ESC HEART FAILURE ORIGINAL ARTICLE

ESC Heart Failure 2021; 8: 4549–4561

Published online 26 October 2021 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.13667

Transthyretin cardiac amyloidosis in patients after

TAVR: clinical and echocardiographic findings and long
term survival
Sara Shimoni1,2* , Meital Zikri1, Dan Haberman1, Shay Livschitz1, Sagi Tshori1,2, Yacov Fabricant1, Valery
Meledin1, Gera Gandelman1, Sorel Goland1,2 and Jacob George1,2
1
The Heart Center, Kaplan Medical Center, Rehovot, Israel; and 2Hadassah Medical School, Hebrew University, Jerusalem, Israel

Abstract
Aims The aim of this study was to examine the prevalence of amyloid transthyretin (ATTR) cardiac amyloidosis in patients
1–2 years after trans-catheter aortic valve replacement (TAVR) and to assess their clinical and echocardiographic outcome
and long-term survival.
Methods and results We enrolled 88 patients, mean age 81 years, 534 (390–711) days after TAVR. Patients underwent a
Tc99m-PYP scintigraphy for the diagnosis of ATTR cardiac amyloidosis. Eleven (12.5%) participants were diagnosed with
ATTR cardiac amyloidosis. Eighty eight per cent of patients without amyloidosis were in New York Heart Association Classes
1–2 after TAVR, compared with 64% patients with ATTR cardiac amyloidosis (P = 0.022). There were no differences in left
ventricular (LV) ejection fraction (P = 0.69) between patients with and without ATTR cardiac amyloidosis at enrolment.
The LV mass index and pulmonary artery pressure were significantly higher in patients with ATTR cardiac amyloidosis
(P = 0.046 and P = 0.002, respectively). Global longitudinal strain and myocardial work efficiency were significantly lower
in patients with ATTR cardiac amyloidosis (P = 0.031 and P = 0.048, respectively). We assessed changes in echocardiographic
data, from the time of TAVR to enrolment, and as expected, there was a significant decrease in aortic valve gradient in both
groups. There was a significant reduction in LV mass and LV mass index and improvement in basal segment LV strain in the
ATTR cardiac amyloidosis negative group (P = 0.045, P = 0.046 and 0.023, respectively). However, in the ATTR cardiac am-
yloidosis group the change in LV mass and LV mass index and LV basal strain values was not significant (P = 0.24, P = 0.13
and P = 0.35, respectively). The were no significant changes in other echocardiographic parameters in both groups. The pa-
tients were followed for 1150 (1086–1221) days after enrolment. Twenty seven patients had at least one cardiac hospital-
ization during of follow up, of them seven were with ATTR cardiac amyloidosis and 20 patients without amyloidosis
(P = 0.017). Eighteen patients (20%) died during follow up; 12 (14%) patients died due to cardiac causes. There was no dif-
ference in all-cause and cardiac mortality between patients with and without ATTR cardiac amyloidosis (P = 0.6 and P = 0.53,
respectively).
Conclusions The long-term survival after TAVR is not significantly affected by the presence of ATTR cardiac amyloidosis.
However, the clinical course of these patients and the LV hemodynamic improvement is less favourable. This
hypothesis-generating study suggests screening for ATTR cardiac amyloidosis in patients who underwent TAVR and have
limited clinical or echocardiographic improvement, because they may potentially improve with new therapies for ATTR
cardiac amyolidosis.

Keywords Amyloidosis; Aortic valve intervention; Myocardial strain

Received: 1 July 2021; Revised: 27 August 2021; Accepted: 27 September 2021
*Correspondence to: Sara Shimoni, The Heart Center, Kaplan Medical Center, Rehovot, Israel. Email: sara_s@clalit.org.il
Sara Shimoni and Meital Zikri contributed equally to the paper.
[Correction added on 05 November 2021, after first online publication: The article title has been corrected in this version as well as the author name ‘Valeri’ has been
corrected to ‘Valery’.]

© 2021 The Authors. ESC 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 me-
dium, provided the original work is properly cited and is not used for commercial purposes.
4550 S. Shimoni et al.

Introduction the valvular disease clinic and undergo echocardiography ev-

ery 6–12 months after TAVR, based on their clinical status.
Amyloidosis is a multi-organ syndrome, with cardiac involve- From this registry, 267 consecutive patients underwent
ment that usually presents as restrictive cardiomyopathy.1 elective TAVR during the years 2014–2016. The patients were
Amyloid Transthyretin (ATTR) amyloidosis is a subtype of am- enrolled prospectively during the years 2016–2017. Upon
yloidosis with abnormal precipitation of transthyretin, a pro- enrolment, patients underwent clinical assessment, echocar-
tein that normally acts as transporter for circulating thyroxin diography and 99mTc-PYP nuclear scintigraphy imaging.
and retinol. The gold standard for the diagnosis of ATTR car- Patients were followed prospectively and hospitalization
diac amyloidosis is the demonstration of ATTR deposits on and mortality data was collected.
endomyocardial biopsy.2 Nuclear cardiac imaging with In addition, retrospective clinical and echocardiographic
radioisotopes, such as technetium-99m pyrophosphate data was collected from the time before TAVR until enrol-
(99mTc-PYP), have shown excellent diagnostic accuracy for ment, using the TAVR registry data and from hospital and
ATTR cardiac amyloidosis obviating the need for cardiac family physician records. Cardiovascular hospitalizations in-
biopsy.3 The prevalence of ATTR cardiac amyloidosis is un- cluded hospitalizations for cardiac cause: chest pain, arrhyth-
known. Amyloid fibrils are present in the myocardium in ap- mia, dyspnoea, and HF. HF hospitalizations were defined as
proximately 25% of patients 80 years or older in autopsy hospitalization due to symptoms and signs of left or right HF.
studies.4 In patients with heart failure (HF) and preserved left The study was approved by the local IRB of Kaplan Medical
ventricular (LV) function the prevalence of ATTR amyloidosis Center (protocol 018-17KMC) and all patients provided
was reported to be 13.3%.5 There is accumulating evidence written consent form.
for a pivotal role of oxidative stress, inflammation, and extra-
cellular remodelling in the ATTR cardiac amyloidosis.6,7
Degenerative aortic valve (AV) stenosis (AS) is currently the Echocardiographic data
most common valvular heart disease in Western developed
countries. Inflammation and oxidative stress play a significant Left ventricular dimension was measured in 2-D parasternal
role in pathogenesis of AS.8 In recent reports on patients with long axis view; LV ejection fraction (LVEF) was estimated using
significant AS, the prevalence of ATTR amyloidosis varied the bi-plane Simpson’s method; diastolic function was
from 6% to 16%.9,10 It is unclear if there is a causative link be- analysed based on mitral Doppler inflow and tissue Doppler
tween AS and ATTR cardiac amyloidosis. Trans-catheter AV imaging (TDI) at the lateral and septal mitral annulus and
replacement (TAVR) is generally indicated for moderate and pulmonary artery pressure (PAP) was calculated by the
high-risk AS.11 There are several reports on possible compli- maximal tricuspid regurgitation velocity. The peak AV pres-
cations and poor prognosis of AV intervention in patients sure gradient was calculated using the Bernoulli equation,
with AS and ATTR cardiac amyloidosis.9,12–14 Recently, new and mean AV pressure gradient was calculated by averaging
studies assessed prospectively the prognosis of patients with the instantaneous gradients over the ejection period on the
ATTR cardiac amyloidosis that underwent TAVR and found continuous-wave Doppler recordings. AV area (AVA) was
that ATTR cardiac amyloidosis does not affect mortality.15–18 calculated using the continuity equations previously
In these studies, the patients were enrolled and the diagnosis described.19,20 LV mass was calculated by Devereux formula.20
was made before performing TAVR. The follow-up data in-
cluded mortality and hospitalizations. There are no data,
however, on the prevalence of ATTR cardiac amyloidosis in Strain measurements
a cohort of patients a year or more after TAVR, and there
are no data on the clinical and echocardiographic findings in Two-dimensional speckle-tracking strain and quantification of
these patients after TAVR. The aim of this study was to exam- myocardial work (MW) analysis were performed offline by
ine the prevalence of ATTR cardiac amyloidosis in post-TAVR using commercially available software (Echo PAC version
patients and study their clinical and echocardiographic 202 GE, Horten, Norway). The global longitudinal strain
changes and long-term prognosis. (GLS) was obtained from the apical four-chamber, two-cham-
ber, and long-axis views in an 18-segment LV model. Subse-
quently, longitudinal strain of all 18 LV segments were
averaged to assess the LVGLS and the basal segments, mid
Methods segments and apical segments were averaged to assess the
basal, mid and apical segments.21,22 Because all included pa-
Population tients had adequate strain tracking, no patient was excluded
form strain analysis.
The Kaplan Medical Center TAVR registry includes all patients After calculating GLS and adding the brachial blood pres-
who underwent TAVR since 2010.The patients are followed in sure and the time of aortic and mitral opening and closure

