Shared and Divergent Features of Cardiac Transcriptome and Glucose Metabolism Markers in Human and Mouse HFpEF

ABSTRACT Heart Failure with Preserved Ejection Fraction (HFpEF) is more prevalent in females and is associated with altered cardiac glucose metabolism. However, whether these metabolic alterations are conserved across sexes and between humans and widely used cardiometabolic mouse model of HFpEF remains unclear. We investigated species-, sex-, and ventricle-specific conserved and divergent features of HFpEF. Cardiometabolic HFpEF was induced in mice using the “two-hit” model (high-fat diet + L-NAME), followed by assessment of cardiac function, RNA sequencing, and protein expression in the right (RV) and left (LV) ventricles. Published human HFpEF RV and LV RNA-seq datasets were reanalyzed and compared with our mouse data. Only male HFpEF mice recapitulated human phenotype of increased RV GLUT1 protein. In contrast, mouse GLUT1 was downregulated in RV of females and in the LV of both sexes, whereas GLUT4 protein remained unchanged. Cardiac PDK4 transcript and protein levels increased in the RV and LV of mice. Conversely, human PDK4 mRNA levels were reduced in the RV with HFpEF and unchanged in LV. Cardiac transcriptome analysis in mice revealed extensive alterations in LV, particularly in females, with enrichment of inflammatory pathways. Cross-species analysis demonstrated greater conservation of HFpEF-associated signatures in the RV than the LV. Furthermore, number of differentially expressed transcripts in human LV increased substantially after excluding patients with atrial fibrillation or diabetes. Overall, the RV of the “two-hit” model more closely resembles human HFpEF. The cardiac transcriptome reflects sexual dimorphism, and conserved signatures are primarily associated with metabolic alteration, mitochondrial dysfunction, and cellular stress. HIGHLIGHTS The human RV GLUT1 phenotype is reproduced in male mice with HFpEF. HFpEF-related cardiac transcriptome changes are more pronounced in female mice. RV shows greater cross-species conservation than LV in HFpEF. Conserved transcriptomic changes primarily reflect alterations in metabolism and cellular stress. Humans and mice with HFpEF have opposite PDK4 expression profiles. GRAPHICAL ABSTRACT