http://informahealthcare.com/amy ISSN: 1350-6129 (print), 1744-2818 (electronic) Amyloid, Early Online: 1–10 ! 2015 Informa UK Ltd. DOI: 10.3109/13506129.2015.1020153

ORIGINAL ARTICLE

Comparison of different types of cardiac amyloidosis by cardiac magnetic resonance imaging Arnt V. Kristen1, Fabian aus dem Siepen1, Katrin Scherer1, Rebekka Kammerer1, Florian Andre1, Sebastian J. Buss1, Ralf Bauer1, Stephanie Lehrke1, Andreas Voss2, Evangelos Giannitsis1, Hugo A. Katus1, and Henning Steen1 Department of Cardiology and 2Institute of Psychology, Heidelberg University, Heidelberg, Germany

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1

Abstract

Keywords

Objectives: We sought to determine cardiac morphological and functional differences between light-chain (AL), mutant-type transthyretin (ATTRmt) and wild-type TTR (ATTRwt) amyloidosis using contrast-enhancement cardiac magnetic resonance imaging (CE-CMR). Finally, we attempted to establish the diagnostic and prognostic impact of these findings. Introduction: The most common forms of cardiac amyloid are AL and ATTR amyloidosis, but the clinical courses of these variants are quite heterogeneous. While CE-CMR is used to evaluate patients with cardiac amyloidosis, its ability to predict prognosis in these patients is debatable. Methods: About 130 patients with cardiac amyloidosis (AL, n ¼ 62; ATTRmt, n ¼ 30, ATTRwt, n ¼ 33) were assessed by CE-CMR (cardiac morphology, cardiac function, late gadolinium enhancement). Results: Left ventricular (LV) mass, basal and mid-ventricular maximal wall thickness, and thickness of the inter-atrial septum were higher in ATTRwt when compared to AL and ATTRmt amyloidosis. Tricuspid annular excursion was lower in ATTRwt amyloidosis than in AL amyloidosis. CE was observed in 94.6% of the patients (AL 80.6%; ATTRmt 90%; ATTRwt 87.9%) with significant differences in quality and intensity between the groups. Differentiation of amyloid types was achieved by combination of age, number of organs, the presence of inferolateral CE-CMR, thickness of inter-atrial septum and troponin T. Overall 1-year-survival rates were 93.3, 93.9 and 70.5% in ATTRwt, ATTRmt and AL amyloidosis, respectively. LV mass, mitral annular excursion and NT-proBNP in AL amyloidosis, LV mass maximal apical wall thickness and troponin T in ATTRwt amyloidosis, and finally NT-proBNP and renal function in ATTRmt amyloidosis were independent predictors of outcome. Conclusions: This study demonstrates that CE-CMR can highlight morphological and functional differences between different types of cardiac amyloidosis. In addition, CE-CMR and cardiac biomarkers provide useful prognostic information in patients with cardiac amyloidosis.

Amyloidosis, cardiac magnetic resonance imaging, contrast enhancement, hypertrophy, risk stratification History Received 15 June 2014 Revised 22 January 2015 Accepted 12 February 2015 Published online 8 June 2015

Abbreviations: AL, amyloid light-chain; ATTRmt, mutant-type transthyretin; ATTRwt, wild-type transthyretin; (CE-)CMR, (contrast enhancement) cardiac magnetic resonance imaging; eGFR, estimated glomerular filtration rate; EF, ejection fraction; EDV, end-diastolic volume; ESV, end-systolic volume; HR, hazard ratio; LV, left ventricular; MAE, mitral annular excursion; RV, right ventricular; TAE, tricuspid annular excursion

Introduction The most common forms of cardiac amyloidosis are immunoglobulin light-chain (AL) and transthyretin (ATTR) amyloidosis, including wild-type (ATTRwt) and mutant-type (ATTRmt) amyloidosis. The clinical courses of these variants are quite heterogeneous. AL amyloidosis may involve almost all organs. Predominantly, it affects kidneys and the heart. In contrast, patients with ATTRmt amyloidosis mainly show Address for correspondence: Arnt V. Kristen, Department of Cardiology, Heidelberg University, INF 410, D-69120 Heidelberg, Germany. Tel: +49-6221-568611. Fax +49-6221-565515. E-mail: [email protected]

senso-motoric polyneuropathy and/or cardiomyopathy [1,2], whereas the heart is almost exclusively affected in ATTRwt amyloidosis. Cardiac involvement is so far the most relevant predictor of outcome in AL and ATTR amyloidosis despite distinct differences of these subtypes regarding phenotype and mortality [3,4]. Although patients with AL amyloidosis are more symptomatic and have shorter survival rates minor cardiac abnormalities can be observed by echocardiography [5]. Contrast-enhancement cardiac magnetic resonance imaging (CE-CMR) is well established for non-invasive morphological and functional evaluation. It is increasingly used in patients with systemic amyloidosis due to its inter- and

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intra-observer variability of only 2–4% regarding cardiac volumes, ejection fraction and myocardial mass [6]. Various morphological and functional characteristics of cardiac amyloidosis have been identified in smaller patient cohorts [7–10]. In this single center study, we sought to determine the morphological and functional differences between AL, ATTRmt and ATTRwt cardiac amyloidosis using CMR scans and attempted to establish the diagnostic and prognostic impact of these findings.

