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Eur. Heart J., May 08 2025, ehaf272 | https://doi.org/10.1093/eurheartj/ehaf272
Spatial transcriptional landscape of human heart failure
Sang Eun Lee1,2,†, Jeong Ho Joo3,†, Hee Sang Hwang4,†, Shang-Fu Chen2, Douglas Evans2, Kyoung Yul Lee5, Kyung-Hee Kim6, Junho Hyun1, Min-Seok Kim1, Sung-Ho Jung7, Jae-Joong Kim1, Jeong Seok Lee3, and Ali Torkamani2,8,*
1Department of Cardiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
2Scripps Research Translational Institute, 3344 North Torrey Pines Court, La Jolla, CA 92037, USA;
3Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea;
4Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
5Pathology Center, Seegene Medical Foundation, Seoul, Korea;
6Division of Cardiology, Cardiovascular Center, Incheon Sejong Hospital, Incheon, Korea;
7Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; and
8Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA, USA
* Corresponding author: Ali Torkamani
† The first three authors contributed equally to the study.
1Department of Cardiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
2Scripps Research Translational Institute, 3344 North Torrey Pines Court, La Jolla, CA 92037, USA;
3Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea;
4Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
5Pathology Center, Seegene Medical Foundation, Seoul, Korea;
6Division of Cardiology, Cardiovascular Center, Incheon Sejong Hospital, Incheon, Korea;
7Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; and
8Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA, USA
* Corresponding author: Ali Torkamani
† The first three authors contributed equally to the study.
Abstract
Background and aims: Heart failure (HF) remains a significant clinical challenge due to its diverse aetiologies and complex pathophysiology. The molecular alterations specific to distinct cell types and histological patterns during HF progression are still poorly characterized. This study aimed to explore cell-type- and histology-specific gene expression profiles in cardiomyopathies.
Methods: Ninety tissue cores from 44 participants, encompassing various forms of cardiomyopathy and control samples with diverse histological features, were analysed using the GeoMx Whole Human Transcriptome Atlas. Data on cell types, clinical information, and histological features were integrated to examine gene expression profiles in cardiomyopathy.
Results: The study characterized the cellular composition of ventricular myocardium and validated the GeoMx platform's efficiency in compartmentalizing specific cell types, demonstrating high accuracy for cardiomyocytes but limitations for endothelial cells and fibroblasts. Differentially expressed genes, including UCHL1 from cardiomyocytes, were associated with degeneration, while CCL14, ACKR1, and PLVAP from endothelial cells were linked to fibrosis. Multiplex immunohistochemistry and integrative analysis of prior sc/snRNA-seq data identified a PLVAP, ACKR1, and CCL14-positive pro-inflammatory endothelial cell subtype linked to fibrosis in HF. Downregulation of ribosomal proteins in cardiomyocytes was associated with myocyte disarray in hypertrophic cardiomyopathy. Additionally, pronounced inflammatory responses were observed in end-stage HF. Combined histological and clinical analysis identified CRIP3, PFKFB2, and TAX1BP3 as novel contributors to HF pathogenesis.
Conclusions: These findings highlight the critical role of cell-enriched and histology-specific transcriptome mapping in understanding the complex pathophysiological landscape of failing hearts, offering molecular insights and potential therapeutic targets for future interventions.
Methods: Ninety tissue cores from 44 participants, encompassing various forms of cardiomyopathy and control samples with diverse histological features, were analysed using the GeoMx Whole Human Transcriptome Atlas. Data on cell types, clinical information, and histological features were integrated to examine gene expression profiles in cardiomyopathy.
Results: The study characterized the cellular composition of ventricular myocardium and validated the GeoMx platform's efficiency in compartmentalizing specific cell types, demonstrating high accuracy for cardiomyocytes but limitations for endothelial cells and fibroblasts. Differentially expressed genes, including UCHL1 from cardiomyocytes, were associated with degeneration, while CCL14, ACKR1, and PLVAP from endothelial cells were linked to fibrosis. Multiplex immunohistochemistry and integrative analysis of prior sc/snRNA-seq data identified a PLVAP, ACKR1, and CCL14-positive pro-inflammatory endothelial cell subtype linked to fibrosis in HF. Downregulation of ribosomal proteins in cardiomyocytes was associated with myocyte disarray in hypertrophic cardiomyopathy. Additionally, pronounced inflammatory responses were observed in end-stage HF. Combined histological and clinical analysis identified CRIP3, PFKFB2, and TAX1BP3 as novel contributors to HF pathogenesis.
Conclusions: These findings highlight the critical role of cell-enriched and histology-specific transcriptome mapping in understanding the complex pathophysiological landscape of failing hearts, offering molecular insights and potential therapeutic targets for future interventions.
논문정보
- Research article
- 2025년 05월 (BRIC 등록일 2025-05-09)
- 국내+국외 연구진
- 의약학 > 분자세포의학
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