European Journal of Heart Failure (2020) 22, 1852–1862 RESEARCH ARTICLE

doi:10.1002/ejhf.1756

Light-chain and transthyretin cardiac

amyloidosis in severe aortic stenosis:
prevalence, screening possibilities,
and outcome
Christian Nitsche1, Stefan Aschauer1, Andreas A. Kammerlander1,
Matthias Schneider1, Thomas Poschner1, Franz Duca1, Christina Binder1,
Matthias Koschutnik1, Julian Stiftinger1, Georg Goliasch1, Jolanta Siller-Matula1,
Max-Paul Winter1, Anahit Anvari-Pirsch1, Martin Andreas2, Alexander Geppert3,
Dietrich Beitzke4, Christian Loewe4, Marcus Hacker5, Hermine Agis6,
Renate Kain7, Irene Lang1, Diana Bonderman1, Christian Hengstenberg1,
and Julia Mascherbauer1*
1 Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria; 2 Department of Cardiac Surgery, Medical University of Vienna, Vienna,
Austria; 3 Department of Internal Medicine III, Division of Cardiology, Wilhelminenspital, Vienna, Austria; 4 Department of Cardiovascular and Interventional Radiology,
Department of Radiology, Medical University of Vienna, Vienna, Austria; 5 Department of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; 6 Division of Oncology,
Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria; and 7 Department of Pathology, Medical University of Vienna, Vienna, Austria

Received 5 June 2019; revised 5 January 2020; accepted 16 January 2020 ; online publish-ahead-of-print 20 February 2020

Aims Concomitant cardiac amyloidosis (CA) in severe aortic stenosis (AS) is difficult to recognize, since both conditions
are associated with concentric left ventricular thickening. We aimed to assess type, frequency, screening parameters,
and prognostic implications of CA in AS.
.....................................................................................................................................................................
Methods A total of 191 consecutive AS patients (81.2 ± 7.4 years; 50.3% female) scheduled for transcatheter aortic valve
and results replacement (TAVR) were prospectively enrolled. Overall, 81.7% underwent complete assessment including echocar-
diography with strain analysis, electrocardiography (ECG), cardiac magnetic resonance imaging (CMR), 99m Tc-DPD
scintigraphy, serum and urine free light chain measurement, and myocardial biopsy in immunoglobulin light chain
(AL)-CA. Voltage/mass ratio (VMR; Sokolow–Lyon index on ECG/left ventricular mass index) and stroke volume
index (SVi) were tested as screening parameters. Receiver operating characteristic curve, binary logistic regression,
and Kaplan–Meier curve analyses were performed. CA was found in 8.4% of patients (n = 16); 15 had transthyretin
(TTR)-CA and one AL-CA. While global longitudinal strain by echo did not reliably differentiate AS from CA-AS
[area under the curve (AUC) 0.643], VMR as well as SVi showed good discriminative power (AUC 0.770 and 0.773,
respectively), which was comparable to extracellular volume by CMR (AUC 0.756). Also, VMR and SVi were inde-
pendently associated with CA by multivariate logistic regression analysis (P = 0.016 and P = 0.027, respectively). CA
did not significantly affect survival 15.3 ± 7.9 months after TAVR (P = 0.972).

*Corresponding author. Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Tel: +43 1 40400-46140, Fax: +43 1 40400-42160, Email: julia.mascherbauer@meduniwien.ac.at

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Cardiac amyloidosis in AS scheduled for TAVR 1853

Conclusion Both TTR- and AL-CA can accompany severe AS. Parameters solely based on ECG and echocardiography allow
for the identification of the majority of CA-AS. In the present cohort, CA did not significantly worsen prognosis
..........................................................................................................
15.3 months after TAVR.
Keywords Aortic stenosis • Cardiac amyloidosis • Transcatheter aortic valve replacement • Screening •
Prognosis

Introduction the basis of echocardiography and electrocardiogram (ECG) would

...........................................................................................................................................
be an important step forward.
Degenerative aortic stenosis (AS) and cardiac amyloidosis (CA) are The present study was designed to systematically assess the
both frequent and serious conditions in the elderly, causing con- prevalence of both TTR- and AL-CA in degenerative AS scheduled
siderable treatment expenditure.1,2 CA is caused by myocardial for TAVR, to investigate the impact of CA on survival following
deposition of amyloid fibrils. The two predominant amyloid pro- TAVR, and to evaluate parameters based on echocardiography and
teins found in the heart are transthyretin (TTR) and immunoglob- ECG that may suggest the presence of CA.
ulin light chain (AL).3 Expansion of the extracellular space result-
ing from amyloid deposition leads to myocardial stiffening and
restrictive filling of the left ventricle. In addition, AL amyloid may Methods
exhibit direct toxic effects on myocardial cells impairing systolic
left ventricular (LV) function.4–6 Affected patients develop severe
Study population
heart failure and face a dismal prognosis.7 Formerly believed to Between October 2017 and January 2019, we prospectively enrolled
consecutive adult patients with severe degenerative AS scheduled
be a rare condition, the use of modern diagnostic modalities such
for TAVR at the Vienna General Hospital, a university-affiliated ter-
as cardiac magnetic resonance (CMR) imaging and 99m Tc-labeled
tiary centre. Eligibility and decision for TAVR were determined by a
3,3-diphosphono-1,2-propanodicarboxylic acid (99m Tc-DPD) bone multidisciplinary Heart Team. Patients underwent clinical and labora-
scintigraphy have recently led to a considerable increase in the tory assessment, ECG, transthoracic echocardiography with strain rate
detection of CA.8,9 analysis, CMR, and 99m Tc-DPD bone scintigraphy prior to TAVR. Over-
Latest studies have drawn attention to coexisting CA in patients all, 81.7% (n = 156/191) underwent all diagnostic modalities, 18.3%
with degenerative AS.8–12 In these patients, significant myocardial (n = 35/191) had contraindications precluding CMR (Figure 1). In case
thickening is naturally attributed to long-standing pressure over- of suspicion of AL-CA (presence of monoclonal protein on serum or
load and not recognized as a potential sign for the presence of urine immunofixation ± abnormal free light chain ratio on serum anal-
a storage disease. Coexisting CA in patients with AS has been ysis ± abnormal urine protein/creatinine or albumin/creatinine ratio
AND abnormal findings on CMR or bone scintigraphy, n = 2), right
reported to be associated with worse outcome.8 Furthermore,
ventricular myocardial biopsy was performed. Patients were followed
management of these patients is a matter of discussion since they
by echocardiography, ECG, and clinical and laboratory assessment.
may benefit less from surgical (SAVR) or transcatheter aortic valve All-cause death and cardiovascular hospitalization were selected as
replacement (TAVR).13 Present data on CA in AS patients largely primary and secondary study endpoints, respectively. All patients pro-
rely on CMR, transthoracic echocardiography, and bone scintigra- vided written informed consent. The study was approved by the Ethics
phy as diagnostic tools. 99m Tc-DPD bone scintigraphy allows for Committee of the Medical University of Vienna (EK no. 2218/2016).
non-invasive detection of TTR-CA with high diagnostic sensitivity
and specificity.14 However, in AL-CA 99m Tc-DPD scintigraphy may
be unremarkable and assessment of serum and urine samples as
Diagnosis of cardiac amyloidosis
well as myocardial biopsy may be required to establish the exact Transthyretin CA was defined as the presence of cardiac tracer uptake
diagnosis.15 Previous studies on CA in AS have not described any Perugini grade ≥ 2 on bone scintigraphy in patients with unremarkable
cases of AL-CA.9,10 serum and urine free light chain assessment.14 AL-CA was diagnosed
if endomyocardial or extracardiac biopsy specimen and consecutive
The presence of TTR-CA has been linked to worse outcomes
immunohistochemical analysis revealed deposition of light chains, com-
following SAVR.8,10 Patients in these former studies were signifi-
bined with elevated serum or urine levels of the corresponding mono-
cantly younger as compared to a classic TAVR cohort. Therefore, clonal light chain. In AL cases with extracardiac biopsies only, cardiac
at this stage it is unclear whether concomitant CA also holds worse imaging indicating cardiac involvement was required for establishing the
survival implications for patients undergoing TAVR. diagnosis.
As the prevalence of AS is high, comprehensive systematic
screening for concomitant CA is difficult, if not sometimes impossi-
ble. Many cardiovascular centres lack nuclear imaging facilities and Clinical, laboratory
will not always have oncologists available to discuss serum/urine and electrocardiographic assessment
sample reports. CMR including contrast studies is also not applica- For the detection of pathological light chains underlying AL-CA, labo-
ble in every single AS patient. Thus, screening possibilities solely on ratory testing included serum electrophoresis, immunoglobin and free

