Pathophysiological pathways in patients with heart failure and atrial fibrillation

Santema, B. T. et al. (2022) Pathophysiological pathways in patients with heart failure and atrial fibrillation. Cardiovascular Research, 118(11), pp. 2478-2487. (doi: 10.1093/cvr/cvab331) (PMID:34687289) (PMCID:PMC9400416)

Abstract

Aims: Atrial fibrillation (AF) and heart failure (HF) are two growing epidemics that frequently co-exist. We aimed to gain insights into underlying pathophysiological pathways in HF patients with AF by comparing circulating biomarkers using pathway overrepresentation analyses. Methods and Results: From a panel of 92 biomarkers from different pathophysiological domains available in 1,620 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 = 1,219, 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 upregulated in patients with AF and HF. In the validation cohort, 8 biomarkers were upregulated, 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 = 1.33x10−12), insulin-like growth factor-binding protein-1 (fold change 1.32, p = 1.08x10−8), and insulin-like growth factor-binding protein-7 (fold change 1.33, p = 1.35x10−18). 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. Conclusion: 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. Translational Perspective: Using an unbiased approach, we identified and validated dysregulation of three amyloid-beta related pathways in patients who had heart failure (HF) with concomitant atrial fibrillation (AF). Amyloid-beta depositions are a hallmark of Alzheimer’s disease, but might also play a role in pathophysiological processes outside the central nervous system. Biopsy studies are needed to confirm the pathophysiological role of amyloid-beta in patients with AF and HF. Diagnostic and therapeutic implications should be investigated in the light of potential pathophysiological overlap between the three aging-related epidemics: Alzheimer’s disease, AF and HF.

• Item Type: Articles
• Additional Information: This work was supported by the European Commission [FP7-242209-BIOSTAT-CHF].
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cleland, Professor John
• Authors: Santema, B. T., Artola Arita, V., Sama, I. E., Kloosterman, M., van den Berg, M. P., Nienhuis, H. L.A., Van Gelder, I. C., van der Meer, P., Zannad, F., Metra, M., Ter Maaten, J. M., Cleland, J. G., Ng, L. L., Anker, S. D., Lang, C. C., Samani, N. J., Dickstein, K., Filippatos, G., van Veldhuisen, D. J., Lam, C. S.P., Rienstra, M., and Voors, A. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
• Journal Name: Cardiovascular Research
• Publisher: Oxford University Press
• ISSN: 0008-6363
• ISSN (Online): 1755-3245
• Published Online: 23 October 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Cardiovascular Research 118(11): 2478-2487
• Publisher Policy: Reproduced under a Creative Commons license