Materials and methods

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Study subjects This single center study was conducted in 125 consecutive patients diagnosed with cardiac amyloidosis (AL, n ¼ 62; ATTRmt, n ¼ 30; ATTRwt, n ¼ 33). Amyloid protein and subtype were diagnosed by Congo-red and immunohistochemical staining. In patients without endomyocardial biopsy, cardiac involvement was defined non-invasively according to consensus criteria [11]. Patients were screened for amyloidogenetic TTR variants by sequencing of genomic DNA. NT-proBNP was measured by ElecsysÕ proBNP, troponin T by ElecsysÕ 2010 (Roche Diagnostics, Mannheim, Germany). Approval was obtained from the institutional review board in conformity with the declaration of Helsinki. All patients signed informed consent sheets. Follow-up assessments were conducted either at the Heidelberg Amyloidosis Center or through telephone calls if the last visit was 3 months prior to the end of the observation period (15 August 2014). Cardiac magnetic resonance imaging All CE-CMR scans were performed on a single 1.5 Tesla whole-body CMR scanner (AchievaÕ Philips Medical Systems, Best, The Netherlands) as described previously

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[12]. In brief, resting left ventricular (LV) function was determined by standard steady-state free precession cine images in short axes, two-, three- and four-chamber views. Gadolinium contrast agent (MagnevistÕ , Bayer Health Care, Leverkusen, Germany, 0.2 mmol/kg bodyweight) was administered if estimated glomerular filtration rate (eGFR) was 430 mL min1  1.73 m2 (n ¼ 112). CE-CMR data were analyzed in a blinded fashion by consensus reading of two experienced investigators unaware of the clinical data (FS, HS). There were no true quantitative measurement tools for the assessment of CE-CMR and indeed, for most clinical indications, visual assessment of CE-CMR images is sufficient. Thus, the MR image windows and levels were modified until any noise was still detectable (meaning that nulled myocardium should not be a single image intensity) and CE regions were not clipped (CE-CMR regions should not be a single image intensity). Regions with CE were verified in at least one other orthogonal plane and/or in the same plane being obtained as a second image after changing the direction of readout [13]. CE-CMR was analyzed semi-quantitatively (0 ¼ absent; 1 ¼ mild; 2 ¼ moderate; 3 ¼ intense; Figure 1) in every of the 16 LV segments (Figure 2). Finally, total CECMR intensity of all 16 segments was calculated to express global CE-CMR intensity. Right ventricular (RV), left and right atrial wall were evaluated for the presence of CE. Shortaxis RV and LV parameters were end-diastolic (EDV), endsystolic (ESV) volumes, ejection fraction (EF), stroke volume as well as LV myocardial mass. Longitudinal function was assessed by mitral (MAE) and tricuspid (TAE) annular plane systolic excursion. Regional wall thickness and CE was analyzed in a modified American Heart Association 16 LV segment model; the inter-atrial wall was measured in four chamber views. Left atrial volume was quantified by biplane area-length-method [V ¼ (8  area2chamber  area4chamber)/ (3 length4chamber)] in systole and diastole.

Figure 1. Qualitative and semi-quantitative analysis of CE-CMR. Schematic illustration of qualitative and semi-quantitative (0 ¼ none; 1 ¼ mild; 2 ¼ moderate; 3 ¼ intense) classification of gadolinium uptake of observed CE-CMR patterns as well as representative images of different CE-CMR patterns. (A) Diffuse CE-CMR of LV and RV, (B) patchy CE-CMR of LV, (C) subendocardial CE-CMR of lateral wall and septum and (D) subepicardial CE-CMR of lateral LV wall.

Cardiac MRI in cardiac amyloidosis

DOI: 10.3109/13506129.2015.1020153

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Statistical analysis Continuous data were expressed as mean ± standard deviation or as median (interquartile range, IQR) if not distributed normally and compared between different amyloid types with analysis of variance and post-hoc testing. Correlation analyses were performed using Spearman’s coefficient. Receiver operating characteristics analyses determined cut-off values. A stepwise discriminant analysis was used to establish those variables for prediction of the different amyloid types. Kaplan–Meier curves plotted for cumulative overall survival (time between CE-CMR and either combined endpoint of death/heart transplantation or death alone) were analyzed using log-rank analysis with right-censoring. Association of CE-CMR and serological parameters with mortality was investigated by univariate Cox regression analysis in the individual amyloid types. Finally, a multivariate Cox proportional hazard analysis with forward progression was conducted. In these analyses, combined endpoint was the dependent variable and possible risk factors as predictors were LV mass, LV ejection fraction, MAE, TAE, maximal basal, mid-ventricular and apical wall thickness, semi-quantitative CE, NT-proBNP, troponin T and eGFR, respectively. To compare the contributions of independent predictors between groups, interaction tests were performed. p50.05 was considered statistically significant. All analyses were performed using StatView, Version 5.0 (SAS Institute, Cary, NC) and SPSS, Version 19 (IBM-Corporation, Armonk, NY).

