Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF

Erik Michaëlsson, Lars H. Lund, Camilla Hage, Sanjiv J. Shah, Adriaan A. Voors, Antti Saraste, Björn Redfors, Erik L. Grove, Anders Barasa, A. Mark Richards, Sara Svedlund, Maria Lagerström-Fermér, Anders Gabrielsen, Pavlo Garkaviy, Li Ming Gan, Carolyn S.P. Lam*

*Corresponding author voor dit werk

OnderzoeksoutputAcademicpeer review

17 Citaten (Scopus)
27 Downloads (Pure)

Samenvatting

Background: Systemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF). Objectives: This study aimed to identify biomarker profiles associated with clinical outcomes in HFpEF and investigate how inhibition of the neutrophil-derived reactive oxygen species–producing enzyme, myeloperoxidase, affects these biomarkers. Methods: Using supervised principal component analyses, the investigators assessed the associations between baseline plasma proteomic Olink biomarkers and clinical outcomes in 3 independent observational HFpEF cohorts (n = 86, n = 216, and n = 242). These profiles were then compared with the biomarker profiles discriminating patients treated with active drug vs placebo in SATELLITE (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure), a double-blind randomized 3-month trial evaluating safety and tolerability of the myeloperoxidase inhibitor AZD4831 in HFpEF (n = 41). Pathophysiological pathways were inferred from the biomarker profiles by interrogation of the Ingenuity Knowledge Database. Results: TNF-R1, TRAIL-R2, GDF15, U-PAR, and ADM were the top individual biomarkers associated with heart failure hospitalization or death, and FABP4, HGF, RARRES2, CSTB, and FGF23 were associated with lower functional capacity and poorer quality of life. AZD4831 downregulated many markers (most significantly CDCP1, PRELP, CX3CL1, LIFR, VSIG2). There was remarkable consistency among pathways associated with clinical outcomes in the observational HFpEF cohorts, the top canonical pathways being associated with tumor microenvironments, wound healing signaling, and cardiac hypertrophy signaling. These pathways were predicted to be downregulated in AZD4831 relative to placebo-treated patients. Conclusions: Biomarker pathways that were most strongly associated with clinical outcomes were also the ones reduced by AZD4831. These results support the further investigation of myeloperoxidase inhibition in HFpEF.

Originele taal-2English
Pagina's (van-tot)775-787
Aantal pagina's13
TijdschriftJACC: Heart Failure
Volume11
Nummer van het tijdschrift7
DOI's
StatusPublished - jul.-2023

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