Larry Scott1, Anke C Fender2, Arnela Saljic3, Luge Li4, Xiaohui Chen4, Xiaolei Wang4, Dominik Linz3,5,6, Jilu Lang7, Mathias Hohl8, Darragh Twomey9, Thuy T Pham4, Rodrigo Diaz-Lankenau4, Mihail G Chelu10, Markus Kamler11, Mark L Entman4, George E Taffet4, Prashanthan Sanders6, Dobromir Dobrev2, Na Li1,4,12. 1. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA. 2. Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany. 3. Laboratory of Cardiac Physiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. 4. Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA. 5. Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands. 6. Centre for Heart Rhythm Disorders, South Australian Health and Medical Research Institute, Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia. 7. Department of Cardiac Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China. 8. Department of Cardiology/Angiology, University-Clinic of Saarland, Internal Medicine III, Homburg/Saar, Germany. 9. James Cook University Hospital, Middlesbrough, UK. 10. Division of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA. 11. Department of Thoracic and Cardiovascular Surgery, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany. 12. Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
Abstract
AIMS: Obesity, an established risk factor of atrial fibrillation (AF), is frequently associated with enhanced inflammatory response. However, whether inflammatory signaling is causally linked to AF pathogenesis in obesity remains elusive. We recently demonstrated that the constitutive activation of the 'NACHT, LRR, and PYD Domains-containing Protein 3' (NLRP3) inflammasome promotes AF susceptibility. In this study, we hypothesized that the NLRP3 inflammasome is a key driver of obesity-induced AF. METHODS AND RESULTS: Western blotting was performed to determine the level of NLRP3 inflammasome activation in atrial tissues of obese patients, sheep, and diet-induced obese (DIO) mice. The increased body weight in patients, sheep, and mice was associated with enhanced NLRP3-inflammasome activation. To determine whether NLRP3 contributes to the obesity-induced atrial arrhythmogenesis, wild-type (WT) and NLRP3 homozygous knockout (NLRP3-/-) mice were subjected to high-fat-diet (HFD) or normal chow (NC) for 10 weeks. Relative to NC-fed WT mice, HFD-fed WT mice were more susceptible to pacing-induced AF with longer AF duration. In contrast, HFD-fed NLRP3-/- mice were resistant to pacing-induced AF. Optical mapping in DIO mice revealed an arrhythmogenic substrate characterized by abbreviated refractoriness and action potential duration (APD), two key determinants of reentry-promoting electrical remodeling. Upregulation of ultra-rapid delayed-rectifier K+-channel (Kv1.5) contributed to the shortening of atrial refractoriness. Increased profibrotic signaling and fibrosis along with abnormal Ca2+ release from sarcoplasmic reticulum (SR) accompanied atrial arrhythmogenesis in DIO mice. Conversely, genetic ablation of Nlrp3 (NLRP3-/-) in HFD-fed mice prevented the increases in Kv1.5 and the evolution of electrical remodeling, the upregulation of profibrotic genes, and abnormal SR Ca2+ release in DIO mice. CONCLUSION: These results demonstrate that the atrial NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmogenesis and establishes a mechanistic link between obesity-induced AF and NLRP3-inflammasome activation. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Obesity, an established risk factor of atrial fibrillation (AF), is frequently associated with enhanced inflammatory response. However, whether inflammatory signaling is causally linked to AF pathogenesis in obesity remains elusive. We recently demonstrated that the constitutive activation of the 'NACHT, LRR, and PYD Domains-containing Protein 3' (NLRP3) inflammasome promotes AF susceptibility. In this study, we hypothesized that the NLRP3 inflammasome is a key driver of obesity-induced AF. METHODS AND RESULTS: Western blotting was performed to determine the level of NLRP3 inflammasome activation in atrial tissues of obese patients, sheep, and diet-induced obese (DIO) mice. The increased body weight in patients, sheep, and mice was associated with enhanced NLRP3-inflammasome activation. To determine whether NLRP3 contributes to the obesity-induced atrial arrhythmogenesis, wild-type (WT) and NLRP3 homozygous knockout (NLRP3-/-) mice were subjected to high-fat-diet (HFD) or normal chow (NC) for 10 weeks. Relative to NC-fed WT mice, HFD-fed WT mice were more susceptible to pacing-induced AF with longer AF duration. In contrast, HFD-fed NLRP3-/- mice were resistant to pacing-induced AF. Optical mapping in DIO mice revealed an arrhythmogenic substrate characterized by abbreviated refractoriness and action potential duration (APD), two key determinants of reentry-promoting electrical remodeling. Upregulation of ultra-rapid delayed-rectifier K+-channel (Kv1.5) contributed to the shortening of atrial refractoriness. Increased profibrotic signaling and fibrosis along with abnormal Ca2+ release from sarcoplasmic reticulum (SR) accompanied atrial arrhythmogenesis in DIO mice. Conversely, genetic ablation of Nlrp3 (NLRP3-/-) in HFD-fed mice prevented the increases in Kv1.5 and the evolution of electrical remodeling, the upregulation of profibrotic genes, and abnormal SR Ca2+ release in DIO mice. CONCLUSION: These results demonstrate that the atrial NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmogenesis and establishes a mechanistic link between obesity-induced AF and NLRP3-inflammasome activation. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Roberto Galea; Maria Teresa Cardillo; Annalisa Caroli; Maria Giulia Marini; Chiara Sonnino; Maria L Narducci; Luigi M Biasucci Journal: Tex Heart Inst J Date: 2014-10-01
Authors: Christos A Goudis; Panagiotis Korantzopoulos; Ioannis V Ntalas; Eleftherios M Kallergis; Dimitrios G Ketikoglou Journal: J Cardiol Date: 2015-05-07 Impact factor: 3.159
Authors: Chunxia Yao; Tina Veleva; Larry Scott; Shuyi Cao; Luge Li; Gong Chen; Prince Jeyabal; Xiaolu Pan; Katherina M Alsina; Issam Abu-Taha; Shokoufeh Ghezelbash; Corey L Reynolds; Ying H Shen; Scott A LeMaire; Wilhelm Schmitz; Frank U Müller; Ali El-Armouche; N Tony Eissa; Christine Beeton; Stanley Nattel; Xander H T Wehrens; Dobromir Dobrev; Na Li Journal: Circulation Date: 2018-11-13 Impact factor: 29.690
Authors: Shanna Hamilton; Radmila Terentyeva; Benjamin Martin; Fruzsina Perger; Jiaoni Li; Andrei Stepanov; Ingrid M Bonilla; Björn C Knollmann; Przemyslaw B Radwański; Sandor Györke; Andriy E Belevych; Dmitry Terentyev Journal: Basic Res Cardiol Date: 2020-05-22 Impact factor: 17.165
Authors: Basil S Karam; Alejandro Chavez-Moreno; Wonjoon Koh; Joseph G Akar; Fadi G Akar Journal: Cardiovasc Diabetol Date: 2017-09-29 Impact factor: 9.951
Authors: Monika Gawałko; Thomas A Agbaedeng; Arnela Saljic; Dominik N Müller; Nicola Wilck; Renate Schnabel; John Penders; Michiel Rienstra; Isabelle van Gelder; Thomas Jespersen; Ulrich Schotten; Harry J G M Crijns; Jonathan M Kalman; Prashanthan Sanders; Stanley Nattel; Dobromir Dobrev; Dominik Linz Journal: Cardiovasc Res Date: 2022-08-24 Impact factor: 13.081