Identifying Cardiac Amyloid in Aortic Stenosis

Abstract

Objectives
To validate computed tomography measured ECV (ECVCT) as part of routine evaluation for the detection of aortic stenosis (AS)-amyloid.

Background
Occult transthyretin AS-amyloid affects 1 in 7 elderly patients referred for transcatheter aortic valve replacement (TAVR). Bone scintigraphy with exclusion of a plasma cell dyscrasia can diagnose transthyretin-related cardiac amyloid noninvasively, for which novel treatments are emerging. Amyloid interstitial expansion increases the myocardial extracellular volume (ECV).

Methods
Patients with severe AS underwent bone scintigraphy (Perugini grade 0, negative; Perugini grades 1 to 3, increasingly positive) and routine TAVR evaluation CT imaging with ECVCT using 3- and 5-min post-contrast acquisitions. Twenty non-AS control patients also had ECVCT performed using the 5-min post-contrast acquisition.

Results
A total of 109 patients (43% male; mean age 86 ± 5 years) with severe AS and 20 control subjects were recruited. Sixteen (15%) had AS-amyloid on bone scintigraphy (grade 1, n = 5; grade 2, n = 11). ECVCT was 32 ± 3%, 34 ± 4%, and 43 ± 6% in Perugini grades 0, 1, and 2, respectively (p < 0.001 for trend) with control subjects lower than lone AS (28 ± 2%; p < 0.001). ECVCT accuracy for AS-amyloid detection versus lone AS was 0.87 (0.95 for 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid Perugini grade 2 only), outperforming conventional electrocardiogram and echocardiography parameters. One composite parameter, the voltage/mass ratio, had utility (similar AUC of 0.87 for any cardiac amyloid detection), although in one-third of patients, this could not be calculated due to bundle branch block or ventricular paced rhythm.

Conclusions
ECVCT during routine CT TAVR evaluation can reliably detect AS-amyloid, and the measured ECVCT tracks the degree of infiltration. Another measure of interstitial expansion, the voltage/mass ratio, also performed well.

Full text

CLINICAL RESEARCH
Identifying Cardiac Amyloid in
Aortic Stenosis
ECV Quantification by CT in TAVR Patients
Paul R. Scully, MBBS, MRES,
a,b
Kush P. Patel, MBBS, BSC,
a,b
Bunny Saberwal, MBBS,
a
Ernst Klotz, DIPLY PHYS,
c
João B. Augusto, MD,
a,b
George D. Thornton, MBBS, BSC,
a
Rebecca K. Hughes, MBBS,
a,b
Charlotte Manisty, PHD,
a,b
Guy Lloyd, MD,
a,b,d
James D. Newton, MBCHB, MD,
e
Nikant Sabharwal, DM,
e
Andrew Kelion, DM,
e
Simon Kennon, MD,
a
Muhiddin Ozkor, MBBS, MD,
a
Michael Mullen, MBBS, MD,
a
Neil Hartman, PHD,
f
João L. Cavalcante, MD,
g
Leon J. Menezes, BA, BM BCH,
a,h,i
Philip N. Hawkins, PHD,
j
Thomas A. Treibel, PHD,
a,b
James C. Moon, MD,
a,b,
*Francesca Pugliese, PHD
a,d,k,
*
ABSTRACT
OBJECTIVES To validate computed tomography measured ECV (ECV
CT
) as part of routine evaluation for the detection
of aortic stenosis (AS)-amyloid.
BACKGROUND Occult transthyretin AS-amyloid affects 1 in 7 elderly patients referred for transcatheter aortic valve
replacement (TAVR). Bone scintigraphy with exclusion of a plasma cell dyscrasia can diagnose transthyretin-related
cardiac amyloid noninvasively, for which novel treatments are emerging. Amyloid interstitial expansion increases the
myocardial extracellular volume (ECV).
METHODS Patients with severe AS underwent bone scintigraphy (Perugini grade 0, negative; Perugini grades 1 to 3,
increasingly positive) and routine TAVR evaluation CT imaging with ECV
CT
using 3- and 5-min post-contrast acquisitions.
Twenty non-AS control patients also had ECV
CT
performed using the 5-min post-contrast acquisition.
RESULTS A total of 109 patients (43% male; mean age 86 5 years) with severe AS and 20 control subjects were
recruited. Sixteen (15%) had AS-amyloid on bone scintigraphy (grade 1, n ¼5; grade 2, n ¼11). ECV
CT
was 32 3%, 34 4%,
and 43 6% in Perugini grades 0, 1, and 2, respectively (p <0.001 for trend) with control subjects lower than lone AS (28 
2%; p <0.001). ECV
CT
accuracy for AS-amyloid detection versus lone AS was 0.87 (0.95 for
99m
Tc-3,3-diphosphono-
1,2-propanodicarboxylic acid Perugini grade 2 only), outperforming conventional electrocardiogram and echocardiography
parameters. One composite parameter, the voltage/mass ratio, had utility (similar AUC of 0.87 for any cardiac amyloid
detection), although in one-third of patients, this could not be calculated due to bundle branch block or ventricular paced
rhythm.
CONCLUSIONS ECV
CT
during routine CT TAVR evaluation can reliably detect AS-amyloid, and the measured ECV
CT
tracks
the degree of infiltration. Another measure of interstitial expansion, the voltage/mass ratio, also performed well.
(J Am Coll Cardiol Img 2020;-:-–-) © 2020 The Authors. Published by Elsevier on behalf of the American College of
Cardiology Foundation. This is an open access article underthe CC BY license (http://creativecommons.org/licenses/by/4.0/).
ISSN 1936-878X https://doi.org/10.1016/j.jcmg.2020.05.029
From the
a
Barts Heart Centre, St. Bartholomew’s Hospital, London, United Kingdom;
b
Institute of Cardiovascular Sciences,
University College London, London, United Kingdom;
c
Siemens Healthineers, Forchheim, Germany;
d
William Harvey Research
Institute, Queen Mary University of London, London, United Kingdom;
e
John Radcliffe Hospital, Oxford University Hospitals,
Oxford, United Kingdom;
f
Nuclear Medicine, Swansea Bay UHB, Port Talbot, United Kingdom;
g
Minneapolis Heart Institute,
Minneapolis, Minnesota;
h
Institute of Nuclear Medicine, University College London, London, United Kingdom;
i
NIHR
University College London Hospitals Biomedical Research Centre, London, United Kingdom;
j
National Amyloidosis Centre,
University College London, London, United Kingdom; and the
k
NIHR Barts Biomedical Research Centre, London, United
Kingdom. *Drs. Moon and Pugliese are joint last authors. Dr. Scully is supported by a British Heart Foundation
Clinical Research Training Fellowship (FS/16/31/32185). Dr. Patel is supported by an unrestricted educational grant from Edwards
JACC: CARDIOVASCULAR IMAGING VOL. -,NO.-,2020
ª2020 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN
COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER
THE CC BY LICENSE (http://creativecommons.org/licenses/by/4.0/).

