European Heart Journal Advance Access published February 22, 2016

European Heart Journal EHJ BRIEF COMMUNICATION

doi:10.1093/eurheartj/ehw033 Valvular heart disease

Aortic stenosis and transthyretin cardiac

amyloidosis: the chicken or the egg?
Arnault Galat1,2,3,4,5, Aziz Guellich 1,2,3,4,5, Diane Bodez 1,2,3,4,5, Michel Slama 6,
Marina Dijos 7, David Messika Zeitoun 8, Olivier Milleron8, David Attias 9,
Jean-Luc Dubois-Randé 1,2,3,4,5, Dania Mohty 10, Etienne Audureau 1,2,4,5,11,12,
Emmanuel Teiger 1,2,3,4,5, Jean Rosso 1,2,13, Jean-Luc Monin 1,2,3,4,5,
and Thibaud Damy 1,2,3,4,5*
1
UPEC, Créteil F-94000, France; 2MondorAmyloidosis Network, Créteil F-94000, France; 3Department of Cardiology, AP-HP, Henri-Mondor Teaching Hospital, Créteil F-94000,

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France; 4INSERM U955, Créteil F-94000, France; 5DHU A-TVB, Créteil F-94000, France; 6Department of Cardiology, AP-HP, Antoine Béclère Teaching Hospital, Clamart F-92140,
France; 7Department of Cardiology, Bordeaux Teaching Hospital, Pessac F-33604, France; 8Department of Cardiology, AP-HP, Bichat Teaching Hospital, Paris F-75018, France;
9
Department of Cardiology, Centre Cardiologique du Nord, Saint-Denis F-93200, France; 10Department of Cardiology, Dupuytren Teaching Hospital, Limoges F-87042, France;
11
Department of Public Health, Henri-Mondor Teaching Hospital, Créteil F-94000, France; 12CEpiA (Clinical Epidemiology and Ageing), EA4393, Université Paris Est (UPE),
UPEC, F-94000, Créteil, France; and 13Department of Nuclear Medicine, AP-HP, Henri-Mondor Teaching Hospital, Créteil F-94000, France

Received 8 July 2015; revised 18 November 2015; accepted 21 January 2016

Background Aortic stenosis (AS) and transthyretin cardiac amyloidosis (TTR-CA) are both frequent in elderly. The combination of
these two diseases has never been investigated.
.....................................................................................................................................................................................
Aims To describe patients with concomitant AS and TTR-CA.
.....................................................................................................................................................................................
Methods Six cardiologic French centres identified retrospectively cases of patients with severe or moderate AS associated with
TTR-CA hospitalized during the last 6 years.
.....................................................................................................................................................................................
Results Sixteen patients were included. Mean + SD age was 79 + 6 years, 81% were men. Sixty per cent were NYHA III –IV,
31% had carpal tunnel syndrome, and 56% had atrial fibrillation. Median (Q1;Q4) NT-proBNP was 4382 (2425;4730)
pg/mL and 91% had elevated cardiac troponin level. Eighty-eight per cent had severe AS (n ¼ 14/16), of whom 86%
(n ¼ 12) had low-gradient AS. Mean + SD interventricular septum thickness was 18 + 4 mm. Mean left ventricular
ejection fraction and global LS were 50 + 13% and 27 + 4%, respectively. Diagnosis of TTR-CA was histologically pro-
ven in 38%, and was based on strong cardiac uptake of the tracer at biphosphonate scintigraphy in the rest. Eighty-one
per cent had wild-type TTR-CA (n ¼ 13), one had mutated Val122I and 19% did not had genetic test (n ¼ 3). Valve
replacement was surgical in 63% and via transcatheter in 13%. Median follow-up in survivors was 33 (16;65) months.
Mortality was of 44% (n ¼ 7) during the whole follow-up period.
.....................................................................................................................................................................................
Conclusions Combination of AS and TTR-CA may occur in elderly patients particularly those with a low-flow low-gradient AS pat-
tern and carries bad prognosis. Diagnosis of TTR-CA in AS is relevant to discuss specific treatment and management.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Aortic stenosis † Transthyretin † Cardiac amyloidosis † Low-flow low-gradient

fraction (LVEF). Low-flow low-gradient AS is a severe form character-

Introduction ized by low cardiac output (CO), or as was defined recently by a
Degenerative aortic stenosis (AS) is currently the most common stroke volume index (SVi),35 mL/m2, and low trans-valvular gradient
valvular heart disease in Western developed countries. Severe AS is (TG). Reduced CO could be due to decreased LVEF or to an exces-
defined as aortic valve area (AVA) ,1.0 cm2, generally with a mean sive cardiac remodelling and/or restrictive physiology with preserved
gradient . 40 mmHg. Several AS patterns have been described de- LVEF also called ‘paradoxical low-flow low-gradient AS’.1 Patients with
pending on AS area, flow, gradient, and left ventricular ejection this last pattern are often older and have poor prognosis.1

* Corresponding author. Tel: +33 149 812 253, Fax: +33 149 812 805, Email: thibaud.damy@hmn.aphp.fr
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2016. For permissions please email: journals.permissions@oup.com.
Page 2 of 7 A. Galat et al.