Results Baseline demographics are shown in Table 1. Mutations were TTRVal30Met (n ¼ 9), TTRVal20Ile (n ¼ 8) and TTRGlu54Lys (n ¼ 2). Further mutations of individual patients were TTRAsp18Glu, TTRAla19Asp, TTRPhe44Val, TTRGly67Glu, TTRIle68Leu, TTRThr49Ala, TTRThr60Asn, TTRIle84Thr, TTRThr79Lys and TTRIle107Val. ATTRwt amyloidosis was diagnosed in 33 patients. Kidney function was significantly better in patients with ATTRmt as compared with AL and ATTRwt amyloidosis. A detailed comparison of CE-CMR findings in AL, ATTRmt and ATTRwt amyloidosis is demonstrated in Table 2. Inter- and intra-observer

1 7

2 8 14 9

inferoseptal

3

6

anterolateral

5

inferolateral

12

13 16 15 10

variability (Bland–Altmann) regarding CE-CMR morphological analysis was 1.2–5.4% and 8–12% for wall thickness, respectively. Median delay between diagnosis of amyloidosis and assessment by cardiac MRI in the whole cohort was 3 months, whereas the median delay in AL amyloidosis was only 1 month. In 14 patients (22.5%) of the AL group, but in none of the other groups causative treatment has already been started at the time of assessment by CMR. Pattern of cardiac hypertrophy Left ventricular (LV) mass and thickness of the inter-atrial septum were higher in ATTRwt when compared to AL and ATTRmt amyloidosis. The distribution of wall thickness in the individual segments is shown in Table 2. Maximal wall thickness in basal and mid-ventricular segments was significantly higher in ATTRwt than in AL amyloidosis. Maximal wall thickness of basal, mid-ventricular infero-septal, anteroseptal as well as infero-lateral segments was significantly higher in ATTRwt when compared to AL amyloidosis (Table 3). Thickness of the inter-atrial septum was more pronounced in ATTRwt than in ATTRmt as well as AL amyloidosis. TAE were lower in ATTRwt amyloidosis than in AL amyloidosis. In addition, left atrial end diastolic volume and left atrial ejection fraction differed between ATTRwt and ATTRmt amyloidosis. Cut-off value for discrimination of ATTRwt and AL amyloidosis by LV mass with highest sensitivity (84.8%) and specificity (54.8%) was 141.8 g (AUC 0.677; 95% CI 0.570–0.738; p50.01); cut-off value of interatrial wall thickness was 6.5 mm (sensitivity 90.6%, specificity 66.7%; AUC 0.827; 95% CI 0.745–0.909; p50.001); cut-off value of TAE was 9.5 mm (sensitivity 75.8%, specificity 26.8%; AUC 0.338; 95% CI 0.238–0.446; p50.01). Corresponding cut-off values for discrimination of ATTRwt and ATTRmt were LV mass of 171.5 g (sensitivity 46.7%, specificity 53.1%; AUC 0.398; 95%CI 0.256–0.541; p ¼ 0.170), inter-atrial wall thickness of 7.5 mm (sensitivity ¼ 43.3%, specificity ¼ 59.4%; AUC 0.590; 95%CI 0.445– 0.734; p ¼ 0.226) and TAE of 12.5 mm (sensitivity ¼ 66.7%, specificity ¼ 56.2%; AUC 0.365; 95%CI 0.224–0.506; p ¼ 0.068), respectively. Pattern of contrast enhancement

anterior

anteroseptal

3

11

4

inferior Figure 2. Definition of segments according to the AHA 16-segment model.

Contrast-enhancement (CE) was observed in 106/112 patients (AL, n ¼ 50; 80.6%; ATTRmt n ¼ 27; 90%; ATTRwt, n ¼ 29; 87.9%). Representative and schematic images of different CE-CMR patterns are shown in Figure 1. In each of the 16 segments, more intense CE was associated with increased LV mass and decreased LV ejection fraction, MAE, as well as TAE, respectively (p50.001). The median of global CECMR intensity was significantly lower in AL [32.5 (33.8)] as compared to ATTRmt [36 (31.5); p50.05] or ATTRwt amyloidosis [49 (32), p50.05]. Significant differences in quality and intensity of CE-CMR by semi-quantitative analysis between the individual groups are shown in Table 4. Subepicardial CE was more intense in anterior ATTRwt when compared to AL. Intensity of subendocardial CE was higher in antero-septal basal segments of ATTRwt and ATTRmt when compared to AL amyloidosis. No differences between the groups have been observed for

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Table 1. Baseline characteristics.

Male Age (years) BMI (kg/m2) NYHA NYHA I NYHA II NYHA III NYHA IV Troponin T (mg/L) NT-proBNP (ng/mL) eGFR (ml min1  1.73 m2) Involved organs Kidney Nervous system Soft tissue GIT Coronary angiography CAD PCI/CABG Unremarkable exercise testing

All patients (n ¼ 125)

AL (n ¼ 62)

ATTRmt (n ¼ 30)

ATTRwt (n ¼ 33)

84 (67%) 62.3 ± 12.9 25.2 ± 4.4 2 (2) 19 (15%) 35 (28%) 54 (44%) 1 (1%) 0.035 (0.054) 3147 (4444) 71.7 ± 27.6 2 (2) 33 (26%) 25 (20%) 25 (21%) 33 (26%) 87 (70%) 12 (9%) 8 (6%) 43 (33%)

36 (58%) 58.4 ± 11.0 25.6 ± 4.7 2 (2) 12 (19%) 14 (23%) 29 (47%) 0 0.04 (0.09) 2582 (5348) 69.7 ± 25.6 2 (1) 33 (53%) 7 (11%) 23 (43%) 17 (27%) 36 (58%) 6 (9%) 4 (6%) 24 (39%)

15 (50%) 59.1 ± 10.6* 24.3 ± 5.0 2 (2) 3 (10%) 11 (37%) 6 (20%) 1 (3%) 0.02 (0.03) 1552 (3569) 84.4 ± 26.1* 2 (2) 0 15 (50%) 1 (3%) 11 (37%) 23 (77%) 2 (7%) 1 (3%) 7 (23%)