Aortic stenosis (AS) is the most com-
mon valve disease in the developed
world (1). Its prevalence increases
with age, with 2.8% to 4.8% of patients $75
years of age having at least moderate AS
(2,3). Once symptomatic with severe AS, out-
comes are poor without intervention (4),
which can be either surgical or transcatheter
aortic valve replacement (TAVR). TAVR
numbers are increasing fast worldwide, in
response to both an aging population and
technological developments (5,6).
Another disease of aging is wild-type
transthyretin-related cardiac amyloidosis
(ATTR-CA); deposits are present within the
myocardium at autopsy in up to 25% of
patients $85 years of age (7). Recent work
has shown a remarkably high prevalence
(14% to 16%) of ATTR-CA in the elderly AS
population being considered for TAVR (AS-
amyloid) (8,9). We do not yet fully under-
stand the significance of this dual pathology,
either for valve intervention or the role for
specific amyloid therapies such as tafamidis
(10), patisiran (11), and inotersen (12), but
detection is likely to be important. Conven-
tional first-line investigations for ATTR-CA,
such as echocardiography, blood bio-
markers, or electrocardiogram (ECG), are
confounded by the dual pathology. ATTR-CA
can now be diagnosed noninvasively by us-
ing bone scintigraphy, such as
99m
Tc-3,3-
diphosphono-1,2-propanodicarboxylic acid (DPD),
99m
Tc-pyrophosphate, and
99m
Tc-hydroxymethylene
diphosphonate, coupled with a negative search for a
plasma cell dyscrasia (13). Although availability and
awareness are increasing, it requires an extra test in
elderly, often frail, patients.
As part of routine TAVR evaluation, patients
typically undergo contrast computed tomography
(CT) imaging to assess annulus dimensions, coronary
artery height (and patency, where possible), and
vascular access. Contrast CT imaging can also be
used to measure the myocardial extracellular vol-
ume (ECV) in a manner similar to cardiovascular
magnetic resonance (CMR) (14,15). The ECV in-
creases moderately with diffuse fibrosis but
massively with amyloidosis (16). Our group has
previously validated ECV quantification by CT im-
aging (ECV
CT
) against CMR and histology (endo-
myocardial biopsy) in severe AS (17,18) and against
CMR in cardiac amyloid (18). Unlike recommended
CMR acquisition, the ECV
CT
acquisition for cardiac
amyloid can be performed earlier at 5 min rather
than 10 min post-contrast (18).
In the current study, we hypothesized that ECV
CT
as part of routine TAVR evaluation CT imaging would
be able to detect AS-amyloid. To improve workflow,
we also sought to optimize the scanning protocol in
terms of dose and timing (shortened scan delay).
METHODS
This work represents a prespecified analysis of a
subset of patients of the ATTRact-AS study (Role of
Occult Cardiac Amyloid in the Elderly With Aortic
Stenosis; NCT03029026). Relevant local ethics ap-
provals were obtained. Patients $75 years of age
with severe AS referred for TAVR at Barts Heart
Centre (London, United Kingdom) and undergoing
CT imaging as part of their clinical evaluation were
included in this substudy. The only exclusion
criterion was being unable to provide informed
consent.
Patients underwent routine clinical TAVR evalua-
tion, including baseline ECG, echocardiography, and
CT imaging. The additional research procedures were
DPD scintigraphy (before TAVR), the additional CT
acquisitions for ECV
CT
,and,ifnotalreadyperformed,
contemporaneous blood tests for hematocrit, high-
sensitivity troponin T (hs-TnT), and N-terminal pro–
B-type natriuretic peptide. Twenty control patients
ABBREVIATIONS
AND ACRONYMS
AS =aortic stenosis
AS-amyloid =dual aortic
stenosis and cardiac amyloid
pathology
ATTR-CA =transthyretin-
related cardiac amyloidosis
AUC =area under the curve
CT =computed tomography
CTCA =computed tomography
coronary angiogram
DPD =
99m
Tc-3,3-diphosphono-
1,2-propanodicarboxylic acid
ECG =electrocardiogram
ECV =extracellular volume
ECV
CT
=extracellular volume
quantification by computed
tomography imaging
hs-TnT =high-sensitivity
troponin T
IVSd =interventricular septal
diameter
MCF =myocardial contraction
fraction
PWd =posterior wall diameter
RBBB =right bundle branch
block
SPECT =single-photon
emission computed
tomography
TAVR =transcatheter aortic
valve replacement
Lifesciences. Dr. Treibel is supported by a clinical lecturer grant by the National Institute of Health Research (NIHR). Dr. Saberwal
is supported by an educational grant from Siemens Healthineers. Mr. Klotz works for Siemens Healthineers. Dr. Mullen has
received grants and personal fees from Edwards Lifesciences and personal fees from Abbotts Vascular. Prof. Moon is directly and
indirectly supported by the University College London Hospitals NHS Foundation and Barts Health NHS Trusts biomedical
research and unit, respectively. Dr. Pugliese has received research support from Siemens Healthineers; and this work forms part of
the translational research portfolio of the NIHR Cardiovascular Biomedical Research Centre at Barts Heart Centre, which is sup-
ported and funded by the NIHR. All other authors have reported that they have no relationships relevant to the contents of this
paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’in-
stitutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit
the JACC: Cardiovascular Imaging author instructions page.
Manuscript received March 24, 2020; revised manuscript received May 18, 2020, accepted May 20, 2020.
Scully et al.JACC: CARDIOVASCULAR IMAGING, VOL. -,NO.-,2020
ECV Quantification by CT in TAVR Patients -2020:-–-
2

