Rabea Hinkel1, Sandor Batkai2, Andrea Bähr3, Tarik Bozoglu3, Sarah Straub4, Tobias Borchert5, Janika Viereck5, Andrea Howe4, Nadja Hornaschewitz4, Lisa Oberberger4, Victoria Jurisch4, Rainer Kozlik-Feldmann6, Franz Freudenthal7, Tilman Ziegler8, Christian Weber9, Markus Sperandio10, Stefan Engelhardt11, Karl Ludwig Laugwitz8, Alessandra Moretti8, Nik Klymiuk8, Thomas Thum12, Christian Kupatt13. 1. Klinik und Poliklinik für Innere Medizin I, University Clinic rechts der Isar, Technical University of Munich, Munich, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany; Laboratory Animal Science Unit, German Primate Centre, Goettingen, Stiftung Tierärztliche Hochschule Hannover, Hannover, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research), partner site Goettingen, Munich, Germany. Electronic address: https://twitter.com/Rabea08515954. 2. Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany; Cardior Pharmaceuticals GmbH, Hannover, Germany. 3. Klinik und Poliklinik für Innere Medizin I, University Clinic rechts der Isar, Technical University of Munich, Munich, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany. 4. Klinik und Poliklinik für Innere Medizin I, University Clinic rechts der Isar, Technical University of Munich, Munich, Germany. 5. Cardior Pharmaceuticals GmbH, Hannover, Germany. 6. Department of Pediatric Cardiology, University Clinic Eppendorf, Hamburg, Germany. 7. Products for Medicine, SRL (sociedad de responsibilidat limitada), Obajes, La Paz, Bolivia. 8. Klinik und Poliklinik für Innere Medizin I, University Clinic rechts der Isar, Technical University of Munich, Munich, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. 9. Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany. 10. Walter-Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, Munich, Germany. 11. Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institut für Pharmakologie und Toxikologie, Technical University of Munich, Munich, Germany. 12. Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany; Cardior Pharmaceuticals GmbH, Hannover, Germany. Electronic address: thum.thomas@mh-hannover.de. 13. Klinik und Poliklinik für Innere Medizin I, University Clinic rechts der Isar, Technical University of Munich, Munich, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany. Electronic address: Christian.kupatt@tum.de.
Abstract
BACKGROUND: Pathological cardiac hypertrophy is a result of afterload-increasing pathologies including untreated hypertension and aortic stenosis. It features progressive adverse cardiac remodeling, myocardial dysfunction, capillary rarefaction, and interstitial fibrosis often leading to heart failure. OBJECTIVES: This study aimed to establish a novel porcine model of pressure-overload-induced heart failure and to determine the effect of inhibition of microribonucleic acid 132 (miR-132) on heart failure development in this model. METHODS: This study developed a novel porcine model of percutaneous aortic constriction by implantation of a percutaneous reduction stent in the thoracic aorta, inducing progressive remodeling at day 56 (d56) after pressure-overload induction. In this study, an antisense oligonucleotide specifically inhibiting miR-132 (antimiR-132), was regionally applied via intracoronary injection at d0 (percutaneous transverse aortic constriction induction) and d28. RESULTS: At d56, antimiR-132 treatment diminished cardiomyocyte cross-sectional area (188.9 ± 2.8 vs. 258.4 ± 9.0 μm2 in untreated hypertrophic hearts) and improved global cardiac function (ejection fraction 48.9 ± 1.0% vs. 36.1 ± 1.7% in control hearts). Moreover, at d56 antimiR-132-treated hearts displayed less increase of interstitial fibrosis compared with sham-operated hearts (Δsham 1.8 ± 0.5%) than control hearts (Δsham 10.8 ± 0.6%). Of note, cardiac platelet and endothelial cell adhesion molecule 1+ capillary density was higher in the antimiR-132-treated hearts (647 ± 20 cells/mm2) compared with in the control group (485 ± 23 cells/mm2). CONCLUSIONS: The inhibition of miR-132 is a valid strategy in prevention of heart failure progression in hypertrophic heart disease and may be developed as a treatment for heart failure of nonischemic origin.
BACKGROUND: Pathological cardiac hypertrophy is a result of afterload-increasing pathologies including untreated hypertension and aortic stenosis. It features progressive adverse cardiac remodeling, myocardial dysfunction, capillary rarefaction, and interstitial fibrosis often leading to heart failure. OBJECTIVES: This study aimed to establish a novel porcine model of pressure-overload-induced heart failure and to determine the effect of inhibition of microribonucleic acid 132 (miR-132) on heart failure development in this model. METHODS: This study developed a novel porcine model of percutaneous aortic constriction by implantation of a percutaneous reduction stent in the thoracic aorta, inducing progressive remodeling at day 56 (d56) after pressure-overload induction. In this study, an antisense oligonucleotide specifically inhibiting miR-132 (antimiR-132), was regionally applied via intracoronary injection at d0 (percutaneous transverse aortic constriction induction) and d28. RESULTS: At d56, antimiR-132 treatment diminished cardiomyocyte cross-sectional area (188.9 ± 2.8 vs. 258.4 ± 9.0 μm2 in untreated hypertrophic hearts) and improved global cardiac function (ejection fraction 48.9 ± 1.0% vs. 36.1 ± 1.7% in control hearts). Moreover, at d56 antimiR-132-treated hearts displayed less increase of interstitial fibrosis compared with sham-operated hearts (Δsham 1.8 ± 0.5%) than control hearts (Δsham 10.8 ± 0.6%). Of note, cardiac platelet and endothelial cell adhesion molecule 1+ capillary density was higher in the antimiR-132-treated hearts (647 ± 20 cells/mm2) compared with in the control group (485 ± 23 cells/mm2). CONCLUSIONS: The inhibition of miR-132 is a valid strategy in prevention of heart failure progression in hypertrophic heart disease and may be developed as a treatment for heart failure of nonischemic origin.
Authors: Antonio Concistrè; Luigi Petramala; Francesco Circosta; Priscilla Romagnoli; Maurizio Soldini; Marco Bucci; Domenico De Cesare; Giuseppe Cavallaro; Giorgio De Toma; Francesco Cipollone; Claudio Letizia Journal: Front Cardiovasc Med Date: 2022-07-28