Maarten Hulsmans1, Aaron D Aguirre1,2, Matthew D Bonner3, Aneesh Bapat4,5, Sebastian Cremer1, Yoshiko Iwamoto1, Kevin R King1,6,7, Filip K Swirski1, David J Milan2,4,8, Ralph Weissleder1,9, Matthias Nahrendorf1,4. 1. From the Department of Radiology, Center for Systems Biology (M.H., A.D.A., S.C., Y.I., K.R.K., F.K.S., R.W., M.N.), Massachusetts General Hospital and Harvard Medical School, Boston. 2. Cardiology Division (A.D.A., D.J.M.), Massachusetts General Hospital and Harvard Medical School, Boston. 3. Cardiac Rhythm and Heart Failure, Medtronic PLC, Mounds View, MN (M.D.B.). 4. Cardiovascular Research Center (A.B., D.J.M., M.N.), Massachusetts General Hospital and Harvard Medical School, Boston. 5. Cardiology Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (A.B.). 6. Department of Bioengineering, Jacobs School of Engineering (K.R.K.), University of California San Diego, La Jolla. 7. Department of Medicine, Cardiology Division (K.R.K.), University of California San Diego, La Jolla. 8. Program in Population and Medical Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA (D.J.M.). 9. Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Abstract
RATIONALE: Cardiac pacing is a critical technology for the treatment of arrhythmia and heart failure. The impact of specific pacing strategies on myocardial function is an area of intense research and high clinical significance. Mouse models have proven extremely useful for probing mechanisms of heart disease, but there is currently no reliable technology for long-term pacing in the mouse. OBJECTIVE: We sought to develop a device for long-term pacing studies in mice. We evaluated the device for (1) treating third-degree atrioventricular block after macrophage depletion, (2) ventricular pacing-induced cardiomyopathy, and (3) high-rate atrial pacing. METHODS AND RESULTS: We developed a mouse pacemaker by refashioning a 26 mm×6.7 mm clinical device powered by a miniaturized, highly efficient battery. The electrode was fitted with a single flexible lead, and custom software extended the pacing rate to up to 1200 bpm. The wirelessly programmable device was implanted in the dorsal subcutaneous space of 39 mice. The tunneled lead was passed through a left thoracotomy incision and attached to the epicardial surface of the apex (for ventricular pacing) or the left atrium (for atrial pacing). Mice tolerated the implantation and both long-term atrial and ventricular pacing over weeks. We then validated the pacemaker's suitability for the treatment of atrioventricular block after macrophage depletion in Cd11b DTR mice. Ventricular pacing increased the heart rate from 313±59 to 550 bpm ( P<0.05). In addition, we characterized tachypacing-induced cardiomyopathy in mice. Four weeks of ventricular pacing resulted in reduced left ventricular function, fibrosis, and an increased number of cardiac leukocytes and endothelial activation. Finally, we demonstrated the feasibility of chronic atrial pacing at 1200 bpm. CONCLUSIONS: Long-term pacing with a fully implantable, programmable, and battery-powered device enables previously impossible investigations of arrhythmia and heart failure in the mouse.
RATIONALE: Cardiac pacing is a critical technology for the treatment of arrhythmia and heart failure. The impact of specific pacing strategies on myocardial function is an area of intense research and high clinical significance. Mouse models have proven extremely useful for probing mechanisms of heart disease, but there is currently no reliable technology for long-term pacing in the mouse. OBJECTIVE: We sought to develop a device for long-term pacing studies in mice. We evaluated the device for (1) treating third-degree atrioventricular block after macrophage depletion, (2) ventricular pacing-induced cardiomyopathy, and (3) high-rate atrial pacing. METHODS AND RESULTS: We developed a mouse pacemaker by refashioning a 26 mm×6.7 mm clinical device powered by a miniaturized, highly efficient battery. The electrode was fitted with a single flexible lead, and custom software extended the pacing rate to up to 1200 bpm. The wirelessly programmable device was implanted in the dorsal subcutaneous space of 39 mice. The tunneled lead was passed through a left thoracotomy incision and attached to the epicardial surface of the apex (for ventricular pacing) or the left atrium (for atrial pacing). Mice tolerated the implantation and both long-term atrial and ventricular pacing over weeks. We then validated the pacemaker's suitability for the treatment of atrioventricular block after macrophage depletion in Cd11b DTR mice. Ventricular pacing increased the heart rate from 313±59 to 550 bpm ( P<0.05). In addition, we characterized tachypacing-induced cardiomyopathy in mice. Four weeks of ventricular pacing resulted in reduced left ventricular function, fibrosis, and an increased number of cardiac leukocytes and endothelial activation. Finally, we demonstrated the feasibility of chronic atrial pacing at 1200 bpm. CONCLUSIONS: Long-term pacing with a fully implantable, programmable, and battery-powered device enables previously impossible investigations of arrhythmia and heart failure in the mouse.