also underwent ECV
CT
. These subjects were recruited
for a separate study evaluating ECV
CT
in patients with
suspected coronary artery disease, and all had
contemporary CMR showing normal biventricular size
and function with no late gadolinium enhancement.
These control patients were included to provide an
estimate of “normal”ECV
CT
and were not used in the
screening calculations.
ELECTROCARDIOGRAM
As we have described previously (19), Sokolow-Lyon
criteria were calculated as the sum of the amplitude
of the S-wave in lead V
1
and the R-wave in lead V
5
or
V
6
(whichever was greater) (20). The voltage/mass
ratio was defined as the Sokolow-Lyon total divided
by the indexed left ventricular (LV) mass on echo-
cardiography. Patients with bundle branch block or a
ventricular paced rhythm were excluded from this
analysis (21). Low limb lead voltages were defined as
all limb leads with an amplitude #0.5 mV.
ECHOCARDIOGRAPHY
AS severity (aortic valve peak velocity, mean
gradient, and valve area), biventricular systolic and
left ventricular diastolic function were assessed using
transthoracic echocardiography (22–26). As we have
described previously (19), LV ejection fraction was
calculated using Simpson’s biplane if possible
(otherwise visually) and the indexed stroke volume
was calculated using the LV outflow tract velocity
time integral and diameter, which was then indexed
to body surface area. Relative wall thickness was
defined as: (2 posterior wall diameter)/(LV internal
diameter at end-diastole) (25). LV mass was calcu-
lated by using the formula from Devereux et al. (26):
LV mass ¼0:81:04 ½ðIVSd þLVIDd þPWdÞ3
LVIDd3iþ0:6
where IVSd is the interventricular septal diameter,
LVIDd is the LV internal dimension at end-diastole,
FIGURE 1 ECV
CT
Protocol and Offline Analysis Integrated Into TAVR Planning Cardiac CT
8:00
6:00
3:30
2:30
1:30
0:30 Topogram
Calcium Score
Baseline (pre-contrast) ASM
3-minute post-contrast ASM
5-minute post-contrast ASM
Contrast injection
Averaged
Averaged
Averaged
Time
(minutes:seconds)
CT Protocol
3:00
Reconstruct CTCA at 250ms R-R interval
Registration and subtraction
Blood pool ROI
Input hematocrit
Automated heart model
Whole heart ECV with polar map
Text in red represents additional image acquisition/reconstruction in scanning protocol for the extracellular volume quantification by computed tomography (ECV
CT
).
Text in blue represents steps in off-line analysis. ASM ¼axial shuttle mode; CT ¼computed tomography; CTCA ¼computed tomography coronary angiography;
ECV ¼extracellular volume; ROI ¼region of interest.
JACC: CARDIOVASCULAR IMAGING, VOL. -,NO.-,2020 Scully et al.
-2020:-–-ECV Quantification by CT in TAVR Patients
3

and PWd is the posterior wall diameter. Longitudinal
strain analysis was performed off-line by an accredi-
ted echocardiographer using 2-D Cardiac Performance
Analysis software (TomTec Imaging Systems GmbH,
Unterschleissheim, Germany).
In view of the fact AS and amyloid may have
myocardial impairment better captured by myocar-
dial contractionfraction(MCF¼stroke volume/
myocardial volume) (27), we calculated this with LV
end-diastolic volume as 4.5 LVIDd
2
;LVend-systolic
volume as 3.72 LVIDs
2
;strokevolumeasLVend-
diastolic volume LV end-systolic volume; LV mass
as 1.04 [(IVSd þLVIDd þPWd)
3
LVIDd
3
]; and the
myocardial volume as the LV mass/mean density of
myocardium (1.04 g/ml).
DPD SCINTIGRAPHY
All DPD scans were performed by using either a
hybrid single-photon emission CT (SPECT)/CT gamma
camera (Philips BrightView, Blue Bell, Pennsylvania)
oraSPECTgammacamera(Symbia,Siemens
Healthineers USA, Malvern, Pennsylvania) following
the injection of 700 MBq DPD. The imaging protocol
consisted of an early and late (5 min and 3 h,
respectively) planar whole-body image, with a
SPECT/CT scan or SPECT scan only of the chest at 3 h.
DPD scans were reported by 2 experienced clinicians
using the Perugini grading system (28), with grade
0beingnegativeandgrades1to3increasinglyposi-
tive. DPD scan findings were independently reviewed
by the National Amyloidosis Centre (London, United
Kingdom). All patients with a positive DPD scan were
discussed with the managing clinicians and, where
appropriate, referred to the National Amyloidosis
Centre for further review.
CT SCANS
All CT scans were performed on a Somatom FORCE
scanner (Siemens Healthineers, Erlangen, Germany).
The TAVR evaluation CT protocol at Barts Heart
Centre involves a topogram, calcium score, timing
bolus, gated CT coronary angiogram (CTCA) acquired
retrospectively, and a FLASH whole-body scan (lung
apices down to the lesser trochanters). The total
volume of Omnipaque 300 (iohexol) contrast (GE
Healthcare, Chicago, Illinois) was fixedat90ml
FIGURE 2 Automated ECV
CT
Heart Model Output With Corresponding 3-h Planar DPD Image
ECV (%)
60.0
0.0
AC
BD
E
ECV
CT
map superimposed on the CTCA images (A to D) and corresponding 3-h planar DPD image (E). The endocardial and epicardial contours can be edited in the short-
axis (A), 4-chamber (B), and 2-chamber (D) views to produce an ECV
CT
American Heart Association 17-segment polar map (C). This is a patient with aortic stenosis (AS)
amyloid (Perugini grade 2
99m
Tc-3,3-diphosphono-1,2-propanodicarboxylic acid [DPD] scintigraphy) with total myocardial ECV
CT
is globally elevated at 47%. Abbre-
viations as in Figure 1.
Scully et al.JACC: CARDIOVASCULAR IMAGING, VOL. -,NO.-,2020
ECV Quantification by CT in TAVR Patients -2020:-–-
4

