Abstract: TH-PO0261
Multimodal Atlas of Human Heart Failure with Preserved Ejection Fraction
Session Information
- Hypertension and CVD: Mechanisms
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Hoeft, Konrad, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Peisker, Fabian, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Tangos, Melina, Ruhr-Universitat Bochum, Bochum, NRW, Germany
- Zhazykbayeva, Saltanat, Ruhr-Universitat Bochum, Bochum, NRW, Germany
- Wahida, Adam, Helmholtz Zentrum Munchen Deutsches Forschungszentrum fur Gesundheit und Umwelt Gmbh, Neuherberg, BY, Germany
- Shaw, Isaac, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Schaefer, Gideon J L, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Hansen, Jens, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Schreibing, Felix, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Schumacher, David, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Zhang, Ling, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Long, Qingqing, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Koch, Lars, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Proneth, Bettina, Helmholtz Zentrum Munchen Deutsches Forschungszentrum fur Gesundheit und Umwelt Gmbh, Neuherberg, BY, Germany
- Hayat, Sikander, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Conrad, Marcus, Helmholtz Zentrum Munchen Deutsches Forschungszentrum fur Gesundheit und Umwelt Gmbh, Neuherberg, BY, Germany
- Hamdani, Nazha, Ruhr-Universitat Bochum, Bochum, NRW, Germany
- Kramann, Rafael, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
Background
CKD and heart failure are closely linked disease conditions. Every 5th CKD patient develops de novo heart failure, while the combination of CKD and heart failure is associated with poor survival. While historically research focused on heart failure with reduced ejection fraction (HFrEF), currently every second heart failure case presents with a preserved ejection fraction, termed HFpEF. Critically, CKD is a major driver of HFpEF. However, the underlying molecular mechanisms that drive HFpEF development, including CKD-driven signaling pathways, remain elusive.
Methods
We performed snRNAseq, spatial transcriptomics, RNAseq and mass spectrometry of cardiac biopsies from HFpEF, HFrEF and control patients (A). Addtionally, we measured cardiac GSSG/GSH ratios and investigated diastolic dysfunction in Ybx1+/- mice.
Results
snRNAseq identified a distinct HFpEF cardiomyocyte trajectory defined by dysregulated ROS metabolism (B-D). Multi-omic data analysis uncoverd a protein-RNA mismatch for reactive oxygen species (ROS) metabolism in HFpEF (D). Myocardial GSSG/GSH ratios corroborated aberrant redox stress (E). In vivo, we demonstrate that loss of YBX1, a compensatory upregulated transcription factor previously linked to an adaptive stress response and regulation of CKD, accelerates development of diastolic dysfunction (F-G).
Conclusion
Our multi-modal analysis uncovers a unique HFpEF cardiomyocyte cell state characterized by aberrant redox stress and compensatory upregulation of Ybx1.
(A) Study schematic. (B) Cardiomyocytes trajectory inference. (C) Density plots along pseudotime for Trajectory 1 and 2 stratified by condition. (D) Expression of Response to ROS genes along cardiomyocyte Trajectory 1 (HFpEF) and 2 (HFrEF) and in mass spectrometry data. (E) GSSG/GSH ratios in cardiac biopsies. (F) Nebulosa YBX1 expression along cardioymyocte trajectories. (G) E/E' ratios [marker of diastolic dysfunction] in WT and Ybx1+/- mice.
Funding
- Government Support – Non-U.S.