Author + information
- Received September 10, 2018
- Revision received January 8, 2019
- Accepted January 11, 2019
- Published online June 24, 2019.
- Mathias Hohl, PhDa,
- Katharina Erba,
- Lisa Langa,
- Sven Ruf, PhDb,
- Thomas Hübschle, PhDb,
- Stefan Dhein, MDc,
- Wolfgang Linz, PhDb,
- Adrian D. Elliott, PhDd,
- Prashanthan Sanders, MBBS, PhDd,
- Olesja Zamyatkina,
- Michael Böhm, MDa,
- Ulrich Schotten, MD, PhDe,
- Thorsten Sadowski, PhDb and
- Dominik Linz, MD, PhDa,d,∗ ()
- aKlinik für Innere Medizin III, Universität des Saarlandes, Homburg/Saar, Germany
- bSanofi-Aventis Deutschland GmbH, Frankfurt, Germany
- cHerzzentrum Leipzig Abt. Herzchirurgie, Leipzig, Germany
- dCentre for Heart Rhythm Disorders, South Australian Health and Medical Research Institute, Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia
- eDepartment of Physiology, University of Maastricht, Maastricht, the Netherlands
- ↵∗Address for correspondence:
Dr. Dominik Linz, Centre for Heart Rhythm Disorders, Department of Cardiology, Royal Adelaide Hospital, University of Adelaide, North Terrace, Adelaide 5000, Australia.
• The role of the protease cathepsin A for the progression of left ventricular remote remodeling and atrial cardiomyopathy in ischemic cardiomyopathy is unknown.
• In rats with ventricular ischemia and reperfusion, cathepsin A is up-regulated in the left ventricular and atrial tissue remote from the infarcted area.
• Pharmacological inhibition of cathepsin A protease activity by SAR significantly reduces remote ventricular remodeling and atrial extracellular matrix remodeling, represented by fibrosis formation and connexin 43 lateralization.
• Prevention of ventricular remote remodeling and atrial cardiomyopathy by SAR increased ventricular viable myocardium and atrial emptying function reducing susceptibility to atrial fibrillation.
• Remote ventricular and atrial extracellular matrix remodeling may represent a promising target for pharmacological atrial fibrillation upstream therapy following myocardial infarction.
After myocardial infarction, remote ventricular remodeling and atrial cardiomyopathy progress despite successful revascularization. In a rat model of ventricular ischemia/reperfusion, pharmacological inhibition of the protease activity of cathepsin A initiated at the time point of reperfusion prevented extracellular matrix remodeling in the atrium and the ventricle remote from the infarcted area. This scenario was associated with preservation of more viable ventricular myocardium and the prevention of an arrhythmogenic and functional substrate for atrial fibrillation. Remote ventricular extracellular matrix remodeling and atrial cardiomyopathy may represent a promising target for pharmacological atrial fibrillation upstream therapy following myocardial infarction.
This research was supported by the German Research Foundation (DFG SFB/TRR219-M02/-S02). Ms. Lang received a scholarship by the “Stiftung Begabtenförderung berufliche Bildung (SBB) GmbH im Auftrag und mit Mitteln des Bundesministeriums für Bildung und Forschung.” Drs. Sadowski, Hübschle, and Ruf are employees of Sanofi-Aventis Deutschland GmbH. Dr. Sanders is an advisory board member for Biosense-Webster, Medtronic, St. Jude Medical, Boston Scientific, and CathRx; has received lecture and/or consulting fees from Biosense-Webster, Medtronic, St. Jude Medical, and Boston Scientific; and is supported by a Practitioner Fellowship from the National Health and Medical Research Council of Australia and by the National Heart Foundation of Australia. Dr. Böhm has received funding from Amgen, Bayer, Servier, Medtronic, Boehringer Ingelheim, Vifor, and Bristol-Myers Squibb. Dr. Schotten has received funding from EP and YourRhythmics BV. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and U.S. Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received September 10, 2018.
- Revision received January 8, 2019.
- Accepted January 11, 2019.
- 2019 The Authors