33 (100%)*,y 73.2 ± 11.5* 25.4 ± 2.8 3 (1) 4 (12%) 10 (30%) 19 (58%) 0 0.04 (0.03) 4150 (2773) 64.8 ± 20.5*,y 1 (1) 0 3 (9%) 1 (3%) 5 (15%) 28 (85%) 4 (12%) 3 (9%) 5 (15%)

AL, light-chain amyloidosis; ATTRmt, mutant-type transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; BMI, body mass index; NYHA, New York Heart Association heart failure class; eGFR, estimated glomerular filtration rate by the modified diet in renal disease formula; GIT, gastrointestinal tract; CAD, coronary artery disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft. Continuous data were expressed as mean ± SD or median (interquartile range) if not distributed normally, categorical variables as absolute numbers and percentages. *p50.05 versus AL yp50.05 versus ATTRmt Table 2. Comparison of wall thickness in patients with different types of cardiac amyloidosis.

Basal anterior (1) Basal anteroseptal (2) Basal inferoseptal (3) Basal inferior (4) Basal inferolateral (5) Basal anterolateral (6) Midventricular anterior (7) Midventricular anteroseptal (8) Midventricular inferoseptal (9) Midventricular inferior (10) Midventricular inferolateral (11) Midventricular anterolateral (12) Apical anterior (13) Apical septal (14) Apical inferior (15) Apical lateral (16)

AL (n ¼ 62)

ATTRmt (n ¼ 30)

ATTRwt (n ¼ 33)

9.2 ± 3.6 12.6 ± 3.8 12.8 ± 4.2 10.1 ± 3.5 8.9 ± 3.4 8.2 ± 3.0 6.7 ± 2.4 9.7 ± 3.6 11.1 ± 4.3 8.0 ± 2.7 6.8 ± 2.2 6.4 ± 2.2 6.3 ± 3.0 7.0 ± 2.9 6.3 ± 2.6 6.2 ± 2.3

9.9 ± 3.7 14.0 ± 3.5 14.1 ± 4.0 10.6 ± 3.5 10.6 ± 3.5* 9.3 ± 2.6 6.8 ± 2.1 11.4 ± 3.5* 12.6 ± 4.6 8.8 ± 2.5 7.6 ± 2.6 7.1 ± 1.9 6.2 ± 2.0 7.5 ± 2.5 6.0 ± 2.4 6.2 ± 1.8

9.8 ± 3.4 15.8 ± 3.4*,y 15.6 ± 3.5* 11.6 ± 2.9* 11.1 ± 2.9* 10.1 ± 3.6* 6.7 ± 2.2 11.2 ± 3.7 13.9 ± 4.2* 8.9 ± 2.4 7.9 ± 2.4* 7.2 ± 2.2 6.1 ± 1.5 7.4 ± 2.6 6.3 ± 2.2 6.7 ± 1.9

Data are mean ± standard deviation in mm of the individual segments according to the 16 segments AHA model. AL, light-chain amyloidosis; ATTRmt, mutant-type transthyretin; ATTRwt, wild-type transthyretin *p50.05 versus AL amyloidosis yp50.05 versus ATTRmt amyloidosis

diffuse and focal patchy CE. Analysis of intra-observer and inter-observer reliability for CE were 93 and 89%, respectively. The prevalence of left atrial was significantly higher in ATTRwt (82%) as compared to AL amyloidosis (45%; p50.001), but did not differ from the prevalence in ATTRmt amyloidosis (70%). No difference was observed regarding right atrial CE (ATTRmt 70%, ATTRwt 76% and AL 50%). Prevalence of right ventricular CE was significantly lower in AL (52%) as compared to ATTRmt (87%; p50.01) or ATTRwt amyloidosis (76%; p50.05). Inter-atrial septal CE was more prevalent in ATTRmt (80%) than in AL

amyloidosis (44%; p50.01), but did not differ significantly from ATTRwt amyloidosis (64%). Significant correlations of CE with logNT–proBNP (r ¼ 0.706, p50.001) or troponin T (r ¼ 0.735, p50.001) were observed. Differentiation of the individual subtypes of amyloidosis by CE-CMR A stepwise discriminant analysis revealed age, number of organs involved, the presence of inferolateral CE-CMR, thickness of inter-atrial septum and troponin T as variables

Cardiac MRI in cardiac amyloidosis

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Table 3. Comparison of cMRI findings in patients with different types of cardiac amyloidosis.

LA ED volume (cm ) LA ES volume (cm3) DLA ED/LA ES volume Inter-atrial septum (mm) LV mass (g) Maximal LV wall thickness Basal (mm) Mid-ventricular (mm) Apical (mm) LV ED diameter (mm) LV ED volume (mL) LV ES volume (mL) LV stroke volume (mL) LV ejection fraction (%) MAE (mm) RV ED volume (mL) RV ES volume (mL) RV stroke volume (mL) RV ejection fraction (%) TAE (mm)

AL (n ¼ 62)

ATTRmt (n ¼ 30)

ATTRwt (n ¼ 33)

20.0 (11.3) 24.8 (10.4) 5.0 (4.9) 5.7 ± 1.9 159 ± 61

18.0 (11.7) 22.6 (12.1) 4.7 ± 2.3 7.3 ± 1.9 164 ± 57

23.0 (7.3)y 26.2 (5.6) 3.3 ± 2.0y 8.1 ± 1.4*,y 184 ± 5.4*,y

14.0 (3.8) 11.0 (7.2) 7.7 (3.0) 47.0 (7.1) 160.1 ± 41.4 73.0 ± 33.9 88 (39.9) 58.0 (18.8) 8.0 (7.0) 151 (52) 69 (43) 78.0 (30) 54.0 (18) 16.0 (13.0)

