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      Imaging and Impact of Myocardial Fibrosis in Aortic Stenosis

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          Abstract

          Aortic stenosis is characterized both by progressive valve narrowing and the left ventricular remodeling response that ensues. The only effective treatment is aortic valve replacement, which is usually recommended in patients with severe stenosis and evidence of left ventricular decompensation. At present, left ventricular decompensation is most frequently identified by the development of typical symptoms or a marked reduction in left ventricular ejection fraction <50%. However, there is growing interest in using the assessment of myocardial fibrosis as an earlier and more objective marker of left ventricular decompensation, particularly in asymptomatic patients, where guidelines currently rely on nonrandomized data and expert consensus. Myocardial fibrosis has major functional consequences, is the key pathological process driving left ventricular decompensation, and can be divided into 2 categories. Replacement fibrosis is irreversible and identified using late gadolinium enhancement on cardiac magnetic resonance, while diffuse fibrosis occurs earlier, is potentially reversible, and can be quantified with cardiac magnetic resonance T 1 mapping techniques. There is a substantial body of observational data in this field, but there is now a need for randomized clinical trials of myocardial imaging in aortic stenosis to optimize patient management. This review will discuss the role that myocardial fibrosis plays in aortic stenosis, how it can be imaged, and how these approaches might be used to track myocardial health and improve the timing of aortic valve replacement.

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          Most cited references44

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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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            Epidemiology of valvular heart disease in the adult.

            Valvular heart disease remains common in industrialized countries, because the decrease in prevalence of rheumatic heart diseases has been accompanied by an increase in that of degenerative valve diseases. Aortic stenosis and mitral regurgitation are the two most common types of valvular disease in Europe. The prevalence of valvular disease increases sharply with age, owing to the predominance of degenerative etiologies. The burden of heart valve disease in the elderly has an important impact on patient management, given the high frequency of comorbidity and the increased risk associated with intervention in this age group. Endocarditis is an important etiology of valvular disease and is most commonly caused by Staphylococci. Rheumatic heart disease remains prevalent in developing countries.
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              Extracellular volume imaging by magnetic resonance imaging provides insights into overt and sub-clinical myocardial pathology.

              Conventional late gadolinium enhancement (LGE) cardiac magnetic resonance can detect myocardial infarction and some forms of non-ischaemic myocardial fibrosis. However, quantitative imaging of extracellular volume fraction (ECV) may be able to detect subtle abnormalities such as diffuse fibrosis or post-infarct remodelling of remote myocardium. The aims were (1) to measure ECV in myocardial infarction and non-ischaemic myocardial fibrosis, (2) to determine whether ECV varies with age, and (3) to detect sub-clinical abnormalities in 'normal appearing' myocardium remote from regions of infarction. Cardiac magnetic resonance ECV imaging was performed in 126 patients with T1 mapping before and after injection of gadolinium contrast. Conventional LGE images were acquired for the left ventricle. In patients with a prior myocardial infarction, the infarct region had an ECV of 51 ± 8% which did not overlap with the remote 'normal appearing' myocardium that had an ECV of 27 ± 3% (P < 0.001, n = 36). In patients with non-ischaemic cardiomyopathy, the ECV of atypical LGE was 37 ± 6%, whereas the 'normal appearing' myocardium had an ECV of 26 ± 3% (P < 0.001, n = 30). The ECV of 'normal appearing' myocardium increased with age (r = 0.28, P = 0.01, n = 60). The ECV of 'normal appearing' myocardium remote from myocardial infarctions increased as left ventricular ejection fraction decreased (r = -0.50, P = 0.02). Extracellular volume fraction imaging can quantitatively characterize myocardial infarction, atypical diffuse fibrosis, and subtle myocardial abnormalities not clinically apparent on LGE images. Taken within the context of prior literature, these subtle ECV abnormalities are consistent with diffuse fibrosis related to age and changes remote from infarction.
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                Author and article information

                Contributors
                Journal
                JACC Cardiovasc Imaging
                JACC Cardiovasc Imaging
                Jacc. Cardiovascular Imaging
                Elsevier
                1936-878X
                1876-7591
                1 February 2019
                February 2019
                : 12
                : 2
                : 283-296
                Affiliations
                [a ]British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
                [b ]Division of Cardiovascular Diseases, Department of Medicine, UPMC Heart & Vascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
                [c ]Quebec Heart & Lung Institute, Laval University, Quebec City, Quebec, Canada
                Author notes
                [] Address for correspondence: Dr. Marc R. Dweck, BHF Centre for Cardiovascular Science, University of Edinburgh, Chancellors Building, 47 Little France Crescent, Edinburgh, Midlothian EH16 4TJ, United Kingdom. Marc.dweck@ 123456ed.ac.uk @ 123456MarcDweck
                Article
                S1936-878X(18)31113-6
                10.1016/j.jcmg.2018.11.026
                6361867
                30732723
                2841934d-8a47-4932-b3c7-44368d1d1dfd
                © 2019 The Authors

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

                History
                : 29 June 2018
                : 16 October 2018
                : 7 November 2018
                Categories
                Article

                aortic stenosis,cardiac magnetic resonance,late gadolinium enhancement,myocardial fibrosis,t1 mapping,avr, aortic valve replacement,ci, confidence interval,cmr, cardiac magnetic resonance,ct, computed tomography,ecv%, extracellular volume fraction,hr, hazard ratio,iecv, indexed extracellular volume,lge, late gadolinium enhancement,savr, surgical aortic valve replacement,tavr, transcatheter aortic valve replacement

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