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ATTR cardiac amyloidosis in post-TAVR patients 4551

events by echocardiography, the software derived Changes in echocardiographic finding in the time between
non-invasive pressure strain loops. When the velocity on AV TAVR and patient’s enrolment in the study were assessed
was above 2 m/s, and in order to correct for underestimation with paired T test.
of intraventricular pressure, we added the mean AV pressure New York Heart Association (NYHA) class difference be-
gradient to the systolic blood pressure used by the software. tween the groups at enrolment and before TAVR was
The area of the loop indicated the regional and global MW. assessed using generalized estimating equations—model of
Using the software, additional indices of MW were obtained repeated measurements of ordinal variables—order scale.
including global constructive work (GCW) (the sum of work C statistics was performed in order to determine the echo-
performed during shortening in systole and the negative cardiographic strain parameters related to ATTR cardiac amy-
work during lengthening in isovolumetric relaxation); global loidosis and the best cut-off was calculated as maximal
wasted work (GWW) (the sum of negative work performed sensitivity + specificity
1. The comparison between the area
during lengthening in systole and the work performed during under the curve (AUC) of different variables was performed
shortening in isovolumetric relaxation); and global work with MedCalc software.
efficiency (GWE) (constructive work divided by the sum of The association between count variables (number of
constructive and wasted work).23 hospitalizations
number of events over a period of time)
was analysed by using a generalized linear model for
Poissonic/negative binomial distribution.
Technetium-99m pyrophosphate scintigraphy for Kaplan–Meier plots were used for drawing survival curve
diagnosis of transthyretin cardiac amyloidosis of the different groups, and Cox proportional hazards regres-
sion analysis was used to evaluate the association of variables
99mTc-PYP planar cardiac scan was performed using dual- with mortality. To test the association between variables and
head SPECT/CT camera (Symbia, Ecam cammera, Siemens) event-free survival after enrolment, Cox regression for
equipped with low-energy, high-resolution collimators. The survival analysis was utilized, using the stepwise, forward,
planar images (anterior and lateral views) were acquired 1– likelihood ratio method.
3 h after injection of 10 mCi of 99mTc-PYP. The images were
acquired for a total of 750 000 counts with the heart centred
in the field of view.
Two nuclear cardiologists blinded to the patients’ clinical Results
status independently evaluated cardiac retention of
99mTc-PYP using a semi quantitative visual scoring method Patient population
(0 = no uptake, 1 = uptake less than ribs, 2 = uptake equal
to ribs, 3 = uptake greater than ribs).3 The scan was defined Two hundred sixty seven elderly patients underwent elective
positive when the score ≥ 2. In six patients with an equivocal TAVR during the years 2014–2016 (Figure 1). Eighty five
ATTR planar scan, in order to minimize the confounding fac- patients died before the current study started. Thirty seven
tors of blood pool imaging and increased bone activity, a sin- patients were not able to consent the study due to cognitive
gle photon emission computed tomography (SPECT) gated or functional impairment. Additional 47 patients refused to
acquisition was performed after planar scan. Twenty mCi of participate in the study and 10 were lost to follow up. The pa-
99mTc-PYP were injected. SPECT gated scan protocol, with tients not included in the study are a heterogenic group. We
image acquisition of 10 min and eight frames, using a CZT compared the baseline parameters (before TAVR) of patients
multi detectors camera (D-SPECT camera, Spectra Dynamic included in the current study and patients that could not be
was performed. Five SPECT studies were negative, most included, and the results are shown in Table 1. As can be seen
probably false positive planar study due to blood pool. One in the table, the populations differ significantly in renal func-
patient that had an equivocal ATTR planar scan had a positive tion that is impaired in patients not included and hyperlipid-
SPECT study. aemia rate that was lower in patients not included. However,
all other clinical data do not differ between the populations.
The final research population included 88 patients (32.9%).
Statistical analysis As seen in Table 2, the mean age was 81 years, 55%
women. The majority of patients had history of hypertension
All analyses were performed by SPSS version 21, a signifi- and dyslipidaemia. Atrial fibrillation was found in 30% of pa-
cance level of P ≤ 0.05 was considered significant. Continuous tients and coronary artery disease in 60% of all patients.
variables were presented as mean ± SD or median (25th; 75th The patients underwent PYP scintigraphy between the
inter-quartile range) and dichotomous as a percentage. Clini- years 2016 and 2017, at enrolment. The median time from
cal and echocardiographic data were compared between the TAVR to enrolment was 534 (390–711) days. Eleven (12.5%)
groups using T test or chi-squared test for categorical data. subjects were diagnosed with ATTR cardiac amyloidosis.

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4552 S. Shimoni et al.

Figure 1 Flow diagram of patient recruitment. TAVR, trans-catheter aortic valve replacement.

Figure 2 shows an example of a patient with a positive scan amyloidosis were in NYHA Class 2 (P = 0.58). At enrolment,
for ATTR cardiac amyloidosis. AL amyloidosis was excluded 88% of patients without ATTR cardiac amyloidosis and 64%
by a negative test for monoclonal gammopathy. with ATTR cardiac amyloidosis were in NYHA Classes 1–2
As seen in Table 2, there were no significant differences (P = 0.022, Figure 3A). In patients with ATTR cardiac amyloid-
between the groups in regard to age, gender and risk factors. osis, the change in NYHA class was not significant (P = 0.28).
The level of haematocrit was significantly lower in patients Patients with no ATTR cardiac amyloidosis improved signifi-
with ATTR cardiac amyloidosis. Creatinine level was higher cantly from the time of TAVR until enrolment (P < 0.001).
in patients with ATTR cardiac amyloidosis, with borderline Using generalized estimating equations analysis for
statistical significance. The level of troponin was significantly assessing interaction of time (TAVR to enrolment) and the
higher in patients with ATTR cardiac amyloidosis. N-terminal presence of ATTR cardiac amyloidosis on NYHA class, we
pro b-type natriuretic peptide levels were higher in patients found that both parameters were significant (P < 0.01 for
with ATTR; however, this difference was not statistically sig- time and P = 0.014 for ATTR-cardiac amyloidosis). The inter-
nificant. There was no difference in the percentage of action time * ATTR-cardiac amyloidosis was also significant
self-expandable or balloon expandable valve in each group (P = 0.047).
(P = 0.64).

