Sven Kaese1, Nils Bögeholz2, Paul Pauls3, Dirk Dechering2, Jan Olligs2, Katharina Kölker2, Sascha Badawi2, Gerrit Frommeyer2, Christian Pott2, Lars Eckardt2. 1. Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany. Electronic address: sven.kaese@ukmuenster.de. 2. Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany. 3. Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany; Institute of Pharmacology and Toxicology, University of Münster, Münster, Germany.
Abstract
BACKGROUND: The cardiac sodium/calcium (Na+/Ca2+) exchanger (NCX) contributes to diastolic depolarization in cardiac pacemaker cells. Increased NCX activity has been found in heart failure and atrial fibrillation. The influence of increased NCX activity on resting heart rate, beta-adrenergic-mediated increase in heart rate, and cardiac conduction properties is unknown. OBJECTIVE: The purpose of this study was to investigate the influence of NCX overexpression in a homozygous transgenic whole-heart mouse model (NCX-OE) on sinus and AV nodal function. METHODS: Langendorff-perfused, beating whole hearts of NCX-OE and the corresponding wild-type (WT) were studied ± isoproterenol (ISO; 0.2 μM). Epicardial ECG, AV nodal Wenckebach cycle length (AVN-WCL), and retrograde AVN-WCL were obtained. RESULTS: At baseline, basal heart rate was unaltered between NCX-OE and WT (WT: cycle length [CL] 177.6 ± 40.0 ms, no. of hearts [n] = 20; NCX-OE: CL 185.9 ± 30.5 ms, n = 18; P = .21). In the presence of ISO, NCX-OE exhibited a significantly higher heart rate compared to WT (WT: CL 133.4 ± 13.4 ms, n = 20; NCX-OE: CL 117.7 ± 14.2 ms, n = 18; P <.001). ISO led to a significant shortening of the anterograde and retrograde AVN-WCL without differences between NCX-OE and WT. CONCLUSION: This study is the first to demonstrate that increased NCX activity enhances beta-adrenergic increase of heart rate. Mechanistically, increased NCX inward mode activity may promote acceleration of diastolic depolarization in sinus nodal pacemaker cells, thus enhancing chronotropy in NCX-OE. These findings suggest a novel potential therapeutic target for heart rate control in the presence of increased NCX activity, such as heart failure.
BACKGROUND: The cardiac sodium/calcium (Na+/Ca2+) exchanger (NCX) contributes to diastolic depolarization in cardiac pacemaker cells. Increased NCX activity has been found in heart failure and atrial fibrillation. The influence of increased NCX activity on resting heart rate, beta-adrenergic-mediated increase in heart rate, and cardiac conduction properties is unknown. OBJECTIVE: The purpose of this study was to investigate the influence of NCX overexpression in a homozygous transgenic whole-heart mouse model (NCX-OE) on sinus and AV nodal function. METHODS: Langendorff-perfused, beating whole hearts of NCX-OE and the corresponding wild-type (WT) were studied ± isoproterenol (ISO; 0.2 μM). Epicardial ECG, AV nodal Wenckebach cycle length (AVN-WCL), and retrograde AVN-WCL were obtained. RESULTS: At baseline, basal heart rate was unaltered between NCX-OE and WT (WT: cycle length [CL] 177.6 ± 40.0 ms, no. of hearts [n] = 20; NCX-OE: CL 185.9 ± 30.5 ms, n = 18; P = .21). In the presence of ISO, NCX-OE exhibited a significantly higher heart rate compared to WT (WT: CL 133.4 ± 13.4 ms, n = 20; NCX-OE: CL 117.7 ± 14.2 ms, n = 18; P <.001). ISO led to a significant shortening of the anterograde and retrograde AVN-WCL without differences between NCX-OE and WT. CONCLUSION: This study is the first to demonstrate that increased NCX activity enhances beta-adrenergic increase of heart rate. Mechanistically, increased NCX inward mode activity may promote acceleration of diastolic depolarization in sinus nodal pacemaker cells, thus enhancing chronotropy in NCX-OE. These findings suggest a novel potential therapeutic target for heart rate control in the presence of increased NCX activity, such as heart failure.
Authors: Leena Otsomaa; Jouko Levijoki; Gerd Wohlfahrt; Hugh Chapman; Ari-Pekka Koivisto; Kaisa Syrjänen; Tuula Koskelainen; Saara-Elisa Peltokorpi; Piet Finckenberg; Aira Heikkilä; Najah Abi-Gerges; Andre Ghetti; Paul E Miller; Guy Page; Eero Mervaala; Norbert Nagy; Zsófia Kohajda; Norbert Jost; László Virág; András Varró; Julius Gy Papp Journal: Br J Pharmacol Date: 2020-11-10 Impact factor: 8.739