Myocardial infarction is a leading cause of death worldwide1. Although advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness of therapies to reduce late-stage mortality2. Here we generate an integrative high-resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from patients with myocardial infarction and controls. Multi-modal data integration enabled us to evaluate cardiac cell-type compositions at increased resolution, yielding insights into changes of the cardiac transcriptome and epigenome through the identification of distinct tissue structures of injury, repair and remodelling. We identified and validated disease-specific cardiac cell states of major cell types and analysed them in their spatial context, evaluating their dependency on other cell types. Our data elucidate the molecular principles of human myocardial tissue organization, recapitulating a gradual cardiomyocyte and myeloid continuum following ischaemic injury. In sum, our study provides an integrative molecular map of human myocardial infarction, represents an essential reference for the field and paves the way for advanced mechanistic and therapeutic studies of cardiac disease.
Bibliographical noteFunding Information:
This work was supported by grants of the German Research Foundation (DFG: SFBTRR219 to R.K.), CRU344-4288578857858 and CRU5011-445703531 to R.K., by two grants from the European Research Council (ERC-StG 677448, ERC-CoG 101043403), a grant from the Else Kroener Fresenius Foundation (EKFS), the Dutch Kidney Foundation (DKF), TASKFORCE EP1805, the NWO VIDI 09150172010072 and a grant from the Leducq Foundation, all to R.K., a grant from the Germany Society of Internal Medicine (DGIM) and a grant from the European Research Council (ERC-StG 101040726) to C.K., and a grant from the IZKF Faculty of Medicine at the RWTH Aachen University to I.G.C. This work was also supported by the BMBF eMed Consortia Fibromap (to I.G.C., R.K. and R.K.S.). J.S.-R., R.O.R.F. and R.T.L. are supported by Informatics for Life funded by the Klaus Tschira Foundation. D.Schapiro. and F.W. are supported by the German Federal Ministry of Education and Research (BMBF 01ZZ2004). P.B. is supported by the German Research Foundation (DFG, Project IDs 322900939, 454024652). 10X Genomics supported the project via the Visium challenge (to C.K.) and provided free data generation for Visium data of 8 specimens. We thank J. Cool and J. Hilton for supporting data submission to cellxgene Data Portal; E. Sapena Ventura and G. Yordanova for their support; J. Chew and S. Williams (10X Genomics) for their support; A. Valdeolivas, J. Lanzer, A. Gabor, P. Badia i Mompel and D. Dimitrov for fruitful discussions that shaped the computational analysis. We also acknowledge the support from E. Siera, U. Förster, V. Künstler, N. Graff, P. Cappelmann, L. Tenten, I.-K. Härthe and L. Palm. R.O.R.F. and J.S.-R. acknowledge support from the High Performance and Cloud Computing Group at the Zentrum für Datenverarbeitung of the University of Tübingen, the state of Baden-Württemberg through bwHPC and the German Research Foundation (DFG) through grant no INST 37/935-1 FUGG.
The authors declare no competing interests directly related to this work. The authors however disclose unrelated funding, honorariums and ownership as follows: R.K. has grants from Travere Therapeutics, Galapagos, Chugai and Novo Nordisk and is a consultant for Bayer, Pfizer, Novo Nordisk and Gruenenthal. J.S.-R. reports funding from GSK and Sanofi and fees from Travere Therapeutics and Astex Therapeutics. K.L. has grants from Novartis and Amgen and receives consulting fees from Medtronic and Implicit Biosciences. I.G.C. has a grant from Illumina. L.S. has received grants from Bayer, Boehringer Ingelheim and Nattopharma, is consultant for ImmunoDiagnostics Systems (IDS) and is a shareholder in Coagulation Profile. L.W.V.L. reports consultancy fees to UMCU from Abbott, Medtronic, Vifor and Novartis.
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