Echocardiographic measurements before

Clinical findings trans-catheter aortic valve replacement

Before TAVR, 49% of patients negative for ATTR cardiac amy- Before TAVR, patients diagnosed later with ATTR cardiac am-
loidosis and 36% of patients positive for ATTR cardiac yloidosis had similar AS severity as subjects with no ATTR car-

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ATTR cardiac amyloidosis in post-TAVR patients 4553

Table 1 Baseline characteristics in patients that underwent TAVR in the years 2014–2016

Included in the study (n = 88) Not included in the study (n = 179)

Age 81 (78–85) 82(79–86) 0.3
BMI 28.79 ± 5.05 27.8 ± 5 0.29
Gender male (%) 45% 39% 0.912
Hypertension (%) 93% 90% 0.99
Diabetes mellitus (%) 43.% 42% 0.99
Dyslipidaemia (%) 91% 76% 0.04
Smoking (%) 31.40% 22% 0.7
Atrial fibrillation (%) 29% 33% 0.8
Coronary artery disease (%) 61.20% 50% 0.63
Haemoglobin (g/dL) 11.4 ± 1.59 11.7 ± 1.4 0.23
Haematocrit (vol %) 34.6 ± 5.16 34.9 ± 5.16 0.3
Platelets (K/uL) 195 ± 66 202 ± 59 0.27
Urea (mg/dL) 45.95 ± 24.96 54 ± 29 0.06
Creatinine (mg/dL) 0.944 ± 0.39 1.22 ± 1.1 0.04
Albumin (g/dL) 3.63 ± 0.44 3.8 ± 0.2 0.03
LVEF% 55 ± 10 53 ± 10 0.66
AV peak gradient (mmHg) 75 ± 15 68 ± 13 0.21
2
AVA (cm ) 0.71 ± 0.14 0.68 ± 0.16 0.13
AV, aortic valve; AVA, aortic valve area; BMI, body mass index; LVEF, left ventricular ejection fraction.
Comparison between patients included in the study and patients not included.

Table 2 Patient’s baseline characteristics at enrolment

All ATTR-CA No ATTR-CA

n = 88 n = 11 n = 77 P value
Clinical parameters
Gender—men N (%) 39(44.3) 7 (64) 32 (41.6) 0.2
Age, year 81 ± 6.4 81.7 ± 7.86 80.9 ± 6.2 0.70
NYHA classification N (%) 0.022
1 34(39) 1(9) 33 (43)
2 41(46) 6(55) 35(45)
3 12(14) 3(27.) 9(12)
4 1 (1.) 1(9) 0
Hypertension (%) 94% 100% 93.5% 0.98
Diabetes mellitus (%) 43.% 54.5% 41.5% 0.52
Dyslipidaemia (%) 92% 90% 92% 0.98
Smoking (%) 31% 20% 33% 0.8
Atrial fibrillation (%) 30% 45% 27% 0.29
Coronary artery disease (%) 60% 82% 57% 0.19
Laboratory results
Haemoglobin (g/dL) 12.18 ± 1.32 11.5 ± 1.9 12.3 ± 1.3 0.08
Haematocrit (vol %) 38.6 ± 4 36.1 ± 4,1 38.95 ± 3.9 0.034
WBC (K/μL) 7.98 ± 1.9 7.1 ± 1.7 8.1 ± 1.8 0.12
Platelets (K/μL) 215 ± 68 210 ± 51 216 ± 70 0.79
Urea (mg/dL) 55.2 ± 23.9 63.8 ± 25 54 ± 24 0.23
Creatinine (mg/dL) 1.1 ± 0.4 1.4 ± 0.6 1.07 ± 0.39 0.056
Troponin I (pg/mL) 13.86 ± 16.9 43.5 ± 9 12.3 ± 14 0.009
NT-pro-BNP (pg/mL) 1511 ± 3056 3963 ± 8411 1259 ± 1814 0.4
Nutritional parameters
2
BMI kg/m 28.63 + 5 28.39 ± 6.3 28.7 ± 4.8 0.87
Albumin (g/dL) 4.01 ± 0.27 3.95 ± 0.22 4.07 ± 0.27 0.17
ALT—GPT (U/L) 18 + 10.1 15.2 ± 7 18.40 + 10 0.35
ALT-GPT, alanine transaminase; BMI, body mass index; NT-pro-BNP, N-terminal pro b-type natriuretic peptide; NYHA, New York Heart As-
sociation; WBC, white blood cells.

diac amyloidosis. The groups had similar LV diastolic diameter for higher PAP in the ATTR cardiac amyloidosis group before
and LVEF. Patients having later a positive scan had a higher intervention. The GLS did not differ between the groups be-
LV mass and LV mass index (252 ± 72 g vs 211 ± 55 g, fore intervention. The basal segments strain was, however,
P = 0.036 and 140 ± 34 g/m2 vs. 119 ± 31 g/m2, P = 0.06, re- lower in patients diagnosed later with ATTR cardiac amyloid-
spectively). There was a trend, but not statistically significant, osis and the apical to basal strain ratio was higher

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4554 S. Shimoni et al.

99m
Figure 2 An example for a patients with a negative (A) and positive (B) Tc-PYP scan for amyloid transthyretin (ATTR) cardiac amyloidosis.

Figure 3 A functional [New York Heart Association (NYHA) class] status at study enrolment and before TVR in patients with and without amyloid
transthyretin (ATTR) cardiac amyloidosis. (B) ROC curves and cut-offs for ATTR cardiac amyloidosis diagnosis by echo parameters (septal and posterior
wall thickness, pulmonary artery pressure and basal segmental LV strain). (C) An example of Bull’s eyes analysis of global strain and myocardial work in
a patient with ATTR cardiac amyloidosis.

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ATTR cardiac amyloidosis in post-TAVR patients 4555

(
12.8 ± 2% vs.
14.7% ± 4.2, P = 0.037, and 1.67 ±
0.2 vs. osis had significantly higher PAP (47.5 ± 4.5mmHG vs.
1.48 ± 0.29, P = 0.051, respectively). No significant differences 38 ± 16mmHG, P = 0.002). GLS was significantly lower in pa-
were observed between the groups in the indices of MW be- tients with ATTR cardiac amyloidosis with higher apical/basal
fore TAVR, however the ratio of apical segments to basal seg- segments strain ratio (
15.9 ± 3% vs.
18.77 ± 5%, P = 0.031,
ments GW was significantly higher in patients diagnosed later 1.62 ± 0.28 vs. 1.42 ± 0.26, P = 0.04, respectively). ROC curves
with ATTR cardiac amyloidosis (1.86 ± 0.2 vs. 1.48 ± 0.5, in Figure 3B show echocardiographic parameters that are sig-
P = 0.001). nificantly related to the presence of ATTR cardiac amyloidosis
and may be ‘red flags’ for ATTR cardiac amyloidosis in pa-
tients after TAVR. Septal and posterior wall thickness, ele-
Echocardiography at enrolment vated PAP and basal segmental strain had a significant area
under the curve, with no significant difference among them
Echocardiographic data of the patients that were performed (P = 0.21). Basal segmental strain of ≥
15.2%, for example,
at enrolment are seen in Table 3. There were no differences showed sensitivity of 80% and specificity of 61% to identify
in LV size and LVEF between patients with and without ATTR ATTR cardiac amyloidosis (Figure 3B). MW index and global
cardiac amyloidosis. The AV pressure gradient was also constructive work were lower in patients with ATTR cardiac
similar. The LV mass and the septal and posterior wall thick- amyloidosis; however the difference was no statistically sig-
ness were significantly higher in patients with ATTR cardiac nificant. The ratio of apical to basal segments MW was higher
amyloidosis, (137 ± 35 g/m2 vs. 113 ± 32 g/m2, P = 0.046, in patients with ATTR cardiac amyloidosis (1.91 ± 0.5 vs.
for LVMi). The MV deceleration time was shorter in patients 1.58 ± 0.26, P = 0.044). MWE was significantly lower in
with ATTR cardiac amyloidosis (214.1 ± 59 ms vs. patients with ATTR cardiac amyloidosis compared with
261.8 ± 71 ms, P = 0.04). Patients with ATTR cardiac amyloid- patients without ATTR cardiac amyloidosis (0.9 ± 0.09% vs.

