Clinical characteristics of HFrEF patients with rare pathogenic variants in DCM-associated genes: a subgroup analysis of the PARADIGM-HF trial

Barat, A. et al. (2023) Clinical characteristics of HFrEF patients with rare pathogenic variants in DCM-associated genes: a subgroup analysis of the PARADIGM-HF trial. European Journal of Heart Failure, 25(8), pp. 1256-1266. (doi: 10.1002/ejhf.2886) (PMID:37191081)

Abstract

Aims: To evaluate the prevalence of pathogenic variants in genes associated with dilated cardiomyopathy (DCM) in a clinical trial population with heart failure and reduced ejection fraction (HFrEF) and describe the baseline characteristics by variant carrier status. Methods and results: This was a post hoc analysis of the Phase 3 PARADIGM-HF trial. Forty-four genes, divided into three tiers, based on definitive, moderate or limited evidence of association with DCM, were assessed for rare predicted loss-of-function (pLoF) variants, which were prioritised using ClinVar annotations, measures of gene transcriptional output and evolutionary constraint, and pLoF confidence predictions. Prevalence was reported for pLoF variant carriers based on DCM-associated gene tiers. Clinical features were compared between carriers and non-carriers. Of the 1412 HFrEF participants with whole-exome sequence data, 68 (4.8%) had at least one pLoF variant in the 8 tier-1 genes (definitive/strong association with DCM), with Titin being most commonly affected. The prevalence increased to 7.5% when considering all 44 genes. Among patients with idiopathic aetiology, 10.0% (23/229) had tier-1 variants only and 12.6% (29/229) had tier-1, -2 or -3 variants. Compared to non-carriers, tier-1 carriers were younger (4 years; adjusted p-value [padj]=4×10−3), leaner (27.8 kg/m2 vs. 29.4 kg/m2; padj=3.2x10−3), had lower EF (27.3% vs. 29.8%; padj=5.8x10−3), and less likely to have ischaemic aetiology (37.3% vs 67.4%; padj=4×10−4). Conclusion: Deleterious pLoF variants in genes with definitive/strong association to DCM were identified in ~5% of HFrEF patients from a PARADIGM-HF trial subset, who were younger, had lower EF and were less likely to have had an ischaemic aetiology.

• Item Type: Articles
• Additional Information: The PARADIGM-HF study was funded by Novartis Pharma AG.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McMurray, Professor John
• Authors: Barat, A., Chen, C.‐W., Patel‐Murray, N., McMurray, J. J.V., Packer, M., Solomon, S. D., Desai, A. S., Rouleau, J. L., Zile, M. R., Attari, Z., Zhang, C., Xu, H., Hartman, N., Hon, C., Healey, M., Chutkow, W., O'Donnell, C. J., Jacob, J., Lefkowitz, M., Mendelson, M. M., Wandel, S., Yates, D., and Gimpelewicz, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: European Journal of Heart Failure
• Publisher: Wiley
• ISSN: 1388-9842
• ISSN (Online): 1879-0844
• Published Online: 16 May 2023
• Copyright Holders: Copyright © 2023 Novartis Pharma AG and The Authors
• First Published: First published in European Journal of Heart Failure 25(8):1256-1266
• Publisher Policy: Reproduced under a Creative Commons License