16.0 14.5 8.0 46.1 148.8 72.8 75.8 52.9 7.0 164 72 78 54 14.0

17.0 (4.8)a 15.0 (5.8)a 8.0 (2.0) 47.0 ± 6.3 164.5 ± 48.2 85.1 ± 58.3 77.5 ± 21.9 51.0 (13.8) 6.0 (4.0) 172 (49) 90 (31) 71 (24) 46 (11) 12.0 (6.0)*

(5.3) (7.0) (3.0) (5.3) ± 38.8 ± 36.8 (23.7) (15.0) (5.0) (66) (58) (23) (18) (9.0)

AL, light-chain amyloidosis; ATTRmt, mutant-type transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; LV, left ventricular; EDV, enddiastolic volume; ES, endsystolic; ED, enddiastolic; M(T)AE, mitral (tricuspidal) annular excursion; RV, right ventricular; LA, left atrial. Continuous data were expressed as mean ± SD or median (interquartile range) if not distributed normally. Categorical variables are absolute numbers and percentages *p50.05 versus AL yp50.05 versus ATTRmt

Table 4. Segmental differences of the quality of CE-CMR in patients with cardiac amyloidosis. Subendocardial ATTRmt versus AL ATTRwt versus AL ATTRwt versus ATTRmt

1*, 2y, 3, 4y, 5y, 6* 10*, 11y, 12* 1y, 2y, 3y, 4y, 5y, 6y 11y

Subepicardial 2y, 3y 9* 1*, 2y,3y 8y, 9y 8*, 9*

Numbers are segments according to the AHA-16-segment model as demonstrated in Figure 2 with significant differences regarding intensity of subendocardial or subepicardial CE-CMR in the individual patient cohorts with different types of cardiac amyloidosis. Higher intensity versus lower intensity of CE-CMR. *p50.05. yp50.01.

for prediction of amyloid subtype. If individual patient data were entered into the three following formula the highest score predicts the particular amyloid subtype: ATTRmt ¼ 0.74  age (metric) + 2.41  number of organs (ordinal) + 2.20  inferolateral CE-CMR (nominal) + 1.70  inter-atrial septum (metric) + 16.76  TnT (logarithmic) – 56.45 ATTRwt ¼ 0.92  age (metric) + 2.12  number of organs (ordinal) + 2.14  inferolateral CE-CMR (nominal) + 1.93  inter-atrial septum (metric) + 15.63  TnT (logarithmic) – 66.86 AL ¼ 0.78  age (metric) + 3.36  number of organs (ordinal) + 1.91  inferolateral CE-CMR (nominal) + 1.11  interatrial septum (metric) + 13.62  TnT (logarithmic) – 49.12 According to these formulas, correct classification of the amyloid subgroup was achieved in 76% of the whole patient

cumulative survival (%)

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3

AL

100

Median survival:

TTR SSA

AL: 27.2 months TTR: 76.9 months SSA: 70.3 months

50

0 0

25

50 time (months)

75

100

27 25 27

18 20 14

10 8 3

0 0 0

number at risk AL TTR SSA

52 28 30

Figure 3. Cumulative survival according to type of amyloidosis. Association of type of amyloidosis with survival in ATTRmt, ATTRwt and AL amyloidosis.

cohort, and in 74% of AL amyloidosis, in 97% of patients with ATTRwt and 59% in patients with ATTRmt. Survival analysis Mean follow-up was 42.3 ± 27.2 months in ATTRmt, 34.0 ± 23.7 in ATTRwt and 42.7 ± 36.7 months in AL amyloidosis. During the follow-up, there were six events in ATTRmt (death n ¼ 2; heart transplant n ¼ 4), three events in ATTRwt (death n ¼ 2; heart transplant n ¼ 1) and 28 events in AL amyloidosis (death n ¼ 15; heart transplant n ¼ 13) resulting in a one-year survival rate of 93.3, 93.9 and 70.5%, respectively (Figure 3). LV mass was significantly lower in survivors of the AL and ATTRwt amyloidosis group compared to deceased patients, but not in ATTRmt amyloidosis (Figure 4). Results of univariate and multivariate analysis for

A. V. Kristen et al.

Amyloid, Early Online: 1–10

ATTRmt

ATTRwt

LV mass (g)

200

LV mass (g)

AL †

400

250

150 100 50 0

200

300 200 100

survivors

150 100 50

0

non-survivors

† 250

LV mass (g)

6

0

non-survivors

survivors

non-survivors

survivors

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Figure 4. LV mass and survival according to type of amyloidosis. Comparisons of LV mass in survivors and non-survivors of the (A) ATTRmt, (B) ATTRwt and (C) AL amyloidosis group. yp50.01.

event-free survival are shown in Tables 5 and 6, respectively. Similar results were observed when survival was used as an endpoint. By interaction testing differences between AL and ATTRwt amyloidosis to predict event-free survival were found regarding LV basal (p50.05) and mid-ventricular maximal wall thickness (p50.05) as well as AL and ATTRmt amyloidosis regarding maximal mid-ventricular LV wall thickness (p50.05). When the combined endpoint (death and heart transplant) was used differences were found for all groups regarding LV maximal mid-ventricular wall thickness (p50.05). In AL amyloidosis, the cut-off for LV mass to predict all-cause mortality was 129.5 g (AUC 0.736; 95%CI 0.603–0.868; sensitivity ¼ 78.4%; specificity ¼ 68.0%), cutoff for NT-proBNP was 1372 ng/mL (AUC 0.745; 95%CI 0.617–0.873; sensitivity ¼ 86.5%; specificity ¼ 60.0%), cutoff for troponin T was 0.0375 mg/mL (AUC 0.717; 95%CI 0.580–0.853; sensitivity ¼ 62.2%; specificity ¼ 75.0%), respectively.

