Reverse Myocardial Remodeling Following€Valve Replacement in Patients€With Aortic Stenosis

ISS Fro Un Un Bio Blo of He Tre Fo an ind no Ma BACKGROUND Left ventricular (LV) hypertrophy, a key process in human cardiac disease, results from cellular (hypertrophy) and extracellular matrix expansion (interstitial fibrosis). OBJECTIVES This study sought to investigate whether human myocardial interstitial fibrosis in aortic stenosis (AS) is plastic and can regress. METHODS Patients with symptomatic, severe AS (n 1⁄4 181; aortic valve area index 0.4 0.1 cm/m) were assessed pre–aortic valve replacement (AVR) by echocardiography (AS severity, diastology), cardiovascular magnetic resonance (CMR) (for volumes, function, and focal or diffuse fibrosis), biomarkers (N-terminal pro–B-type natriuretic peptide and high-sensitivity troponin T), and the 6-min walk test. CMR was used to measure the extracellular volume fraction (ECV), thereby deriving matrix volume (LV mass ECV) and cell volume (LV mass [1 ECV]). Biopsy excluded occult bystander disease. Assessment was repeated at 1 year post-AVR. RESULTS At 1 year post-AVR in 116 pacemaker-free survivors (age 70 10 years; 54% male), mean valve gradient had improved (48 16 mm Hg to 12 6 mm Hg; p < 0.001), and indexed LV mass had regressed by 19% (88 26 g/m to 71 19 g/m; p < 0.001). Focal fibrosis by CMR late gadolinium enhancement did not change, but ECV increased (28.2 2.9% to 29.9 4.0%; p < 0.001): this was the result of a 16% reduction in matrix volume (25 9 ml/m to 21 7 ml/m; p < 0.001) but a proportionally greater 22% reduction in cell volume (64 18 ml/m to 50 13 ml/m; p < 0.001). These changes were accompanied by improvement in diastolic function, N-terminal pro–B-type natriuretic peptide, 6-min walk test results, and New York Heart Association functional class. CONCLUSIONS Post-AVR, focal fibrosis does not resolve, but diffuse fibrosis and myocardial cellular hypertrophy regress. Regression is accompanied by structural and functional improvements suggesting that human diffuse fibrosis is plastic, measurable by CMR and a potential therapeutic target. (Regression of Myocardial Fibrosis After Aortic Valve Replacement; NCT02174471) (J Am Coll Cardiol 2018;71:860–71) © 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). N 0735-1097 https://doi.org/10.1016/j.jacc. 2017.12. 035 m the Barts Heart Centre, St. Bartholomew’s Hospital, London, United Kingdom; Institute for Cardiovascular Sciences, iversity College London, London, United Kingdom; Program of Cardiovascular Diseases, Center for Applied Medical Research, iversity ofNavarra, Pamplona, Spain; Institutode Investigación Sanitaria deNavarra (IdiSNA), Pamplona, Spain; Cardiovascular medical Research Center Network (CIBERCV), Carlos III National Institute of Health, Madrid, Spain; National Heart, Lung, and od Institute, National Institutes of Health, Department ofHealth andHumanServices, Bethesda,Maryland; and the Department CardiologyandCardiacSurgery,UniversityofNavarraClinic, Pamplona, Spain.Thisprojectwas fundedby theNational Instituteof alth Research (NIHR) and European Commission FP7 Programme, Brussels, Belgium (FIBRO-TARGETS project 2013-602904). Dr. ibelwas supportedbyadoctoral research fellowship fromtheNational InstituteofHealthResearch (NIHR) (DRF-2013-06-102). Dr. ntana was supported by a doctoral research fellowship from the British Heart Foundation (FS/12/56/29723). Dr. Moon is directly d indirectly supported by the University College London Hospitals NIHR Biomedical Research Centre. Dr. Manisty is directly and irectly supported by the Biomedical Research Unit at St. Bartholomew’s Hospital. All other authors have reported that they have relationships relevant to the contents of this paper to disclose. nuscript received September 6, 2017; revised manuscript received December 12, 2017, accepted December 12, 2017. J A C C V O L . 7 1 , N O . 8 , 2 0 1 8 Treibel et al. F E B R U A R Y 2 7 , 2 0 1 8 : 8 6 0 – 7 1 Regression of Diffuse Fibrosis After Aortic Valve Replacement 861 AB BR E V I A T I O N S