Table 3 Echocardiographic parameters before TAVR and at study enrolment (12–24 months)

Before intervention-(TAVR) At enrolment (1–2 years after intervention)

Positive scan Negative scan Positive scan Negative scan
for TTR for TTR P value for TTR for TTR P value
Aortic valve peak gradient (mmHg) 71.50 ± 15.69 76 ± 21 0.42 21.6 ± 16* 20.2 ± 11* 0.73
Aortic valve mean gradient (mmHg) 44.83 ± 8.40 46 ± 16 0.71
2)
Aortic valve area (cm 0.72 ± 0.06 0.7 ± 0.16 0.8
LVEDd (mm) 47 ± 4.47 45 ± 5.5 0.30 45.1 ± 6 44.7 ± 6.5 0.96
Interventricular septal wall thickness (mm) 14.00 ± 1.9 13.0 ± 2.1 0.16 14.33 ± 1.3 12.7 ± 1.7 0.01
Posterior wall thickness (mm) 12.70 ± 1.49 11.8 ± 1.7 0.12 14 ± 2.3 11.3 ± 1.6 0.04
LVM (g) 252 ± 72 211 ± 55 0.036 247 ± 70 201 ± 61* 0.042
LVMi (g/m2) 140 ± 34 119 ± 31 0.06 137 ± 35 113 ± 32* 0.046
LVEF % 54.5 ± 6 53.6 ± 10 0.78 52.8 ± 6.6 53.8 ± 6.6 0.69
SVi (mL/beat/m2) 39.7 ± 7 42.2 ± 12 0.81
Pulmonary artery systolic pressure (mmHg) 45.7 ± 15 38.9 ± 13 0.13 47.5 ± 4.5 38 ± 16 0.002
Aortic regurgitation grade (%) 0.94 0.96
no or mild 82 81 88 87
moderate or severe 18 19 12 13
Mitral E wave (cm/s) 1.11 ± 0.4 0.99 ± 0.4 0.38 1.14 ± 0.36 1.04 ± 0.34 0.41
Deceleration time (ms) 197 ± 77 261 ± 102 0.09 214.1 ± 59 261.8 ± 71 0.041
Mitral A wave (cm/s) 0.86 ± 0.22 1.01 ± 0.4 0.68 0.65 ± 0.36 0.89 ± 46 0.128
e0 (cm/s) 0.072 ± 0.02 0.057 ± 0.03 0.07 0.067 ± 0.019 0.058 ± 0.02 0.2
a0 (cm/s) 0.087 ± 0.026 0.093 ± 0.026 0.17 0.065 ± 0.023 0.081 ± 0.035 0.18
s0 (cm/s) 0.06 ± 0.016 0.062 ± 0.02 0.83 0.063 ± 0.014 0.07 ± 0.02 0.41
GLS (%)
16.2 ± 2.9
17.1 ± 5.2 0.46
15.9 ± 3
18.77 ± 5 0.031
Basal strain (%)
12.8 ± 2
14.7 ± 4.2 0.037
13.6 ± 3
16.4 ± 3.6* 0.03
Mid strain (%)
15.8 ± 2.5
17 ± 5 0.25
16.77 ± 3.4
18.9 ± 4.5 0.172
Apical strain (%)
21.8 ± 3.8
21.6 ± 6.9 0.93
21.6 ± 4.7
23.5 ± 6.9 0.426


Apical/basal strain ratio 1.67 ± 0.2 1.48 ± 0.29 0.051 1.62 ± 0.28 1.42 ± 0.26 0.04
Apical/mid + basal strain ratio 0.75 ± 0.07 0.68 ± 0.1 0.044 0.71 ± 0.09 0.66 ± 0.09 0.087
LVMWI (mmHG%) 2,120 ± 534 2,231 ± 919 0.74 1904 ± 889 2,245 ± 697 0.25
LVGCW (mmHG%) 2,349 ± 446 2,553 ± 993 0.55 2,177 ± 787 2,253 ± 754 0.24
LVMWE (%) 0.94 ± 0.028 0.92 ± 0.07 0.26 0.9 ± 0.09 0.94 ± 0.03 0.048
LVGWW (mmHG%) 103 ± 59 193 ± 72 0.36 225 ± 88 123 ± 77 0.053
Apical/basal GWI ratio 1.86 ± 0.2 1.48 ± 0.5 0.001 1.91 ± 0.5 1.58 ± 0.26 0.044
GLS, global longitudinal strain; LVEDd, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; LVM, left ventricular
mass; LVMi, left ventricular mass index; LVMWI-left ventricular myocardial work index, LVGCW-LV global constructive work; LVGWW-LV
global wasted work; LVMWE-LV myocardial wasted work; TAVR, trans-catheter aortic valve replacement.
*
P < 0.05 difference between enrolment and before TAVR.

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4556 S. Shimoni et al.

0.94 ± 0.03%, P = 0.048). It should be noticed that these Hospitalization due to cardiac causes and heart
patients had also a higher rate of conduction abnormalities. failure from trans-catheter aortic valve
An example showing GLS and MW analysis in a patient with replacement to enrolment
ATTR cardiac amyloidosis is shown in Figure 3C.
We assessed changes in echocardiographic data, from the We studied retrospectively cardiac hospitalization rate during
time of TAVR to enrolment, and as expected there was a sig- 24 months after TAVR. There were no significant difference in
nificant decrease in AV gradient in both groups. There was procedure related hospitalizations in both groups (P = 0.7).
also a significant reduction in LV mass and LV mass index There were total 37 cardiac hospitalizations, of which 13
and improvement in basal segment LV strain in the ATTR car- were in ATTR cardiac amyloidosis patients. Twenty two of
diac amyloidosis negative group (P = 0.045, P = 0.046 and the hospitalizations were due to HF, 11 of which were in
0.023, respectively). However, in the ATTR cardiac amyloid- the ATTR cardiac amyloidosis group. As seen in Figure 4A,B,
osis group the changes in LV mass and LV mass index and ATTR cardiac amyloidosis is significantly related to cardiac
LV basal strain values were not significant (P = 0.24, hospitalizations and HF hospitalizations (P = 0.002, and
P = 0.13 and 0.35, respectively). The were no significant P = 0.001, respectively). Patients with ATTR cardiac amyloid-
changes in other echocardiographic parameters in both osis had 5.1 times more cardiac hospitalizations and 4.8 times
groups. more HF hospitalizations than the ATTR cardiac amyloidosis

Figure 4 (A) Rate of cardiac hospitalizations in patients with and without amyloid transthyretin (ATTR) cardiac amyloidosis. (B) Rate of heart failure
hospitalizations in patients with and without ATTR cardiac amyloidosis. (C) Conduction abnormalities in patients with and without ATTR cardiac am-
yloidosis. (D) Kaplan–Meier plot of cardiac death in patients with and without ATTR cardiac amyloidosis. (E) Kaplan–Meier plot of combined cardiac
hospitalizations and cardiac death in patients with and without ATTR cardiac amyloidosis.

