Fibroblast-Restricted Inflammasome Activation Promotes Atrial Fibrillation and Heart Failure With Diastolic Dysfunction

Luge Li; Cristian Coarfa; Yue Yuan; Issam Abu-Taha; Xiaolei Wang; Jia Song; Yuying Zeng; Xiaohui Chen; Amrit Koirala; Sandra L Grimm; Markus Kamler; Lisa K McClendon; Michelle Tallquist; Stanley Nattel; Dobromir Dobrev; Na Li

doi:10.1016/j.jacbts.2025.02.004

Fibroblast-Restricted Inflammasome Activation Promotes Atrial Fibrillation and Heart Failure With Diastolic Dysfunction

JACC Basic Transl Sci. 2025 Apr 16:101244. doi: 10.1016/j.jacbts.2025.02.004. Online ahead of print.

Authors

Luge Li¹, Cristian Coarfa², Yue Yuan¹, Issam Abu-Taha³, Xiaolei Wang¹, Jia Song¹, Yuying Zeng¹, Xiaohui Chen¹, Amrit Koirala⁴, Sandra L Grimm², Markus Kamler⁵, Lisa K McClendon⁴, Michelle Tallquist⁶, Stanley Nattel⁷, Dobromir Dobrev⁸, Na Li⁹

Affiliations

¹ Department of Medicine (Section of Cardiovascular Research), Baylor College of Medicine, Houston, Texas, USA.
² Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
³ Institute of Pharmacology, University Duisburg-Essen, Essen, Germany.
⁴ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
⁵ Department of Thoracic and Cardiovascular Surgery, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany.
⁶ Center for Cardiovascular Research, University of Hawaii, Honolulu, Hawaii, USA.
⁷ Institute of Pharmacology, University Duisburg-Essen, Essen, Germany; Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada; IHU LIRYC and Fondation Bordeaux Université, Bordeaux, France.
⁸ Institute of Pharmacology, University Duisburg-Essen, Essen, Germany; Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada; Department of Integrative Physiology, Baylor College of Medicine, Houston, Texas, USA.
⁹ Department of Medicine (Section of Cardiovascular Research), Baylor College of Medicine, Houston, Texas, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas, USA. Electronic address: nal@bcm.edu.

PMID: 40243956
DOI: 10.1016/j.jacbts.2025.02.004

Abstract

Atrial fibrillation (AF) often coexists with heart failure, both involving inflammatory signaling and cardiac fibroblasts. To understand the role of fibroblast NLR family pyrin domain containing 3 (NLRP3) inflammasome in cardiac function, we found that NLRP3 was up-regulated in atrial fibroblasts from AF patients. Fibroblast-specific activation of NLRP3 in mice induced AF-promoting atrial myopathy and heart failure with diastolic dysfunction, accompanied by increased fibrosis, and reduced conduction velocity. Knockdown of NLRP3 prevented the AF-promoting atrial substrate and cardiomyopathy in the context of NLRP3 activation in fibroblasts. We identify the fibroblast NLRP3 inflammasome as a key pathway governing the promotion of proarrhythmic fibrosis in AF and cardiomyopathy.

Keywords: atrial cardiomyopathy; atrial fibrillation; cardiac fibroblast; fibrosis; inflammasome.