Transcriptomic and spatial dissection of human ex vivo right atrial tissue reveals proinflammatory microvascular changes in ischemic heart disease

Suvi Linna-Kuosmanen; Eloi Schmauch; Kyriakitsa Galani; Johannes Ojanen; Carles A Boix; Tiit Örd; Anu Toropainen; Prosanta K Singha; Pierre R Moreau; Kristiina Harju; Adriana Blazeski; Åsa Segerstolpe; Veikko Lahtinen; Lei Hou; Kai Kang; Elamaran Meibalan; Leandro Z Agudelo; Hannu Kokki; Jari Halonen; Juho Jalkanen; Jarmo Gunn; Calum A MacRae; Maija Hollmén; Juha E K Hartikainen; Minna U Kaikkonen; Guillermo García-Cardeña; Pasi Tavi; Tuomas Kiviniemi; Manolis Kellis

doi:10.1016/j.xcrm.2024.101556

Transcriptomic and spatial dissection of human ex vivo right atrial tissue reveals proinflammatory microvascular changes in ischemic heart disease

Cell Rep Med. 2024 May 21;5(5):101556. doi: 10.1016/j.xcrm.2024.101556.

Authors

Suvi Linna-Kuosmanen¹, Eloi Schmauch², Kyriakitsa Galani³, Johannes Ojanen², Carles A Boix³, Tiit Örd⁴, Anu Toropainen⁴, Prosanta K Singha⁴, Pierre R Moreau⁴, Kristiina Harju⁴, Adriana Blazeski⁵, Åsa Segerstolpe⁶, Veikko Lahtinen⁷, Lei Hou³, Kai Kang³, Elamaran Meibalan⁵, Leandro Z Agudelo³, Hannu Kokki⁸, Jari Halonen⁹, Juho Jalkanen¹⁰, Jarmo Gunn¹¹, Calum A MacRae¹², Maija Hollmén¹⁰, Juha E K Hartikainen⁹, Minna U Kaikkonen⁴, Guillermo García-Cardeña¹³, Pasi Tavi⁴, Tuomas Kiviniemi¹⁴, Manolis Kellis¹⁵

Affiliations

¹ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland. Electronic address: suvi.linna-kuosmanen@uef.fi.
² Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
³ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Heart Center, Turku University Hospital, 20521 Turku, Finland; MediCity Research Laboratories and InFLAMES Flagship, University of Turku, 20500 Turku, Finland.
⁸ School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
⁹ School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland; Heart Center, Kuopio University Hospital, 70200 Kuopio, Finland.
¹⁰ MediCity Research Laboratories and InFLAMES Flagship, University of Turku, 20500 Turku, Finland.
¹¹ Heart Center, Turku University Hospital, 20521 Turku, Finland; Department of Medicine, University of Turku, 20500 Turku, Finland.
¹² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Cardiovascular Medicine and Network Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
¹³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
¹⁴ Heart Center, Turku University Hospital, 20521 Turku, Finland; Department of Medicine, University of Turku, 20500 Turku, Finland; Cardiovascular Medicine and Network Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹⁵ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: manoli@mit.edu.

Abstract

Cardiovascular disease plays a central role in the electrical and structural remodeling of the right atrium, predisposing to arrhythmias, heart failure, and sudden death. Here, we dissect with single-nuclei RNA sequencing (snRNA-seq) and spatial transcriptomics the gene expression changes in the human ex vivo right atrial tissue and pericardial fluid in ischemic heart disease, myocardial infarction, and ischemic and non-ischemic heart failure using asymptomatic patients with valvular disease who undergo preventive surgery as the control group. We reveal substantial differences in disease-associated gene expression in all cell types, collectively suggesting inflammatory microvascular dysfunction and changes in the right atrial tissue composition as the valvular and vascular diseases progress into heart failure. The data collectively suggest that investigation of human cardiovascular disease should expand to all functionally important parts of the heart, which may help us to identify mechanisms promoting more severe types of the disease.

Keywords: cardiovascular disease; disease mechanism; genetic variation; heart; heart failure; inflammation; ischemic heart disease; single cell; spatial transcriptomics; transcriptomics.

MeSH terms

Aged
Female
Gene Expression Regulation
Heart Atria* / metabolism
Heart Atria* / pathology
Humans
Inflammation / genetics
Inflammation / pathology
Male
Microvessels* / pathology
Middle Aged
Myocardial Ischemia* / genetics
Myocardial Ischemia* / metabolism
Myocardial Ischemia* / pathology
Transcriptome* / genetics