TABLE 1 Basic Demographic Characteristics and Clinical, Echocardiography, and Computed Tomography Parameters for Patients With Lone
AS and AS-Amyloid
Overall (N ¼109) Lone AS (n ¼93) AS-Amyloid (n ¼16) p Value
Demographic characteristics
Male 47 (43) 38 (41) 9 (56) 0.25
Age (yrs) 86 5855885 0.08
Clinical parameters
Hypertension 86 (79) 73 (78) 13 (81) 1.00
Hypercholesterolemia 44 (40) 37 (40) 7 (44) 0.77
Diabetes mellitus 25 (23) 24 (26) 1 (6) 0.11
Atrial fibrillation 49 (45) 41 (44) 8 (50) 0.66
Permanent pacemaker 14 (13) 12 (13) 2 (13) 1.00
ECG parameters
Heart rate (beats/min) 73 15 73 16 70 14 0.46
Low-voltage limb leads 1 (1) 1 (1) 0 (0) 1.00
S-L criteria (mV) 2.5 1.0 2.6 1.0 1.8 0.5 0.048
First-degree HB*21 (19) 20 (22) 1 (7) 0.30
QRS duration (ms) 106 25 103 26 120 20 0.01
LBBB*10 (10) 8 (9) 2 (13) 1.00
RBBB*12 (12) 6 (7) 6 (38) 0.002
Echocardiogram parameters
Left ventricle
LVEF (%) 54 11 54 10 58 10 0.18
Indexed SV (ml/m
2
)3811 38 12 35 9 0.29
IVSd (cm) 1.3 0.2 1.3 0.2 1.4 0.3 0.002
PWd (cm) 1.1 0.3 1.1 0.2 1.3 0.3 <0.001
Relative wall thickness (cm) 0.50 0.15 0.48 0.13 0.61 0.20 0.002
Indexed LV mass (g/m
2
) 116 37 113 37 137 31 0.01
MCF (%) 23.7 8.4 24.5 8.4 19.4 7.2 0.02
Mitral annulus S0(m/s) 0.06 0.01 0.06 0.01 0.05 0.01 0.08
Global LV LS (%) –15 6–15 7–16 6 0.62
Diastolic function
E/A ratio 0.8 (0.7–1.3) 0.8 (0.7–1.1) 1.4 (0.9–2.3) 0.07
Lateral E/E017 10 17 82115 0.28
MV deceleration time (ms) 235 90 234 92 238 80 0.87
LA diameter (cm) 4.1 0.7 4.0 0.7 4.4 0.6 0.08
RV function
TAPSE (cm) 1.91 0.46 1.92 0.48 1.89 0.36 0.82
AV
Peak velocity (m/s) 4.10 0.63 4.12 0.63 4.02 0.62 0.55
Mean gradient (mm Hg) 69 21 42 14 38 12 0.36
AVA (cm
2
) 0.71 0.23 0.71 0.23 0.72 0.21 0.92
CT parameters
AV calcium score (HU) 2,115 (1,497–3,184) 2,107 (1,491–3,109) 2,170 (1,665–3,602) 0.60
Indexed LV mass (g/m
2
)7419 72 17 91 24 0.01
Composite parameters
V/M ratio (mV/g/m
2
) 0.025 0.01 0.026 0.011 0.013 0.004 <0.001
Blood results
Hematocrit 0.38 0.04 0.38 0.04 0.38 0.05 0.92
Creatinine (mmol/l) 108 38 106 37 120 38 0.16
eGFR (ml/min/1.73 m
2
)5316 54 17 47 12 0.12
hs-TnT (ng/l) 34 (15–38) 20 (14–34) 43 (28–75) 0.001
NT-proBNP (ng/l) 1,517 (671–3,703) 1,361 (593–2,816) 3,668 (1,259–5,165) 0.03
Values are n (%), mean SD, or median (interquartile range). *Missing electrocardiogram (ECG) data in 4 lone aortic stenosis (AS) patients and 1 AS-amyloid patient; per-
centages and statistics quoted reflect this.
AV ¼aortic valve; AVA ¼aortic valve area; HB ¼heart block; E/A ¼early to atrial wave ratio; eGFR ¼estimated glomerular filtration rate; hs-TnT ¼high-sensitivity troponin T;
HU ¼Hounsfield units; IVSd ¼interventricular septum diameter; LA ¼left atrial; LBBB ¼left bundle branch block; LS ¼longitudinal strain; LV ¼left ventricular; LVEF ¼left
ventricular ejection fraction; MCF ¼myocardial contraction fraction; MV ¼mitral valve; NT-proBNP ¼N-terminal pro–B-type natriuretic peptide; PWd ¼posterior wall diameter;
RBBB ¼right bundle branch block; S-L ¼Sokolow-Lyon criteria; SV ¼stroke volume; TAPSE ¼tricuspid annular plane systolic excursion; V/M ¼voltage mass ratio.
JACC: CARDIOVASCULAR IMAGING, VOL. -,NO.-,2020 Scully et al.
-2020:-–-ECV Quantification by CT in TAVR Patients
5

