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T1 mapping and survival in systemic light-chain amyloidosis

T1 mapping and survival in systemic light-chain amyloidosis Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 CLINICAL RESEARCH European Heart Journal (2015) 36, 244–251 doi:10.1093/eurheartj/ehu444 Imaging T1 mapping and survival in systemic light-chain amyloidosis 1,2,3 1,2 1 1 Sanjay M. Banypersad , Marianna Fontana , Viviana Maestrini , Daniel M. Sado , 1,2 4 5 2 Gabriella Captur , Aviva Petrie , Stefan K. Piechnik , Carol J. Whelan , 1 2 2 2 Anna S. Herrey , Julian D. Gillmore , Helen J. Lachmann , Ashutosh D. Wechalekar , 2 1,3 Philip N. Hawkins , and James C. Moon 1 2 The Heart Hospital, 16-18 Westmoreland Street, London W1G 8PH, UK; The National Amyloidosis Centre, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland 3 4 Hill Street, London NW3 2PF, UK; Institute of Cardiovascular Science, University College London, Gower Street, London WC1E 6BT, UK; Biostatistics Unit, UCL Eastman Dental Institute, 256 Grays Inn Road, London WC1X 8LD, UK; and Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK Received 9 April 2014; revised 20 October 2014; accepted 21 October 2014; online publish-ahead-of-print 17 November 2014 See page 203 for the editorial comment on this article (doi:10.1093/eurheartj/ehu442) Aims To assess the prognostic value of myocardial pre-contrast T1 and extracellular volume (ECV) in systemic amyloid light- chain (AL) amyloidosis using cardiovascular magnetic resonance (CMR) T1 mapping. ..................................................................................................................................................................................... Methods One hundred patients underwent CMR and T1 mapping pre- and post-contrast. Myocardial ECV was calculated at con- and results trast equilibrium (ECV ) and 15 min post-bolus (ECV ). Fifty-four healthy volunteers served as controls. Patients were i b followed up for a median duration of 23 months and survival analyses were performed. Mean ECV was raised in amyloid (0.44+ 0.12) as was ECV (mean 0.44+ 0.12) compared with healthy volunteers (0.25+ 0.02), P , 0.001. Native pre-contrast T1 was raised in amyloid (mean 1080+ 87 ms vs. 954+ 34 ms, P , 0.001). All three correlated with pre-test probability of cardiac involvement, cardiac biomarkers, and systolic and diastolic dysfunction. During follow-up, 25 deaths occurred. An ECV of .0.45 carried a hazard ratio (HR) for death of 3.84 [95% confidence interval (CI): 1.53–9.61], P ¼ 0.004 and pre-contrast T1 of .1044 ms ¼ HR 5.39 (95% CI: 1.24–23.4), P ¼ 0.02. Extracellular volume after primed infusion and ECV performed similarly. Isolated post-contrast T1 was non-predictive. In Cox regres- sion models, ECV was independently predictive of mortality (HR ¼ 4.41, 95% CI: 1.35–14.4) after adjusting for E:E , ejection fraction, diastolic dysfunction grade, and NT-proBNP. ..................................................................................................................................................................................... Conclusion Myocardial ECV (bolus or infusion technique) and pre-contrast T1 are biomarkers for cardiac AL amyloid and they predict mortality in systemic amyloidosis. --- -- -- -- --- -- -- -- --- -- -- --- -- -- -- --- -- -- -- --- -- -- --- -- -- -- --- -- -- -- --- -- -- --- -- -- -- --- -- -- -- --- -- -- --- -- -- -- --- -- -- -- --- -- -- -- - - - - - - - --- -- -- -- --- -- -- --- -- Keywords ECV † Amyloid † CMR † Cardiomyopathy † Heart failure † T1 mapping Current predictors of survival rely on measuring surrogate rather Introduction than direct markers of interstitial expansion. Concentration of the Systemic amyloid light-chain (AL) amyloidosis is a multiorgan, infiltra- serum biomarkers NT-proBNP and Troponin T form the basis of tive disorder caused by an underlying plasma cell dyscrasia and is the Mayo Staging classification but are influenced by renal impair- characterized by tissue and organ amyloid deposition with interstitial ment which is present in a quarter of patients at presentation. ECG 3 4 expansion. Cardiac involvement is present in 50% of patients at criteria, low limb lead voltages, or fragmented QRS complexes presentation and is the principal driver of prognosis. Treatment are also predictive, but are confounded by pericardial effusions comprises chemotherapy or autologous stem cell transplantation and conduction abnormalities. Echocardiographic parameters also 5 – 7 to suppress clonal light-chain production, which may retard disease predict outcome, but coexisting causes of left ventricular hyper- progression or facilitate regression. trophy or diastolic impairment may affect interpretation. * Corresponding author. Tel: +44 203 456 3081, Fax: +44 203 456 3086, Email: [email protected] & The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 T1 mapping and survival in systemic AL amyloidosis 245 Figure1 Showing (A) pre-contrast and (B) post-contrast, four-chamber ShMOLLI image with regions of interest drawn in the left atrium for blood T1 measurement and in the basal septum of left ventricle, excluding at least the first two pixels of endocardium on either side of the septum in order to avoid through planing of blood pool. (known atrial fibrillation at first visit) were recruited. These 100 patients Cardiovascularmagneticresonance(CMR)usingthelate-gadolinium include all 60 patients studied previously in the baseline study. Approxi- enhancement (LGE) technique adds value in the diagnosis of cardiac mately 25% of patients with systemic AL amyloidosis seen at the centre involvement in AL amyloidosis. Altered gadolinium kinetics also 8 during this period had an eGFR of ,30 mL/min/1.73 m and were there- shows some correlation with survival. Recently we have shown that fore excluded. Six patients who were found to have atrial fibrillation/ pre-contrast, native myocardial T1 mapping correlates with cardiac flutter once in the scanner after they had consented were not excluded. disease burden and detects early disease. T1 mapping pre- and post- All patients had histological proof of systemic AL amyloidosis except 2 contrast can be used to derive the partition coefficient and, with the (2%), who died before biopsy could be undertaken, but in whom mono- 10–12 haematocrit, the myocardial extracellular volume (ECV) which clonal gammopathies were present and the organ distribution of amyloid is a direct measurement of myocardial interstitium and therefore on SAP scintigraphy was characteristic of AL type. Histology was per- 13,14 likely a surrogate marker of amyloid burden. The ECV can also formed with Congo red followed by immunohistochemical staining; assess amyloid burden in other organs. Furthermore, in other tissues examined were: kidney (26%), endomyocardium (7%), bone cardiac diseases, myocardial ECV predicts outcome. marrow (13%), upper gastrointestinal tract (7%), liver (3%), fat (15%), spleen (1%), lung (1%), rectum (9%), soft tissues (12%, included skin, Technically, measurement of the ECV requires equilibration of tongue, buccal mucosa, labia), lymph node (3%), and peritoneum (1%). contrast concentrations between blood and myocardium, which All patients underwent 12 lead ECG, assays of the cardiac biomarkers can be achieved precisely using a somewhat cumbersome primed NT-proBNP and Troponin T, and echocardiography at baseline. Mean contrast infusion, or sufficiently through delayed study following ECG QRS voltage in limb and praecordial leads were calculated. Echocar- administration of a bolus of gadolinium. Both techniques measure diographic assessment of diastolic function was performed using the E:E ECV the same where the ECVs are typically 0.4 or less, but one ratio. Where transmitral E-wave decelerationtime andisovolumetric relax- paper has shown a bias towards over-estimation of the true ECV in ation time were available, a diastolic dysfunction grade of 0–3 was assigned high ECV conditions (including n ¼ 20 amyloid patients). according to established British Society of Echocardiography (BSE) criteria. We hypothesized firstly that the myocardial ECV and pre-contrast All additionally underwent conventional CMR on a 1.5 T magnet T1 would correlate with disease burden in cardiac AL amyloidosis as (Avanto, Siemens). T1 mapping was performed using the Shortened Modified Look Lockers Inversion (ShMOLLI) recovery sequence pre- assessed by current measures. Additionally, we tested the ability of and post-contrast (0.1 mmol/kg bolus and 0.0011 mmol/kg/min infusion bothbiomarkersaspredictorsofsurvivalinALamyloidosisbycompar- TM of Dotarem ) as part of the Equilibrium CMR (EQ-CMR) technique, the ing the predictive power of: ECV after primed infusion (ECV ); post-contrast T1 map being performed at 15 min and after equilibration pre-contrast T1; bolus-only ECV (ECV ); and post-contrast T1. (mean time from bolus 45 min), as previously described. Methods Analysis The research was approved by The UCL/UCLH Joint Committees on the Standard CMR parameters of structure (left ventricle (LV) mass, left atrial Ethics of Human Research Committee and all participants provided area with/without