A team from AstraZeneca in Gothenburg carried out a study aimed at identifying protein biomarker profiles associated with clinical outcomes in heart failure with preserved ejection fraction (HFpEF) and investigate how inhibition of myeloperoxidase (MPO) with an investigational drug during a phase II clinical trial affects these biomarkers. Four Olink® Target 96 panels were used to assess the associations between baseline plasma proteins and clinical outcomes in 3 independent observational HFpEF cohorts and these were then compared to profiles discriminating patients treated with active drug vs placebo in the SATELLITE trial of the MPO inhibitor, AZD4831.
In the prospective observational cohorts, plasma levels of TNF-R1, TRAIL-R2, GDF15, U-PAR, and ADM were most strongly associated with heart failure hospitalization or death, while FABP4, HGF, RARRES2, CSTB, and FGF23 were associated with lower functional capacity and poorer quality of life. Pathway analysis showed remarkable consistency among pathways associated with clinical outcomes in the observational cohorts, the top canonical pathways being associated with tumor microenvironments, wound healing signaling, and cardiac hypertrophy signaling.
In the clinical trial cohort, AZD4831 downregulated 45/266 proteins measured (most significantly CDCP1, PRELP, CX3CL1, LIFR, VSIG2). A multivariate statistical analysis identified a model that could classify 11 and 4 of the patients as AZD4831 or placebo-treated, respectively with 95% certainty. Most significantly, the biomarker data revealed that the pathways most strongly associated with poor HF clinical outcomes in the observational cohorts were also the ones reduced by AZD4831 treatment. These data add to the evidence supporting inflammation as a potential target in HF and build evidence for ongoing clinical trials into the use of MPO inhibitors.
Michaëlsson E, Lund LH, Hage C, et al. Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF. (2023) JACC. Heart Failure, DOI: 10.1016/j.jchf.2023.03.002
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.
Michaëlsson et al. (2023)
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