{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T02:13:22Z","timestamp":1768011202663,"version":"3.49.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":918,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Novartis Pharma AG"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>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 prioritized 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\u2009years; adjusted p-value [padj]\u2009=\u20094\u2009\u00d7\u200910\u22123), leaner (27.8\u2009kg\/m2 vs. 29.4\u2009kg\/m2; padj\u2009=\u20093.2\u2009\u00d7\u200910\u22123), had lower ejection fraction (27.3% vs. 29.8%; padj\u2009=\u20095.8\u2009\u00d7\u200910\u22123), and less likely to have ischaemic aetiology (37.3% vs. 67.4%; padj\u2009=\u20094\u2009\u00d7\u200910\u22124).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Deleterious pLoF variants in genes with definitive\/strong association with DCM were identified in \u223c5% of HFrEF patients from a PARADIGM-HF trial subset, who were younger, had lower ejection fraction and were less likely to have had an ischaemic aetiology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.2886","type":"journal-article","created":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T05:49:56Z","timestamp":1684216196000},"page":"1256-1266","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Clinical Characteristics of Heart Failure with Reduced Ejection Fraction Patients with Rare Pathogenic Variants in Dilated Cardiomyopathy-Associated Genes: A Subgroup Analysis of the PARADIGM-HF Trial"],"prefix":"10.1093","volume":"25","author":[{"given":"Ana","family":"Barat","sequence":"first","affiliation":[{"name":"Novartis Ireland Ltd , Dublin ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chien-Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation , East Hanover, NJ ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natasha","family":"Patel-Murray","sequence":"additional","affiliation":[{"name":"Novartis Institutes for Biomedical Research , Cambridge, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John J.V.","family":"McMurray","sequence":"additional","affiliation":[{"name":"University of Glasgow, BHF Cardiovascular Research Centre , Glasgow ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milton","family":"Packer","sequence":"additional","affiliation":[{"name":"Baylor University Medical Center, Baylor Heart and Vascular Institute , Dallas, TX ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott D.","family":"Solomon","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women's Hospital , Boston, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akshay S.","family":"Desai","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women's Hospital , Boston, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean L.","family":"Rouleau","sequence":"additional","affiliation":[{"name":"Institut de Cardiologie de Montr\u00e9al, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael R.","family":"Zile","sequence":"additional","affiliation":[{"name":"Medical University of South Carolina , Charleston, SC ,","place":["USA"]},{"name":"Ralph H. 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