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DOI: 10.1002/ehf2.13667
ATTR cardiac amyloidosis in post-TAVR patients 4557

negative group. We also assessed other factors that are yloidosis 1 to 2 years [534 (390–711) days] after TAVR. We
related to cardiac hospitalizations and found that patients assessed retrospectively the clinical and echocardiographic
age, presence of diabetes mellitus, atrial fibrillation and finding during the time period from TAVR to the diagnostic
CAD were related to cardiac hospitalization (all P < 0.05), In PYP scan at enrolment and prospectively after the enrolment.
addition PAP, LVEF and GLS were related to cardiac The study main findings are (i) ATTR cardiac amyloidosis was
hospitalization. After correcting for other confounders, ATTR seen in 12.5% of this patients group; (ii) GLS and MWE were
cardiac amyloidosis remained significantly related to cardiac lower and LV mass higher in patients with ATTR cardiac amy-
hospitalization (P = 0.024). Other independent factors were loidosis compared patients with no ATTR cardiac amyloidosis.
LVEF and GLS before TAVR (P = 0.023 and P = 0.009, (iii) The functional status of patients diagnosed with ATTR
respectively). cardiac amyloidosis was lower compared with those without
In addition to hospitalization, conduction disorders (need ATTR cardiac amyloidosis with significantly higher rate of car-
for permanent pacemaker or new and persistent LBBB) were diac hospitalizations; (iv) however, there was no difference in
found in 39% of all patients at enrolment. Eight patients all-cause or cardiac mortality between patients with and
(73%) with ATTR cardiac amyloidosis had conduction without ATTR cardiac amyloidosis during follow up.
abnormalities within a month after TAVR compared with 23 Various clinical and echocardiographic ‘red flags’ were sug-
(30%) patients in the control group (P = 0.014, Figure 4C). gested to identify the presence of amyloidosis in patients
Four additional patients underwent pacemaker implantation with AS.24,25 The studies usually looked on patients with AS
from the time of TAVR to enrolment; all were negative for before intervention-with dual pathology. None of the studies
ATTR cardiac amyloidosis. So at enrolment, 73% of ATTR looked on patient’s functional class a year or more after
cardiac amyloidosis patients and 35% of ATTR cardiac amy- TAVR, when the valvular pathology was treated, and there
loidosis negative patients had conduction abnormalities are no data on the clinical course and echocardiographic find-
(P = 0.023). ings of these patients. Our study is the first, to our knowl-
edge, that compared the functional class of patients with
and without ATTR cardiac amyloidosis after TAVR. Thirty
Prospective clinical follow up after enrolment seven per cent of patients with ATTR cardiac amyloidosis
were in NYHA functional Class 3 or 4 a year after TAVR, and
The median follow up after enrolment was 1,150 there was no significant improvement in NYHA class in these
(1,086–1,221) days. Twenty seven patients had at least one patients after TAVR. So it appears that these patients are clin-
cardiac hospitalization during follow up, of them 7 were with ically ‘poor responders’.
ATTR cardiac amyloidosis and 20 patients were ATTR cardiac In addition, these patients showed persistent LV remodel-
amyloidosis negative (P = 0.017). Eighteen patients (20%) ling. There were differences between the groups in systolic
died during follow up, 12 (14%) patients died due to cardiac function as shown by GLS and basal segmental LS and in
causes, mainly congestive HF, arrhythmia and endocarditis. diastolic function as shown by shorter mitral E wave deceler-
There was no difference in all-cause mortality and cardiac ation time and higher PAP. In addition, the MWE was lower in
mortality between patients ATTR cardiac amyloidosis positive patients with ATTR-CA, in line with a recent report on pa-
and negative (P = 0.6 and P = 0.53, respectively, Figure 4D). As tients with cardiac amyloidosis without AS.26 An index of
seen in Table 4, the independent predictors for all-cause basal segmental strain could identify ATTR cardiac amyloid-
mortality were age and GLS [1.213 95% confidence interval osis in this population with a fair accuracy. Septal and
(CI) 1.065–1.382, P = 0.004, and 1.128 95% CI 1.004–1.267, posterior wall thickness and elevated PAP are other echocar-
P = 0.043] and for cardiac mortality the predictor was GLS diographic signs to suspect ATTR-CA.
(1.532 95% CI 1.105–2.125, P = 0.011). Using a composite The echocardiographic findings together with the lower
endpoint of cardiac hospitalization or cardiac death, patients haematocrit levels and higher creatinine in patients with
with ATTR cardiac amyloidosis had significantly more events ATTR cardiac amyloidosis are associated with the lower func-
(P = 0.04, Figure 4C). The other factors related to combined tional class of these patients.
endpoint were NYHA class and LVEF. However, only NYHA Wild-type ATTR affects almost exclusively the heart and is
class was found to be an independent factor for cardiac frequently associated with AS. In retrospective case series
hospitalization and death (1.807 95% CI 1.130–2.889, and studies, the mortality of patients with AS and ATTR car-
P = 0.015). diac amyloidosis was high.9,14,27,28 Chacko et al. assessed
echocardiographic parameters in patients with ATTR cardiac
amyloidosis and found that the presence of severe AS was
Discussion independently associated with significantly reduced
patient survival, that was significantly worse if treated
In this study, we evaluated the clinical and echocardiographic conservatively.29 A review of several studies, support the
findings of patients’ diagnosed positive for ATTR cardiac am- finding of higher risk of mortality in patients with AS and

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DOI: 10.1002/ehf2.13667
 Table 4 Clinical and echocardiographic predictors of all-cause mortality, cardiac mortality, cardiac hospitalizations and hospitalization or cardiac mortality
4558

Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis

All-cause
mortality P HR (95%CI) P HR (95%CI) Cardiac mortality P HR (95%CI) P HR (95%CI)
Age 0.006 1.143 (1.039–1.257) 0.004 1.213 (1.065–1.382) Age 0.027 1.142 (1.106–1.285) 0.056
Gender 0.171 Gender 0.298
Hypertension 0.896 Hypertension 0.786
Diabetes mellitus 0.439 Diabetes mellitus 0.876
Atrial fibrillation 0.786 Atrial fibrillation 0.343
Coronary artery 0.546 Coronary artery disease 0.509
disease
NYHA 0.086 1.676 (0.930–3.021) NYHA 0.106
ATTR–cardiac 0.6 ATTR-CA 0.763
amyloidosi
Haemoglobin 0.225 Haemoglobin 0.062 0.661 (0.428–1.022)
Creatinine 0.82 Creatinine 0.114
LVEF 0.826 LVEF 0.15
Pulmonary artery 0.006 1.987 (1.214–3.251) 0.643 Pulmonary artery 0.029 1.973 (1.071–3.635) 0.309
pressure pressure
LV mass 0.295 LV mass 0.737
GLS 0.036 1.130 (1.008–1.127) 0.043 1.128 (1.004–1.267) GLS 0.011 1.532 (1.010–2.125) 0.024 1.579 (1.061–2.351)
RV strain 0.139 RV strain 0.098 0.901 (0.797–1.019)

Hospitalization or
Hospitalizations P HR (95%CI) P HR (95%CI) cardiac death P HR (95%CI) P HR (95%CI)
Age 0.702 Age 0.186
Gender 0.907 Gender 0.627
Hypertension 0.663 Hypertension 0.465
Diabetes mellitus 0.045 2.335 (1.018–5.356) 0.067 Diabetes mellitus 0.092 1.865 (0.902–3.855)
Atrial fibrillation 0.127 Atrial fibrillation 0.066 1.962 (0.936–4.027)
Coronary artery 0.269 Coronary artery disease 0.127
disease
NYHA 0.04 2.536 (1.041–6.179) 0.04 2.536 (1.041–6.179) NYHA 0.013 2.738 (1.241–6.043) 0.015 1.807 (1.130–2.889)
ATTR-CA 0.048 2.566 (1.009–6.524) 0.149 ATTR-CA 0.041 2.367 (1.007–5.163) 0.179
Haemoglobin 0.448 Haemoglobin 0.289
Creatinine 0.110 Creatinine 0.078 1.790 (0.936–3.423)
LVEF 0.119 LVEF 0.035 0.948 (0.901–0.996) 0.079
Pulmonary artery 0.352 Pulmonary artery 0.132
pressure pressure
LV mass 0.426 LV mass 0.193
GLS 0.572 GLS 0.297
RV strain 0.447 RV strain 0.111

GLS, global longitudinal strain; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; RV, right ventricle.

