Single cell transcriptomic analyses of human heart failure with preserved ejection fraction

Area of Science:

• Cardiovascular Biology
• Genomics
• Translational Medicine

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a complex, multi-system disease with significant morbidity and mortality.
• Understanding the underlying molecular mechanisms of HFpEF is crucial for developing effective treatments.

Purpose of the Study:

• To characterize cell-specific gene expression patterns in human HFpEF myocardium using single-nucleus RNA sequencing (snRNA-seq).
• To identify distinct transcriptional changes in various cell types within the HFpEF heart compared to non-failing controls.

Main Methods:

• Septal myocardial biopsies from HFpEF patients and controls were analyzed using snRNA-seq.
• Genotype-based demultiplexing (souporcell) was employed to assign nuclei to individual patients.
• Differential gene expression and functional pathway analyses were performed on identified cell types.

Main Results:

• Cardiomyocytes and fibroblasts exhibited the highest number of differentially expressed genes in HFpEF.
• Enriched pathways across multiple cell types included transcription/translation, immune activation, and metabolism.
• Transcriptional differences between HFpEF and dilated cardiomyopathy (DCM) were primarily observed in cardiomyocytes.

Conclusions:

• Genotype-based demultiplexing is effective for single-cell transcriptomic analysis of small biopsies.
• Cardiomyocytes show distinct transcriptional alterations in HFpEF, differentiating it from DCM.
• These findings highlight key HFpEF pathways and nominate potential therapeutic targets.