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
1854 C. Nitsche et al.

Figure 1 Patient population: 238 patients scheduled for transcatheter aortic valve replacement (TAVR) were screened. Reasons for
exclusion and screening modalities are displayed. AS, aortic stenosis; CA, cardiac amyloidosis; CMR, cardiac magnetic resonance; 99m Tc-DPD,
99m Tc-labelled3,3-diphosphono-1,2-propanodicarboxylic-acid scintigraphy; echo, transthoracic echocardiography.

light chain quantification and immunofixation. Urine analysis consisted Cardiac magnetic resonance imaging
...........................................................................................

of electrophoresis, immunofixation, protein/creatinine ratio and albu-

min/creatinine ratio. Rare causes of CA were ruled out via quantifica- Cardiac magnetic resonance examinations were performed on a 1.5 T
tion of serum amyloid A and 𝛽2-microglobulin. Additionally, N-terminal scanner (MAGNETOM Avanto; Siemens Healthcare GmbH, Erlangen,
pro-brain natriuretic peptide (NT-proBNP) serum levels were deter- Germany), following standard protocols that included late gadolinium
mined in all patients. enhancement (LGE) imaging (0.1 mmol/kg gadobutrol; Gadovist, Bayer
Electrocardiograms were recorded according to current Vital GmbH, Leverkusen, Germany) if estimated glomerular filtration
recommendations.16 Voltage/mass ratio (VMR) was determined in rate was ≥30 mL/min/1.73 m2 .20 At the time of insertion of the intra-
patients without bundle branch block and paced rhythm by dividing the venous cannula, blood was drawn for haematocrit and serum creatinine
Sokolow–Lyon index by the LV mass index on echocardiography. The measurement. For analysis of LGE images, two independent reviewers
Sokolow–Lyon index was calculated as the sum of precordial voltage judged whether a typical pattern for CA was present or not.21 Elec-
[S-wave in lead V1 plus R-wave in lead V5 or V6 (SV1 + RV5 or V6 )]. trocardiographically triggered modified look-locker inversion recovery
(MOLLI) using a 5(3)3 prototype (5 acquisition heartbeats followed by
three recovery heartbeats and further three acquisition heartbeats)
was applied for pre-contrast T1 mapping. This method generates an
Echocardiographic assessment inline, pixel-based T1 map by acquiring a series of images over sev-
Transthoracic echocardiography was performed by board certified eral heartbeats with shifted T1 times, inline motion correction, and
cardiologists with echocardiography systems equipped with 3.5 MHz inline calculation of the T1 relaxation curve within one breath hold. T1
transducers (Vivid E95, Vivid E9, Vivid S70; General Electric Health- sequence parameters were as follows: starting inversion time 120 ms,
care). LV ejection fraction was calculated with the biplane Simpson’s inversion time increment 80 ms, reconstructed matrix size 256 × 218,
method and valvular stenosis and regurgitation severity were quantified and measured matrix size 256 × 144 (phase-encoding resolution 66%
according to the respective guidelines.17 Strain analysis was performed and phase-encoding field of view 85%). T1 maps were created both
in the 4-, 3-, and 2-chamber apical views. Regional longitudinal strain before and 15 min after contrast agent application. For post-contrast
(LS) was determined in 17 segments of the left ventricle.18 Global LS T1 mapping, a 4(1)3(1)2 prototype was used. T1 values from a midcav-
was calculated as the average LS of these 17 segments. Relative api- ity short-axis slice and a midcavity 4-chamber view were averaged for
cal LS was calculated as average apical LS/(average basal LS + average assessment of entire LV myocardium. For extracellular volume (ECV)
mid LS). LV mass was determined by anatomical M-mode as previ- calculation the following formula was used22 :
( ) ( )
ously described.19 LV stroke volume was derived from the LV outflow 1 1
T1myopost
− T1myopre
tract pulsed-wave Doppler signals and indexed to body surface area to MOLLI − ECV = 1 − haematocrit x ( ) ( )
receive stroke volume index (SVi). Myocardial contraction fraction was 1 1
T1bloodpost
− T1bloodpre
calculated as the ratio of stroke volume to myocardial volume, with
the latter being calculated from linear dimensions in the parasternal T1 myo pre/T1 blood pre indicates myocardial/blood native T1
long-axis view. times and T1 myo post/T1 blood post indicates T1 times of

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
Cardiac amyloidosis in AS scheduled for TAVR 1855

myocardium/blood 15 min after gadobutrol application. The local within the multivariate model, scaled hazard ratios (Z-scores) were