indexing for body surface area, maximal septal thick- informed, written consent prior to enrolment. One hundred consecutive ness) and systolic function [ejection fraction, mitral annular plane systolic patients with systemic AL amyloidosis who were assessed between 2010 excursion (MAPSE), Tricuspid annular plane systolic excursion (TAPSE)] and 2012 at the National Amyloidosis Centre (Royal Free Hospital, were assessed. A region of interest (ROI) was drawn in the basal septum London, UK) and in whom there were no contraindications to CMR in a four-chamber view in all patients and in the left atrium for blood T1 (presence of non-MR compatible devices) or contrast administration measurement as papillary muscle hypertrophy made drawing an ROI in (GFR , 30 mLs/min) or potential confounders to T1 measurement the LV cavity challenging (see Figure 1); ROIs were mid-myocardial (at Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 246 S.M. Banypersad et al. least two pixels away from the apparent blood:myocardial boundary) and To test the prognostic value of ECV and pre-contrast T1, survival was were drawn without reference to the LGE images (see Figure 1). We evaluated using Cox proportional hazards regression analysis, providing quantified interstitial expansion with the ECV as described previously: estimated hazard ratios (HRs) with 95% confidence intervals (CIs) and ECV ¼ l(1 2 haematocrit), where l ¼ [DR1 ]/[DR1 ] Kaplan–Meier curves. Conventional ROC analysis could not be per- myocardium blood pool pre- and post-Gd (where R1 ¼ 1/T1). formed because the follow-up period was not the same for each Some ECV data (n ¼ 19 of the 100) pre-dated availability of ShMOLLI patient. Therefore, time-dependent ROC curves were used to assess T1 mapping and had utilized multibreath-hold T1 measurement. We the capacity of ECV compared with ECV and pre-contrast myocardial i b have demonstrated equivalence of ECV values derived from this tech- T1 for discriminating between surviving and dying patients with AL amyl- nique with ShMOLLI ECV and so these data were not excluded from oidosis. For fixed times (t ¼ 12 months, t ¼ 24 months) and specificity the analyses. level, we have compared the sensitivity of ECV , ECV , and pre-contrast i b That said, these patients did not have an ECV value or the subsidiary myocardial T1 measurements for detecting patients who will die by time component of the ECV equation, pre-contrast T1; multibreath-hold meas- t. For the ROC curves constructed using the nearest neighbour estimator 20.20 urement has been shown to be inferior to T1 mapping, so accordingly, (NNE) we used a narrow span of l (0.25 × nobs ) to yield only mod- these were excluded from the sub-analysis comparing techniques—this erate smoothing. To permit comparison of ROCs by the NNE estimator, particular analysis therefore consists of 81 rather than 100 patients. a set of simple KM estimator ROC curves for this data at t ¼ 24 months Extracellular volume and myocardial T1 results were compared with are also provided (see Supplementary material online, Figure S1). 54 healthy volunteers who underwent pre-contrast T1 mapping and Optimal myocardial T1 and ECV values were explored by Cox regres- ECV measurement (bolus and infusion). The number of patients dead sion, using the median and the 1st or 2nd tertiles as cut-off values. The and alive was assessed after a median duration of 23 (interquartile two groups resulting from each cut-off were comparedusing the Harrell’s range: 6–25) months. Some analysis involved sub-grouping patients C statistic (a measure of discrimination between groups) to determine into pre-test probability of cardiac involvement. This was done as previ- the better model and thus biomarker for predicting survival. All variables ously described and as stated below. were first explored with univariate Cox regression. Multivariable models Definite cardiac involvement—any of: evaluated the independent predictive value of ECV above other clinically and statistically significant covariates. † Left ventricle (LV) wall thickness of ≥12 mm by echocardiography in the absence of any other known cause Results † Right ventricle (RV) free wall thickening co-existing with LV thickening by echocardiography in the absence of systemic or pulmonary Table 1 summarizes baseline characteristics for patients and healthy hypertension volunteers. Within the patient cohort, 14 (14%) patients were on Possible cardiac involvement—any of: treatment for hypertension; 10 (10%) had confirmed coronary artery disease by angiography, 1 (1%) had had a stroke, and 2 (2%) † LV wall thickening by echocardiography in the presence of had diabetes. Fifty patients were treated with chemotherapy for hypertension the first time which comprised triple therapy with either cyclophos- † RV thickening by echocardiography in the presence of pulmonary phamide, thalidomide, and dexamethasone or cyclophosphamide, hypertension bortezomib and dexamethasone (CVD), depending on local guide- † Normal wall thickness by echocardiography with diastolic dysfunction lines of regional NHS Trusts within the UK. Seventeen patients and raised serum biomarkers were treated for a 2nd or 3rd time having relapsed—treatment No suspected involvement: was either with CVD or a lenalidomide-containing regimen in these instances. Nine patients had not received any chemotherapy as † Normal wall thickness by echocardiography with normal serum there was no clinical indication (e.g. renal amyloid with established biomarkers renal failure, isolated neuropathic presentations) and 24 patients were under a stable follow-up with no indication for further chemo- Statistical analysis therapy at the time of scan. Study data were collected and managed using REDCap (Research Elec- Twenty-one patients had a pre-test probability of no cardiac in- tronic Data Capture) electronic data capture tools hosted at University volvement, 26 had possible cardiac involvement, and 53 had definite College London. Analysis was performed using SPSS (IBM Corp. cardiac involvement. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. All ECV values are the ECV from infusion measurement unless Armonk, NY: IBM Corp), R programming language for statistical comput- ing (version 3.0.1, The R Foundation for Statistical Computing) and in otherwise stated. Healthy controls were younger on average, but Stata (StataCorp. 2011. Stata Statistical Software: Release 12. College our work and others suggests any ECV changes with age are small 23,24 Station, TX: StataCorp LP). All continuous variables were normally dis- compared with amyloid changes. There were proportionately tributed except NT-proBNP and Troponin T which were log (ln) trans- more females in the control vs. the patient group. This slightly formed (base e) to achieve normality for further analysis. Linear increases the control group ECV and pre-contrast T1 compared regression models measured the association between quantitative ECV with that of a gender-matched group (male vs. female: ECV 0.24 vs. and other variables; variance inflation factors ,2 excluded collinearity. 0.27, P , 0.001; T1 940 vs. 966 ms, P ¼ 0.006). Pearson’s correlation coefficients are presented in terms of R values. 2 As in previous work, mean cardiac ECV was greater in patients Means are presented+SD. The x test was used to compare categorical compared with healthy volunteers with a wider range (0.44+ 0.12 variables between patients and controls whilst the unpaired t-test was vs. 0.25+ 0.02, P , 0.001) and correlated with pre-test probability used to compare continuous variables betweenthe patients and controls. of cardiac involvement by conventional parameters (P , 0.001) A one-way ANOVA with Bonferroni correction was used to test ECV with pre-test clinical probability of cardiac involvement. (see Supplementary material online, Figure S2). Mean pre-contrast Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 T1 mapping and survival in systemic AL amyloidosis 247 Table 1 Baseline characteristics of the 100 AL amyloidosis patients and 54 healthy controls Characteristic Patients Healthy controls P value ............................................................................................................................................................................... Male/female 67/33 25/29 0.01 Mean age+ SD (years) 62+ 10 46+ 15 0.001 Mean creatinine+ SD (mmol/L) 89+ 32 74+ 13 0.001 Mean NYHA (I/II/III/IV) 29/56/15/0 – Mean EF+ SD (%) 66+ 11 67+ 6 0.42 Diastolic dysfunction grade (0/1/2/3) 15/36/25/22 – Mean indexed end-diastolic LV volume+ SD (mLs) 60+ 14 73+ 12 0.001 Mean indexed end-systolic LV volume+ SD (mLs) 19+ 10 25+ 7 0.001 Mean indexed LV mass+ SD(g/m)96+ 34 65+ 15 0.001 Mean indexed LA area 13+39+ 1.5 0.001 Median NT-proBNP in pmol/L (IQ range) 146 (38–359) – Median troponin T in ng/L (IQ range) 0.03 (0.01–0.06) – AF/atrial flutter (%) 6 (6) 0 Two patients did not have all three diastolic markers measured due to poor windows and therefore could not be graded as per BSE guidelines. myocardial T1 values were raised in patients compared with healthy The value ECV . 