Table 5. Univariate Cox regression analysis in the subgroups using combined endpoint.

LV mass LV ejection fraction MAE TAE LV wall basal max LV wall mid max LV wall apical max CE-CMR quantitative logNT-proBNP logtroponin T eGFR

AL (n ¼ 62)

ATTRmt (n ¼ 30)

ATTRwt (n ¼ 33)

1.01y 0.97* 0.85* 0.95* 1.15* 1.16ô 1.20ô 1.01z 1.56ô 1.41y 1.00

1.01* 0.97 1.03 0.98 1.03 1.07 1.21z 1.01 2.9z 3.12z 0.97z

1.01 0.96z 0.88 0.99 1.01 1.03 1.19 0.99 1.35 3.05y 0.97z

Data are hazard ratio. AL, light-chain amyloidosis; ATTRmt, mutanttype transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis CE-CMR contrast-enhanced cardiac magnetic resonance imaging; eGFR, estimated glomerular filtration rate; LV, left ventricular; TAE, tricuspid annular excursion; MAE, mitral annular excursion *p50.05; yp50.01; zp50.10ôp50.001

Discussion This single center CMR study compared non-invasive myocardial tissue texture and functional parameters in a large cohort of well-characterized patients with cardiac AL, ATTRmt and ATTRwt amyloidosis. In addition, these findings were associated with mortality. For ATTRwt amyloidosis, LV mass, basal and mid-centricular LV wall thickness and atrial septum thickness were higher than in AL. Functionally, the TAE was markedly reduced, and thirdly, contrast enhancement patterns for subepicardial and subendocardial for basal LV segments, the left atrium and the right ventricle were more pronounced. Diverse independent predictors of the combined endpoint of mortality and heart transplantation have been observed in the different forms of amyloidosis, namely, LV mass, MAE and NT-proBNP in AL amyloidosis, LV mass maximal apical wall thickness and troponin T in ATTRwt amyloidosis, and finally NT-proBNP and renal function in patients with ATTRmt amyloidosis. According to the present results, CE-CMR appears to be of clinical interest regarding differentiation and risk stratification of different types of cardiac amyloidosis. Cardiac involvement is one of the most relevant factors of outcome in both AL and ATTR amyloidosis [3,4]. Especially in AL amyloidosis, clinical assessment with respect to risk prediction has been increasingly focused on cardiac tools, e.g. electrocardiography, echocardiography and cardiac

Table 6. Multivariate Cox regression analysis in the different study cohorts. Event-free survival ATTRmt (n ¼ 30) LV mass LV ejection fraction MAE TAE LV wall basal max LV wall mid max LV wall apical max CE-CMR quantitative logNT-proBNP logtroponin T eGFR

ATTRwt (n ¼ 33)

AL (n ¼ 62)

1.12*

1.01* 0.92y

9.96y 2.49*

1.31* 15.57*

0.97y

Data are hazard ratio. AL, light-chain amyloidosis; ATTRmt, mutanttype transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; CE-CMR, contrast-enhanced cardiac magnetic resonance imaging; eGFR, estimated glomerular filtration rate; LV, left ventricular; TAE, tricuspid annular excursion; MAE, mitral annular excursion. Notes: *p50.05; yp50.10.

biomarkers [14–18]. In recent years, CMR has additionally been used in patients with systemic amyloidosis; however, data on morphological, functional and tissue texture differences between AL, ATTRmt and ATTRwt amyloidosis is limited.

DOI: 10.3109/13506129.2015.1020153

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Morphological and functional analysis of CMR High-resolution image quality and excellent tissue differentiation render CE-CMR a potential non-invasive tool for evaluation for the different types of cardiac diseases and for the assessment of unexplained cardiac hypertrophy. In this detailed comparison of CMR findings in patients with ATTRmt, ATTRwt and AL amyloid type, respectively, assessed with a standardized routine scanning protocol at a single CMR scanner, LV mass was more pronounced in ATTRwt rather than in ATTRmt and AL amyloidosis most likely caused by more pronounced hypertrophy of basal segments. This finding is in line with a recent echocardiography study demonstrating higher LV mass in ATTRwt than in AL amyloidosis [5] as well as increased LV wall thickness in TTRVal122Ile when compared to AL amyloidosis [19]. In general, patients with AL amyloidosis were more symptomatic than patients with ATTR amyloidosis despite lesser morphological alterations [5]. This phenomenon is most likely explained due to myocardial toxicity of circulating amyloidogenic light-chains [20]. An increased thickness of the inter-atrial septum was previously reported to identify cardiac amyloidosis in general (without any differentiation of subtype) among different forms of cardiac hypertrophy [9]. According to the present data, thickness of the inter-atrial septum was more pronounced in ATTRwt than in ATTRmt and AL amyloidosis. Moreover, differences regarding right ventricular longitudinal function indicated by TAE were observed between ATTRwt and AL. Impairment of longitudinal left and right ventricular function is a common finding in amyloidosis, moreover being an indicator of survival [16]. The clinical impact of reduction of left atrial ejection fraction has not been reported so far and needs to be evaluated in more detail in future studies as they might help to differentiate different amyloid types. Contrast-enhancement Excellent image quality and tissue texture analysis by the use of gadolinium were claimed to be major advantages of CE-CMR. Different CE patterns are helpful for, e.g. the differentiation between myocardial infarction versus other forms of myocardial scar forming lesions (i.e. myocarditis) or different types of cardiomyopathies [4,8,21–23]. In this study, after application of only one type of gadolinium contrast agent CE was demonstrated in 94.6% of the patients. The prevalence of CE in cardiac amyloidosis in general has been reported to be as high as 97% [23] with a promising accuracy (sensitivity ¼ 88%, specificity ¼ 93%) for the diagnosis of cardiac amyloidosis [24]. In contrast to defined infarct-typical CE-CMR patterns always affecting the subendocardium with various degrees of transmurality and always being attributable to one specific coronary territory, CE patterns in cardiac amyloidosis, however, are highly variable [10,12,21,22,25,26]. Nevertheless, a detailed comparison of the CE distribution patterns in AL and different forms of ATTR amyloidosis has not been reported so far. According to this study, subepicardial CE of basal and mid-ventricular septal segments and subendocardial CE of the basal and mid-ventricular lateral segments differed significantly between ATTRwt and AL amyloidosis.