........................................................................................................................................................................
reference range for normal MOLLI-ECV values is 25.4 ± 2.7%, derived created by subtracting the mean from individual values and divid-
from 36 healthy sex-matched controls.23 ECV quantification applying ing them by the respective SD. Kaplan–Meier curves were used to
the MOLLI sequence has been shown to correlate strongly with evaluate the prognostic significance of CA in patients after TAVR.
histological fibrosis.24 A P-value ≤ 0.05 was considered statistically significant. All statis-
tical analyses were computed using SPSS 24 (IBM SPSS, Chicago,
IL, USA).
99m Tc-DPD bone scintigraphy
All patients were scanned using either a General Electric (GE) Infinia
Hawkeye 4 or GE Discovery 670 hybrid gamma camera 3 h after Results
intravenous administration of 700 MBq of 99m Tc-DPD. Whole body
images were acquired at a scan speed of 10 cm/min using low-energy Patient population
high-resolution collimators.25 The expected radiation dose from the A total of 238 consecutive patients scheduled for TAVR were
entire procedure was 4 mSv per patient. Intensity of myocardial uptake included (online supplementary Table S1). Contraindications for
on planar 99m Tc-DPD bone scintigraphy was categorized as 0–3
CMR were present in 46 subjects, who were still included in the
according to the Perugini grading system.26 This visual categorization
final analysis if the remaining screening was complete (n = 35).
can be summed up as follows: grade 0, no cardiac uptake and normal
bone uptake; grade 1, cardiac uptake which is less intense than the Whenever AL-CA was suspected, patients underwent additional
bone signal; grade 2, cardiac uptake with intensity similar or greater bone marrow and myocardial biopsy. The patient population eligi-
than bone signal; and grade 3, cardiac uptake with much attenuated or ble for final analysis is displayed in Figure 1.
absent bone signal. The heart-to-contralateral ratio was determined by In total, 16 (8.4%) CA cases were observed. TTR-CA was diag-
drawing a region of interest over the heart, copying it and mirroring it nosed in 15 subjects, one patient suffered from AL-CA. Genetic
over the contralateral chest.27 analysis confirmed wild-type TTR amyloidosis in all 15 cases, the
patient with AL-amyloidosis had monoclonal IgG gammopathy with
excess production of 𝜅-light chains.
Myocardial biopsy and genetic testing
Biopsies were harvested from the left ventricle using a 6 F bioptome.
Histological analysis was performed by Congo red staining on 6 μm Clinical, laboratory
formalin-fixed and paraffin-embedded sections and viewed in brightfield and electrocardiographic assessment
and cross-polarized light. When amyloid was confirmed by display-
ing apple green birefringence under cross-polars, immunohistochem- Detailed baseline characteristics of patients stratified according to
ical analysis (AmY-kit amyloid antibodies, Martinsried, Germany) was presence of coexisting CA are displayed in Tables 1 and 2. Patients
performed to determine the amyloid subtype. For genetic testing in with CA were older [84.0 years (IQR 82.0–89.0) vs. 82.0 years
patients with TTR-CA, the complete coding regions of the TTR gene (77.0–85.2), P = 0.024], had lower systolic blood pressure levels
were amplified by polymerase chain reaction assay. Amplified DNA [119 mmHg (108–130) vs. 132 mmHg (120–145); P = 0.010], and
fragments were directly sequenced using an ABI 3130xl Genetic Ana- a higher prevalence of cardiac pacemakers pre-TAVR (31.2% vs.
lyzer (Applied Biosystems). 11.7%; P = 0.040) as compared to AS subjects without concomi-
tant CA. Regarding the cardiovascular risk profile, no significant dif-
ferences were observed between groups. NT-proBNP [3634 ng/dL
Statistical methods
(1241–6323) vs. 1839 ng/dL (727–5664)] as well as troponin
Continuous data are expressed as mean ± standard deviation (SD), or T serum levels [47.0 ng/L (24.0–72.0) vs. 28.0 ng/L (20.0–48.7)]
as median with corresponding interquartile range (IQR) and categor-
did not differ significantly between CA and non-CA (P for
ical variables are presented as percentages or total numbers. Differ-
both >0.05).
ences between groups were analysed with the Wilcoxon rank sum
test. Chi-square tests or Fisher exact tests were used for categori-
On ECG, patients with coexisting CA displayed a signifi-
cal variables as appropriate. To analyse ECV expansion with respect to cantly lower Sokolow–Lyon index [1.7 mV (1.1–2.3) vs. 2.2 mV
different health conditions, MOLLI-ECV was presented as mean ± SD (1.6–2.8); P = 0.028].
and compared using box-plots. To estimate the discriminative power
of parameters in the distinction of AS and CA-AS, areas under the
corresponding receiver operating characteristic (ROC) curves with Transthoracic echocardiography
respective 95% confidence intervals (CI) were established and com- Echocardiographic details are shown in Table 2. CA patients dis-
pared. Uni- and multivariate binary logistic regression analysis were played lower transvalvular aortic mean [35.0 mmHg (26.0–48.5)
applied to evaluate the association of parameters with the presence
vs. 47.0 mmHg (40.0–56.0); P = 0.004] and peak pressure gra-
of CA. For each group (baseline clinical, echo-, and electrocardio-
dients [60.0 mmHg (43.0–73.5) vs. 77.0 mmHg (67.0–92.0);
graphic values) multivariate analysis was performed using a stepwise
forward selection with the cut-off P-value to enter the multivariate P = 0.001]. Moreover, patients with CA-AS had higher LV mass
model being ≤ 0.05 (online supplementary Table S2). The parameter indices [159.0 g/m2 (132.0–185.5) vs. 135.0 g/m2 (111.8–162.3);
remaining in the model was then selected to enter the final multi- P = 0.016] and a lower myocardial contraction fraction [15.1%
variate non-stepwise analysis alongside with SVi and VMR, respec- (9.8–19.1) vs. 21.9% (17.1–27.2); P = 0.001]. On the contrary,
tively. To allow better comparison between continuous parameters LV ejection fraction was similar [62.0% (44.0–70.0) vs. 62.0%

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
1856 C. Nitsche et al.

Table 1 Baseline clinical parameters

All patients (n = 191) No CA (n = 175, 91.6%) CA (n = 16, 8.4%) P-value

...........................................................................................................................................
Age, years 82.0 (78.0–86.0) 82.0 (77.0–85.2) 84.0 (81.0–89.0) 0.024
Male sex 49.7 48.3 62.5 0.196
BMI, kg/m2 26.1 (23.4–29.7) 26.1 (23.5–29.9) 25.7 (22.9–29.5) 0.405
Arterial hypertension 87.3 87.2 87.5 0.904
Systolic BP, mmHg 130 (118–145) 132 (120–145) 119 (108–130) 0.010
Diastolic BP, mmHg 67 (58–78) 67 (58–78) 67 (60–78) 0.908
Pre-interventional PM 13.1 11.7 31.2 0.040
Diabetes 26.2 25.9 31.2 0.751
Atrial fibrillation 37.7 35.6 56.3 0.060
Hyperlipidaemia 66.0 65.5 68.8 0.673
CAD 48.7 50.0 37.5 0.247
PAD 12.2 13.5 0.0 0.107
Severe symptomatic AS stage 0.026
High gradient 72.3 75.4 43.8
LF-LG + EF <50% 9.4 9.2 12.5
LF-LG + EF ≥50% 18.2 15.5 43.8
NYHA class ≥III 62.4 62.4 62.5 0.995
CCS class ≥III 7.2 7.3 6.3 0.875
Syncope 10.9 12.0 0.0 0.142
Troponin T, ng/L 29 (20–50) 28 (20–49) 47 (24–72) 0.107
NT-proBNP, ng/dL 1917 (783–5893) 1839 (727–5664) 3634 (1241–6323) 0.316
eGFR, mL/min/1.73 m2 55.1 (42.7–73.2) 55.4 (42.9–73.0) 55.1 (42.3–80.2) 0.831
EuroSCORE II, % 4.2 (3.9–4.7) 4.2 (3.9–4.7) 4.5 (4.0–4.6) 0.419
STS score, % 3.7 (2.5–5.3) 3.5 (2.5–5.1) 4.7(3.5–5.7) 0.037

Values are given as %, or median (interquartile range).