(including the 10 ml timing bolus) for the clinical
scan, with no additional contrast used for research
purposes. The additional acquisitions for research
were a baseline “axial shuttle mode”pre-contrast
after the calcium score and further pseudo-
equilibrium axial shuttle mode datasets, both trig-
gered 250 ms after the R-wave, at 3 and 5 min post-
contrast (following the FLASH whole-body scan). All
axialshuttlemodedatasets(4 repetitions every other
heartbeat, single breath hold) were acquired at a fixed
tube voltage of 80 kV and tube current-time product
of 370 mA. Image reconstruction was performed by
using the same field of view in all 3 datasets. An
additional dataset was reconstructed from the retro-
spectively acquired CTCA at 250 ms of the R-R inter-
val, with a field of view matching that of the axial
shuttlemodedatasets(Figure 1)tobeusedasa
landmark for ECV
CT
measurement and overlay.
ECV ANALYSIS
We have briefly described this technique previously
(29). Nonrigid registration software (Hepacare,
Siemens Healthineers) allowed averaging and align-
ing of the axial shuttle mode datasets to improve
image quality and reduce noise. The averaged base-
line image was then subtracted from the averaged 3-
and 5-min post-contrast images (providing a partition
coefficient) and then registered with the CTCA image.
A region of interest was placed in the LV blood pool
on the CTCA image and the hematocrit (usually taken
on the same day) inputted, generating a myocardial
ECV
CT
map via the formula: ECV
CT
¼(1 hematocrit) 
(
D
HU
myo
/
D
HU
blood
), where
D
HUisthechangein
Hounsfield unit attenuation pre-contrast and post-
contrast (i.e., HU
post-contrast
HU
pre-contrast
)(18,30,31).
This information was loaded into prototype software
(Cardiac Function, Siemens Healthineers), which
allowed the ECV
CT
map to be superimposed on the
CTCA image, the myocardial contours to be edited,
and the results to be displayed as a 17-segment polar
map (Figures 1 and 2). When calculating total ECV
CT
,
focally elevated ECV
CT
(e.g., likely myocardial infarc-
tion) were not excluded, but American Heart Associ-
ation segments with significant beam-hardening
artifacts from adjacent pacing wires (n ¼4) were
excluded. LV mass was calculated using the standard
automated software on clinical syngo.via (Siemens
Healthineers) workstations.
STATISTICAL ANALYSIS. Statistical analysis was
performed by using IBM SPSS Statistics version 25
(IBM SPSS Statistics, IBM Corporation, Armonk, New
York) software. Where appropriate, results are
described as mean SD or median (interquartile
range). Kruskal-Wallis analysis of variance was used
when comparing >2groupsastheomnibustest,with
the Dunn-Bonferroni test for pairwise comparison.
Bland-Altman analysis was performed to compare 3-
and 5-min post-contrast time points, as well as the
impact of dose reduction. Receiver-operating char-
acteristic curve analysis was used to assess diag-
nostic performance. Student’st-test or the Mann-
Whitney Utest was used to compare continuous
variables and either chi-squared or Fisher exact
testing for categorical data was used as appropriate.
Univariate and multivariate analyses were performed
by using binary logistic regression, with the presence
of AS-amyloid as the dependent variable. Variables
for the multivariate analysis were selected based on
statistical significance on univariate analysis and
clinical relevance, while avoiding multicollinearity
(e.g., only 1 parameter reflecting LV mass was
included). Variance inflation factors for each inde-
pendent variable used in the multivariate analysis
were calculated as one divided by the tolerance
(defined as 1 R
2
of the regression model for the
studied variable). The voltage/mass ratio was not
included in the multivariate analysis to avoid
excluding nearly one-third of patients (32 in total)
with bundle branch block or ventricular paced
rhythm. The DeLong test was used to compare areas
under the curves (AUCs). A 2-sided p value <0.05
was considered statistically significant.
FIGURE 3 Box and Whisker Plot Showing the Variation in ECV
CT
With DPD Perugini
Grade
25
012
30
35
40
Global ECV at 3 Min (%)
DPD Perugini Grade
45
p = 0.57
50
55 p = 0.20
p < 0.001
p<0.001 for trend and for the pairwise comparison of grade 0 versus grade 2. Ab-
breviations as in Figures 1 and 2.
Scully et al.JACC: CARDIOVASCULAR IMAGING, VOL. -,NO.-,2020
ECV Quantification by CT in TAVR Patients -2020:-–-
6

RESULTS
A total of 109 patients (43% male; mean age 86 5
years) with severe AS were included in this substudy
of ATTRact-AS. Overall, LV ejection fraction was 54 
10%, peak aortic valve velocity was 4.1 0.6 m/s, the
mean pressure gradient was 41 14 mm Hg, and the
aortic valve area was 0.71 0.23 cm
2
.Patientchar-
acteristics (demographics, comorbidities, ECG, echo-
cardiography, CT scan, and blood test results) are
described in Table 1. As might be expected, hyper-
tension, hypercholesterolemia, diabetes mellitus, and
CENTRAL ILLUSTRATION ECV
CT
for the Detection of Cardiac Amyloidosis in Aortic Stenosis
ECV 24% ECV 29% ECV 36% ECV 46%
NOT DONE
Lone AS Grade 1 AS-Amyloid Grade 2 AS-AmyloidControl
Scully, P.R. et al. J Am Coll Cardiol Img. 2020;-(-):-–-.
Extracellular volume (ECV) quantification by computed tomography (ECV
CT
) polar maps (top),
99m
Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) planar
(middle), and axial single-photon emission computed tomography images (bottom) from control (far left) through lone aortic stenosis (AS), DPD Perugini grade 1, and
DPD Perugini grade 2 (far right).
JACC: CARDIOVASCULAR IMAGING, VOL. -,NO.-,2020 Scully et al.
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7

