Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF. / Michaëlsson, Erik; Lund, Lars H.; Hage, Camilla; Shah, Sanjiv J.; Voors, Adriaan A.; Saraste, Antti; Redfors, Björn; Grove, Erik L.; Barasa, Anders; Richards, A. Mark; Svedlund, Sara; Lagerström-Fermér, Maria; Gabrielsen, Anders; Garkaviy, Pavlo; Gan, Li Ming; Lam, Carolyn S.P.
I: JACC: Heart Failure, Bind 11, Nr. 7, 2023, s. 775-787.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF
AU - Michaëlsson, Erik
AU - Lund, Lars H.
AU - Hage, Camilla
AU - Shah, Sanjiv J.
AU - Voors, Adriaan A.
AU - Saraste, Antti
AU - Redfors, Björn
AU - Grove, Erik L.
AU - Barasa, Anders
AU - Richards, A. Mark
AU - Svedlund, Sara
AU - Lagerström-Fermér, Maria
AU - Gabrielsen, Anders
AU - Garkaviy, Pavlo
AU - Gan, Li Ming
AU - Lam, Carolyn S.P.
N1 - Publisher Copyright: © 2023 The Authors
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - AZD4831
KW - heart failure
KW - HFpEF
KW - inflammation
KW - microvascular dysfunction
KW - myeloperoxidase
U2 - 10.1016/j.jchf.2023.03.002
DO - 10.1016/j.jchf.2023.03.002
M3 - Journal article
C2 - 37140510
AN - SCOPUS:85162262488
VL - 11
SP - 775
EP - 787
JO - J A C C: Heart Failure
JF - J A C C: Heart Failure
SN - 2213-1779
IS - 7
ER -
ID: 371192161