Revealing the molecular links between coronary heart disease and cognitive impairment: the role of aging-related genes and therapeutic potential of stellate ganglion block

Abstract

Coronary heart disease (CHD) and cognitive impairment frequently co-occur in aging populations, yet the molecular mechanisms linking these conditions remain unclear. This study aims to elucidate the roles of key aging-related genes (ARGs), specifically FKBP5 and DDIT3, in the pathophysiology of CHD and cognitive impairment, and to evaluate the therapeutic potential of stellate ganglion block (SGB). Using single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) data, we identified FKBP5 and DDIT3 as pivotal genes upregulated in both conditions. Experimental findings show that SGB effectively modulates these ARG-related pathways through autonomic regulation, specifically suppressing estrogen and NF-κB signaling pathways, thereby reducing the expression of pro-inflammatory cytokines such as SRC, MMP2, FKBP5, IRAK1, and MYD88, while upregulating the vasodilation-related gene NOS3. This modulation improved endothelial and cardiac function and enhanced cerebral blood flow (CBF), leading to cognitive improvement. Behavioral assessments, including novel object recognition (NOR) and Morris water maze (MWM) tests, demonstrated that SGB-treated rats outperformed untreated MI rats, with significant cognitive recovery over time. Further support from laser Doppler flowmetry (LDF) and electroencephalogram (EEG) analyses revealed increased left frontal blood flow and stabilized neural activity, indicating a favorable neurophysiological environment for cognitive rehabilitation. Our findings suggest that left stellate ganglion block (LSGB) provides both cardiac and cognitive benefits through targeted gene modulation, establishing its therapeutic potential for addressing the intersecting pathologies of CHD and cognitive impairment.