AS, aortic stenosis; BMI, body mass index; BP, blood pressure; CA, cardiac amyloidosis; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; EF, ejection
fraction; eGFR, estimated glomerular filtration rate; LF-LG, low-flow low-gradient; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association;
PAD, peripheral artery disease; PM, pacemaker; STS, Society of Thoracic Surgeons.

(54.0–70.0); P = 0.576]. This is also reflected by a higher per- were not remarkably elevated and typical LGE pattern was absent
........................................................................

centage of paradoxical low-flow low-gradient AS among CA-AS (online supplementary Table S3).
(43.8% vs. 15.5%). While speckle-tracking analysis revealed more
severe basal and midventricular LS impairment in CA-AS (P
99m Tc-DPD bone scintigraphy
for both <0.05), there were no significant differences between
groups with respect to global [−13.8% (−16.6; −10.2) vs. -16.9% Among TTR-CA patients (n = 15), 99m Tc-DPD bone scintigraphy
(−19.6; −12.3)] and relative apical LS [0.92 (0.81–1.20) vs. 0.81 revealed grade 1 [n = 1 who underwent confirmatory endomy-
(0.73–0.96); P > 0.05]. In addition, CA patients more often suf- ocardial biopsy (EMB)], grade 2 (n = 10) and grade 3 (n = 4) car-
fered from moderate or severe tricuspid regurgitation (62.5% vs. diac uptake, whereas no cardiac uptake was seen in the patient with
29.4; P = 0.017). isolated AL-CA. The TTR patient with grade 1 uptake underwent
additional cardiac biopsy, which eventually confirmed the diagno-
sis. Conversely, grade 1 uptake was seen in another five subjects
Cardiac magnetic resonance imaging with unremarkable free light chain assessment, who all declined
Detailed CMR data are shown in Table 2. Patients with and to undergo cardiac biopsy. Therefore, according to consensus
without CA did not display significant differences with respect criteria,14 the diagnosis of TTR-CA could not be confirmed in these
to left and right heart dimensions (P-values for all chambers patients. By quantitative assessment of 99m Tc-DPD myocardial
>0.05) and LV mass indices [93.9 g/m2 (61.3–100.5) vs. 79.4 g/m2 uptake, CA patients showed an increased heart-to-contralateral
(63.3–90.2); P = 0.163]. On the contrary, ECV values were sig- ratio [1.79 (1.59–2.31) vs. 1.05 (0.95–1.15); P < 0.001].
nificantly higher among CA-AS [(30.3% (28.1–33.5) vs. 26.7%
(24.6–29.0); P = 0.003], even though there was a considerable
overlap of isolated AS and CA-AS (online supplementary Figure S1). Voltage/mass ratio
Importantly, among the 11 CA patients who underwent CMR, The VMR was significantly lower in CA patients
characteristic transmural LGE pattern was only present in four [0.9 × 10−2 mV/g/m2 (0.6–1.6) vs. 1.6 × 10−2 mV/g/m2 (1.1–2.3);
cases (all TTR-CA). In the remaining seven CA patients, ECV values P = 0.001]. By ROC analysis, VMR demonstrated good

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
Cardiac amyloidosis in AS scheduled for TAVR 1857

Table 2 Baseline parameters of diagnostic modalities

All patients (n = 191) No CA (n = 175, 91.6%) CA (n = 16, 8.4%) P-value

...........................................................................................................................................
Echocardiographic parameters
LA diameter, mm 61.0 (55.8–67.3) 61.0 (55.0–68.0) 64.0 (60.0–67.0) 0.215
RA diameter, mm 57.0 (51.0–64.0) 56.0 (51.0–63.0) 63.0 (54.0–70.0) 0.029
LVEDD, mm 44.0 (39.0–48.0) 44.0 (39.3–48.0) 41.5 (37.0–48.8) 0.246
RVEDD, mm 33.0 (29.3–38.0) 33.0 (29.5–37.0) 36.0 (28.0–43.0) 0.144
IVS, mm 15.0 (14.0–17.0) 15.0 (14.0–17.0) 15.5 (13.3–19.8) 0.183
AVA, cm2 0.6 (0.5–0.8) 0.6 (0.5–0.8) 0.6 (0.5–0.9) 0.669
AV PPG, mmHg 73.0 (64.0–92.0) 77.0 (67.0–92.0) 60.0 (43.0–73.5) 0.001
AV MPG, mmHg 46.0 (38.0–55.5) 47.5 (40.0–56.0) 35.0 (26.0–48.5) 0.004
MR grade ≥ II 31.2 29.1 56.3 0.065
TR grade ≥ II 32.1 29.4 62.5 0.017
LVEF, % 62.0 (52.5–70.0) 62.0 (54.0–70.0) 62.0 (44.0–70.0) 0.576
LVEDV, mL 79.5 (62.0–108.5) 81.0 (62.5–111.0) 72.0 (59.0–89.5) 0.117
LVEDVi, mL/m2 44.3 (33.7–57.3) 44.6 (34.9–58.9) 37.5 (31.5–48.5) 0.097
LVESV, mL 30.0 (20.8–49.0) 30.0 (20.5–49.0) 27.0 (20.0–45.5) 0.567
SVi, mL/m2 42.5 (27.5–61.6) 46.6 (29.0–63.7) 27.4 (22.3–33.7) <0.001
Peak TR velocity, m/s 3.0 (2.7–3.5) 3.0 (2.7–3.4) 3.3 (2.6–4.1) 0.357
sPAP, mmHg 46.0 (39.0–59.0) 46.0 (38.5–57.5) 53.0 (42.0–77.8) 0.173
LV mass index, g/m2 136.0 (115.0–164.0) 135.0 (111.8–162.3) 159.0 (132.0–185.5) 0.016
Deceleration time, ms 206 (159–268) 212 (160–275) 199 (145–232) 0.161
MCF, % 21.0 (16.0–26.4) 21.9 (17.1–27.2) 15.1 (9.75–19.1) 0.001
Apical LS, % −22.0 (−27.5; −16.8) −22.2 (−28.2; −16.8) −20.2 (−25.2; −16.0) 0.253
Midventricular LS, % −15.0 (−18.0; −10.7) −15.6 (−18.0; −11.1) −12.8 (−13.8; −9.5) 0.043
Basal LS, % −10.8 (−13.5; −8.5) −11.2 (−14.1; −8.8) −9.7 (−10.8; −5.3) 0.040
GLS, % −16.6 (−19.5; −11.3) −16.9 (−19.6; −12.3) −13.8 (−16.6; −10.2) 0.072
Apical/(mid + basal) 0.83 (0.73–0.98) 0.81 (0.73–0.96) 0.92 (0.81–1.20) 0.061
Cutoff ≥1.0a 23.8 21.4 43.8 0.071
Apical/basal 1.89 (1.61–2.41) 1.87 (1.59–2.38) 2.02 (1.58–3.25) 0.378
(Apical+mid)/basal 3.22 (2.76–3.83) 3.20 (2.76–3.78) 3.35 (2.83–5.18) 0.400
Cardiac magnetic resonance parameters
LVEF, % 61.0 (44.5–72.0) 61.5 (44.0–72.0) 55.0 (47.0–66.0) 0.521
LVEDV, mL 136.0 (106.0–169.5) 134.5 (106.0–169.0) 157.0 (99.0–184.0) 0.374
LVESV, mL 52.0 (32.0–93.5) 51.0 (30.0–94.3) 62.0 (44.0–85.0) 0.362
LV CO, L/min 5.4 (4.2–6.4) 5.4 (4.2–6.4) 5.1(4.6–6.8) 0.936
RVEF, % 55.0 (43.8–63.0) 55.0 (44.6–63.0) 48.0 (36.0–63.0) 0.271
RVEDV, mL 127.5 (108.0–166.0) 126.0 (107.0–163.0) 163.0 (125.0–203.0) 0.064
RVESV, mL 60.0 (42.8–82.3) 59.0 (42.0–81.0) 82.0 (50.0–123.0) 0.089
RV CO, L/min 4.6 (3.8–5.7) 4.6 (3.7–5.7) 5.0 (4.8–5.8) 0.252
LA area, cm2 29.0 (26.0–35.0) 29.0 (26.0–35.0) 31.0 (23.0–34.0) 0.854
RA area, cm2 25.0 (20.0–30.0) 25.0 (20.0–30.0) 26.0 (23.0–35.0) 0.428
LV mass, g 147.0 (119.0–182.0) 145.0 (118.0–177.0) 175.0 (130.0–189.0) 0.151
LV mass index, g/m2 80.0 (63.2–94.6) 79.4 (63.3–90.2) 93.9 (61.3–100.5) 0.163
Native T1 LV, ms 1036 (1009–1066) 1033 (1008–1063) 1051 (1013–1080) 0.196
MOLLI-ECV LV, % 27.0 (24.9–29.4) 26.7 (24.6–29.0) 30.3 (28.1–33.5) 0.003
ECG parameters
Heart rate, bpm 70 (62–78) 70 (62–78) 71 (66–77) 0.741
Sokolow–Lyon index, mV 2.1 (1.6–2.8) 2.2 (1.6–2.8) 1.7 (1.1–2.3) 0.028
VMR, mV/g/m2 × 10−2 1.5 (1.0–2.2) 1.6 (1.1–2.3) 0.9 (0.6–1.6) 0.001
Low voltage limb 6.3 6.4 5.9 0.938
QRS duration, ms 98 (86–118) 96 (84–116) 111 (90–132) 0.086
LBBB 6.6 7.3 0.0 0.262
RBBB 12.0 11.3 18.8 0.386
LAFB 16.3 14.7 31.3 0.088
1st degree AV block 20.0 18.6 33.3 0.225