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Leone et al. [27] reported on regional differences of amyloid deposition in explanted hearts. These results are not comparable with our results as composition of the analyzed regions differs between both studies. While Leone et al. either analyzed the subendocardial, middle or subepicardial layer or all six radial segments of at mid-ventricular level we analyzed regional differences according to the 16 segment model. Accordingly, the mid-ventricular layer was divided in six segments and each segment was analyzed for the subepicardial, mid-ventricular and subendocardial CE. However, it appears that amyloid deposition is more pronounced in the subendocardial layers of ATTR patients comparable to more pronounced CE enhancement in our study. Moreover, a higher prevalence of left atrial, right ventricular and inter-atrial CE in ATTRwt (and in part ATTRmt) was observed in AL amyloidosis is well in line with results recently published [28]. In previous studies, a global subendocardial CE pattern was reported to be characteristic of cardiac amyloidosis [22–24] in addition, being a strong non-invasive predictor of cardiac amyloidosis even in patients with a normal echocardiographic LV wall thickness [24]. This study demonstrated that there were significant differences between types of amyloidosis that needs to be taken into account when CE-CMR is analyzed in patients with cardiac amyloidosis. As mean age of the present patients is above 60 years, coronary artery disease is a common differential diagnosis of subendocardial CE. The amount of patients with significant coronary artery disease was limited and did not differ between the groups. In our study, subendocardial CE was observed in several different coronary segments of the LV, thus unlikely being caused by coronary artery disease. Regionally transmural infarct-typical CE, which is distinctive for myocardial infarction, was not seen in any of our patients. Accordingly, subendocardial CE appears to be indicative of ischemia due to marked myocardial hypertrophy. In contrast, subepicardial CE was deemed negative for CA. It was excluded from previous analyses as proposed to be suggestive of myocarditis [24]. Despite distinct differences between amyloid types, it appears worth to evaluate subepicardial pattern of CE. Myocarditis in patients with cardiac amyloidosis might be explained by inflammation due to amyloid deposition and was associated with poor prognosis [29]. Tissue characterization by CE-CMR was reported to have a high potential for the detection of incipient (ATTR) amyloid deposition prior to the occurrence of heart failure [30]. Abnormal CE was found in all patients with ATTR amyloidosis and heart retention of 99mTc-3,3-diphosphono1,2-propanodicarboxylic acid, but not if scintigraphy was unremarkable. In this study, the presence and pattern of CE-CMR were strongly associated with clinical, morphological, and functional markers of prognosis, but not with mortality itself [30]. There were no true quantitative measurement tools for the assessment of CE-CMR and indeed, for most clinical indications, visual assessment of CE-CMR images is sufficient. Thus, the MR image windows and levels were modified until any noise was still detectable (meaning that nulled myocardium should not be a single image intensity) and regions with late gadolinium enhancement were not clipped

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(CE-CMR regions should not be a single image intensity). Regions with late gadolinium enhancement were verified in at least one other orthogonal plane and/or in the same plane being obtained as a second image after changing the direction of readout. This is in accordance with the recently published Society of Cardiac Magnetic Resonance (SCMR) imaging guidelines for qualitative image assessment of late gadolinium enhancement images [31]. We are fully aware of the fact that there is room for subjective image interpretation but readers were blinded to patient history and analysis was conducted according to guidelines.

