Immune-Inflammatory, Autophagy, and JNK Remodeling in Ischemic and Nonischemic Human Myocardium

This study investigated ischemic versus nonischemic human myocardium across disease phenotypes, sex, and race, prioritizing genes involved in immune-inflammatory signaling, autophagy, JNK-associated stress responses, innate immune recognition, and solute transport. Bulk RNA sequencing was performed in 75 human heart tissue samples, including 13 controls, 18 ischemic samples, and 44 nonischemic samples. Primary models tested ischemic versus control, nonischemic versus control, and nonischemic versus ischemic contrasts. Secondary models evaluated sex- and race-associated expression while adjusting for disease status and sequencing batch. Ischemic versus control comparison identified 3974 genes and nonischemic versus control identified 4276 genes at adjusted p < 0.05, while nonischemic versus ischemic identified only two genes. After adjustment for disease status and sequencing batch, 108 genes (including 64 autosomal genes) were associated with sex and 128 with race at FDR < 0.05. In the adjusted race analysis, SLC39A4 was higher and MAP1LC3B2 lower in White samples after FDR correction. Ischemic and nonischemic myocardium showed extensive shared remodeling with exploratory nominal differences. Sex and race were associated with additional variation in immune, proteostatic, and nutrient-transport programs. BAG3 transcript abundance was not significantly altered, consistent with prior evidence that transcript and protein abundance may be uncoupled in failing myocardium.