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
1858 C. Nitsche et al.

Table 2 (Continued)

All patients (n = 191) No CA (n = 175, 91.6%) CA (n = 16, 8.4%) P-value

...........................................................................................................................................
Bone scintigraphy parameters
Perugini grading scale <0.001
0 89.0 97.1 6.3
1 3.1 2.9 6.3b
2 5.8 0.0 62.5
3 2.1 0.0 25.0
H/L ratio 1.07 (0.96–1.19) 1.05 (0.95–1.15) 1.79 (1.59–2.31) <0.001

Values are given as %, or median (interquartile range).

AV, aortic valve/atrioventricular; AVA, aortic valve area; CO, cardiac output; GLS, global longitudinal strain; H/L ratio, heart-to-contralateral ratio; IVS, interventricular septum;
LA, left atrial; LAFB, left anterior fascicular block; LBBB, left bundle branch block; LS, longitudinal strain; LV, left ventricular; LVEDD, left ventricular end-diastolic diameter; LVEDV,
left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; MCF, myocardial contraction fraction; MOLLI-ECV,
extracellular volume fraction as determined by modified look-locker inversion recovery; MPG, mean pressure gradient; MR, mitral regurgitation; PPG, peak pressure gradient;
RA, right atrial; RBBB, right bundle branch block; RV, right ventricular; RVEDD, right ventricular end-diastolic diameter; RVEDV, right ventricular end-diastolic volume; RVEF,
right ventricular ejection fraction; sPAP, systolic pulmonary artery pressure; SVi, stroke volume index; T1, T1 relaxation time; TR, tricuspid regurgitation; VMR, voltage/mass
ratio.
a Cutoff value for relative apical strain selected according to study by Phelan et al.28
b Transthyretin cardiac amyloidosis in this patient with grade 1 uptake was confirmed by endomyocardial biopsy.

Table 3 Uni- and multivariate binary logistic regression analysis assessing the association of parameters with the
presence of cardiac amyloidosis

Univariate OR (95% CI) P-value Multivariate OR (95% CI) P-value

...........................................................................................................................................
Model 1
Age (per year increase) 1.108 (1.012–1.213) 0.027 4.686 (1.467–14.975) 0.009
MCF 0.353 (0.181–0.691) 0.002 0.657 (0.303–1.422) 0.286
Sokolow–Lyon index 0.481 (0.232–0.998) 0.049 2.740 (0.690–10.886) 0.152
VMR 0.230 (0.084–0.626) 0.004 0.063 (0.007–0.593) 0.016
Model 2
Age (per year increase) 1.108 (1.012–1.213) 0.027 2.369 (0.906–6.197) 0.079
MCF 0.353 (0.181–0.691) 0.002 0.588 (0.271–1.275) 0.179
Sokolow–Lyon index 0.481 (0.232–0.998) 0.049 0.768 (0.347–1.703) 0.516
SVi 0.209 (0.078–0.559) 0.002 0.296 (0.101–0.869) 0.027

CI, confidence interval; MCF, myocardial contraction fraction; OR, odds ratio; SVi, stroke volume index; VMR, voltage/mass ratio.

discriminative power for the detection of CA-AS [area under the Outcome
......................................................

curve (AUC) 0.770, 95% CI 0.641–0.900; P = 0.001] (Figure 2).