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Diagnosis of amyloid type by CE-CMR In previous reports, amyloid differentiation solely based on CE-CMR features was claimed to be unfeasible [31,32]. 99m Technetium-3,3-diphosphono-1,2-propanodicarboxylic acid was proposed to be helpful to diagnose ATTR and AL type of cardiac amyloidosis non-invasively [33,34]. Recently, transmural pattern of CE-CMR was reported to distinguish ATTR from AL amyloidosis with higher accuracy than observed in this study [29]. They reported about sensitivity of 87% and specificity of 96% for differentiation ATTR vs. AL amyloidosis when age, interventricular septum thickness and a novel late gadolinium scoring system (Query Amyloid Late Enhancement) were incorporated into a logistic regression model. In this study, non-invasive discrimination of ATTRmt, ATTRwt and AL amyloidosis was performed with correct classification of the amyloid type in 76% when a formula including age, number of organs involved, inter-atrial septum thickness, troponin T and the presence of inferolateral CE was applied to the whole patient cohort. When discrimination was solely focused on ATTRwt correct classification was achieved in 97%. These apparently conflicting results regarding classification of the whole cohort might be explained by methodological difference. First, both study cohorts are slightly different for instance regarding genotype of transthyretin amyloidosis (wild-type versus hereditary form). In general, patients with ATTRwt are older and present with more pronounced left ventricular wall thickness than patients with AL amyloidosis. Second, the study by Dungu et al. [29] analyzed DICOM images obtained from 46 centers with two different field strengths CMRs, 1.5 and 3 Tesla. In their study, neither information was given about type of gadolinium contrast agent used in 46 centers nor timing of imaging acquisition. In contrast, the present single center study was performed on a single 1.5 Tesla high resolution MRI scanner (with 32 receiving channels) with a limited number of technical personnel and one single type of gadolinium contrast agent. As it is well known, late gadolinium enhancement imaging is a T1-dependent measurement. Field strength (1.5 or 3 Tesla), type of contrast agent as well as timing of image acquisition have tremendous impact on CMR image quality [23,35]. Finally, for the first time, non-invasive differentiation of ATTRmt and ATTRwt by CMR was elucidated in this single center study. According to this study and the recent report of Dungu et al. [29] distinct morphological differences were observed between different types of amyloidosis. Thus, differentiation of AL, ATTR in general and even ATTRmt and ATTRwt by CE-CMR appears to be feasible.

Amyloid, Early Online: 1–10

Thus, this imaging tool provided useful information for clinical routine. Risk stratification In this study, diverse independent predictors of the combined endpoint of mortality and heart transplantation have been observed in the different forms of amyloidosis, namely, LV mass, MAE and NT-proBNP in AL amyloidosis, LV mass maximal apical wall thickness, and troponin T in ATTRwt amyloidosis, and finally, NT-proBNP and renal function in patients with ATTRmt amyloidosis. Similar results were observed when mortality alone was used as an endpoint. Cardiac amyloid type per se is claimed to be the most important predictor of mortality. In general, AL amyloidosis is associated with a poorer survival than ATTR amyloidosis [5]. Nevertheless, even among patients with AL or ATTR amyloidosis, outcome differs widely indicating the unmet need of further risk predictors besides the type of amyloid [36]. In this context, ECG and echocardiography findings have been established for risk stratification especially in AL amyloidosis, including interventricular wall thickness, low voltage ECG patterns, rate of progression of wall thickness or left ventricular longitudinal strain [14–16]. While cardiac biomarkers provide potent information on disease severity and response to treatment in AL amyloidosis [17,18], data on risk prediction by CE-CMR is limited in AL, ATTRmt as well as ATTRwt amyloidosis. In general, the present results are well in line with previous reports on risk stratification in AL using echocardiography and biomarkers, even if troponin T was not predictive of mortality in the present cohort [14–18]. Moreover, this is the first report on the use of cardiac biomarkers (troponin T) for prediction of mortality in patients with ATTRmt. Unfortunately, the CE measurement as the main advantage of CMR appears not to be of relevance for predicting mortality in both, ATTR and AL amyloidosis. In a previous study, a characteristic CE pattern was a stronger predictor of 1-year mortality in patients with cardiac amyloidosis when compared with other non-invasive parameters [25]. However, that study was limited by a single analysis of patients with AL and ATTR amyloidosis. A recent study by Syed et al. reported that the presence and pattern of CE-CMR were strongly associated with clinical, morphological, functional and biochemical markers of prognosis without any direct association to survival [24]. Moreover, there was no prognostic impact of CE in two smaller studies of AL amyloidosis [4,37]. It was concluded that the absence of CE appears to be a better predictor of survival than the presence of CE-CMR is a predictor of mortality [37]. These in part conflicting results of previous CE-CMR studies might be explained by the fact that those studies combined AL and ATTR amyloidosis in their survival analysis. This descriptive study is hypothesis generating and should stimulate further research. It is so far the largest single center study comparing results of CE-CMR in patients with AL, ATTRmt and ATTRwt amyloidosis. Although potential differences have been observed by CE-CMR between the different types of amyloidosis it is unlikely that CMR phenotype alone is powerful enough to differentiate AL

Cardiac MRI in cardiac amyloidosis

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from different forms of ATTR amyloidosis in individual patients. Moreover, CE-CMR could be used in concert with other methods to more fully understand the patients’ cardiac phenotype and risk. In addition, a comparison of echocardiography and CE-CMR with respect to diagnosis and prognosis of cardiac amyloidosis is urgently needed to evaluate the additional benefit of CE-CMR for risk stratification if echocardiography data is already available. However, this was beyond the scope of this study.

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Conclusions This study demonstrates that CE-CMR can uniquely highlight both morphological and functional differences between cardiac AL, ATTRmt and ATTRwt amyloidosis that needs to be taken into account for further studies with CE-CMR in patients with amyloidosis. In addition, morphological and functional assessment by CE-CMR in combination with cardiac biomarkers provides useful prognostic information in patients with AL cardiac amyloid.

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Declaration of interest The authors declare no conflict of interest.

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Comparison of different types of cardiac amyloidosis by cardiac magnetic resonance imaging.

We sought to determine cardiac morphological and functional differences between light-chain (AL), mutant-type transthyretin (ATTRmt) and wild-type TTR...
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