Abstract
Introduction: Atrial fibrillation (AF) commonly occurs in patients with heart failure with preserved ejection fraction (HFpEF). Recent studies showed a high prevalence of coronary microvascular dysfunction (CMD) in patients with HFpEF and a likely association with AF. Yet, the biomarkers and mechanisms of their association have not been characterized. Hypothesis: Plasma proteomic analysis can identify novel biomarkers of the association between AF, CMD and HFpEF, and mechanistic pathways of their association. Methods: We studied the plasma samples from the patients with AF, CMD and/or HFpEF. Liquid chromatography-mass spectrometry based untargeted and label-free quantification proteomic analysis was performed. Circulating plasma proteins were screened to determine candidate biomarkers and the mutual mechanistic pathways in these disease processes. Results: We identified 130 dysregulated proteins across the groups with the independent patient replicates. Discovery-based untargeted plasma proteomic analysis identified 35 proteins in association with AF, CMD and HFpEF candidate biomarkers of their association (Fig). SAA1, LRG1 and APOC3 were significantly elevated in the coexistence of AF, CMD and HFpEF. LCP1, PON1 and C1S were markedly downregulated in their associations. Combined downregulation of PON1 and C1S was a marker of the HFpEF and CMD. Low PON1 was associated with HFpEF. Low C1S was a marker of CMD. Reduced levels of LCP1, KLKB1 and C4A were associated with AF in patients with CMD and HFpEF. These dysregulated proteins are associated with inflammatory processes, coagulation pathways, oxidative stress, metabolism, complement system and extracellular matrix remodeling. Conclusions: Plasma proteomic profile provides biomarkers and mechanistic insight into the association of AF, CMD and HFpEF. Circulation dysregulated proteins can be clinically useful for risk stratification.
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