Pathophysiological pathways in patients with heart failure and atrial fibrillation.

Atrial fibrillation (AF) and heart failure (HF) are two growing epidemics that frequently co-exist. We aimed to gain insights into the underlying pathophysiological pathways in HF patients with AF by comparing circulating biomarkers using pathway overrepresentation analyses. From a panel of 92 biomarkers from different pathophysiological domains available in 1620 patients with HF, we first tested which biomarkers were dysregulated in patients with HF and AF (n = 648) compared with patients in sinus rhythm (n = 972). Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in patients who had HF and AF. Findings were validated in an independent HF cohort (n = 1219, 38% with AF). Patient with AF and HF were older, less often women, and less often had a history of coronary artery disease compared with those in sinus rhythm. In the index cohort, 24 biomarkers were up-regulated in patients with AF and HF. In the validation cohort, eight biomarkers were up-regulated, which all overlapped with the 24 biomarkers found in the index cohort. The strongest up-regulated biomarkers in patients with AF were spondin-1 (fold change 1.18, P = 1.33 × 10-12), insulin-like growth factor-binding protein-1 (fold change 1.32, P = 1.08 × 10-8), and insulin-like growth factor-binding protein-7 (fold change 1.33, P = 1.35 × 10-18). Pathway overrepresentation analyses revealed that the presence of AF was associated with activation amyloid-beta metabolic processes, amyloid-beta formation, and amyloid precursor protein catabolic processes with a remarkable consistency observed in the validation cohort. In two independent cohorts of patients with HF, the presence of AF was associated with activation of three pathways related to amyloid-beta. These hypothesis-generating results warrant confirmation in future studies.

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© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Déclaration de conflit d'intérêts

Conflict of interest: A.A.V. and/or his institution received grants and/or consultancy reimbursements from Amgen, AstraZeneca, Bayer AG, Boehringer, Cytokinetics, Merck, Myokardia, Novartis, Roche, and Novo Nordisk. B.T.S. received funding from the Dutch Heart Foundation (2019T094). I.C.V.G. reports support from the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch heart Foundation (CVON 2014-9 and CVON 2018-28) and support from Medtronic to the institution. F.Z. reports personal fees from Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer, Boston Scientific, Cardior, Cardiorenal, Cereno pharmaceutical, Cirius, CVCT, CVRx, Janssen, Novartis, Merck, and Vifor Fresenius. P.v.d.M. received consultancy fees and/or grants from Novartis, Servier, Vifor, Pharma, Astra Zeneca, Pfizer, and Ionis. C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global LLC, Radcliffe Group Ltd and Corpus; and serves as co-founder and non-executive director of eKo.ai. G.F. is committee member in trials and/or registries sponsored by Medtronic, Novartis, BI, Vifor, Servier, outside the submitted work. S.D.A. reports receiving fees from Abbott Vascular, Bayer, Boehringer Ingelheim, Cardiac Dimension, Impulse Dynamics, Novartis, Servier, and Vifor Pharma, and grant support from Abbott Vascular and Vifor Pharma. V.A.A. received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant (754425). None of the funders had any role in the trial design, the collection or analysis of the data, or the writing of the manuscript. All other authors declare no conflict of interest.