0.45 remained significantly associated with volunteers (1080+ 87 ms vs. 954+ 34 ms, P , 0.001) and also cor- mortality (HR ¼ 4.41, 95% CI 1.35–14.4; P ¼ 0.01) in multivariable related with pre-test probability of cardiac involvement (P , 0.001). Cox models that included measures of systolic and diastolic function Table 2 provides the Pearson correlation coefficients of ECV, and serum biomarkers: E:E , diastolic dysfunction grade (≥2), pre-contrast and post-contrast myocardial T1 to other cardiac ejection fraction, and LnNT-proBNP (troponin was not available in parameters, many of which typically change in cardiac amyloid. Extra- all patients). E:E and NT-ProBNP also remained independently cellular volume correlated significantly with 17 of 19; pre-contrast predictive. T1 with 12, and post-contrast T1 with 10. With regards LGE, 25 patients had no LGE, 50 had global subendo- Discussion cardial enhancement, and 10 had extensive enhancement. Eight had patchy enhancement and seven had evidence of only altered Extracellular volume is the first, non-invasive quantifier of the cardiac gadolinium kinetics, i.e. reversed nulling of myocardium and blood interstitium, while pre-contrast T1 is a composite measure of inter- after gadolinium administration. Extracellular volume correlated stitium and myocardial cells. This study demonstrated that ECV and significantly with increasing degrees of LGE (P , 0.001) as shown native myocardial T1 as measured by the newer T1 mapping techni- in Figure 2. ques, both correlate with current markers of disease severity in 11 – 13 At follow-up (median 23 months), 25 of 100 patients had died. cardiac AL amyloidosis, supporting previous work. We have For each potential predictor, median and tertile cut-points were also demonstrated that both these biomarkers have ‘real-world’ assessed for predictive power and the best result presented (see clinical significance in that both are predictors of mortality in AL Table 3). amyloidosis. For ECV , a median ECV of 0.45 was the best predictor of survival: Amyloidosis is the exemplary interstitial disease of the myocar- HR 3.84 (1.53–9.61), P ¼ 0.004 (Figure 3). The survival curve indi- dium. Cardiac involvement portends a poor prognosis which has cates that there is an 40% chance of death at 23 months in patients driven the need for better methods of detecting early cardiac with an ECV ≥ 0.45 compared with 15% for patients with an ECV , disease. We previously described both pre-contrast T1 mapping 0.45. For pre-contrast myocardial T1, the 1st tertile (cut-point and ECV measurement as potential, non-invasive techniques for 1044 ms) was the best predictor: HR 5.39 (1.24–23.4), P ¼ 0.02 directly measuring the cardiac AL disease burden in amyloid. (Figure 4A). ECV with median of 0.44 also predicted survival with Here, these early results are strengthened by increased numbers an HR of 5.09 (1.09–23.7), P ¼ 0.04 (Figure 4B). Post-contrast T1 and, additionally, prognostic significance of the biomarkers is demon- did not predict survival (HR ¼ 0.5, P ¼ 0.11). strated, even with therapy. The half of AL amyloid patients with an When the three predictive models ECV , ECV , and pre-contrast ECV . 0.45 had a three- to four-fold increased likelihood of i b T1 were compared to determine the stronger discriminator using death—roughly a 35–40% chance of death at 23 months compared the Harrell’s C statistic (the higher the number, the stronger discrim- with lower ECV patients despite therapy, lending support to ECV as a inator), all three performed similarly (see Table 3). The time- key amyloid biomarker. dependent ROC analysis revealed that overall (considering both Recent work published in this journal in non-amyloid patients, earlier [t ¼ 12] and later [t ¼ 24] follow-up times), the three ROC where ECV likely measures diffuse fibrosis, has also showed predict- curves for ECV , ECV , and pre-contrast T1 show quite similar dis- ive power—in 1176 consecutive CMR referral patients over a median i b crimination for cumulative mortality (see Figure 5). of 1.3 years follow-up, 24 deaths occurred with ECV carrying a hazard Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 248 S.M. Banypersad et al. Table 2 Extracellular volume, pre-, and post-contrast T1 correlations (Pearson’s R correlations) with cardiac structure and function, biomarkers and ECG changes in light-chain amyloid patients ECV Myocardial T1 ........................................................................ Pre-contrast Post-contrast ............................. ............................. ............................. RP-value RP-value RP-value ............................................................................................................................................................................... LV structure by CMR LV mass 0.49 ,0.001 0.44 0.001 0.44 0.001 Indexed LV mass 0.50 0.001 0.44 0.001 0.41 0.001 Septal thickness 0.61 0.001 0.54 0.001 0.35 0.001 LA area 0.31 0.002 0.13 0.25 0.22 0.054 Indexed LA area 0.29 0.003 0.11 0.35 0.11 0.35 ............................................................................................................................................................................... LV systolic function by CMR Ejection fraction 0.46 0.001 0.31 0.004 0.22 0.045 MAPSE 0.59 0.001 0.53 0.001 0.25 0.023 LV end-diastolic volume 0.05 0.64 0.12 0.28 0.15 0.18 LV end-systolic volume 0.31 0.002 0.15 0.19 0.06 0.58 Indexed LV end-diastolic volume 0.10 0.32 0.17 0.13 0.27 0.01 Indexed LV end-systolic volume 0.31 0.002 0.13 0.23 0.04 0.73 ............................................................................................................................................................................... LV diastolic function by echo E:E 0.35 0.001 0.25 0.03 0.34 0.002 IVRT 0.37 0.002 0.32 0.02 0.19 0.17 E-deceleration time 0.24 0.02 0.37 0.001 0.07 0.51 ............................................................................................................................................................................... RV systolic function by CMR TAPSE 0.53 0.001 0.50 0.001 0.42 0.001 ............................................................................................................................................................................... Biomarkers Serum NT-pro-BNP (LnNT-proBNP) 0.65 0.001 0.58 0.001 0.35 0.001 Troponin T (lnTropT) 0.43 0.02 0.28 0.07 0.24 0.12 ............................................................................................................................................................................... ECG ECG limb lead mean voltage 0.43 0.001 0.37 0.001 0.10 0.40 ECG chest lead mean voltage 0.22 0.03 0.13 0.27 0.24 0.03 Mitral annular plane systolic excursion. $b Tricuspid annular plane systolic excursion. ratio of 1.52 (1.21–1.89) for admissions with heart failure and all- cause mortality. Here, we have demonstrated that ECV adds incre- mental value over and above existing clinical markers when risk- stratifying patients. Unfortunately, it was not possible to include NYHA class in the multivariable model because this information was not available in all patients due to other factors limiting exertion such as peripheral and autonomic neuropathy due to systemic amyl- oidosis. Additionally, the limited number of deaths limits very exten- sive multivariable analysis so this may not represent the optimal multivariable model. We used an arbitrary categorization for the presence or otherwise of cardiac amyloid. The Mayo staging system is the most recognized predictor of survival in systemic AL amyloidosis. In new presenta- tions, median survival was reduced from 26 to 10 months when either NT-proBNP or Troponin T was raised and reduced further still to only 3 months if both biomarkers were raised, although the Figure 2 Dot plot showing correlation between extracellular authors are in the process of further refining this model with inclusion volume and late-gadolinium enhancement. of values for serum-free light-chain concentration. Our survival Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 T1 mapping and survival in systemic AL amyloidosis 249 Table 3 Median and tertiles for extracellular volume after primed infusion and pre-contrast T1 with associated Hazard Ratios by Cox regression and Harrell’s C statistic Tertile Cut-point HR (95% CI) P-value Harrell’s C statistic ............................................................................................................................................................................... ECV Tertile 1 0.40 4.67 (1.39–15.5) 0.013 0.63 Median 0.45 3.83 (1.53–9.61) 0.004 0.66 Tertile 2 0.49 3.61 (1.56–8.38) 0.003 0.65 Pre-contrast myocardial T1 Tertile 1 1044 ms 5.39 (1.24–23.4) 0.02 0.64 Median 1080 ms 3.01 (1.08–8.44) 0.035 0.62 Tertile 2 1116 ms 3.22 (1.30–8.04) 0.01 0.63 ECV Median 0.44 5.09 (1.09–23.7) 0.03 0.68 Post-contrast T1 Median 565 ms 0.45 (0.17–1.20) 0.11 0.41 Cox regression and Harrell’s C statistic also shown for median ECV and post-contrast T1. available on all platforms. We have previously demonstrated that when ROIs are drawn in LGE-positive and LGE-negative areas in the same patient, the ECV, whilst lower in LGE-negative areas, is still not normal. The simpler pre-contrast myocardial T1 technique does