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S. Shimoni et al.
ATTR cardiac amyloidosis in post-TAVR patients 4559

ATTR-CA.30 Recently, studies with quit similar design showed abnormalities in patients with ATTR amyloidosis.1,35 Castano
prospectively that in patients with ATTR cardiac amyloidosis et al. suggested that the correlation between late gadolinium
and AS, that undergo AVR, the presence of ATTR cardiac am- enhancement on CMR and conduction abnormalities in pa-
yloidosis, does not affect survival or combined endpoint of tients with AS undergoing TAVR, can be explained by occult
survival and time to first HF hospitalization, in up to 2 years amyloidosis.36 Later, they and others showed higher inci-
follow up.15–17,24 Our study is in line with these studies and dence of right bundle branch block in patients with AS and
extends the prospective follow in additional 3 years, showing ATTR cardiac amyloidosis but no significant difference in the
no difference in mortality over late follow up. However, there need for permanent pacemaker after TAVR.10,16 We looked
was a higher rate of cardiac and HF hospitalizations in pa- on combined endpoint of pacemaker and new LBBB. LBBB
tients with ATTR cardiac amyloidosis, similarly to the findings was reported more frequently with wild-type ATTR cardiac
of Rosenblum et al. The cardiac death was relatively low, amyloidosis.1 The effect of AV intervention on a compro-
especially compared with hospitalizations number and this mised conduction system due to infiltration explains the
can explain the significant difference in combined endpoint higher rate of conduction abnormalities.
result between patients with and without ATTR cardiac
amyloidosis, although, the independent predictor for the
combined endpoint was NYHA functional class. Limitations
Cardiac amyloidosis is a chronic disease. Itzhaki Ben Zudok
et al. showed that increased wall thickness and diastolic dys- The main limitation of this research is the relative small study
function develop in cardiac amyloidosis over a time course of cohort and enrolling only patients in relatively good func-
several years.31 In AS patients, however, the echocardio- tional and cognitive status. We do not know the rates of
graphic findings can be similar. Since the diagnosis of ATTR cardial amyloidosis in patients who died before the study pe-
cardiac amyloidosis was performed at enrolment, we cannot riod or who were not enrolled. Although the baseline,
know whether the patients were positive for ATTR cardiac pre-TAVR data, in these patients does not differ significantly,
amyloidosis before TAVR, but we assume that these subjects the renal function in this population is impaired. In addition,
had a milder form of the disease at the time of TAVR. Before the cognitive status of the patients before and after TAVR is
TAVR, patients had higher LV mass and lower basal segmental not known. Because 32% of patients died within 2 years after
LS. The apical to basal segments GLS and MW ratio was TAVR, we cannot extrapolate from the population included to
higher in these patients. The findings of relative low MW in the population that could not be included. In addition, the
basal segments compared with apical segments, in cardiac survival analysis is limited and underpowered due to the
amyloidosis was recently reported by Clemmensen et al.26 small cohort. So although the results go along with other
Relative apical sparing is specific for cardiac amyloidosis.32 studies, they should be interpreted with caution. Another
In patients with AS and ATTR cardiac amyloidosis, this find- limitation is the retrospective analysis of the clinical and
ings are less specific, because AS also reduces basal strain.22 echocardiographic data before TAVR. However, all the pa-
In patients with AS, apical sparing is related to worse progno- tients are part of the TAVR registry in our institution and all
sis and this may be due to undiagnosed amyloidosis.33 So, al- the patients underwent a complete echocardiographic study
though the relative apical sparing is less pronounced in AS before the procedure. The forth limitation is that we did
and ATTR cardiac amyloidosis patients and may not reach not perform genetic testing since it is an elderly population
the cut-offs suggested for the diagnosis of cardiac amyloid- and most probably have wild type ATTR. Another limitation
osis without AS, it should rise a clinical suspicion on the pres- is the assessment of MW analysis from pressure strain loops
ence of ATTR cardiac amyloidosis in patents with AS before by echocardiography using echo-PAC software. We added
AVR and also after the AV underwent treatment. mean aortic pressure gradient to systolic blood pressure for
Patients with cardiac amyloidosis can present with pressure analysis, however the software is not validated in
different degrees of involvement of amyloid infiltration, which these patients, so the pre TAVR data should be taken with
might significantly alter the prognosis. ATTR cardiac amyloid- caution. The MW index is relatively high compared with pre-
osis may be a disease modifier in patients with AS and vice vious reports,23 however a high proportion of patients were
versa.9,34 Recently, Scully et al. suggested that AS primes the with hypertension and the numbers are quint similar to the
myocardium for amyloid deposition and that TAVR may be preliminary reports on patients before and after TAVR.37
beneficial in these patients.16 Our findings show that in ATTR
cardiac amyloidosis patients diagnosed after TAVR there was
a progression in LV thickness and reduction in LV longitudinal Conclusions
function compared with pre-TAVR study.
Another finding of the study is higher incidence of Our study adds information on late clinical and echocardio-
conduction abnormalities in ATTR cardiac amyloidosis pa- graphic follow up of a subgroup of patients with ATTR cardiac
tients. Previous studies showed more frequent conduction amyloidosis that underwent TAVR. The long-term survival is

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DOI: 10.1002/ehf2.13667
4560 S. Shimoni et al.

not significantly affected by the presence of ATTR cardiac in patients who underwent TAVR and have limited clinical or
amyloidosis, further supporting the need for intervention in echocardiographic improvement, screening for ATTR cardiac
these patients. However, these patients showed a less amyloidosis should be considered. Future studies are
favourable clinical course with poorer functional status and warranted to explore the potential role and the benefit of
higher rate of hospitalization as compared with patients new and novel cardiac amyloidosis therapies (e.g. tafamidis)
without ATTR cardiac amyloidosis. The systolic and diastolic in post-TAVR patients with ATTR cardiac amyloidosis, in
function indices as well as MW efficiency are lower in pa- improving NYHA class and reducing recurrent cardiac
tients with ATTR cardiac amyloidosis. Our results suggest that hospitalizations.