atrial fibrillation were common in this group of pa-
tients. Venous hematocrit was 0.38 0.04, which was
usually taken on the same day as the CT scan (median
0 days; interquartile range 0 to 22 days). Twenty
control subjects were also recruited separately to
provide an idea of “normal”ECV
CT
(65% male; mean
age 60 11 years).
DETECTION OF AS-AMYLOID. In this substudy, 16
patients (15%) had AS-amyloid diagnosed according
to bone scintigraphy (grade 1, n ¼5; grade 2, n ¼11);
their average age was 88 5 years, and 56% were
male. A plasma cell dyscrasia was detected in 6 pa-
tients (38%), who were either referred to the National
Amyloidosis Centre or reviewed with the clinical
team, and light-chain (AL) amyloid was believed un-
likely in all cases. All patients genotyped so far (n ¼9
[56%]) were wild type.
Therewasnodifferenceintheage(885yearsvs.
85 5years;p¼0.08) or proportion of male patients
(56% vs 41%; p ¼0.25) when comparing patients with
AS-amyloid versus those with lone AS. The cardio-
vascular risk profile (hypertension, hypercholester-
olemia, and diabetes mellitus), presence of AF, or
permanent pacemaker pre-procedure were similar.
Patients with AS-amyloid had a longer QRS duration
and higher prevalence of right bundle branch block
(RBBB), as well as lower ECG voltage according to
Sokolow-Lyon criteria and lower voltage/mass ratio.
In AS-amyloid, parameters reflecting LV thickness
and mass were higher, whereas the MCF was lower.
Global longitudinal strain was impaired in both AS-
amyloid and lone AS but did not differ. Both hs-TnT
and N-terminal pro–B-type natriuretic peptide levels
were higher in AS-amyloid (Table 1).
ECV
CT
findings. ECV
CT
was feasible for measurement in
all patients for whom data were obtained. ECV
CT
was
32 3%, 34 4%, and 43 6% in those patients with
Perugini grades 0, 1, and 2, respectively, using a 3-
min post-contrast acquisition (p <0.001 for trend)
(Figure 3, Central Illustration). By comparison, ECV
CT
in control subjects was 28 2% using a 5-min post-
contrast protocol, lower than in those patients with
lone AS at similar post-contrast timing (33 4%;
p<0.001). For the detection of any cardiac amyloid in
patients with AS (DPD Perugini grade 1 or 2), the AUC
was 0.87 (95% confidence interval: 0.75 to 0.98) using
a 3-min post-contrast acquisition (Figure 4). Different
ECV
CT
thresholds could be set: 29.2% (sensitivity
100%, specificity 19%, negative predictive value
100%); 31.4% (sensitivity 94%, specificity 48%,
negative predictive value 98%); or 33.4% (sensitivity
88%, specificity of 66%, negative predictive value
97%). If repeated for the detection of only grade 2
AS-amyloid (because there is more uncertainty about
the clinical significance of a Perugini grade 1 DPD), the
AUC improved to 0.95 (95% confidence interval: 0.89
to 1.00), and an ECV
CT
of 33.4% offered 100% sensi-
tivity and 64% specificity, with a negative predictive
value of 100%.
Combined parameters. The voltage/mass ratio was
lower in AS-amyloid and performed similar to ECV
CT
for the detection of any cardiac amyloid (AUC: 0.87)
but not as well for the detection of DPD grade 2 car-
diac amyloidosis (AUC: 0.85). However, nearly one-
third of patients (32 in total) had to be excluded
from this analysis due to the presence of bundle
branch block or a ventricular paced rhythm. MCF also
performed reasonably well as a screening tool for any
cardiac amyloid (AUC: 0.67), similar to PWd (AUC:
0.75; p ¼0.12) but not as well as ECV
CT
(AUC: 0.87;
p¼0.003) (Figure 4).
Predictors of amyloid presence. Univariate analysis
identified ECV
CT
, the presence of RBBB, and param-
eters associated with LV wall thickness or mass (IVSd,
PWd, indexed LV mass, MCF, and voltage/mass ratio)
FIGURE 4 Receiver-Operating Characteristic Curve for the
Detection of Any Cardiac Amyloid (DPD Perugini Grade 1 or 2)
Using ECV
CT
With a 3-Min Post-Contrast Acquisition, PWd, and
MCF
0.0
0.0
0.2
0.4
0.6
0.8
1.0
0.2 0.4 0.6
Sensitivity
0.8 1.0
ECV (AUC 0.87, 95% CI 0.75 – 0.98)
PWd (AUC 0.75, 95% CI 0.62 – 0.87)
MCF (AUC 0.67, 95% CI 0.52 – 0.81)
The voltage/mass ratio was not included because this approach
would have excluded nearly one-third of patients (32 in total)
due to bundle branch block or ventricular paced rhythm.
AUC ¼area under the curve; CI ¼confidence interval;
MCF ¼myocardial contraction fraction; PWd ¼posterior wall
diameter; other abbreviations as in Figure 1.
Scully et al.JACC: CARDIOVASCULAR IMAGING, VOL. -,NO.-,2020
ECV Quantification by CT in TAVR Patients -2020:-–-
8

