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

Heart Failure with Preserved Ejection Fraction (HFpEF) affects more women than men and is linked to changes in how the heart uses glucose. Yet, it remains unknown if these metabolic changes are consistent across genders and between humans and a mouse model commonly used to study HFpEF. Researchers studied these differences by inducing cardiac HFpEF in mice using a two-hit model (high-fat diet plus L-NAME) and examining cardiac function, RNA sequencing, and protein expression in both right and left ventricles. They compared these results with human HFpEF data already available.

Their findings revealed that only male mice exhibited an increase in the protein levels of GLUT1 (a glucose transporter) in the right ventricle, similar to the human condition. Conversely, female mice and the left ventricles of both sexes showed a decrease in GLUT1 protein levels. Similarly, cardiac PDK4 (a gene involved in glucose metabolism) had increased expression in both the right and left ventricles of mice, while human PDK4 mRNA levels were lower in the right ventricle of HFpEF patients and unchanged in the left ventricle.

These protein and gene expression differences suggest that the metabolic alterations observed in HFpEF might vary between males and females and between mice and humans.

The researchers also conducted a comprehensive analysis of the cardiac transcriptome in mice and found extensive alterations in the left ventricle, particularly in females, with an enrichment of inflammatory pathways. When comparing cross-species data, the researchers discovered greater conservation of HFpEF-associated signatures in the right ventricle than in the left ventricle.

Additionally, they observed that the number of differentially expressed transcripts in the human left ventricle increased significantly when excluding patients with atrial fibrillation or diabetes. Overall, the researchers concluded that the right ventricle of the mouse model more closely mirrors the human HFpEF condition. They also noted that the cardiac transcriptome reflects sexual dimorphism and that the conserved signatures are primarily related to metabolic alterations, mitochondrial dysfunction, and cellular stress.