Referencesok
1. Ruberg FL, Berk JL. Transthyretin (TTR) inflammation, myocardial fibrosis and D, Georgiou GM, Linhartova K, Ihlemann
cardiac amyloidosis. Circulation 2012; cardiac remodelling in patients with mild N, Abdelhamid M, Pern T, Turpeinen A,
126: 1286–1300. aortic stenosis as assessed by biomarkers Srbinovska-Kostovska E, Cohen A,
2. Gertz MA, Benson MD, Dyck PJ, Grogan and echocardiography. Clin Exp Bakhutashvili Z, Ince H, Vavuranakis M,
M, Coelho T, Cruz M, Berk JL, Plante- Pharmacol Physiol. 2014; 41: 185–191. Temesvári A, Gudnason T, Mylotte D,
Bordeneuve V, Schmidt HHJ, Merlini G. 9. Treibel TA, Fontana M, Gilbertson JA, Kuperstein R, Indolfi C, Pya Y, Bajraktari
Diagnosis, prognosis, and therapy of Castelletti S, White SK, Scully PR, G, Kerimkulova A, Rudzitis A, Mizariene
transthyretin amyloidosis. J Am Coll Roberts N, Hutt DF, Rowczenio DM, V, Lebrun F, Demarco DC, Oukerraj L,
Cardiol 2015; 66: 2451–2466. Whelan CJ, Ashworth MA, Gillmore JD, Bouma BJ, Steigen TK, Komar M, de
3. Gillmore JD, Maurer MS, Falk RH, Hawkins PN, Moon JC. Occult Moura Branco LM, Popescu BA,
Merlini G, Damy T, Dispenzieri A, transthyretin cardiac amyloid in severe Uspenskiy V, Foscoli M, Jovovic L,
Wechalekar AD, Berk JL, Quarta CC, calcific aortic stenosis: prevalence and Simkova I, Bunc M, de Prada JAV,
Grogan M, Lachmann HJ, Bokhari S, prognosis in patients undergoing surgi- Stagmo M, Kaufmann BA, Mahdhaoui
Castano A, Dorbala S, Johnson GB, cal aortic valve replacement. Circ A, Bozkurt E, Nesukay E, Brecker SJD.
Glaudemans AWJM, Rezk T, Fontana Cardiovasc Imaging 2016; 9: e005066. 2017 ESC/EACTS guidelines for the
M, Palladini G, Milani P, Guidalotti PL, 10. Castano A, Narotsky DL, Hamid N, management of valvular heart disease.
Flatman K, Lane T, Vonberg FW, Whelan Khalique OK, Morgenstern R, DeLuca Eur Heart J 2017; 38: 2739–2791.
CJ, Moon JC, Ruberg FL, Miller EJ, Hutt A, Castaño A, Narotsky DL, Hamid N, 12. Monticelli FC, Kunz SN, Keller T,
DF, Hazenberg BP, Rapezzi C, Hawkins Khalique OK, Morgenstern R, DeLuca Bleiziffer S. Cardiac amyloidosis as a
PN. Nonbiopsy diagnosis of cardiac A, Rubin J, Chiuzan C, Nazif T, Vahl T, potential risk factor for transapical
transthyretin amyloidosis. Circulation George I, Kodali S, Leon MB, Hahn R, transcatheter aortic valve implantation.
2016; 133: 2404–2412. Bokhari S, Maurer MS. Unveiling J Card Surg 2014; 29: 623–624.
4. Tanskanen M, Peuralinna T, Polvikoski transthyretin cardiac amyloidosis and 13. Nietlispach F, Webb JG, Ye J, Cheung A,
T, Notkola IL, Sulkava R, Hardy J, its predictors among elderly patients Lichtenstein SV, Carere RG, Gurvitch R,
Singleton A, Kiuru-Enari S, Paetau A, with severe aortic stenosis undergoing Thompson CR, Ostry AJ, Matzke L,
Tienari PJ, Myllykangas L. Senile sys- transcatheter aortic valve replacement. Allard MF. Pathology of transcatheter
temic amyloidosis affects 25% of the Eur Heart J 2017; 38: 2879–2887. valve therapy. JACC Cardiovasc Interv
very aged and associates with genetic 11. Baumgartner H, Falk V, Bax JJ, De Bonis 2012; 5: 582–590.
variation in alpha2-macroglobulin and M, Hamm C, Holm PJ, de Bonis M, 14. Sperry BW, Jones BM, Vranian MN,
tau: a population-based autopsy study. Hamm C, Holm PJ, Iung B, Lancellotti P, Hanna M, Jaber WA. Recognizing
Ann Med 2008; 40: 232–239. Lansac E, Rodriguez Muñoz D, Rosenhek transthyretin cardiac amyloidosis in pa-
5. Gonzalez-Lopez E, Gallego-Delgado M, R, Sjögren J, Tornos Mas P, Vahanian A, tients with aortic stenosis: impact on
Guzzo-Merello G, de Haro-Del Moral FJ, Walther T, Wendler O, Windecker S, prognosis. J Am Coll Cardiol Img 2016;
Cobo-Marcos M, Robles C, Bornstein B, Zamorano JL, ESC Scientific Document 9: 904–906.
Salas C, Lara-Pezzi E, Alonso-Pulpon L, Group, Roffi M, Alfieri O, Agewall S, 15. Nitsche C, Aschauer S, Kammerlander
Garcia-Pavia P. Wild-type transthyretin Ahlsson A, Barbato E, Bueno H, Collet AA, Schneider M, Poschner T, Duca F,
amyloidosis as a cause of heart failure JP, Coman IM, Czerny M, Delgado V, Binder C, Koschutnik M, Stiftinger J,
with preserved ejection fraction. Eur Fitzsimons D, Folliguet T, Gaemperli O, Goliasch G, Siller-Matula J, Winter MP,
Heart J. 2015; 36: 2585–2594. Habib G, Harringer W, Haude M, Anvari-Pirsch A, Andreas M, Geppert A,
6. Zhao L, Buxbaum JN, Reixach N. Hindricks G, Katus HA, Knuuti J, Kolh P, Beitzke D, Loewe C, Hacker M, Agis H,
Age-related oxidative modifications of Leclercq C, McDonagh TA, Piepoli MF, Kain R, Lang I, Bonderman D,
transthyretin modulate its amyloido- Pierard LA, Ponikowski P, Rosano GMC, Hengstenberg C, Mascherbauer J. Light-
genicity. Biochemistry 2013; 52: Ruschitzka F, Shlyakhto E, Simpson IA, chain and transthyretin cardiac amyloid-
1913–1926. Sousa-Uva M, Stepinska J, Tarantini G, osis in severe aortic stenosis: prevalence,
7. George J, Rappaport M, Shimoni S, Tchétché D, Aboyans V, Windecker S, screening possibilities, and outcome. Eur
Goland S, Voldarsky I, Fabricant Y, Edri Aboyans V, Agewall S, Barbato E, Bueno J Heart Fail 2020; 22: 1852–1862.
O, Cuciuc V, Lifshitz S, Tshori S, Fassler H, Coca A, Collet JP, Coman IM, Dean 16. Scully PR, Patel KP, Treibel TA,
M. A novel monoclonal antibody V, Delgado V, Fitzsimons D, Gaemperli Thornton GD, Hughes RK, Chadalavada
targeting aggregated transthyretin facili- O, Hindricks G, Iung B, Jüni P, Katus S, Katsoulis M, Hartman N, Fontana M,
tates its removal and functional recovery HA, Knuuti J, Lancellotti P, Leclercq C, Pugliese F, Sabharwal N, Newton JD,
in an experimental model. Eur Heart J McDonagh T, Piepoli MF, Ponikowski P, Kelion A, Ozkor M, Kennon S, Mullen
2020; 41: 1260–1270. Richter DJ, Roffi M, Shlyakhto E, M, Lloyd G, Menezes LJ, Hawkins PN,
8. Park JY, Ryu SK, Choi JW, Ho KM, Jun Simpson IA, Zamorano JL, Kzhdryan Moon JC. Prevalence and outcome of
JH, Rha SW, Park SM, Kim HJ, Choi BG, HK, Mascherbauer J, Samadov F, dual aortic stenosis and cardiac amyloid
Noh YK, Kim S. Association of Shumavets V, Camp GV, Lončar D, Lovric pathology in patients referred for trans-