as predictors of AS-amyloid (Table 2). Multivariate
analysis of age, ECV
CT
,malesex,PWd,andRBBB
showed that only ECV
CT
and the presence of RBBB
was associated with AS-amyloid (p ¼0.001 and p ¼
0.01, respectively). For every 1% increase in ECV
CT
,
there was a 1.6-fold increase in the likelihood of AS-
amyloid (95% confidence interval: 1.21 to 2.10). Vari-
ance inflation factors for each multivariable were all
close to 1, suggesting little multicollinearity (Supple-
mental Table 1).
PROTOCOL OPTIMIZATION. A total of 104 patients
completed both 3- and 5-min post-contrast acquisi-
tions. The 3-min acquisition resulted in an acceptable
ECV
CT
result with very little bias; that is, 0.68 1.2%
lower than the 5-min acquisition (Supplemental
Figure 1A). This bias appeared to increase above an
ECV
CT
of 40%, where such increases would not alter
diagnostic accuracy.
DOSE REDUCTION STRATEGY. The dose length
product for the full baseline and 3- and 5-min axial
shuttlemodedatasetswas18226 mGy$cm, 183 24
mGy$cm, and 180 24 mGy$cm, respectively. To
investigatedosereductionstrategies,wereanalyzed
ECV
CT
derived by using fewer shuttles (1 or 2 vs. 4) for
the baseline and 3-min post-contrast acquisitions to
assess any possible impact on diagnostic accuracy.
Including 13 patients with lone AS and 14 patients
with cardiac amyloid (grade 2, n ¼9), there was
minimal bias for 1 versus 4 shuttles (0.85 2.1%) or 1
versus 2 shuttles (0.58 1.47%) (Supplemental
Figure 1B). Two outliers with differences beyond the
95% limits of agreement were patients both weighing
>90 kg, for whom dose modulation would likely be
used clinically. Reducing the protocol to a single
shuttle pre-contrast and 3-min post-contrast reduces
the dose by a factor of 4 (total dose length product of
TABLE 2 Univariate and Multivariate Binary Logistic Regression Analysis
Variable
Univariate Analysis Multivariate Analys is
p Value Exp (B) p Value Exp (B) 95% CI for Exp (B)
Age (per yr increase) 0.08 1.10 0.38 1.09 0.90–1.30
ECV
CT
(per % increase) <0.001 1.49 0.001 1.60 1.21–2.10
AVA (per cm
2
increase) 0.92 1.12 –
AV mean gradient (per mm Hg decrease) 0.36 0.98 –
AV V
max
(per m/s decrease) 0.55 0.77 –
AV calcium score (per HU increase) 0.56 1.00 –
E/A ratio (per U increase) 0.04 1.74 –
Male 0.26 1.86 0.81 0.81 0.14–4.60
GLS (per % decrease) 0.61 0.98 –
hs-TnT (per ng/l increase) 0.06 1.01 –
Indexed LV mass on echo (per g/m
2
increase) 0.02 1.02 –
Indexed SV (per ml/m
2
decrease) 0.28 0.97 –
IVSd (per cm increase) 0.005 44.66 –
LA diameter (per cm increase) 0.08 2.04 –
Lateral E/E0(per U increase) 0.11 1.04 –
LBBB 0.60 1.56 –
LVEF (per % increase) 0.18 1.04 –
MCF (per % decrease) 0.02 0.91 –
Mitral annulus S0(per m/s decrease) 0.08 0.00 –
MV Dec time (per ms increase) 0.87 1.00 –
NT-proBNP (per ng/l increase) 0.41 1.00 –
PWd (per cm increase) 0.003 53.83 0.46 4.04 0.10–162.36
RBBB 0.001 9.22 0.01 16.84 1.87–148.54
RWT (per cm increase) 0.006 178.47 –
S-L criteria (per mV decrease) 0.06 0.26 –
TAPSE (per cm decrease) 0.81 0.87 –
V/M ratio (per mV/g/m
2
decrease) 0.02 0.00 –
ECV
CT
and the presence of RBBB were associated with AS-Amyloid on univariate and multivariate analysis. For every 1% increase in extracellular volume quantification by
computed tomography imaging (ECV
CT
), there was a 1.6-fold increased likelihood of AS-amyloid. The V/M ratio was not included in the multivariate analysis because this would
have excluded nearly one-third of patients (32 in total) due to bundle branch block or ventricular paced rhythm. Only 1 parameter representing LV wall thickness or mass was
included in the multivariate analysis to avoid multicollinearity (in this case, PWd, as it had the strongest association on univariate analysis).
Exp (B) ¼exponentiation of the B coefficient; GLS ¼global longitudinal strain; MV ¼mitral valve; RWT ¼relative wall thickness; other abbreviations as in Table 1.
JACC: CARDIOVASCULAR IMAGING, VOL. -,NO.-,2020 Scully et al.
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9

w90 mGy$cm,effectivedose2.3mSv,usingthe
higher cardiac k-factor of 0.026) (32).
DISCUSSION
ECV
CT
can reliably detect dual AS-amyloid pathology
in potential TAVR patients, with only an additional
3 min on top of the standard CT imaging evaluation
and a small radiation burden (w2.3 mSv), with
measured ECV
CT
not just detecting but tracking the
degree of infiltration.
The ability to detect ATTR-CA noninvasively using
bone scintigraphy has led to the increased realization
that particularly wild-type ATTR-CA is not rare in the
elderly. Recent research has shown just how common
it is in elderly subjects with AS (8,9,33,34),butitisnot
limited to this population; indeed, 13% of patients
with heart failure with preserved ejection fraction may
have underlying cardiac amyloid (35), and 5% of those
with LV hypertrophy may have variant ATTR-CA (this
study used genotyping to screen LV hypertrophy pa-
tients and thus will have missed those with wild-type
ATTR-CA) (36).Theclinicalimpactofmyocardialam-
yloid deposition in these patients with AS, however,
remains unclear. We know that there may be a long
preclinical phase and that prevalence increases with
age, becoming the primary cause of death in super-
centenarians (37). The spectrum therefore potentially
extends from “bystander”to the primary cause of
symptoms and adverse outcome, depending on the
timeofdiagnosisandthemyocardialtolerance.In
turn, these are likely to be affected by amyloid burden,
rate of amyloid deposition, the ability of the myocar-
dium to adapt, and other myocardial “hits”such as, in
this case, the increased afterload from AS. These may
not be independent (the prevalence of AS-amyloid
seems to be higher than what would be expected
from age alone, suggesting that there may be an
interaction), with an increased likelihood of amyloid
in the interstitium of myocardium with afterload. This
uncertainty of significance cascades into our termi-
nology, which is not fixed. Should this be AS-amyloid
or amyloid-AS? Similarly, is it cardiac amyloidosis
(implies pathological) or cardiac amyloid (might be
bystanderdeposition)?HerewehavechosenAS-
amyloid. These questions are about to become
nonacademic and pressingly so, with the availability
of3novel,potential,butcostlymedicaltherapiesfor
cardiac amyloidosis (10–12)thathaveyettobevali-
dated in patients with AS-amyloid. Clearly, an indi-
vidualized treatment strategy is going to be needed,
and answers will hopefully prove more forthcoming
with the increasing availability of bone scintigraphy
that will enable increased diagnostic rates and
research activity.
Thefactthatpre-existingRBBBisassociatedwith
cardiac amyloidosis is intriguing and may prove rele-
vant in the TAVR cohort given that we know RBBB is
FIGURE 5 Proposed ECV
CT
Screening Algorithm for Incorpora tion Into Routine Clinical Workflow
(additional 3-minutes)
TAVI work-up CT
(or other clinical CT)
Global ECV ≥31%
Cardiac amyloidosis possible Cardiac amyloidosis unlikely
No further investigation necessary
Bone scintigraphy
+
Urine and serum immunoxation
+
Serum free light chains
Global ECV <31%
The algorithm can be adjusted to an ECV
CT
threshold of $29% for the detection of all grade 1 DPD patients. TAVR ¼transcatheter aortic valve
replacement; other abbreviations as in Figures 1 and 2.
Scully et al.JACC: CARDIOVASCULAR IMAGING, VOL. -,NO.-,2020
ECV Quantification by CT in TAVR Patients -2020:-–-
10