not require a contrast agent and shows promise, particularly as 20– 30% of patients with systemic AL amyloidosis have an eGFR of ,30 mL/min at presentation and in these patients, the Mayo staging system is in part confounded by elevation of serum biomar- kers due to renal dysfunction. Here, pre-contrast myocardial T1 by ShMOLLI is an alternative to ECV. It is an equally strong predictor but as mentioned earlier, it represents a composite signal from cells and interstitium, not just the interstitium alone like ECV. Some work may be needed to derive normal pre-contrast T1 values in patients with renal impairment due to non-amyloid-related patholo- gies. An additional issue is that pre-contrast T1 presents greater standardization challenges. From a practical perspective, the bolus only approach to ECV Figure 3 Kaplan–Meier survival curves for extracellular volume (ECV ) was as good as ECV . Our previous work showed that, in b i after primed infusion. most disease states, ECV carried excellent agreement with ECV b i when the tissue ECV was ,0.4, but generated higher results in high ECV scenarios—such as areas of scar and amyloid. Nonethe- data in the 49 patients scanned at presentation is currently under- less, this studysuggeststhatthe ECV passes a key clinical utility test of powered to determine any incremental benefit of ECV in this specific being prognostic. Post-contrast T1, however, was not useful either at patient group; this remains work in progress. baseline or to predict outcome. Extracellular volume is predictive, regardless of treatment status Limitations of the study are that patients were followed up for dif- and indeed irrespective of whether patients are presenting at diagno- ferent time periods and are at different disease and treatment stages, sis or years into the disease process. Some patients in the cohort had with treatment here reflecting current UK practice. The causes of modest ECV increases (ECV 0.30–0.40) without any other evidence death are not known as patients die locally and the National Amyloid- of cardiac involvement (no LGE, no wall thickness increase, and no osis centre receives only notification of death rather than cause of biomarker elevation), reinforcing our original findings that even death; however, it is widely accepted that most deaths are cardiac. patients classified as having no cardiac amyloid do in fact have Studies looking to correlate ECV change with haematological and raised ECVs, suggestive of low-grade cardiac disease. A plausible clinical response as well as histology in AL amyloidosis have yet to role for aggressive therapy in such patients to prevent progression be performed. Whole heart ECV calculations were not possible in to overt cardiac disease can be entertained. this study because of through-planning of blood pool (due to Although T1 mapping is now more mature with sequences avail- cardiac motion in the superior–inferior plane) in areas of thinner able on all platforms, it is difficult to compare ECV and T1 to LGE myocardium towards the apex but as technology advances with because, as previously stated, the absence of LGE likely does not motion correction T1 mapping sequences, this will become possible. equate to the absolute absence of cardiac amyloid and PSIR As stated earlier, the number of events limits extensive analysis. imaging which can be helpful with LGE imaging in amyloid, is not That said, these are nevertheless hard endpoints and multivariable Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 250 S.M. Banypersad et al. Figure 4 Kaplan–Meier survival curves for (A) pre-contrast myocardial T1 and (B) extracellular volume at bolus (NB: although the median of 0.44 was used, the groups are not equal because more than 1 patient had an extracellular volume of 0.44). Figure 5 Time-dependent receiver operating characteristic curves for extracellular volume after primed infusion, extracellular volume at bolus and pre-contrast myocardial T1 and survival using nearest neighbour estimator method at time: (top 3) 12 months and (bottom 3) 24 months. Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 T1 mapping and survival in systemic AL amyloidosis 251 strain imaging: an observational cohort study. J Am Soc Echocardiogr 2010;23: analysis can still be performed in these situations. Whether ECV 643–652. and pre-contrast T1—which are not entirely concordant—provide 8. Maceira AM, Prasad SK, Hawkins PN, Roughton M, Pennell DJ. Cardiovascular mag- different pathological insights is at this stage unknown. netic resonance and prognosis in cardiac amyloidosis. J Cardiovasc Magn Reson 2008; 10:54. 9. Karamitsos TD, Piechnik SK, Banypersad SM, Fontana M, Ntusi NB, Ferreira VM, Whelan CJ, Myerson SG, Robson MD, Hawkins PN, Neubauer S, Moon JC. Noncon- Conclusions trast t1 mapping for the diagnosis of cardiac amyloidosis. JACC Cardiovasc Imaging 2013;6:488–497. The myocardialextracellular volume, ECV, is a recently developed, 10. Flett AS, Hayward MP, Ashworth MT, Hansen MS, Taylor AM, Elliott PM, non-invasive quantifier of cardiac amyloidosis. We confirm earlier McGregor C, Moon JC. Equilibrium contrast cardiovascular magnetic resonance results that ECV increases with established disease and detects for the measurement of diffuse myocardial fibrosis: preliminary validation in early cardiac involvement. Extracellular volume after primed infusion humans. Circulation 2010;122:138–144. 11. Brooks J, Kramer CM, Salerno M. Markedly increased volume of distribution of gado- is a promising clinical biomarker which passes a key test as a predictor linium in cardiac amyloidosis demonstrated by T mapping. J Magn Reson Imaging 2013; of mortality. The pre-contrast T1 mapping method and the faster 38:1591–1595. bolus-only ECV measurement techniques are equally prognostic, 12. Mongeon FP, Jerosch-Herold M, Coelho-Filho OR, Blankstein R, Falk RH, Kwong RY. Quantification of extracellular matrix expansion by CMR in infiltrative heart disease. providing options for patients in renal failure or, in combination JACC Cardiovasc Imaging 2012;5:897–907. add robustness and diagnostic confidence. 13. Banypersad SM, Sado DM, Flett AS, Gibbs SD, Pinney JH, Maestrini V, Cox AT, Fontana M, Whelan CJ, Wechalekar AD, Hawkins PN, Moon JC. Quantification of myocardial extracellular volume fraction in systemic AL amyloidosis: an equilibrium Supplementary material contrast cardiovascular magnetic resonance study. Circ Cardiovasc Imaging 2013;6: 34–39. Supplementary material is available at European Heart Journal online. 14. Robbers LF, Baars EN, Brouwer WP, Beek AM, Hofman MB, Niessen HW, van Rossum AC, Marcu CB. T1 mapping shows increased extracellular matrix size in the myocardium due to amyloid depositions. Circ Cardiovasc Imaging 2012;5: Acknowledgements 423–426. We gratefully acknowledge the contributions of the clinical fellows, 15. Bandula S, Banypersad SM, Sado D, Flett AS, Punwani S, Taylor SA, Hawkins PN, Moon JC. Measurement of tissue interstitial volume in healthy patients and those nursing staff, histopathologists, geneticists, and echocardiographers with amyloidosis with equilibrium contrast-enhanced MR imaging. Radiology 2013; at the National Amyloidosis Centre and the clinical fellows, radiogra- 268:858–864. phers, and secretarial staff at the Heart Hospital MRI Department. 16. Wong TC, Piehler KM, Kang IA, Kadakkal A, Kellman P, Schwartzman DS, Mulukutla SR, Simon MA, Shroff SG, Kuller LH, Schelbert EB. Myocardial extracellu- lar volume fraction quantified by cardiovascular magnetic resonance is increased in Funding diabetes and associated with mortality and incident heart failure admission. Eur Heart This work was supported by GlaxoSmithKline for some of our research J 2014;35:657–664. studies in amyloid and are supported by researchers at the National Insti- 17. White SK, Sado DM, Fontana M, Banypersad SM, Maestrini V, Flett AS, Piechnik SK, tute for Health Research University College London Hospitals Biomed- Robson MD, Hausenloy DJ, Sheikh AM, Hawkins PN, Moon JC. T1 mapping for myo- cardial extracellular volume measurement by CMR: bolus only versus primed infu- ical Research Centre. Funding to pay the Open Access publication sion technique. JACC Cardiovasc Imaging 2013;6:955–962. charges for this article was provided by the British Heart Foundation. 18. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization by a distinctive voltage/mass relation. Am J Cardiol 1982;49:9–13. Conflict of interest: S.M.B. reports the following disclosure: Project 19. Piechnik SK, Ferreira VM, Dall’Armellina E, Cochlin LE, Greiser A, Neubauer S, part funded by GSK. A.D.W. reports the following disclosure: received Robson MD. Shortened modified Look-Locker Inversion recovery (ShMOLLI) for money in relation to consultancy with GSK. J.C.M. reports the following clinical myocardial T1-mapping at 1.5 and 3T within a 9 heartbeat breathhold. J Cardiovasc Magn Reson 2010;12:69. disclosure: consultancy agreement with GSK subsequent to this manu- 20. Fontana M, White SK, Banypersad SM, Sado DM, Maestrini V, Flett AS, Piechnik SK, script being submitted. S.K.P. reports the following disclosure: NIHR Neubauer S, Roberts N, Moon JC. Comparison of T1 mapping techniques for ECV BRC Research grant. All other authors do not have anything to disclose. quantification. Histological validation and reproducibility of ShMOLLI versus multibreath-hold T1 quantification equilibrium contrast CMR. J Cardiovasc Magn Reson 2012;14:88. References 21. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic 1. Banypersad SM, Moon JC, Whelan C, Hawkins PN, Wechalekar AD. Updates in data capture (REDCap)--a metadata-driven methodology and workflow process for cardiac amyloidosis: a review. J Am Heart Assoc 2012;1:e000364. providing translational research informatics support. J Biomed Inform 2009;42: 2. Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, Greipp PR, 377–381. Witzig TE, Lust JA, Rajkumar SV, Fonseca R, Zeldenrust SR, McGregor CG, Jaffe AS. 22. Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored survival Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging data and a diagnostic marker. Biometrics 2000;56:337–344. system for primary systemic amyloidosis. J Clin Oncol 2004;22:3751–3757. 23. Sado DM, Flett AS, Banypersad SM, White SK, Maestrini V, Quarta G, Lachmann RH, 3. Dubrey SW, Cha K, Anderson J, Chamarthi B, Reisinger J, Skinner M, Falk RH. The Murphy E, Mehta A, Hughes DA, McKenna WJ, Taylor AM, Hausenloy DJ, clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involve- Hawkins PN, Elliott PM, Moon JC. Cardiovascularmagnetic resonance measurement ment. QJM 1998;91:141–157. of myocardial extracellular volume in health and disease. Heart 2012;98:1436–1441. 4. Perlini S, Salinaro F, Cappelli F, Perfetto F, Bergesio F, Alogna A, Mussinelli R, 24. Ugander M, Oki AJ, Hsu LY, Kellman P, Greiser A, Aletras AH, Sibley CT, Chen MY, Boldrini M, Raimondi A, Musca F, Palladini G, Merlini G. Prognostic value of fragmen- Bandettini WP, Arai AE. Extracellular volume imaging by magnetic resonance ted QRS in cardiac AL amyloidosis. Int J Cardiol 2013;167:2156–2161. imaging provides insights into overt and sub-clinical myocardial pathology. Eur 5. Miller F Jr, Bellavia D. Comparison of right ventricular longitudinal strain imaging, tri- Heart J 2012;33:1268–1278. cuspid annular plane systolic excursion, and cardiac biomarkers for early diagnosis of 25. Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Colby C, Laumann K, cardiac involvement and risk stratification in primary systematic (AL) amyloidosis: a Zeldenrust SR, Leung N, Dingli D, Greipp PR, Lust JA, Russell SJ, Kyle RA, 5-year cohort study: reply. Eur Heart J Cardiovasc Imaging 2013;14:91–92. Rajkumar SV, Gertz MA. Revised prognostic staging system for light chain amyloid- 6. Koyama J, Falk RH. Prognostic significance of strain Doppler imaging in light-chain amyloidosis. JACC Cardiovasc Imaging 2010;3:333–342. osis incorporating cardiac biomarkers and serum free light chain measurements. 7. Bellavia D, Pellikka PA, Al-Zahrani GB, Abraham TP, Dispenzieri A, Miyazaki C, J Clin Oncol 2012;30:989–995. Lacy M, Scott CG, Oh JK, Miller FA Jr. Independent predictors of survival in 26. Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic primary systemic (Al) amyloidosis, including cardiac biomarkers and left ventricular and Cox regression. Am J Epidemiol 2007;165:710–718. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

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Abstract

Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 CLINICAL RESEARCH European Heart Journal (2015) 36, 244–251 doi:10.1093/eurheartj/ehu444 Imaging T1 mapping and survival in systemic light-chain amyloidosis 1,2,3 1,2 1 1 Sanjay M. Banypersad , Marianna Fontana , Viviana Maestrini , Daniel M. Sado , 1,2 4 5 2 Gabriella Captur , Aviva Petrie , Stefan K. Piechnik , Carol J. Whelan , 1 2 2 2 Anna S. Herrey , Julian D. Gillmore , Helen J. Lachmann , Ashutosh D. Wechalekar , 2 1,3 Philip N. Hawkins , and James C. Moon 1 2 The Heart Hospital, 16-18 Westmoreland Street, London W1G 8PH, UK; The National Amyloidosis Centre, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland 3 4 Hill Street, London NW3 2PF, UK; Institute of Cardiovascular Science, University College London, Gower Street, London WC1E 6BT, UK; Biostatistics Unit, UCL Eastman Dental Institute, 256 Grays Inn Road, London WC1X 8LD, UK; and Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK Received 9 April 2014; revised 20 October 2014; accepted 21 October 2014; online publish-ahead-of-print 17 November 2014 See page 203 for the editorial comment on this article (doi:10.1093/eurheartj/ehu442) Aims To assess the prognostic value of myocardial pre-contrast T1 and extracellular volume (ECV) in systemic amyloid light- chain (AL) amyloidosis using cardiovascular magnetic resonance (CMR) T1 mapping. ..................................................................................................................................................................................... Methods One hundred patients underwent CMR and T1 mapping pre- and post-contrast. Myocardial ECV was calculated at con- and results trast equilibrium (ECV ) and 15 min post-bolus (ECV ). Fifty-four healthy volunteers served as controls. Patients were i b followed up for a median duration of 23 months and survival analyses were performed. Mean ECV was raised in amyloid (0.44+ 0.12) as was ECV (mean 0.44+ 0.12) compared with healthy volunteers (0.25+ 0.02), P , 0.001. Native pre-contrast T1 was raised in amyloid (mean 1080+ 87 ms vs. 954+ 34 ms, P , 0.001). All three correlated with pre-test probability of cardiac involvement, cardiac biomarkers, and systolic and diastolic dysfunction. During follow-up, 25 deaths occurred. An ECV of .0.45 carried a hazard ratio (HR) for death of 3.84 [95% confidence interval (CI): 1.53–9.61], P ¼ 0.004 and pre-contrast T1 of .1044 ms ¼ HR 5.39 (95% CI: 1.24–23.4), P ¼ 0.02. Extracellular volume after primed infusion and ECV performed similarly. Isolated post-contrast T1 was non-predictive. In Cox regres- sion models, ECV was independently predictive of mortality (HR ¼ 4.41, 95% CI: 1.35–14.4) after adjusting for E:E , ejection fraction, diastolic dysfunction grade, and NT-proBNP. ..................................................................................................................................................................................... Conclusion Myocardial ECV (bolus or infusion technique) and pre-contrast T1 are biomarkers for cardiac AL amyloid and they predict mortality in systemic amyloidosis. --- -- -- -- --- -- -- -- --- -- -- --- -- -- -- --- -- -- -- --- -- -- --- -- -- -- --- -- -- -- --- -- -- --- -- -- -- --- -- -- -- --- -- -- --- -- -- -- --- -- -- -- --- -- -- -- - - - - - - - --- -- -- -- --- -- -- --- -- Keywords ECV † Amyloid † CMR † Cardiomyopathy † Heart failure † T1 mapping Current predictors of survival rely on measuring surrogate rather Introduction than direct markers of interstitial expansion. Concentration of the Systemic amyloid light-chain (AL) amyloidosis is a multiorgan, infiltra- serum biomarkers NT-proBNP and Troponin T form the basis of tive disorder caused by an underlying plasma cell dyscrasia and is the Mayo Staging classification but are influenced by renal impair- characterized by tissue and organ amyloid deposition with interstitial ment which is present in a quarter of patients at presentation. ECG 3 4 expansion. Cardiac involvement is present in 50% of patients at criteria, low limb lead voltages, or fragmented QRS complexes presentation and is the principal driver of prognosis. Treatment are also predictive, but are confounded by pericardial effusions comprises chemotherapy or autologous stem cell transplantation and conduction abnormalities. Echocardiographic parameters also 5 – 7 to suppress clonal light-chain production, which may retard disease predict outcome, but coexisting causes of left ventricular hyper- progression or facilitate regression. trophy or diastolic impairment may affect interpretation. * Corresponding author. Tel: +44 203 456 3081, Fax: +44 203 456 3086, Email: [email protected] & The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 T1 mapping and survival in systemic AL amyloidosis 245 Figure1 Showing (A) pre-contrast and (B) post-contrast, four-chamber ShMOLLI image with regions of interest drawn in the left atrium for blood T1 measurement and in the basal septum of left ventricle, excluding at least the first two pixels of endocardium on either side of the septum in order to avoid through planing of blood pool. (known atrial fibrillation at first visit) were recruited. These 100 patients Cardiovascularmagneticresonance(CMR)usingthelate-gadolinium include all 60 patients studied previously in the baseline study. Approxi- enhancement (LGE) technique adds value in the diagnosis of cardiac mately 25% of patients with systemic AL amyloidosis seen at the centre involvement in AL amyloidosis. Altered gadolinium kinetics also 8 during this period had an eGFR of ,30 mL/min/1.73 m and were there- shows some correlation with survival. Recently we have shown that fore excluded. Six patients who were found to have atrial fibrillation/ pre-contrast, native myocardial T1 mapping correlates with cardiac flutter once in the scanner after they had consented were not excluded. disease burden and