Single-Cell Analysis of Human Heart Failure With Preserved Ejection Fraction.

Area of Science:

• Cardiovascular Biology
• Genomics
• Molecular Pathology

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a complex multisystem disease with significant morbidity and mortality.
• The precise pathobiology of HFpEF remains poorly understood, necessitating advanced molecular investigations.

Purpose of the Study:

• To elucidate the cellular and molecular mechanisms underlying HFpEF.
• To identify cell-type-specific transcriptomic alterations in the human HFpEF myocardium.
• To compare HFpEF transcriptomic signatures with those of dilated cardiomyopathy.

Main Methods:

• Single-nucleus RNA sequencing was performed on septal myocardial biopsies from HFpEF patients and nonfailing controls.
• Nuclei were pooled, demultiplexed, and analyzed for gene expression quantification and cell type annotation.
• Differential gene expression and pathway analyses were conducted to identify molecular differences between HFpEF and control groups.

Main Results:

• 14 distinct cell types were identified, with numerous differentially expressed genes found across multiple cell types in HFpEF.
• Common enriched pathways included immune activation, metabolism, and protein quality control, particularly between cardiomyocytes and fibroblasts.
• HFpEF showed unique transcriptomic signatures in cardiomyocytes compared to dilated cardiomyopathy, with two genes (MAP2K6 and PLPP3) validated at the protein level.

Conclusions:

• The human HFpEF myocardium exhibits a unique, cell-type-specific transcriptomic landscape.
• While sharing pathways with dilated cardiomyopathy, HFpEF has distinct cardiomyocyte alterations suggesting a specific pathological driver.
• These findings offer a high-resolution map for identifying novel precision therapeutic targets for HFpEF.