After a median follow-up of 15.3 ± 7.9 months, 33 patients (3
In addition, VMR was associated with CA by univariate linear
CA-AS, 30 AS) had died and 22 patients (2 CA-AS, 20 AS) had
regression analysis [odds ratio (OR) 0.230, 95% CI 0.084–0.626;
experienced cardiovascular hospitalizations. One patient without
P = 0.004]. After multivariate adjustment, VMR remained inde-
CA died prior to the intervention. Moreover, TAVR was not
pendently linked to the presence of CA (OR 0.063, 95% CI
performed in another five patients (1 CA-AS, 4 AS) due to various
0.007–0.593; P = 0.016) (Table 3).
reasons, and those subjects were excluded from the outcome
analysis. By Kaplan–Meier estimates, the presence of CA was
Stroke volume index not associated with poorer outcome following TAVR (P = 0.972
and P = 0.915 for primary and secondary endpoints, respectively)
Cardiac amyloidosis patients exhibited a significantly lower SVi
(Figure 3).
[27.4 mL/m2 (22.3–33.7) vs. 46.6 mL/m2 (29.0–63.7); P < 0.001].
SVi showed good discriminative power by ROC analysis [AUC
0.773, 95% CI 0.688–0.857; P < 0.001 (Figure 2)], and logistic
regression analysis revealed a strong association with CA by Discussion
univariate (OR 0.209, 95% CI 0.078–0.559; P = 0.002), and also The present study has four main conclusions: (i) it is the first to
multivariate analysis (OR 0.296, 95% CI 0.101–0.869; P = 0.027) describe the presence of AL- as well as TTR-CA among patients
(Table 3). with severe AS; (ii) parameters based solely on echocardiography

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
Cardiac amyloidosis in AS scheduled for TAVR 1859

patterns on CMR, and no distinction between TTR- and AL-CA

........................................................................................................................................................................
was made.10

Screening for cardiac amyloidosis

in aortic stenosis
After systematic screening, a prevalence of 8.4% of concomitant
CA was found in the present series, including one case of AL-CA.
All previous studies on the prevalence of CA-AS used either CMR
or 99m Tc-DPD bone scintigraphy or myocardial biopsy as single
diagnostic modalities. CMR was diagnostic in only 36% of CA-AS in
the present study, which confirms the formerly reported low sen-
sitivity of distinctive LGE patterns. In the remainder, 99m Tc-DPD
bone scintigraphy, laboratory assessment, and myocardial biopsy
were necessary for CA diagnosis. Interestingly, 37% of CA-AS
patients were female, which is in line with previous data on CA
among heart failure patients with preserved ejection fraction.31
However, other investigators reported a significantly lower pro-
portion of women among TTR-CA patients.14,25,29 The high pro-
portion of females in the present series may be the result of the
active screening approach, and may indicate that currently women
with CA are potentially missed in clinical routine. Nuclear cardiac
imaging with bone seeking radioisotopes allows for non-invasive
Figure 2 Stroke volume index (SVi) and voltage/mass ratio
(VMR) for the discrimination of aortic stenosis with/without car- diagnosis of TTR-CA with high specificity and sensitivity.14 In con-
diac amyloidosis. SVi as well as VMR showed good discriminative trast, only 30% to 50% of AL-CA patients also display cardiac
power for the distinction of aortic stenosis with/without cardiac uptake on DPD bone scans. These patients mostly present with
amyloidosis. AUC, area under the curve; MCF, myocardial con- Perugini grade 1 uptake, frequently difficult to detect, also for
traction fraction; MR-ECV, extracellular volume by cardiac mag- experienced bone scan readers.25 In our cohort, 99m Tc-DPD bone
netic resonance. scintigraphy detected the majority of CA-AS cases, but was nega-
tive in the patient with isolated AL-CA. Myocardial biopsy, finally,
should be performed according to the respective recommenda-
and ECG, that are applicable for CA screening in AS patients, are tions whenever light chain analysis and consecutive bone marrow
presented; (iii) the vast majority of CA cases can be detected biopsy show abnormal results and AL-CA is suspected.14 However,
with 99m Tc-DPD bone scintigraphy, whereas CMR frequently lacks it is an invasive procedure carrying inherent risks that is, there-
diagnostic accuracy; and (iv) the presence of CA did not signifi- fore, only recommended in cases with significant probability for
cantly alter prognosis 15.3 months after TAVR. AL-CA. In the present cohort of patients with severe AS, myocar-
In AS, CA is a difficult diagnosis to make. Due to concentric dial biopsy was performed after TAVR when indicated. Taken alto-
LV thickening caused by outflow tract obstruction, the distinc- gether, alternative means for the screening for CA-AS based on
tion between isolated severe AS and AS with coexisting CA is widely available and low-cost modalities such as echocardiography
challenging. Recent studies have revealed CA rates ranging from and ECG appear highly desirable. Speckle tracking-derived strain
5% to 16% in patients with severe AS.8–11 In light of emerging parameters by transthoracic echocardiography have been demon-
treatment options currently tested in clinical trials (TTR-CA29 and strated to be more sensitive than conventional echocardiographic
AL-CA30 ), an exact diagnosis deciphering the underlying pathol- parameters for the detection of CA.32 Characteristic strain pattern
ogy to the molecular level is becoming increasingly important. Two of relative apical sparing in CA describes reduced LS at the LV base
previous studies investigated the prevalence of TTR-CA among AS with progressively increased strain near the LV apex. However, api-
patients scheduled for TAVR using DPD bone scans and identified cal sparing was shown insufficient for the detection of CA-AS.9 This
16% and 14% of CA, respectively.9,11 However, in both studies fur- finding is in line with our results and may reflect the haemodynamic
ther testing for AL-CA was not pursued despite the presence of load imposed on the left ventricle by severe AS. It could be hypoth-
monoclonal serum proteins in several patients. Thus, it is possible esized that relative apical sparing becomes manifest only after aor-
that subjects in those series suffered from AL-CA or a combina- tic valve replacement. This, however, needs to be proven in further
tion of AL- and TTR-CA but remained undiagnosed. In the work studies. ECG of CA patients can display a variety of non-specific
by Treibel et al.,8 5.2% (n = 6) of patients undergoing SAVR were abnormalities, such as atrial fibrillation, conduction disturbances,
diagnosed with TTR-CA based on intraoperative biopsy. Caval- and pseudo-infarct pattern. Moreover, affected patients frequently
cante et al.,10 finally, retrospectively analysed CMR scans of 113 AS present with low-voltage, which should raise suspicion given the
patients for coexisting CA, and found a prevalence of 8.0%. How- oftentimes heavily thickened myocardium. The VMR is a parame-
ever, the diagnosis of CA here was solely based on typical LGE ter that combines LV mass and signs of hypertrophy on ECG.33 Its

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
1860 C. Nitsche et al.

Figure 3 Kaplan–Meier curves of patients with aortic stenosis (AS) with/without cardiac amyloidosis (CA). Concomitant cardiac amyloidosis
(CA-AS) was not associated with all-cause mortality (A) or cardiovascular (CV) hospitalization (B) over 15.3 ± 7.9 months following
transcatheter aortic valve replacement. One CA-AS patient died prior to transcatheter aortic valve replacement and was therefore excluded
from outcome analysis.

diagnostic ability is explained by significantly increased LV mass in (99m Tc-DPD bone scintigraphy, CMR, blood and urine tests) is
.............................

