largest transthyretin amyloidosis with cardiomyopathy study to date, it will evaluate whether eplontersen improves cardiovascular outcomes in patients receiving locally available standard of care, including TTR stabilizers. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04136171. URL: http://ClinicalTrialsRegister.eu ; Unique identifier: EudraCT number 2019-002835-27.