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      Is Open Access

      Extracellular Myocardial Volume in Patients With Aortic Stenosis

      research-article
      , MD, PhD a , , , MD, PhD b , , MD c , , MD d , , MD, DPhil e , , MD, PhD f , , MA g , , MSc h , , MD g , , MD g , , MD, PhD i , , MD, PhD j , , MD k , , MD l , , MD, DPhil e , , PhD e , , MD l , , MD c , , DVM, PhD h , , MD, PhD a , , MD e , , DVM, PhD h , , MD k , , MD c , , MD, PhD d , , MD f , , MD, PhD g , , MD b , , MD, PhD a
      Journal of the American College of Cardiology
      Elsevier Biomedical
      aortic stenosis, cardiovascular magnetic resonance, diffuse myocardial fibrosis, T1 mapping, CI, confidence interval, CMR, cardiovascular magnetic resonance, ECV, extracellular volume, ECV%, extracellular volume fraction, HR, hazard ratio, iECV, indexed extracellular volume, LA, left atrial, LV, left ventricular, NYHA, New York Heart Association, STS-PROM, Society of Thoracic Surgeons Predicted Risk of Mortality

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          Abstract

          Background

          Myocardial fibrosis is a key mechanism of left ventricular decompensation in aortic stenosis and can be quantified using cardiovascular magnetic resonance (CMR) measures such as extracellular volume fraction (ECV%). Outcomes following aortic valve intervention may be linked to the presence and extent of myocardial fibrosis.

          Objectives

          This study sought to determine associations between ECV% and markers of left ventricular decompensation and post-intervention clinical outcomes.

          Methods

          Patients with severe aortic stenosis underwent CMR, including ECV% quantification using modified Look-Locker inversion recovery–based T1 mapping and late gadolinium enhancement before aortic valve intervention. A central core laboratory quantified CMR parameters.

          Results

          Four-hundred forty patients (age 70 ± 10 years, 59% male) from 10 international centers underwent CMR a median of 15 days (IQR: 4 to 58 days) before aortic valve intervention. ECV% did not vary by scanner manufacturer, magnetic field strength, or T1 mapping sequence (all p > 0.20). ECV% correlated with markers of left ventricular decompensation including left ventricular mass, left atrial volume, New York Heart Association functional class III/IV, late gadolinium enhancement, and lower left ventricular ejection fraction (p < 0.05 for all), the latter 2 associations being independent of all other clinical variables (p = 0.035 and p < 0.001). After a median of 3.8 years (IQR: 2.8 to 4.6 years) of follow-up, 52 patients had died, 14 from adjudicated cardiovascular causes. A progressive increase in all-cause mortality was seen across tertiles of ECV% (17.3, 31.6, and 52.7 deaths per 1,000 patient-years; log-rank test; p = 0.009). Not only was ECV% associated with cardiovascular mortality (p = 0.003), but it was also independently associated with all-cause mortality following adjustment for age, sex, ejection fraction, and late gadolinium enhancement (hazard ratio per percent increase in ECV%: 1.10; 95% confidence interval [1.02 to 1.19]; p = 0.013).

          Conclusions

          In patients with severe aortic stenosis scheduled for aortic valve intervention, an increased ECV% is a measure of left ventricular decompensation and a powerful independent predictor of mortality.

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          Most cited references33

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          2017 ESC/EACTS Guidelines for the management of valvular heart disease.

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            Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms.

            The progression of compensated hypertrophy to heart failure (HF) is still debated. We investigated patients with isolated valvular aortic stenosis and differing degrees of left ventricular (LV) systolic dysfunction to test the hypothesis that structural remodeling, as well as cell death, contributes to the transition to HF. Structural alterations were studied in LV myectomies from 3 groups of patients (group 1: ejection fraction [EF] >50%, n=12; group 2: EF 30% to 50%, n=12; group 3: EF <30%, n=10) undergoing aortic valve replacement. Control patients were patients with mitral valve stenosis but normal LV (n=6). Myocyte hypertrophy was accompanied by increased nuclear DNA and Sc-35 (splicing factor) content. ACE and TGF-beta1 were upregulated correlating with fibrosis, which increased 2.3-, 2.2-, and 3.2-fold over control in the 3 groups. Myocyte degeneration increased 10, 22, and 32 times over control. A significant correlation exists between EF and myocyte degeneration or fibrosis. Ubiquitin-related autophagic cell death was 0.5 per thousand in control and group 1, 1.05 in group 2, and 6.05 per thousand in group 3. Death by oncosis was 0 per thousand in control, 3 per thousand in group 1, and increased to 5 per thousand (groups 2 and 3). Apoptosis was not detectable in control and group 3, but it was present at 0.02 per thousand in group 1 and 0.01 per thousand in group 2. Cardiomyocyte mitosis was never observed. These structure-function correlations confirm the hypothesis that transition to HF occurs by fibrosis and myocyte degeneration partially compensated by hypertrophy involving DNA synthesis and transcription. Cell loss, mainly by autophagy and oncosis, contributes significantly to the progression of LV systolic dysfunction.
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              2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.

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                Author and article information

                Contributors
                Journal
                J Am Coll Cardiol
                J. Am. Coll. Cardiol
                Journal of the American College of Cardiology
                Elsevier Biomedical
                0735-1097
                1558-3597
                28 January 2020
                28 January 2020
                : 75
                : 3
                : 304-316
                Affiliations
                [a ]Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, United Kingdom
                [b ]Barts Health NHS Trust and University College London, London, United Kingdom
                [c ]UPMC Cardiovascular Magnetic Resonance Center, Heart and Vascular Institute, Pittsburgh, Pennsylvania
                [d ]Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
                [e ]University of Oxford Centre for Clinical Magnetic Resonance Research, BHF Centre of Research Excellence (Oxford), NIHR Biomedical Research Centre (Oxford), Oxford, United Kingdom
                [f ]Department of Cardiovascular Sciences, University of Leicester and the NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
                [g ]Multidisciplinary Cardiovascular Research Centre & The Division of Biomedical Imaging, Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
                [h ]Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart and Lung Institute, Université Laval, Québec City, Québec, Canada
                [i ]National Heart Center Singapore, Singapore
                [j ]Inherited Heart Muscle Disease Clinic, Department of Cardiology, Royal Free Hospital, NHS Foundation Trust, London, United Kingdom
                [k ]Division of Cardiology, Asan Medical Center Heart Institute, University of Ulsan College of Medicine, Seoul, Republic of Korea
                [l ]Charité Campus Buch ECRC, Berlin, and Helios Clinics Cardiology Germany, DZHK partner site, Berlin, Germany
                Author notes
                [] Address for correspondence: Dr. Russell Everett, Room SU:305, Centre for Cardiovascular Sciences, Chancellor’s Building, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, United Kingdom. Russell.everett@ 123456ed.ac.uk @ 123456russeverett3
                Article
                S0735-1097(19)38514-6
                10.1016/j.jacc.2019.11.032
                6985897
                31976869
                5222a167-0a92-4f29-aaf8-f0775277f1ed
                © 2020 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 3 October 2019
                : 31 October 2019
                : 4 November 2019
                Categories
                Article

                Cardiovascular Medicine
                aortic stenosis,cardiovascular magnetic resonance,diffuse myocardial fibrosis,t1 mapping,ci, confidence interval,cmr, cardiovascular magnetic resonance,ecv, extracellular volume,ecv%, extracellular volume fraction,hr, hazard ratio,iecv, indexed extracellular volume,la, left atrial,lv, left ventricular,nyha, new york heart association,sts-prom, society of thoracic surgeons predicted risk of mortality

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