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Publications

Journal Article Ahead of print

PubMed: 42616515 DOI: 10.1001/jamacardio.2026.2992

Left Atrial Structure and Function, Clinical Outcomes, and Efficacy of Vutrisiran in Transthyretin Amyloidosis With Cardiomyopathy: A Secondary Analysis of the HELIOS-B Randomized Clinical Trial.

JAMA Cardiol

Authors: Karola S Jering, Alireza Manafi, Brian L Claggett, Nicole K Bart, Narayana Prasad, Sarah M Birkhoelzer, Yasuhiro Hamatani, Olivier Lairez, Kenichi Tsujita, Julian D Gillmore, Mathew S Maurer, Patrick Y Jay, Hicham Skali, Marianna Fontana, Scott D Solomon

Affiliations

  • Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Internal Medicine, University of Pittsburgh Medical Center Harrisburg, Harrisburg, Pennsylvania.
  • Department of Cardiology, St Vincent's Hospital, Sydney, New South Wales, Australia.
  • University Hospitals Dorset, Bournemouth, United Kingdom.
  • HealthAge Institute, Department of Cardiology, Toulouse University Hospital, University of Toulouse, Toulouse, France.
  • Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan.
  • National Amyloidosis Centre, University College London, London, United Kingdom.
  • Division of Cardiology, Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, New York.
  • Alnylam Pharmaceuticals, Cambridge, Massachusetts.

Abstract

IMPORTANCE

Left atrial (LA) dysfunction may play an important role in the pathophysiology of transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and is driven by LA remodeling and amyloid infiltration.

OBJECTIVES

To evaluate the prognostic significance of LA structure and function among patients with ATTR-CM and to assess the effects of vutrisiran on these parameters.

DESIGN, SETTING, AND PARTICIPANTS

Post hoc analyses were conducted of the HELIOS-B phase 3 randomized clinical trial, which enrolled patients with ATTR-CM between December 2019 and August 2021 at 87 sites in 26 countries. Median (IQR) follow-up was 36 (33-36) months. Data were analyzed from July through November 2025.

INTERVENTIONS

Vutrisiran (25 mg subcutaneously every 3 months) vs placebo.

MAIN OUTCOMES AND MEASURES

The primary outcome was all-cause mortality (ACM) and recurrent cardiovascular events. LA structure (LA volume index [LAVi]) and function (LA reservoir [LASr], conduit [LAScd], and contractile strain [LASct]) were assessed, including the effect of vutrisiran on these measures at 30 months.

RESULTS

A total of 655 patients were enrolled. Among 644 patients with measurable LA strain (median [IQR] age, 77 [72-80] years; 48 female patients [7.5%]; 569 (88.4%) with wild-type ATTR), mean (SD) LA strain measures were substantially below normal (LASr: 9.5% [6.0%]; LAScd: 6.9% [3.9%]; LASct: 4.2% [4.0%]). Patients with worse LASr had more advanced disease, more atrial fibrillation, and more left ventricular systolic and diastolic dysfunction. LASr and LASct were independently associated with ACM and recurrent cardiovascular events (LASr: hazard ratio [HR] per 5% worsening, 1.37; 95% CI, 1.13-1.68; P = .002; LASct: HR per 5% worsening, 1.53; 95% CI, 1.08-2.17; P = .02), recurrent heart failure hospitalizations (LASr: HR, 1.66; 95% CI, 1.22-2.25; P = .001; LASct: HR, 2.23; 95% CI. 1.46-3.71; P < .001), and incident atrial fibrillation (LASr: HR, 1.30; 95% CI, 1.03-1.63; P = .03; LASct: HR, 2.02; 95% CI, 1.38-2.96; P < .001). In contrast, LAVi was not associated with these outcomes. LA strain measures at baseline did not modify the treatment effect of vutrisiran on ACM and recurrent cardiovascular events (LASr: P value for interaction = .60; LAScd: P value for interaction = .58; LASct: P value for interaction = .47). Vutrisiran attenuated worsening in LA strain vs placebo at month 30 (LASr: +1.2%; 95% CI, +0.4% to +1.9%; LAScd: +0.8%; 95% CI, +0.3% to +1.4%; LASct: +0.8%; 95% CI, 0% to +1.6%).

CONCLUSIONS AND RELEVANCE

Per the results of this secondary analysis of the HELIOS-B randomized clinical trial, LA dysfunction is common among patients with ATTR-CM and portends a worse prognosis. Consistent with its beneficial effects on other measures of cardiac structure and function, vutrisiran attenuated worsening in LA strain at 30 months, supporting the importance of LA function in the pathophysiology of ATTR-CM and the ability of silencer therapy with vutrisiran to attenuate worsening atrial myopathy in amyloid heart disease.

TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT04153149.

MeSH

Muscular Diseases, Heart, Cardiovascular Diseases, Prealbumin, Atrial Fibrillation, Amyloidosis, Therapeutics, Amyloid, Cardiomyopathies, Transthyretin Amyloidosis