Authors: Michele Brignole; Angelo Auricchio; Gonzalo Baron-Esquivias; Pierre Bordachar; Giuseppe Boriani; Ole-A Breithardt; John Cleland; Jean-Claude Deharo; Victoria Delgado; Perry M Elliott; Bulent Gorenek; Carsten W Israel; Christophe Leclercq; Cecilia Linde; Lluís Mont; Luigi Padeletti; Richard Sutton; Panos E Vardas; Jose Luis Zamorano; Stephan Achenbach; Helmut Baumgartner; Jeroen J Bax; Héctor Bueno; Veronica Dean; Christi Deaton; Cetin Erol; Robert Fagard; Roberto Ferrari; David Hasdai; Arno W Hoes; Paulus Kirchhof; Juhani Knuuti; Philippe Kolh; Patrizio Lancellotti; Ales Linhart; Petros Nihoyannopoulos; Massimo F Piepoli; Piotr Ponikowski; Per Anton Sirnes; Juan Luis Tamargo; Michal Tendera; Adam Torbicki; William Wijns; Stephan Windecker; Paulus Kirchhof; Carina Blomstrom-Lundqvist; Luigi P Badano; Farid Aliyev; Dietmar Bänsch; Helmut Baumgartner; Walid Bsata; Peter Buser; Philippe Charron; Jean-Claude Daubert; Dan Dobreanu; Svein Faerestrand; David Hasdai; Arno W Hoes; Jean-Yves Le Heuzey; Hercules Mavrakis; Theresa McDonagh; Jose Luis Merino; Mostapha M Nawar; Jens Cosedis Nielsen; Burkert Pieske; Lidija Poposka; Frank Ruschitzka; Michal Tendera; Isabelle C Van Gelder; Carol M Wilson Journal: Eur Heart J Date: 2013-06-24 Impact factor: 29.983
Authors: Kenneth C Bilchick; Sudip K Saha; Ed Mikolajczyk; Leslie Cope; Will J Ferguson; Wayne Yu; Steven Girouard; David A Kass Journal: Physiol Genomics Date: 2006-05-02 Impact factor: 3.107
Authors: Hendrik B Sager; Maarten Hulsmans; Kory J Lavine; Marina B Moreira; Timo Heidt; Gabriel Courties; Yuan Sun; Yoshiko Iwamoto; Benoit Tricot; Omar F Khan; James E Dahlman; Anna Borodovsky; Kevin Fitzgerald; Daniel G Anderson; Ralph Weissleder; Peter Libby; Filip K Swirski; Matthias Nahrendorf Journal: Circ Res Date: 2016-07-21 Impact factor: 17.367
Authors: Yangyang Bao; B Cicero Willis; Chad R Frasier; Luis F Lopez-Santiago; Xianming Lin; Roberto Ramos-Mondragón; David S Auerbach; Chunling Chen; Zhenxun Wang; Justus Anumonwo; Héctor H Valdivia; Mario Delmar; José Jalife; Lori L Isom Journal: Circ Arrhythm Electrophysiol Date: 2016-12
Authors: Xudong Liao; Yuyan Shen; Rongli Zhang; Keiki Sugi; Neelakantan T Vasudevan; M Amer Alaiti; David R Sweet; Lin Zhou; Yulan Qing; Stanton L Gerson; Chen Fu; Anthony Wynshaw-Boris; Rui Hu; Martin A Schwartz; Hisashi Fujioka; Brian Richardson; Mark J Cameron; Hiroki Hayashi; Jonathan S Stamler; Mukesh K Jain Journal: Proc Natl Acad Sci U S A Date: 2018-04-30 Impact factor: 11.205
Authors: Maarten Hulsmans; Hendrik B Sager; Jason D Roh; María Valero-Muñoz; Nicholas E Houstis; Yoshiko Iwamoto; Yuan Sun; Richard M Wilson; Gregory Wojtkiewicz; Benoit Tricot; Michael T Osborne; Judy Hung; Claudio Vinegoni; Kamila Naxerova; David E Sosnovik; Michael R Zile; Amy D Bradshaw; Ronglih Liao; Ahmed Tawakol; Ralph Weissleder; Anthony Rosenzweig; Filip K Swirski; Flora Sam; Matthias Nahrendorf Journal: J Exp Med Date: 2018-01-16 Impact factor: 14.307
Authors: Kevin R King; Aaron D Aguirre; Yu-Xiang Ye; Yuan Sun; Jason D Roh; Richard P Ng; Rainer H Kohler; Sean P Arlauckas; Yoshiko Iwamoto; Andrej Savol; Ruslan I Sadreyev; Mark Kelly; Timothy P Fitzgibbons; Katherine A Fitzgerald; Timothy Mitchison; Peter Libby; Matthias Nahrendorf; Ralph Weissleder Journal: Nat Med Date: 2017-11-06 Impact factor: 53.440