detects early disease. T1 mapping pre- and post- All patients had histological proof of systemic AL amyloidosis except 2 contrast can be used to derive the partition coefficient and, with the (2%), who died before biopsy could be undertaken, but in whom mono- 10–12 haematocrit, the myocardial extracellular volume (ECV) which clonal gammopathies were present and the organ distribution of amyloid is a direct measurement of myocardial interstitium and therefore on SAP scintigraphy was characteristic of AL type. Histology was per- 13,14 likely a surrogate marker of amyloid burden. The ECV can also formed with Congo red followed by immunohistochemical staining; assess amyloid burden in other organs. Furthermore, in other tissues examined were: kidney (26%), endomyocardium (7%), bone cardiac diseases, myocardial ECV predicts outcome. marrow (13%), upper gastrointestinal tract (7%), liver (3%), fat (15%), spleen (1%), lung (1%), rectum (9%), soft tissues (12%, included skin, Technically, measurement of the ECV requires equilibration of tongue, buccal mucosa, labia), lymph node (3%), and peritoneum (1%). contrast concentrations between blood and myocardium, which All patients underwent 12 lead ECG, assays of the cardiac biomarkers can be achieved precisely using a somewhat cumbersome primed NT-proBNP and Troponin T, and echocardiography at baseline. Mean contrast infusion, or sufficiently through delayed study following ECG QRS voltage in limb and praecordial leads were calculated. Echocar- administration of a bolus of gadolinium. Both techniques measure diographic assessment of diastolic function was performed using the E:E ECV the same where the ECVs are typically 0.4 or less, but one ratio. Where transmitral E-wave decelerationtime andisovolumetric relax- paper has shown a bias towards over-estimation of the true ECV in ation time were available, a diastolic dysfunction grade of 0–3 was assigned high ECV conditions (including n ¼ 20 amyloid patients). according to established British Society of Echocardiography (BSE) criteria. We hypothesized firstly that the myocardial ECV and pre-contrast All additionally underwent conventional CMR on a 1.5 T magnet T1 would correlate with disease burden in cardiac AL amyloidosis as (Avanto, Siemens). T1 mapping was performed using the Shortened Modified Look Lockers Inversion (ShMOLLI) recovery sequence pre- assessed by current measures. Additionally, we tested the ability of and post-contrast (0.1 mmol/kg bolus and 0.0011 mmol/kg/min infusion bothbiomarkersaspredictorsofsurvivalinALamyloidosisbycompar- TM of Dotarem ) as part of the Equilibrium CMR (EQ-CMR) technique, the ing the predictive power of: ECV after primed infusion (ECV ); post-contrast T1 map being performed at 15 min and after equilibration pre-contrast T1; bolus-only ECV (ECV ); and post-contrast T1. (mean time from bolus 45 min), as previously described. Methods Analysis The research was approved by The UCL/UCLH Joint Committees on the Standard CMR parameters of structure (left ventricle (LV) mass, left atrial Ethics of Human Research Committee and all participants provided area with/without indexing for body surface area, maximal septal thick- informed, written consent prior to enrolment. One hundred consecutive ness) and systolic function [ejection fraction, mitral annular plane systolic patients with systemic AL amyloidosis who were assessed between 2010 excursion (MAPSE), Tricuspid annular plane systolic excursion (TAPSE)] and 2012 at the National Amyloidosis Centre (Royal Free Hospital, were assessed. A region of interest (ROI) was drawn in the basal septum London, UK) and in whom there were no contraindications to CMR in a four-chamber view in all patients and in the left atrium for blood T1 (presence of non-MR compatible devices) or contrast administration measurement as papillary muscle hypertrophy made drawing an ROI in (GFR , 30 mLs/min) or potential confounders to T1 measurement the LV cavity challenging (see Figure 1); ROIs were mid-myocardial (at Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 246 S.M. Banypersad et al. least two pixels away from the apparent blood:myocardial boundary) and To test the prognostic value of ECV and pre-contrast T1, survival was were drawn without reference to the LGE images (see Figure 1). We evaluated using Cox proportional hazards regression analysis, providing quantified interstitial expansion with the ECV as described previously: estimated hazard ratios (HRs) with 95% confidence intervals (CIs) and ECV ¼ l(1 2 haematocrit), where l ¼ [DR1 ]/[DR1 ] Kaplan–Meier curves. Conventional ROC analysis could not be per- myocardium blood pool pre- and post-Gd (where R1 ¼ 1/T1). formed because the follow-up period was not the same for each Some ECV data (n ¼ 19 of the 100) pre-dated availability of ShMOLLI patient. Therefore, time-dependent ROC curves were used to assess T1 mapping and had utilized multibreath-hold T1 measurement. We the capacity of ECV compared with ECV and pre-contrast myocardial i b have demonstrated equivalence of ECV values derived from this tech- T1 for discriminating between surviving and dying patients with AL amyl- nique with ShMOLLI ECV and so these data were not excluded from oidosis. For fixed times (t ¼ 12 months, t ¼ 24 months) and specificity the analyses. level, we have compared the sensitivity of ECV , ECV , and pre-contrast i b That said, these patients did not have an ECV value or the subsidiary myocardial T1 measurements for detecting patients who will die by time component of the ECV equation, pre-contrast T1; multibreath-hold meas- t. For the ROC curves constructed using the nearest neighbour estimator 20.20 urement has been shown to be inferior to T1 mapping, so accordingly, (NNE) we used a narrow span of l (0.25 × nobs ) to yield only mod- these were excluded from the sub-analysis comparing techniques—this erate smoothing. To permit comparison of ROCs by the NNE estimator, particular analysis therefore consists of 81 rather than 100 patients. a set of simple KM estimator ROC curves for this data at t ¼ 24 months Extracellular volume and myocardial T1 results were compared with are also provided (see Supplementary material online, Figure S1). 54 healthy volunteers who underwent pre-contrast T1 mapping and Optimal myocardial T1 and ECV values were explored by Cox regres- ECV measurement (bolus and infusion). The number of patients dead sion, using the median and the 1st or 2nd tertiles as cut-off values. The and alive was assessed after a median duration of 23 (interquartile two groups resulting from each cut-off were comparedusing the Harrell’s range: 6–25) months. Some analysis involved sub-grouping patients C statistic (a measure of discrimination between groups) to determine into pre-test probability of cardiac involvement. This was done as previ- the better model and thus biomarker for predicting survival. All variables ously described and as stated below. were first explored with univariate Cox regression. Multivariable models Definite cardiac involvement—any of: evaluated the independent predictive value of ECV above other clinically and statistically significant covariates. † Left ventricle (LV) wall thickness of ≥12 mm by echocardiography in the absence of any other known cause Results † Right ventricle (RV) free wall thickening co-existing with LV thickening by echocardiography in the absence of systemic or pulmonary Table 1 summarizes baseline characteristics for patients and healthy hypertension volunteers. Within the patient cohort, 14 (14%) patients were on Possible cardiac involvement—any of: treatment for hypertension; 10 (10%) had confirmed coronary artery disease by angiography, 1 (1%) had had a stroke, and 2 (2%) † LV wall thickening by echocardiography in the presence of had diabetes. Fifty patients were treated with chemotherapy for hypertension the first time which comprised triple therapy with either cyclophos- † RV thickening by echocardiography in the presence of pulmonary phamide, thalidomide, and dexamethasone or cyclophosphamide, hypertension bortezomib and dexamethasone (CVD), depending on local guide- † Normal wall thickness by echocardiography with diastolic dysfunction lines of regional NHS Trusts within the UK. Seventeen patients and raised serum biomarkers were treated for a 2nd or 3rd time having relapsed—treatment No suspected involvement: was either with CVD or a lenalidomide-containing regimen in these instances. Nine patients had not received any chemotherapy as † Normal wall thickness by echocardiography with normal serum there was no clinical indication (e.g. renal amyloid with established biomarkers renal failure, isolated neuropathic presentations) and 24 patients were under a stable follow-up with no indication for further chemo- Statistical analysis therapy at the time of scan. Study data were collected and managed using REDCap (Research Elec- Twenty-one patients had a pre-test probability of no cardiac in- tronic Data Capture) electronic data capture tools hosted at University volvement, 26 had possible cardiac involvement, and 53 had definite College London. Analysis was performed using SPSS (IBM Corp. cardiac involvement. