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Hinkel, Rabea; Batkai, Sandor; Baehr, Andrea; Bozoglu, Tarik; Straub, Sarah; Borchert, Tobias; Viereck, Janika; Howe, Andrea; Hornaschewitz, Nadja; Oberberger, Lisa; Jurisch, Victoria; Kozlik-Feldmann, Rainer; Freudenthal, Franz; Ziegler, Tilman; Weber, Christian; Sperandio, Markus; Engelhardt, Stefan; Laugwitz, Karl Ludwig; Moretti, Alessandra; Klymiuk, Nik; Thum, Thomas and Kupatt, Christian (2021): AntimiR-132 Attenuates Myocardial Hypertrophy in an Animal Model of Percutaneous Aortic Constriction. In: Journal of the American College of Cardiology, Vol. 77, No. 23: pp. 2923-2935

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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 mu m(2) 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 (Delta sham 1.8 +/- 0.5%) than control hearts (Delta sham 10.8 +/- 0.6%). Of note, cardiac platelet and endothelial cell adhesion molecule 1 thorn capillary density was higher in the antimiR-132-treated hearts (647 +/- 20 cells/mm(2)) compared with in the control group (485 +/- 23 cells/mm(2)). 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. (C) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

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