CA-AS patients that is, in contrast to isolated AS, not reflected by indicated.
ECG alterations. We showed here that VMR effectively discrimi-
nated between AS and CA-AS (AUC 0.770, P = 0.001). Further-
more, we tested SVi for the detection of CA-AS. The underly-
Outcome after transcatheter aortic
ing idea is related to the fact that CA-AS patients often display valve replacement
low flow pattern, as known from previous reports.9,34 Indeed, To our knowledge, this is the first trial to investigate the prognostic
SVi was able to detect CA-AS with an AUC of 0.773. Based significance of coexisting CA in a large TAVR cohort. In contrast
on our results, VMR and SVi are useful tools to screen TAVR to previous studies following SAVR,8,10 CA-AS patients were not
patients for coexisting CA. In case of CA suspicion, further testing found to experience worse outcomes 15.3 ± 7.9 months after

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
Cardiac amyloidosis in AS scheduled for TAVR 1861

TAVR. It is uncertain whether this also applies to long-term Acknowledgements

........................................................................................................................................................................
outcome.
We thank Robin Ristl for statistical support.

Limitations Funding
The data presented were collected in a single-centre setting. This study received support from the Austrian Society of Cardiol-
Therefore, a centre-specific bias cannot be excluded. However, ogy (to F.D., J.M. and S.A.).
the major advantages of limiting data collection to a single centre Conflict of interest: none declared.
are (i) adherence to a constant clinical routine, (ii) constant quality
of work-up, (iii) and constant follow-up. Unfortunately, out of six
patients with Perugini grade 1 uptake on bone scintigraphy, only References
one patient agreed to perform EMB and was eventually diagnosed 1. Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities
in the elderly: an echocardiographic study of a random population sample. J Am
with TTR-CA. The remaining five patients declined EMB, which Coll Cardiol 1993;21:1220–1225.
would have been necessary to diagnose CA according to current 2. Thaden JJ, Nkomo VT, Enriquez-Sarano M. The global burden of aortic stenosis.
consensus criteria.14 Therefore, it cannot be excluded that further Prog Cardiovasc Dis 2014;56:565–571.
3. Gertz MA, Dispenzieri A, Sher T. Pathophysiology and treatment of cardiac
CA cases were missed in the present series. Moreover, in one amyloidosis. Nat Rev Cardiol 2015;12:91–102.
patient with Perugini grade 2 uptake and monoclonal gammopathy 4. Mewton N, Liu CY, Croisille P, Bluemke D, Lima JA. Assessment of myocar-
dial fibrosis with cardiovascular magnetic resonance. J Am Coll Cardiol
of undetermined significance based on bone marrow biopsy, EMB
2011;57:891–903.
was not performed. Given the known coexistence of TTR-CA and 5. Falk RH, Alexander KM, Liao R, Dorbala S. AL (light-chain) cardiac amyloidosis:
monoclonal protein without AL-CA14 and the low percentage of a review of diagnosis and therapy. J Am Coll Cardiol 2016;68:1323–1341.
AL-CA with Perugini uptake ≥2,25 this subject was classified as 6. Bonderman D, Agis H, Kain R, Mascherbauer J. Amyloid in the heart: an
under-recognized threat at the interface of cardiology, haematology, and pathol-
TTR-CA. Unfortunately, mass spectroscopy was not available in ogy. Eur Heart J Cardiovasc Imaging 2016;17:978–980.
our institution for patients undergoing EMB. However, in the two 7. Wechalekar AD, Schonland SO, Kastritis E, Gillmore JD, Dimopoulos MA, Lane T,
Foli A, Foard D, Milani P, Rannigan L, Hegenbart U, Hawkins PN, Merlini G,
CA subjects with EMB (one TTR, one AL), immunohistochemical
Palladini G. A European collaborative study of treatment outcomes in 346 patients
analysis did not show ambiguous results, and mass spectroscopy with cardiac stage III AL amyloidosis. Blood 2013;121:3420–3427.
was not essential for an accurate diagnosis according to recent 8. Treibel TA, Fontana M, Gilbertson JA, Castelletti S, White SK, Scully PR,
Roberts N, Hutt DF, Rowczenio DM, Whelan CJ, Ashworth MA, Gillmore JD,
recommendations.5 The mean age of the present population was
Hawkins PN, Moon JC. Occult transthyretin cardiac amyloid in severe calcific
81 ± 8.0 years. Our results may, therefore, not be transferable to aortic stenosis: prevalence and prognosis in patients undergoing surgical aortic
younger, low-risk AS populations. Furthermore, AL-CA has an age valve replacement. Circ Cardiovasc Imaging 2016;9:e005066.
9. Castano A, Narotsky DL, Hamid N, Khalique OK, Morgenstern R, DeLuca A,
peak of 60–69 years35 and may therefore be more prevalent among
Rubin J, Chiuzan C, Nazif T, Vahl T, George I, Kodali S, Leon MB, Hahn R,
younger AS patients. Since this cohort mostly comprised cases Bokhari S, Maurer MS. Unveiling transthyretin cardiac amyloidosis and its predic-
of TTR-CA, the applicability of VMR and SVi for the screening tors among elderly patients with severe aortic stenosis undergoing transcatheter
aortic valve replacement. Eur Heart J 2017;38:2879–2887.
for AL-CA has yet to be evaluated. The small number of CA
10. Cavalcante JL, Rijal S, Abdelkarim I, Althouse AD, Sharbaugh MS, Fridman Y,
cases limited the number of factors that could be included in the Soman P, Forman DE, Schindler JT, Gleason TG, Lee JS, Schelbert EB. Cardiac
multivariate regression analysis and precluded multivariate analysis amyloidosis is prevalent in older patients with aortic stenosis and carries worse
prognosis. J Cardiovasc Magn Reson 2017;19:98.
in the subpopulation with all screening modalities, including CMR.
11. Scully PR, Treibel TA, Fontana M, Lloyd G, Mullen M, Pugliese F, Hartman N,
Moreover, the lack of follow-up echo strain data precluded an Hawkins PN, Menezes LJ, Moon JC. Prevalence of cardiac amyloidosis in
analysis of whether relative apical sparing becomes overt in CA-AS patients referred for transcatheter aortic valve replacement. J Am Coll Cardiol
2018;71:463–464.
after valve replacement.
12. Ternacle J, Krapf L, Mohty D, Magne J, Nguyen A, Galat A, Gallet R, Teiger E,
Côté N, Clavel MA, Tournoux F, Pibarot P, Damy T. Aortic stenosis and
cardiac amyloidosis: JACC review topic of the week. J Am Coll Cardiol
Conclusions 2019;74:2638–2651.
13. Monticelli FC, Kunz SN, Keller T, Bleiziffer S. Cardiac amyloidosis as a potential
In the present study, comprehensive screening for CA in AS sched- risk factor for transapical transcatheter aortic valve implantation. J Card Surg
2014;29:623–624.
uled for TAVR for the first time revealed not only TTR- but also 14. Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar
AL-CA. Most CA patients identified had TTR-CA. Parameters AD, Berk JL, Quarta CC, Grogan M, Lachmann HJ, Bokhari S, Castano A,
Dorbala S, Johnson GB, Glaudemans AW, Rezk T, Fontana M, Palladini G, Milani P,
solely based on ECG and echocardiography allow for the identifica-
Guidalotti PL, Flatman K, Lane T, Vonberg FW, Whelan CJ, Moon JC, Ruberg FL,
tion of the majority of CA-AS. As 15-month survival did not differ Miller EJ, Hutt DF, Hazenberg BP, Rapezzi C, Hawkins PN. Nonbiopsy diagnosis
significantly between AS with and without CA, TAVR appears ben- of cardiac transthyretin amyloidosis. Circulation 2016;133:2404–2412.
15. Gertz MA. Immunoglobulin light chain amyloidosis: 2013 update on diagnosis,
eficial in CA-AS. However, further studies are needed to elucidate
prognosis, and treatment. Am J Hematol 2013;88:416–425.
potential benefits of TAVR in CA-AS on the long run. 16. Kligfield P, Gettes LS, Bailey JJ, Childers R, Deal BJ, Hancock EW, van Herpen G,
Kors JA, Macfarlane P, Mirvis DM, Pahlm O, Rautaharju P, Wagner GS, Joseph-
son M, Mason JW, Okin P, Surawicz B, Wellens H; American Heart Association
Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiol-
Supplementary Information ogy, American College of Cardiology Foundation, Heart Rhythm Society. Recom-
mendations for the standardization and interpretation of the electrocardiogram:
Additional supporting information may be found online in the part I: the electrocardiogram and its technology: a scientific statement from the
Supporting Information section at the end of the article. American Heart Association Electrocardiography and Arrhythmias Committee,

