Mario Boehm1,2,3, Xuefei Tian1,2, Yuqiang Mao1,2,4, Kenzo Ichimura1,2, Melanie J Dufva5,6, Khadem Ali1,2, Svenja Dannewitz Prosseda1,2, Yiwei Shi1,2, Kazuya Kuramoto1,2, Sushma Reddy7,8, Vitaly O Kheyfets5,6, Ross J Metzger2,7, Edda Spiekerkoetter1,2,8. 1. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, 300 Pasteur Drive, Grand Bld Rm S126B, Stanford, CA 94305, USA. 2. Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford School of Medicine, Stanford University, Stanford, CA, USA. 3. Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig University Giessen, German Center for Lung Research (DZL), Giessen, Germany. 4. Department of Thoracic Surgery, Shengjing Hospital, China Medical University, Shenyang, China. 5. Department of Bioengineering, University of Colorado Denver, Denver, CO, USA. 6. Section of Cardiology, Department of Pediatrics, Children's Hospital Colorado, Denver, CO, USA. 7. Division of Cardiology, Department of Pediatrics, Stanford University, Stanford, CA, USA. 8. Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Abstract
AIMS: The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload is unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodelling events. METHODS AND RESULTS: Surgical pulmonary artery banding (PAB) around a 26-G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic, and vascular myocardial remodelling within 5 weeks of chronic RV pressure overload in mice. Gradual reduction of the afterload burden through PA band absorption (de-PAB)-after RV dysfunction and structural remodelling were established-initiated recovery of RV function (cardiac output and exercise capacity) along with rapid normalization in RV hypertrophy (RV/left ventricular + S and cardiomyocyte area) and RV pressures (right ventricular systolic pressure). RV fibrotic (collagen, elastic fibres, and vimentin+ fibroblasts) and vascular (capillary density) remodelling were equally reversible; however, reversal occurred at a later timepoint after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher Scientific, Waltham, MA, USA) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators, and apoptosis mediators as major cellular components underlying functional RV recovery. CONCLUSION: We established a novel gradual de-PAB mouse model and used it to demonstrate that established pulmonary hypertension-associated RV dysfunction is fully reversible. Mechanistically, we link functional RV improvement to hypertrophic normalization that precedes fibrotic and vascular reverse-remodelling events. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload is unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodelling events. METHODS AND RESULTS: Surgical pulmonary artery banding (PAB) around a 26-G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic, and vascular myocardial remodelling within 5 weeks of chronic RV pressure overload in mice. Gradual reduction of the afterload burden through PA band absorption (de-PAB)-after RV dysfunction and structural remodelling were established-initiated recovery of RV function (cardiac output and exercise capacity) along with rapid normalization in RV hypertrophy (RV/left ventricular + S and cardiomyocyte area) and RV pressures (right ventricular systolic pressure). RV fibrotic (collagen, elastic fibres, and vimentin+ fibroblasts) and vascular (capillary density) remodelling were equally reversible; however, reversal occurred at a later timepoint after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher Scientific, Waltham, MA, USA) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators, and apoptosis mediators as major cellular components underlying functional RV recovery. CONCLUSION: We established a novel gradual de-PAB mouse model and used it to demonstrate that established pulmonary hypertension-associated RV dysfunction is fully reversible. Mechanistically, we link functional RV improvement to hypertrophic normalization that precedes fibrotic and vascular reverse-remodelling events. Published on behalf of the European Society of Cardiology. All rights reserved.
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