ESC Heart Failure 2021; 8: 4549–4561

DOI: 10.1002/ehf2.13667
ATTR cardiac amyloidosis in post-TAVR patients 4561

catheter aortic valve implantation. Eur Barone D, Baroni M, Cardim N, transthyretin cardiac amyloidosis. Eur
Heart J 2020; 41: 2759–2767. Hagendorff A, Hristova K, Lopez T, de Heart J 2020; 41: 1439–1447.
17. Rosenblum H, Masri A, Narotsky DL, la Morena G, Popescu BA, Penicka M, 30. Ricci F, Ceriello L, Khanji MY, Dangas G,
Goldsmith J, Hamid N, Hahn RT, Kodali Ozyigit T, Rodrigo Carbonero JD, van Bucciarelli-Ducci C, Di Mauro M, di
S, Vahl T, Nazif T, Khalique OK, Bokhari de Veire N, von Bardeleben RS, Mauro M, Fedorowski A, Zimarino M,
S, Soman P, Cavalcante JL, Maurer MS, Vinereanu D, Zamorano JL, Rosca M, Gallina S. Prognostic significance of car-
Castaño A. Unveiling outcomes in Calin A, Moonen M, Magne J, Cosyns B, diac amyloidosis in patients with aortic
coexisting severe aortic stenosis and Galli E, Donal E, Carerj S, Zito C, Santoro stenosis: a systematic review and meta-
transthyretin cardiac amyloidosis. Eur J C, Galderisi M, Badano LP, Lang RM, analysis. J Am Coll Cardiol Img 2021;
Heart Fail 2020; 23: 250–258. Lancellotti P. Correlation between 14: 293–295.
18. Harbaoui B, Durand E, Dupre M, non-invasive myocardial work indices 31. Itzhaki Ben Zadok O, Eisen A, Shapira Y,
Rabilloud M, Souteyrand G, Courand and main parameters of systolic and dia- Monakier D, Iakobishvili Z,
PY, Dupré M, Rabilloud M, Souteyrand stolic function: results from the EACVI Schwarzenberg S, Abelow A, Ofek H,
G, Courand PY, Boussel L, Lefevre T, NORRE study. Eur Heart J Cardiovasc Im- Kazum S, Ben-Avraham B, Hamdan A,
Eltchaninoff H, Lantelme P. Significance aging 2020; 21: 533–541. Bental T, Sagie A, Kornowski R, Vaturi
of the CAPRI risk score to predict heart 24. Nitsche C, Scully PR, Patel KP, M. Natural history and disease progres-
failure hospitalization post-TAVI: the CA- Kammerlander AA, Koschutnik M, Dona sion of early cardiac amyloidosis evalu-
PRI-HF study. Int J Cardiol 2019; 296: C, Wollenweber T, Ahmed N, Thornton ated by echocardiography. Am J Cardiol
98–102. GD, Kelion AD, Sabharwal N, Newton 2020; 133: 126–133.
19. Quinones MA, Otto CM, Stoddard M, JD, Ozkor M, Kennon S, Mullen M, 32. Phelan D, Collier P, Thavendiranathan P,
Waggoner A, Zoghbi WA, Doppler Quan- Lloyd G, Fontana M, Hawkins PN, Popovic ZB, Hanna M, Plana JC,
tification Task Force of the Nomencla- Pugliese F, Menezes LJ, Moon JC, Popović ZB, Hanna M, Plana JC,
ture and Standards Committee of the Mascherbauer J, Treibel TA. Prevalence Marwick TH, Thomas JD. Relative apical
American Society of Echocardiography. and outcomes of concomitant aortic ste- sparing of longitudinal strain using two-
Recommendations for quantification of nosis and cardiac amyloidosis. J Am Coll dimensional speckle-tracking echocardi-
Doppler echocardiography: a report Cardiol 2021; 77: 128–139. ography is both sensitive and specific for
from the Doppler Quantification Task 25. Ternacle J, Krapf L, Mohty D, Magne J, the diagnosis of cardiac amyloidosis.
Force of the Nomenclature and Stan- Nguyen A, Galat A, Gallet R, Teiger E, Heart 2012; 98: 1442–1448.
dards Committee of the American Soci- Côté N, Clavel MA, Tournoux F, Pibarot 33. Saito M, Imai M, Wake D, Higaki R,
ety of Echocardiography. J Am Soc P, Damy T. Aortic stenosis and cardiac Nakao Y, Morioka H, Sumimoto T, Inoue
Echocardiogr. 2002; 15: 167–184. amyloidosis: JACC review topic of the K. Prognostic assessment of relative api-
20. Lang RM, Badano LP, Mor-Avi V, Afilalo week. J Am Coll Cardiol 2019; 74: cal sparing pattern of longitudinal strain
J, Armstrong A, Ernande L, Flachskampf 2638–2651. for severe aortic valve stenosis. Int J
FA, Foster E, Goldstein SA, Kuznetsova 26. Clemmensen TS, Eiskjaer H, Mikkelsen Cardiol Heart Vasc 2020; 29: 100551.
T, Lancellotti P, Muraru D, Picard MH, F, Granstam SO, Flachskampf FA, 34. Koyama J. Prognostic significance of oc-
Rietzschel ER, Rudski L, Spencer KT, Sorensen J, Eiskjær H, Mikkelsen F, cult transthyretin cardiac amyloidosis
Tsang W, Voigt JU. Recommendations Granstam SO, Flachskampf FA, in patients with severe aortic stenosis
for cardiac chamber quantification by Sørensen J, Poulsen SH. Left ventricular undergoing surgical aortic valve replace-
echocardiography in adults: an update pressure-strain-derived myocardial work ment: an unrecognized disease modifier.
from the American Society of Echocardi- at rest and during exercise in patients Circ Cardiovasc Imaging 2016; 9:
ography and the european Association with cardiac amyloidosis. J Am Soc e005320.
of Cardiovascular Imaging. journal of Echocardiogr 2020; 33: 573–582. 35. Gonzalez-Lopez E, Gagliardi C,
the American Society of Echocardiogra- 27. Galat A, Guellich A, Bodez D, Slama M, Dominguez F, Quarta CC, de Haro-
phy: official publication of the american Dijos M, Zeitoun DM, Milleron O, Attias DelMoral FJ, Milandri A, Milandri A,
society of. Echocardiography 2015; 28: D, Dubois-Randé JL, Mohty D, Audureau Salas C, Cinelli M, Cobo-Marcos M,
1–39 e14. E, Teiger E, Rosso J, Monin JL, Damy T. Lorenzini M, Lara-Pezzi E, Foffi S,
21. Shimoni S, Gendelman G, Ayzenberg O, Aortic stenosis and transthyretin cardiac Alonso-Pulpon L, Rapezzi C, Garcia-Pa-
Smirin N, Lysyansky P, Edri O, Deutsch amyloidosis: the chicken or the egg? Eur via P. Clinical characteristics of
L, Caspi A, Friedman Z. Differential Heart J 2016; 37: 3525–3531. wild-type transthyretin cardiac amyloid-
effects of coronary artery stenosis on 28. Cavalcante JL, Rijal S, Abdelkarim I, osis: disproving myths. Eur Heart J
myocardial function: the value of myo- Althouse AD, Sharbaugh MS, Fridman 2017; 38: 1895–1904.
cardial strain analysis for the detection Y, Soman P, Forman DE, Schindler JT, 36. Castano A, Bokhari S, Maurer MS. Could
of coronary artery disease. J Am Soc Gleason TG, Lee JS, Schelbert EB. Car- late enhancement and need for perma-
Echocardiogr 2011; 24: 748–757. diac amyloidosis is prevalent in older nent pacemaker implantation in patients
22. Levy-Neuman S, Meledin V, Gandelman patients with aortic stenosis and carries undergoing TAVR be explained by undi-
G, Goland S, Zilberman L, Edri O, worse prognosis. J Cardiovasc Magn agnosed transthyretin cardiac amyloid-
Shneider N, Abaeh N, Bdolah-Abram T, Reson 2017; 19: 98. osis? J Am Coll Cardiol 2015; 65:
George J, Shimoni S. The association be- 29. Chacko L, Martone R, Bandera F, Lane T, 311–312.
tween longitudinal strain at rest and Martinez-Naharro A, Boldrini M, Rezk T, 37. Jasaityte R, Thiele A, Ernst LP,
stress and outcome in asymptomatic pa- Whelan C, Quarta C, Rowczenio D, Baldenhofer G, Spethmann M, Laule M,
tients with moderate and severe aortic Gilbertson JA, Wongwarawipat T, Dreger H, Stangl K, Knebel F. Myocardial
stenosis. J Am Soc Echocardiogr 2019; Lachmann H, Wechalekar A, work in patients with aortic stenosis be-
32: 722–729. Sachchithanantham S, Mahmood S, fore and short term after transcatheter
23. Manganaro R, Marchetta S, Dulgheru R, Marcucci R, Knight D, Hutt D, Moon J, aortic valve replacement. Eur Heart J
Sugimoto T, Tsugu T, Ilardi F, Cicenia M, Petrie A, Cappelli F, Guazzi M, Hawkins Cardiovasc Imaging 2020; 21:
Ancion A, Postolache A, Martinez C, PN, Gillmore JD, Fontana M. Echocar- ez319–ez958.
Kacharava G, Athanassopoulos GD, diographic phenotype and prognosis in

ESC Heart Failure 2021; 8: 4549–4561

DOI: 10.1002/ehf2.13667