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      Myocardial Fibrosis and Cardiac Decompensation in Aortic Stenosis

      , MD a , b , , MD a , , MD a , c , , MD, PhD a , a , a , , MD a , a , , MD a , a , , MD, PhD a , , MD d , , PhD e , , MD, PhD a , , MD, PhD a ,

      Jacc. Cardiovascular Imaging

      Elsevier

      aortic stenosis, fibrosis, hypertrophy, magnetic resonance imaging, myocardium, T1 mapping, AVR, aortic valve replacement, BNP, brain natriuretic peptide, CMR, cardiac magnetic resonance, cTnI, cardiac troponin I, ECV, extracellular volume, ECG, electrocardiogram, iECV, indexed extracellular volume, IQR, interquartile range, LGE, late gadolinium enhancement, LV, left ventricular, LVH, left ventricular hypertrophy

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          Abstract

          Objectives

          Cardiac magnetic resonance (CMR) was used to investigate the extracellular compartment and myocardial fibrosis in patients with aortic stenosis, as well as their association with other measures of left ventricular decompensation and mortality.

          Background

          Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis. Diffuse fibrosis is associated with extracellular volume expansion that is detectable by T1 mapping, whereas late gadolinium enhancement (LGE) detects replacement fibrosis.

          Methods

          In a prospective observational cohort study, 203 subjects (166 with aortic stenosis [69 years; 69% male]; 37 healthy volunteers [68 years; 65% male]) underwent comprehensive phenotypic characterization with clinical imaging and biomarker evaluation. On CMR, we quantified the total extracellular volume of the myocardium indexed to body surface area (iECV). The iECV upper limit of normal from the control group (22.5 ml/m 2) was used to define extracellular compartment expansion. Areas of replacement mid-wall LGE were also identified. All-cause mortality was determined during 2.9 ± 0.8 years of follow up.

          Results

          iECV demonstrated a good correlation with diffuse histological fibrosis on myocardial biopsies (r = 0.87; p < 0.001; n = 11) and was increased in patients with aortic stenosis (23.6 ± 7.2 ml/m 2 vs. 16.1 ± 3.2 ml/m 2 in control subjects; p < 0.001). iECV was used together with LGE to categorize patients with normal myocardium (iECV <22.5 ml/m 2; 51% of patients), extracellular expansion (iECV ≥22.5 ml/m 2; 22%), and replacement fibrosis (presence of mid-wall LGE, 27%). There was evidence of increasing hypertrophy, myocardial injury, diastolic dysfunction, and longitudinal systolic dysfunction consistent with progressive left ventricular decompensation (all p < 0.05) across these groups. Moreover, this categorization was of prognostic value with stepwise increases in unadjusted all-cause mortality (8 deaths/1,000 patient-years vs. 36 deaths/1,000 patient-years vs. 71 deaths/1,000 patient-years, respectively; p = 0.009).

          Conclusions

          CMR detects ventricular decompensation in aortic stenosis through the identification of myocardial extracellular expansion and replacement fibrosis. This holds major promise in tracking myocardial health in valve disease and for optimizing the timing of valve replacement. (The Role of Myocardial Fibrosis in Patients With Aortic Stenosis; NCT01755936)

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          Most cited references 6

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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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            Normalized left ventricular systolic and diastolic function by steady state free precession cardiovascular magnetic resonance.

            We used state of the art CMR to define ranges for normal left ventricular volumes and systolic/diastolic function normalized to the influence of gender, body surface area and age. New CMR normalized ranges were modeled and displayed in graphical form for clinical use, with normalization for body surface area, gender, and age. The determination of normality, or the severity of abnormality, depends on the use of the appropriate reference ranges normalized to all 3 variables. These novel data have particular importance for clinical practice and clinical trials using CMR.
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              High-sensitivity troponin I concentrations are a marker of an advanced hypertrophic response and adverse outcomes in patients with aortic stenosis

              Aims High-sensitivity cardiac troponin I (cTnI) assays hold promise in detecting the transition from hypertrophy to heart failure in aortic stenosis. We sought to investigate the mechanism for troponin release in patients with aortic stenosis and whether plasma cTnI concentrations are associated with long-term outcome. Methods and results Plasma cTnI concentrations were measured in two patient cohorts using a high-sensitivity assay. First, in the Mechanism Cohort, 122 patients with aortic stenosis (median age 71, 67% male, aortic valve area 1.0 ± 0.4 cm2) underwent cardiovascular magnetic resonance and echocardiography to assess left ventricular (LV) myocardial mass, function, and fibrosis. The indexed LV mass and measures of replacement fibrosis (late gadolinium enhancement) were associated with cTnI concentrations independent of age, sex, coronary artery disease, aortic stenosis severity, and diastolic function. In the separate Outcome Cohort, 131 patients originally recruited into the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact of REgression (SALTIRE) study, had long-term follow-up for the occurrence of aortic valve replacement (AVR) and cardiovascular deaths. Over a median follow-up of 10.6 years (1178 patient-years), 24 patients died from a cardiovascular cause and 60 patients had an AVR. Plasma cTnI concentrations were associated with AVR or cardiovascular death HR 1.77 (95% CI, 1.22 to 2.55) independent of age, sex, systolic ejection fraction, and aortic stenosis severity. Conclusions In patients with aortic stenosis, plasma cTnI concentration is associated with advanced hypertrophy and replacement myocardial fibrosis as well as AVR or cardiovascular death.
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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 November 2017
                November 2017
                : 10
                : 11
                : 1320-1333
                Affiliations
                [a ]BHF/Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
                [b ]Department of Cardiovascular Science, National Heart Center, Singapore
                [c ]First Department of Cardiology, Poznan University of Medical Sciences, Poznan, Poland
                [d ]Royal Brompton Hospital, London, United Kingdom
                [e ]Clinical Research Imaging Centre, University of Edinburgh, Edinburgh, United Kingdom
                Author notes
                [] Address for correspondence: Dr. Marc R. Dweck, BHF/Centre for Cardiovascular Science, Chancellor’s Building, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, United Kingdom.BHF/Centre for Cardiovascular ScienceChancellor’s BuildingUniversity of Edinburgh49 Little France CrescentEdinburgh EH16 4SBUnited Kingdom marc.dweck@ 123456ed.ac.uk
                Article
                S1936-878X(16)30902-0
                10.1016/j.jcmg.2016.10.007
                5683736
                28017384
                © 2017 Elsevier Inc. All rights reserved.

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

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