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

doi:10.1016/j.jchf.2023.03.002

Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF

JACC Heart Fail. 2023 Jul;11(7):775-787. doi: 10.1016/j.jchf.2023.03.002. Epub 2023 May 3.

Authors

Erik Michaëlsson¹, Lars H Lund², Camilla Hage³, Sanjiv J Shah⁴, Adriaan A Voors⁵, Antti Saraste⁶, Björn Redfors⁷, Erik L Grove⁸, Anders Barasa⁹, A Mark Richards¹⁰, Sara Svedlund⁷, Maria Lagerström-Fermér¹, Anders Gabrielsen¹, Pavlo Garkaviy¹, Li-Ming Gan⁷, Carolyn S P Lam¹¹

Affiliations

¹ Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
² Department of Medicine, Cardiology Unit, Karolinska Institutet, Stockholm, Sweden.
³ Department of Medicine, Cardiology Unit, Karolinska Institutet, Stockholm, Sweden; Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
⁴ Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
⁵ University of Groningen, Groningen, the Netherlands.
⁶ Heart Center, Turku University Hospital, University of Turku, Turku, Finland.
⁷ Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
⁸ Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Faculty of Health, Aarhus University, Aarhus, Denmark.
⁹ Department of Medicine, Glostrup Hospital, Copenhagen, Denmark.
¹⁰ Department of Medicine, University of Otago, Christchurch, New Zealand; National University Heart Centre Singapore (NUHCS), National University of Singapore, Singapore.
¹¹ University of Groningen, Groningen, the Netherlands; National Heart Centre Singapore, Duke-National University of Singapore, Singapore. Electronic address: Carolyn.lam@duke-nus.edu.sg.

PMID: 37140510
DOI: 10.1016/j.jchf.2023.03.002

Abstract

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.

Keywords: AZD4831; HFpEF; heart failure; inflammation; microvascular dysfunction; myeloperoxidase.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Neoplasm / therapeutic use
Biomarkers
Cell Adhesion Molecules / therapeutic use
Heart Failure*
Humans
Peroxidase / therapeutic use
Proteomics
Quality of Life
Stroke Volume / physiology

Substances

Antigens, Neoplasm
Biomarkers
CDCP1 protein, human
Cell Adhesion Molecules
Peroxidase