Mathias Hohl1, Simina-Ramona Selejan1, Jan Wintrich1, Ulrike Lehnert1, Thimoteus Speer2,3, Clara Schneider1, Muriel Mauz1, Philipp Markwirth1, Dickson W L Wong4, Peter Boor4, Andrey Kazakov1, Martin Mollenhauer5, Benedikt Linz6, Barbara Mara Klinkhammer4, Ulrich Hübner7, Christian Ukena1, Julia Moellmann8, Michael Lehrke8, Stefan Wagenpfeil9, Christian Werner1, Dominik Linz1,10, Felix Mahfoud1, Michael Böhm1. 1. Department of Internal Medicine III, Saarland University Hospital and Saarland University, Homburg/Saar, Germany (M.H., S.-R.S., J.W., U.L., C.S., M. Mauz, P.M., A.K., C.U., C.W., D.L., F.M., M.B.). 2. Klinik für Innere Medizin IV, Universität des Saarlandes, Homburg/Saar, Germany (T.S.). 3. Translational Cardio-Renal Medicine, Saarland University, Homburg/Saar, Germany (T.S.). 4. Institut für Pathologie Universitätsklinikum Aachen, Germany (D.W.L.W., P.B., B.M.K.). 5. Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Germany (M. Mollenhauer). 6. Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Denmark (B.L.). 7. Department of Clinical Chemistry and Laboratory Medicine, Saarland University Hospital, Homburg/Saar, Germany (U.H.). 8. Department of Internal Medicine I-Cardiology, University Hospital Aachen, Germany (J.M., M.L.). 9. Institut für Medizinische Biometrie, Epidemiologie und Medizinische Informatik, Saarland University, Homburg/Saar, Germany (S.W.). 10. Cardiovascular Research Institute Maastricht, University Maastricht, the Netherlands (D.L.).
Abstract
BACKGROUND: In patients with chronic kidney disease (CKD), atrial fibrillation (AF) is highly prevalent and represents a major risk factor for stroke and death. CKD is associated with atrial proarrhythmic remodeling and activation of the sympathetic nervous system. Whether reduction of the sympathetic nerve activity by renal denervation (RDN) inhibits AF vulnerability in CKD is unknown. METHODS: Left atrial (LA) fibrosis was analyzed in samples from patients with AF and concomitant CKD (estimated glomerular filtration rate [eGFR], <60 mL/min per 1.73 m2) using picrosirius red and compared with AF patients without CKD and patients with sinus rhythm with and without CKD. In a translational approach, male Sprague Dawley rats were fed with 0.25% adenine (AD)-containing chow for 16 weeks to induce CKD. At week 5, AD-fed rats underwent RDN or sham operation (AD). Rats on normal chow served as control. After 16 weeks, cardiac function and AF susceptibility were assessed by echocardiography, radiotelemetry, electrophysiological mapping, and burst stimulation, respectively. LA tissue was histologically analyzed for sympathetic innervation using tyrosine hydroxylase staining, and LA fibrosis was determined using picrosirius red. RESULTS: Sirius red staining demonstrated significantly increased LA fibrosis in patients with AF+CKD compared with AF without CKD or sinus rhythm. In rats, AD demonstrated LA structural changes with enhanced sympathetic innervation compared with control. In AD, LA enlargement was associated with prolonged duration of induced AF episodes, impaired LA conduction latency, and increased absolute conduction inhomogeneity. RDN treatment improved LA remodeling and reduced LA diameter compared with sham-operated AD. Furthermore, RDN decreased AF susceptibility and ameliorated LA conduction latency and absolute conduction inhomogeneity, independent of blood pressure reduction and renal function. CONCLUSIONS: In an experimental rat model of CKD, RDN inhibited progression of atrial structural and electrophysiological remodeling. Therefore, RDN represents a potential therapeutic tool to reduce the risk of AF in CKD, independent of changes in renal function and blood pressure.
BACKGROUND: In patients with chronic kidney disease (CKD), atrial fibrillation (AF) is highly prevalent and represents a major risk factor for stroke and death. CKD is associated with atrial proarrhythmic remodeling and activation of the sympathetic nervous system. Whether reduction of the sympathetic nerve activity by renal denervation (RDN) inhibits AF vulnerability in CKD is unknown. METHODS: Left atrial (LA) fibrosis was analyzed in samples from patients with AF and concomitant CKD (estimated glomerular filtration rate [eGFR], <60 mL/min per 1.73 m2) using picrosirius red and compared with AF patients without CKD and patients with sinus rhythm with and without CKD. In a translational approach, male Sprague Dawley rats were fed with 0.25% adenine (AD)-containing chow for 16 weeks to induce CKD. At week 5, AD-fed rats underwent RDN or sham operation (AD). Rats on normal chow served as control. After 16 weeks, cardiac function and AF susceptibility were assessed by echocardiography, radiotelemetry, electrophysiological mapping, and burst stimulation, respectively. LA tissue was histologically analyzed for sympathetic innervation using tyrosine hydroxylase staining, and LA fibrosis was determined using picrosirius red. RESULTS: Sirius red staining demonstrated significantly increased LA fibrosis in patients with AF+CKD compared with AF without CKD or sinus rhythm. In rats, AD demonstrated LA structural changes with enhanced sympathetic innervation compared with control. In AD, LA enlargement was associated with prolonged duration of induced AF episodes, impaired LA conduction latency, and increased absolute conduction inhomogeneity. RDN treatment improved LA remodeling and reduced LA diameter compared with sham-operated AD. Furthermore, RDN decreased AF susceptibility and ameliorated LA conduction latency and absolute conduction inhomogeneity, independent of blood pressure reduction and renal function. CONCLUSIONS: In an experimental rat model of CKD, RDN inhibited progression of atrial structural and electrophysiological remodeling. Therefore, RDN represents a potential therapeutic tool to reduce the risk of AF in CKD, independent of changes in renal function and blood pressure.