Pathophysiological pathways in patients with heart failure and atrial fibrillation

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.

Integrative proteomic analyses across common cardiac diseases yield new mechanistic insights and enhanced prediction

“…WFDC2 (also known as HE4)—a profibrotic protease inhibitor with a potential role in natural immunity 17 —emerged as the strongest proteomic predictor of heart failure. Previous research in hospitalized heart failure patients demonstrated associations of circulating WFDC2 with disease severity as well as kidney function 30 . As WFDC2 is expressed exclusively in non-cardiovascular tissues such as the respiratory tract, male and female genitourinary system, and kidneys 31 , it is likely that the strong associations of WFDC2 with cardiac outcomes stem from peripheral organ responses rather than indicating direct cardiac dysfunction or vascular damage.…”

Diminished α7 nicotinic acetylcholine receptor (α7nAChR) rescues amyloid-β induced atrial remodeling by oxi-CaMKII/MAPK/AP-1 axis-mediated mitochondrial oxidative stress

“…Previous studies have shown that cardiac amyloidosis is associated with a high prevalence of AF [ 32 , 33 ]. A further study revealed that pathways of Aβ metabolic processes, Aβ formation and APP catabolic processes were activated in patients suffered from heart failure with concomitant AF [ 34 ], suggesting that Aβ deposition, as the marker of AD, also involved in pathophysiological processes of cardiac diseases. The pulmonary vein contains abundant amyloid peptides and directly influences atrial remodeling as a major substrate of AF [ 35 ].…”

Biomarker signature and pathophysiological pathways in patients with chronic heart failure and metabolic syndrome

“…13,14 The elevated protein biomarkers were assessed in pathways from the databases gene ontology (GO) biological processes, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathways. 15 The statistical parameters applied were the hypergeometric test and the default Bonferroni step-down method for multiple testing corrections. The whole annotation option was used as a reference set, and only pathways with a corrected p-value ≤0.05 were considered significant.…”

“…The overlapping common elevated protein biomarkers between the index and validation cohort were selected and further investigated in a pathway overrepresentation analysis, performed using the ClueGo plug‐in app (version 2.5.8) in Cytoscape (version 3.9.0), a software platform for visualizing biomolecular networks 13,14 . The elevated protein biomarkers were assessed in pathways from the databases gene ontology (GO) biological processes, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathways 15 . The statistical parameters applied were the hypergeometric test and the default Bonferroni step‐down method for multiple testing corrections.…”