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. All ECV values are the ECV from infusion measurement unless Armonk, NY: IBM Corp), R programming language for statistical comput- ing (version 3.0.1, The R Foundation for Statistical Computing) and in otherwise stated. Healthy controls were younger on average, but Stata (StataCorp. 2011. Stata Statistical Software: Release 12. College our work and others suggests any ECV changes with age are small 23,24 Station, TX: StataCorp LP). All continuous variables were normally dis- compared with amyloid changes. There were proportionately tributed except NT-proBNP and Troponin T which were log (ln) trans- more females in the control vs. the patient group. This slightly formed (base e) to achieve normality for further analysis. Linear increases the control group ECV and pre-contrast T1 compared regression models measured the association between quantitative ECV with that of a gender-matched group (male vs. female: ECV 0.24 vs. and other variables; variance inflation factors ,2 excluded collinearity. 0.27, P , 0.001; T1 940 vs. 966 ms, P ¼ 0.006). Pearson’s correlation coefficients are presented in terms of R values. 2 As in previous work, mean cardiac ECV was greater in patients Means are presented+SD. The x test was used to compare categorical compared with healthy volunteers with a wider range (0.44+ 0.12 variables between patients and controls whilst the unpaired t-test was vs. 0.25+ 0.02, P , 0.001) and correlated with pre-test probability used to compare continuous variables betweenthe patients and controls. of cardiac involvement by conventional parameters (P , 0.001) A one-way ANOVA with Bonferroni correction was used to test ECV with pre-test clinical probability of cardiac involvement. (see Supplementary material online, Figure S2). Mean pre-contrast Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 T1 mapping and survival in systemic AL amyloidosis 247 Table 1 Baseline characteristics of the 100 AL amyloidosis patients and 54 healthy controls Characteristic Patients Healthy controls P value ............................................................................................................................................................................... Male/female 67/33 25/29 0.01 Mean age+ SD (years) 62+ 10 46+ 15 0.001 Mean creatinine+ SD (mmol/L) 89+ 32 74+ 13 0.001 Mean NYHA (I/II/III/IV) 29/56/15/0 – Mean EF+ SD (%) 66+ 11 67+ 6 0.42 Diastolic dysfunction grade (0/1/2/3) 15/36/25/22 – Mean indexed end-diastolic LV volume+ SD (mLs) 60+ 14 73+ 12 0.001 Mean indexed end-systolic LV volume+ SD (mLs) 19+ 10 25+ 7 0.001 Mean indexed LV mass+ SD(g/m)96+ 34 65+ 15 0.001 Mean indexed LA area 13+39+ 1.5 0.001 Median NT-proBNP in pmol/L (IQ range) 146 (38–359) – Median troponin T in ng/L (IQ range) 0.03 (0.01–0.06) – AF/atrial flutter (%) 6 (6) 0 Two patients did not have all three diastolic markers measured due to poor windows and therefore could not be graded as per BSE guidelines. myocardial T1 values were raised in patients compared with healthy The value ECV . 0.45 remained significantly associated with volunteers (1080+ 87 ms vs. 954+ 34 ms, P , 0.001) and also cor- mortality (HR ¼ 4.41, 95% CI 1.35–14.4; P ¼ 0.01) in multivariable related with pre-test probability of cardiac involvement (P , 0.001). Cox models that included measures of systolic and diastolic function Table 2 provides the Pearson correlation coefficients of ECV, and serum biomarkers: E:E , diastolic dysfunction grade (≥2), pre-contrast and post-contrast myocardial T1 to other cardiac ejection fraction, and LnNT-proBNP (troponin was not available in parameters, many of which typically change in cardiac amyloid. Extra- all patients). E:E and NT-ProBNP also remained independently cellular volume correlated significantly with 17 of 19; pre-contrast predictive. T1 with 12, and post-contrast T1 with 10. With regards LGE, 25 patients had no LGE, 50 had global subendo- Discussion cardial enhancement, and 10 had extensive enhancement. Eight had patchy enhancement and seven had evidence of only altered Extracellular volume is the first, non-invasive quantifier of the cardiac gadolinium kinetics, i.e. reversed nulling of myocardium and blood interstitium, while pre-contrast T1 is a composite measure of inter- after gadolinium administration. Extracellular volume correlated stitium and myocardial cells. This study demonstrated that ECV and significantly with increasing degrees of LGE (P , 0.001) as shown native myocardial T1 as measured by the newer T1 mapping techni- in Figure 2. ques, both correlate with current markers of disease severity in 11 – 13 At follow-up (median 23 months), 25 of 100 patients had died. cardiac AL amyloidosis, supporting previous work. We have For each potential predictor, median and tertile cut-points were also demonstrated that both these biomarkers have ‘real-world’ assessed for predictive power and the best result presented (see clinical significance in that both are predictors of mortality in AL Table 3). amyloidosis. For ECV , a median ECV of 0.45 was the best predictor of survival: Amyloidosis is the exemplary interstitial disease of the myocar- HR 3.84 (1.53–9.61), P ¼ 0.004 (Figure 3). The survival curve indi- dium. Cardiac involvement portends a poor prognosis which has cates that there is an 40% chance of death at 23 months in patients driven the need for better methods of detecting early cardiac with an ECV ≥ 0.45 compared with 15% for patients with an ECV , disease. We previously described both pre-contrast T1 mapping 0.45. For pre-contrast myocardial T1, the 1st tertile (cut-point and ECV measurement as potential, non-invasive techniques for 1044 ms) was the best predictor: HR 5.39 (1.24–23.4), P ¼ 0.02 directly measuring the cardiac AL disease burden in amyloid. (Figure 4A). ECV with median of 0.44 also predicted survival with Here, these early results are strengthened by increased numbers an HR of 5.09 (1.09–23.7), P ¼ 0.04 (Figure 4B). Post-contrast T1 and, additionally, prognostic significance of the biomarkers is demon- did not predict survival (HR ¼ 0.5, P ¼ 0.11). strated, even with therapy. The half of AL amyloid patients with an When the three predictive models ECV , ECV , and pre-contrast ECV . 0.45 had a three- to four-fold increased likelihood of i b T1 were compared to determine the stronger discriminator using death—roughly a 35–40% chance of death at 23 months compared the Harrell’s C statistic (the higher the number, the stronger discrim- with lower ECV patients despite therapy, lending support to ECV as a inator), all three performed similarly (see Table 3). The time- key amyloid biomarker. dependent ROC analysis revealed that overall (considering both Recent work published in this journal in non-amyloid patients, earlier [t ¼ 12] and later [t ¼ 24] follow-up times), the three ROC where ECV likely measures diffuse fibrosis, has also showed predict- curves for ECV , ECV , and pre-contrast T1 show quite similar dis- ive power—in 1176 consecutive CMR referral patients over a median i b crimination for cumulative mortality (see Figure 5). of 1.3 years follow-up, 24 deaths occurred with ECV carrying a hazard Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 248 S.M. Banypersad et al. Table 2 Extracellular volume, pre-, and post-contrast T1 correlations (Pearson’s R correlations) with cardiac structure and function, biomarkers and ECG changes in light-chain amyloid patients ECV Myocardial T1 ........................................................................ Pre-contrast Post-contrast ............................. ............................. ............................. RP-value RP-value RP-value ............................................................................................................................................................................... LV structure by CMR LV mass 0.49 ,0.001 0.44 0.001 0.44 0.001 Indexed LV mass 0.50 0.001 0.44 0.001 0.41 0.001 Septal thickness 0.61 0.001 0.54 0.001 0.35 0.001 LA area 0.31 0.002 0.13 0.25 0.22 0.054 Indexed LA area 0.29 0.003 0.11 0.35 0.11 0.35 ............................................................................................................................................................................... LV systolic function by CMR Ejection fraction 0.46 0.001 0.31 0.004 0.22 0.045 MAPSE 0.59 0.001 0.53 0.001 0.25 0.023 LV end-diastolic volume 0.05 0.64 0.12 0.28 0.15 0.18 LV end-systolic volume 0.31 0.002 0.15 0.19 0.06 0.58 Indexed LV end-diastolic volume 0.10 0.32 0.17 0.13 0.27 0.01 Indexed LV end-systolic volume 0.31 0.002 0.13 0.23 0.04 0.73 ............................................................................................................................................................................... LV diastolic function by echo E:E 0.35 0.001 0.25 0.03 0.34 0.002 IVRT 0.37 0.002 0.32 0.02 0.19 0.17 E-deceleration time 0.24 0.02 0.37 0.001 0.07 0.51 ............................................................................................................................................................................... RV systolic function by CMR TAPSE 0.53 0.001 0.50 0.001 0.42 0.001 ............................................................................................................................................................................... Biomarkers Serum NT-pro-BNP (LnNT-proBNP) 0.65 0.001 0.58 0.001 0.35 0.001 Troponin T (lnTropT) 0.43 0.02 0.28 0.07 0.24 0.12 ............................................................................................................................................................................... ECG ECG limb lead mean voltage 0.43 0.001 0.37 0.001 0.10 0.40 ECG chest lead mean voltage 0.22 0.03 0.13 0.27 0.24 0.03 Mitral annular plane systolic excursion. $b Tricuspid annular plane systolic excursion. ratio of 1.52 (1.21–1.89) for admissions with heart failure and all- cause mortality. Here, we have demonstrated that ECV adds incre- mental value over and above existing clinical markers when risk- stratifying patients. Unfortunately, it was not possible to include NYHA class in the multivariable model because this information was not available in all patients due to other factors limiting exertion such as peripheral and autonomic neuropathy due to systemic amyl- oidosis. Additionally, the limited number of deaths limits very exten- sive multivariable analysis so this may not represent the optimal multivariable model. We used an arbitrary categorization for the presence or otherwise of cardiac amyloid. The Mayo staging system is the most recognized predictor of survival in systemic AL amyloidosis. In new presenta- tions, median survival was reduced from 26 to 10 months when either NT-proBNP or Troponin T was raised and reduced further still to only 3 months if both biomarkers were raised, although the Figure 2 Dot plot showing correlation between extracellular authors are in the process of further refining this model with inclusion volume and late-gadolinium enhancement. of values for serum-free light-chain concentration. Our survival Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 T1 mapping and survival in systemic AL amyloidosis 249 Table 3 Median and tertiles for extracellular volume after primed infusion and pre-contrast T1 with associated Hazard Ratios by Cox regression and Harrell’s C statistic Tertile Cut-point HR (95% CI) P-value Harrell’s C statistic ............................................................................................................................................................................... ECV Tertile 1 0.40 4.67 (1.39–15.5) 0.013 0.63 Median 0.45 3.83 (1.53–9.61) 0.004 0.66 Tertile 2 0.49 3.61 (1.56–8.38) 0.003 0.65 Pre-contrast myocardial T1 Tertile 1 1044 ms 5.39 (1.24–23.4) 0.02 0.64 Median 1080 ms 3.01 (1.08–8.44) 0.035 0.62 Tertile 2 1116 ms 3.22 (1.30–8.04) 0.01 0.63 ECV Median 0.44 5.09 (1.09–23.7) 0.03 0.68 Post-contrast T1 Median 565 ms 0.45 (0.17–1.20) 0.11 0.41 Cox regression and Harrell’s C statistic also shown for median ECV and post-contrast T1. available on all platforms. We have previously demonstrated that when ROIs are drawn in LGE-positive and LGE-negative areas in the same patient, the ECV, whilst lower in LGE-negative areas, is still not normal. The simpler pre-contrast myocardial T1 technique does not require a contrast agent and shows promise, particularly as 20– 30% of patients with systemic AL amyloidosis have an eGFR of ,30 mL/min at presentation and in these patients, the Mayo staging system is in part confounded by elevation of serum biomar- kers due to renal dysfunction. Here, pre-contrast myocardial T1 by ShMOLLI is an alternative to ECV. It is an equally strong predictor but as mentioned earlier, it represents a composite signal from cells and interstitium, not just the interstitium alone like ECV. Some work may be needed to derive normal pre-contrast T1 values in patients with renal impairment due to non-amyloid-related patholo- gies. An additional issue is that pre-contrast T1 presents greater standardization challenges. From a practical perspective, the bolus only approach to ECV Figure 3 Kaplan–Meier survival curves for extracellular volume (ECV ) was as good as ECV . Our previous work showed that, in b i after primed infusion. most disease states, ECV carried excellent agreement with ECV b i when the tissue ECV was ,0.4, but generated higher results in high ECV scenarios—such as areas of scar and amyloid. Nonethe- data in the 49 patients scanned at presentation is currently under- less, this studysuggeststhatthe ECV passes a key clinical utility test of powered to determine any incremental benefit of ECV in this specific being prognostic. Post-contrast T1, however, was not useful either at patient group; this remains work in progress. baseline or to predict outcome. Extracellular volume is predictive, regardless of treatment status Limitations of the study are that patients were followed up for dif- and indeed irrespective of whether patients are presenting at diagno- ferent time periods and are at different disease and treatment stages, sis or years into the disease process. Some patients in the cohort had with treatment here reflecting current UK practice. The causes of modest ECV increases (ECV 0.30–0.40) without any other evidence death are not known as patients die locally and the National Amyloid- of cardiac involvement (no LGE, no wall thickness increase, and no osis centre receives only notification of death rather than cause of biomarker elevation), reinforcing our original findings that even death; however, it is widely accepted that most deaths are cardiac. patients classified as having no cardiac amyloid do in fact have Studies looking to correlate ECV change with haematological and raised ECVs, suggestive of low-grade cardiac disease. A plausible clinical response as well as histology in AL amyloidosis have yet to role for aggressive therapy in such patients to prevent progression be performed. Whole heart ECV calculations were not possible in to overt cardiac disease can be entertained. this study because of through-planning of blood pool (due to Although T1 mapping is now more mature with sequences avail- cardiac motion in the superior–inferior plane) in areas of thinner able on all platforms, it is difficult to compare ECV and T1 to LGE myocardium towards the apex but as technology advances with because, as previously stated, the absence of LGE likely does not motion correction T1 mapping sequences, this will become possible. equate to the absolute absence of cardiac amyloid and PSIR As stated earlier, the number of events limits extensive analysis. imaging which can be helpful with LGE imaging in amyloid, is not That said, these are nevertheless hard endpoints and multivariable Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 250 S.M. Banypersad et al. Figure 4 Kaplan–Meier survival curves for (A) pre-contrast myocardial T1 and (B) extracellular volume at bolus (NB: although the median of 0.44 was used, the groups are not equal because more than 1 patient had an extracellular volume of 0.44). Figure 5 Time-dependent receiver operating characteristic curves for extracellular volume after primed infusion, extracellular volume at bolus and pre-contrast myocardial T1 and survival using nearest neighbour estimator method at time: (top 3) 12 months and (bottom 3) 24 months. Downloaded from https://academic.oup.com/eurheartj/article/36/4/244/2293404 by DeepDyve user on 13 July 2022 T1 mapping and survival in systemic AL amyloidosis 251 strain imaging: an observational cohort study. J Am Soc Echocardiogr 2010;23: analysis can still be performed in these situations. Whether ECV 643–652. and pre-contrast T1—which are not entirely concordant—provide 8. Maceira AM, Prasad SK, Hawkins PN, Roughton M, Pennell DJ. 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Radiology 2013; at the National Amyloidosis Centre and the clinical fellows, radiogra- 268:858–864. phers, and secretarial staff at the Heart Hospital MRI Department. 16. Wong TC, Piehler KM, Kang IA, Kadakkal A, Kellman P, Schwartzman DS, Mulukutla SR, Simon MA, Shroff SG, Kuller LH, Schelbert EB. Myocardial extracellu- lar volume fraction quantified by cardiovascular magnetic resonance is increased in Funding diabetes and associated with mortality and incident heart failure admission. Eur Heart This work was supported by GlaxoSmithKline for some of our research J 2014;35:657–664. studies in amyloid and are supported by researchers at the National Insti- 17. White SK, Sado DM, Fontana M, Banypersad SM, Maestrini V, Flett AS, Piechnik SK, tute for Health Research University College London Hospitals Biomed- Robson MD, Hausenloy DJ, Sheikh AM, Hawkins PN, Moon JC. T1 mapping for myo- cardial extracellular volume measurement by CMR: bolus only versus primed infu- ical Research Centre. 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Journal

European Heart JournalOxford University Press

Published: Jan 21, 2015

Keywords: amyloid; myocardium; biological markers; heart; primary amyloidosis; external cephalic version; infusion procedures; cardiac mri; nt-probnp; mortality; follow-up; amyloidosis; heart failure, diastolic; systole; pretest probability of disease; patient prognosis; antigens, cd98 light chains; ejection fraction; amyloidosis, systemic; cardiac markers

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