GATA3 and IFNG as Potential Molecular Biomarkers for Differentiating Heart Failure with Preserved Ejection Fraction with Normal Versus Elevated BNP Levels

This study aimed to investigate differentially expressed mRNA transcripts between patients with heart failure with preserved ejection fraction (HFpEF) exhibiting normal versus elevated B-type natriuretic peptide (BNP) levels, thereby seeking novel early diagnostic molecular biomarkers and therapeutic targets to facilitate precision medicine in heart failure management.First, using mRNA transcriptomics, we analyzed 10 patients with HFpEF and normal BNP levels, 10 patients with HFpEF and elevated BNP levels, and 10 healthy controls. Compared with the BNP elevated group, the BNP normal group exhibited upregulated WEE1, GATA3, MLC1, SH2D1B, NLRP2, and SLC12A1, as well as downregulated ST3GAL6 and NUDT16. Relative to controls, HFpEF-N demonstrated 147 upregulated (e.g., BMP2, GPR84, and IL1B) and 24 downregulated (e.g., HIST1H1B/D and PRSS21) mRNAs. Second, the differentially expressed genes in the BNP normal group were significantly enriched in pathways including mitotic nuclear division (GO:0140014), regulation of hormone metabolic processes (GO:0032350), and regulation of mitotic nuclear division (GO:0007088). In addition, key pathways including IL-17 (hsa04657) and chemokine signaling (hsa04062) were upregulated. Finally, in an additional cohort (60 HFpEF with normal BNP versus 61 HFpEF with elevated BNP), three upregulated mRNAs were validated: GATA3, IFNG, and GPR84. IFNG and GATA3 were significantly upregulated in the BNP normal group compared with the BNP elevated and healthy groups (P-value < 0.001 for both). GATA3 demonstrated an auxiliary diagnostic utility for HFpEF with normal BNP levels, area under the receiver operating characteristic curve (AUC) = 0.77, P < 0.001, whereas IFNG exhibited a higher diagnostic value (AUC = 0.81, P < 0.001).Notably, IFNG and GATA3 were identified as potential molecular biomarkers for patients with HFpEF with normal BNP levels, highlighting their roles in the underlying inflammatory mechanisms of this distinct phenotype.