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
1862 C. Nitsche et al.

Council on Clinical Cardiology; the American College of Cardiology Founda- and limitations of 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy in

..........................................................................................
tion; and the Heart Rhythm Society endorsed by the International Society for systemic amyloidosis. Eur Heart J Cardiovasc Imaging 2014;15:1289–1298.
Computerized Electrocardiology. J Am Coll Cardiol 2007;49:1109–1127. 26. Perugini E, Guidalotti PL, Salvi F, Cooke RM, Pettinato C, Riva L,
17. Lancellotti P, Tribouilloy C, Hagendorff A, Moura L, Popescu BA, Agricola E, Leone O, Farsad M, Ciliberti P, Bacchi-Reggiani L, Fallani F, Branzi A,
Monin JL, Pierard LA, Badano L, Zamorano JL, Sicari R, Vahanian A, Roelandt Rapezzi C. Noninvasive etiologic diagnosis of cardiac amyloidosis using
JR; European Association of Echocardiography. European Association of Echocar- 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll

diography recommendations for the assessment of valvular regurgitation. Part Cardiol 2005;46:1076–1084.
1: aortic and pulmonary regurgitation (native valve disease). Eur J Echocardiogr 27. Bokhari S, Castano A, Pozniakoff T, Deslisle S, Latif F, Maurer MS.
2010;11:223–244. 99m Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloi-

18. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf dosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ
FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Cardiovasc Imaging 2013;6:195–201.
Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU. Recommendations for 28. Phelan D, Collier P, Thavendiranathan P, Popovic ZB, Hanna M, Plana JC,
cardiac chamber quantification by echocardiography in adults: an update from Marwick TH, Thomas JD. Relative apical sparing of longitudinal strain using
the American Society of Echocardiography and the European Association of two-dimensional speckle-tracking echocardiography is both sensitive and specific
Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16:233–270. for the diagnosis of cardiac amyloidosis. Heart 2012;98:1442–1448.
19. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. 29. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G,
Echocardiographic assessment of left ventricular hypertrophy: comparison to Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drach-
necropsy findings. J Am Coll Cardiol 1986;57:450–458. man BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P, Patterson TA,
20. Kramer CM, Barkhausen J, Flamm SD, Kim RJ, Nagel E. Standardized cardiovas- Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C; ATTR-ACT Study
cular magnetic resonance imaging (CMR) protocols, Society for Cardiovascular Investigators. Tafamidis treatment for patients with transthyretin amyloid
Magnetic Resonance: Board of Trustees Task Force on Standardized Protocols. cardiomyopathy. N Engl J Med 2018;379:1007–1016.
J Cardiovasc Magn Reson 2008;10:35. 30. Khouri J, Kin A, Thapa B, Reu FJ, Bumma N, Samaras CJ, Liu HD, Karam MA,
21. Vogelsberg H, Mahrholdt H, Deluigi CC, Yilmaz A, Kispert EM, Greulich S, Reed J, Mathur S, Faiman BM, Devries G, Zonder J, Valent J. Daratumumab proves
Klingel K, Kandolf R, Sechtem U. Cardiovascular magnetic resonance in clinically safe and highly effective in AL amyloidosis. Br J Haematol 2019;185:342–344.
suspected cardiac amyloidosis: noninvasive imaging compared to endomyocardial 31. Gonzalez-Lopez E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral FJ,
biopsy. J Am Coll Cardiol 2008;51:1022–1030. Cobo-Marcos M, Robles C, Bornstein B, Salas C, Lara-Pezzi E, Alonso-Pulpon L,
22. Kellman P, Wilson JR, Xue H, Ugander M, Arai AE. Extracellular volume Garcia-Pavia P. Wild-type transthyretin amyloidosis as a cause of heart failure
fraction mapping in the myocardium, part 1: evaluation of an automated method. with preserved ejection fraction. Eur Heart J 2015;36:2585–2594.
J Cardiovasc Magn Reson 2012;14:63. 32. Quarta CC, Solomon SD, Uraizee I, Kruger J, Longhi S, Ferlito M, Gagliardi C,
23. Duca F, Kammerlander AA, Zotter-Tufaro C, Aschauer S, Schwaiger ML, Marzluf Milandri A, Rapezzi C, Falk RH. Left ventricular structure and function
BA, Bonderman D, Mascherbauer J. Interstitial fibrosis, functional status, and in transthyretin-related versus light-chain cardiac amyloidosis. Circulation
outcomes in heart failure with preserved ejection fraction: insights from a 2014;129:1840–1849.
prospective cardiac magnetic resonance imaging study. Circ Cardiovasc Imaging 33. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization
2016;9:e005277. by a distinctive voltage/mass relation. J Am Coll Cardiol 1982;49:9–13.
24. Kammerlander AA, Marzluf BA, Zotter-Tufaro C, Aschauer S, Duca F, Bach- 34. Longhi S, Lorenzini M, Gagliardi C, Milandri A, Marzocchi A, Marrozzini C, Saia F,
mann A, Knechtelsdorfer K, Wiesinger M, Pfaffenberger S, Greiser A, Lang IM, Ortolani P, Biagini E, Guidalotti PL, Leone O, Rapezzi C. Coexistence of degener-
Bonderman D, Mascherbauer J. T1 mapping by CMR imaging: from histological ative aortic stenosis and wild-type transthyretin-related cardiac amyloidosis. JACC
validation to clinical implication. JACC Cardiovasc Imaging 2016;9:14–23. Cardiovasc Imaging 2016;9:325–327.
25. Hutt DF, Quigley AM, Page J, Hall ML, Burniston M, Gopaul D, Lane T, 35. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features
Whelan CJ, Lachmann HJ, Gillmore JD, Hawkins PN, Wechalekar AD. Utility in 474 cases. Semin Hematol 1995;32:45–59.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.