associated with a higher likelihood of post-TAVR
pacemaker implantation (38) and worse outcomes
(38,39). Although the authors did not investigate for
the presence of concomitant cardiac amyloidosis, it is
possible that the presence of RBBB at baseline might
be an ominous sign that deserves further
investigation.
We propose CT imaging as a technique to increase
AS-amyloid detection and present a diagnostic algo-
rithm (Figure 5). Because ECV
CT
is easy to implement,
and the patient is already in the CT scanner, we think
adoption of this technique could be high. This algo-
rithm still uses bone scintigraphy (and exclusion of
light-chain [AL] amyloid by serum free light chains,
and serum and urine immunofixation) (13)butsub-
stantially increases the test yield by gatekeeping ac-
cess. ECV
CT
also seems to track cardiac amyloid
burden and, as a result, may also have a future role in
monitoring response to therapy, in the same way that
CMR-derived ECV can track primary light-chain (AL)
cardiac amyloid regression with therapy (40). Normal
ECV
CT
is in the region of 27% (adjusted down by 0.68
1.2% for the averaged, 3-min post-contrast equiva-
lent), which is consistent with the published data in
both CT imaging (41)andCMR(15). Patients with lone
AS had a higher ECV
CT
(32% with an averaged, 3-min
post-contrast), likely reflecting a degree of myocar-
dial fibrosis (15,42).
We propose different thresholds for onward
referral depending on how important grade 1 versus 2
is discovered to be, and whether specificity or sensi-
tivity becomes the priority. A lower threshold of 29%
using a 3-min post-contrast acquisition would never
miss a case (sensitivity 100%) but would probably
result in an unacceptably high referral rate for bone
scintigraphy (specificity 19%). A threshold of 31.4%
would have a sensitivity of 94% and not miss DPD
grade 2 cases but would miss a proportion of DPD
grade 1 cases (1 of 5 in our cohort); however, the
trade-off is that fewer cases would be referred for an
unnecessary DPD (specificity 48%).
Technological developments often result in new
insights into established techniques. We were not
surprised to find that AS-amyloid was hard to detect
based on ECG (e.g., small voltages) or echocardio-
graphic (e.g., reduced MCF) changes because both AS
and amyloid can have widely different influences on
heart muscle. RBBB being associated with AS-amyloid
is interesting and may prove important given that we
know it is both common in patients with TAVR and is
associated with worse outcome (including higher
likelihood of post-TAVR pacemaker insertion) (38).
Another interesting finding is that a combination
parameter of both ECG and echocardiography, the
voltage/mass ratio, performed exceptionally well for
amyloid detection compared with parameters derived
from just one technique. This is perhaps not surprising
as ECV
CT
and voltage/mass ratio are effectively
measuring the same thing: ECV
CT
measures the pro-
portional size of the water gap between myocytes, and
the voltage/mass ratio measures effectively the deficit
of electric depolarization from what is expected for a
measured wall thickness, which are both measures of
myocyte dilution by cardiac amyloid. Unfortunately,
Sokolow-Lyon criteria are not validated in patients
with bundle branch block (21), either native or from a
ventricular paced rhythm, which effectively excluded
one-third of our patients. Furthermore, the need to
combine information from 2 different measurement
techniques is a potential barrier.
STUDY LIMITATIONS. This was a single-center, sin-
gle-vendor study. ECV
CT
performance on other ven-
dors has not been assessed but should follow similar
methodology. Focal ECV
CT
elevations were included
in the calculated global ECV
CT
,andexcludingthese
areas may increase performance. Our mean patient
age was 86 years. Younger cohorts will have possibly
lower rates of discovered AS-amyloid. This study is a
CT technical development subset of a larger study
(including, for example, only those patients who had
not already had a CT scan at the time of recruitment);
although prevalence and other clinical information
informs, this is not the primary focus of this paper.
Inline ECV
CT
software is not yet available, and the
work presented here will need to be optimized for
integration into the daily CT workflow. Although
global longitudinal strain data were included in this
study, unfortunately we did not have regional longi-
tudinal strain data available at the time of submis-
sion, which may have proven additive in identifying
cardiac amyloidosis. The relatively small number of
patients with AS-amyloid in this study may also have
affected our results.
CONCLUSIONS
Lone AS results in detectable increases in ECV
CT
compared with control subjects. ECV
CT
using a low-
dose protocol, with a 3-min post-contrast acquisi-
tion, can detect AS-amyloid and grade its severity in
the TAVR population, and it could be used as a
screening tool in those patients already undergoing a
clinically indicated CT scan.
ADDRESS FOR CORRESPONDENCE: Dr. Francesca
Pugliese, Barts Heart Centre, St. Bartholomew’sHos-
pital, West Smithfield, London EC1A 7BE, United
Kingdom. E-mail: f.pugliese@qmul.ac.uk.
JACC: CARDIOVASCULAR IMAGING, VOL. -,NO.-,2020 Scully et al.
-2020:-–-ECV Quantification by CT in TAVR Patients
11

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PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: Pre-
TAVR cardiac CT scans can be used to quantify myocardial
ECV using a low-dose protocol, with additional baseline
and 3-min post-contrast acquisitions.
TRANSLATIONAL OUTLOOK 1: ECV
CT
during routine
CT TAVR evaluation can reliably detect AS-amyloid and
track the degree of infiltration, offering a potential
screening tool in patients already undergoing a clinically
indicated CT scan.
TRANSLATIONAL OUTLOOK 2: ECV
CT
is higher in
lone AS compared with control subjects due to myocar-
dial fibrosis. Whether this correlates with prognosis in
lone AS (as seen in the CMR published data) needs
investigation.
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KEY WORDS aortic stenosis, cardiac
amyloidosis, computed tomography,
extracellular volume
APPENDIX For a supplemental figure and
table, please see the online version of this
paper.
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