The clinical association between atrial fibrillation (AF), coronary microvascular disease (CMD) and heart failure with preserved ejection fraction (HFpEF) is highly prevalent, however the mechanism behind this association is not known. We hypothesized that plasma proteomic analysis can identify novel biomarkers and the mechanistic pathways in concomitant AF, CMD and HFpEF. To discover circulating biomarkers for the association between AF, CMD and HFpEF, an unbiased label-free quantitative proteomics approach was used in plasma derived from patients who underwent coronary physiology studies (n=18). Circulating proteins were analyzed by liquid chromatography-mass spectrometry and screened to determine candidate biomarkers of the concomitant AF, CMD and HFpEF. We identified 130 dysregulated proteins across the groups with the independent patient replicates. Among those, 35 proteins were candidate biomarkers of the association between AF, CMD and HFpEF. We found significantly elevated SAA1, LRG1 and APOC3 proteins in the coexistence of AF, CMD and HFpEF, whereas LCP1, PON1 and C1S were markedly downregulated in their associations. AF was associated with reduced LCP1, KLKB1 and C4A in these patients. Combined downregulation of PON1 and C1S was a marker of concurrent HFpEF and CMD. PON1 was associated with HFpEF while C1S was a marker of CMD. These proteins are related to inflammation, extra cellular remodeling, oxidative stress, and coagulation. In conclusion, plasma proteomic profile provides biomarkers and mechanistic insight into the association of AF, CMD and HFpEF. SAA1, LRG1, APOC3, LCP1, PON1 and C1S are candidate markers for the risk stratification of their associations and potential underlying mechanistic pathways.
Keywords: Atrial fibrillation; biomarkers; coronary microvascular dysfunction; heart failure; proteomics.
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