Interestingly, excessive cardiac remodelling and/or a restrictive The mean age was 79 + 6 years, 81% were men (n ¼ 13), 60%
physiology are both features of another frequent disease en- (n ¼ 9/14) were in NYHA-class III or IV. Carpal tunnel syndrome
countered in elderly known as transthyretin (TTR) cardiac amyloid- was observed in 31% of the patients (n ¼ 5/16), atrial fibrillation
osis (TTR-CA). This disorder is characterized by extracellular in 56% (n ¼ 9/16). The patients had also elevated levels of biomar-
deposits of fibrillar TTR proteins in different organs including kers of HF with a median of NT-proBNP of 4382(2425;4730) pg/mL.
the heart, resulting in LV dysfunction.2 The two common types Troponin was elevated in 10 of the 11 patients with available data.
are wild-type transthyretin (WT-TTR) and hereditary-transthyretin Before AS management, 88% (n ¼ 14) had severe AS of whom 86%
(h-TTR) amyloidosis.2 Wild-type transthyretin is also known as (n ¼ 12/14) had low transaortic gradient and 87% had low-flow AS de-
‘senile systemic amyloidosis’ with a prevalence of 25% in the gen- fined by SVi , 35 ml/m2 (n ¼ 13/15). They all had increased interven-
eral population .80 years according to post-mortem studies.3 tricular septum thickness (18 + 4 mm). Left ventricular dysfunction
Hereditary-transthyretin is inherited in an autosomal dominant was moderate when estimated by LVEF (50 + 13%). However, when
mode with .120 identified mutations.4 The penetrance and sever- it was available, global LS was dramatically decreased (27 + 4%).
ity of the disease are variable and depend on the mutation with
some associated almost exclusively with cardiac involvement (e.g. Diagnosis of transthyretin cardiac
Val122Ile). Transthyretin cardiac amyloidosis (TTR-CA) patients amyloidosis
usually have biventricular increased wall thicknesses, diffuse late Eighty-one per cent (n ¼ 13) had WT-TTR and one h-TTR with
gadolinium enhancement (LGE) on cardiac magnetic resonance im- Val122I mutation. Three did not have genetic sequencing of TTR.
aging (MRI) and cardiac uptake at biphosphonate scintigraphy (BS).5 The diagnosis of TTR-CA was histologically proved in 6 (38%) and

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Transthyretin cardiac amyloidosis carries poor prognosis and is on scintigraphy for the other patients. Seventy-five per cent of the
often complicated by HF. patients (n ¼ 12) had cardiac MRI with all showing diffuse LGE.
Although aging associated factors may influence the development
or progression of AS, the combination AS and TTR-CA remains Management of aortic stenosis/
poorly described. transthyretin cardiac amyloidosis
The aims of this study were to report cases of patients with patients and outcomes
both TTR-CA and AS in order to describe their specific phenotype, Based on Heart-Team decision, 10 patients (63%) were referred
management, and outcomes. for aortic valve replacement (AVR), of whom one refused surgery;
transcatheter aortic valve implantation (TAVI) was scheduled in two
Methods cases (12%), of whom one died before the procedure. Conservative
treatment was indicated in four patients (25%). The follow-up for
Six centres had to identify in their records patients with AS and TTR-CA the survivors was 33 (16;65) months. Forty-four (n ¼ 7) died during
for the last 6 years. Inclusion criteria were diagnosis of CA associated with follow-up, four from HF, one from pneumopathy, one of cardiogenic
a moderate or severe aortic valve stenosis (aortic valve area ,1.5 cm2).
shock (before undergoing TAVI), and one at home from unknown
Diagnosis of TTR-CA had to be confirmed on endomyocardial biopsy or
cause. There were no significant differences in baseline characteris-
by strong cardiac retention (visual score ≥ 2) at BS (99mTc-HMDP or
99m
Tc-DPD). Patients were managed according to contemporary guide-
tics between the alive and the dead groups (Table 2). Figure 1 shows
lines.6 The investigation was in line with the Declaration of Helsinki. an example of a patient with the combination of AS and TTR-CA
Clinical, biological, trans-thoracic echocardiography (TTE), cardiac treated by TAVI.
MRI, BS, histology, and treatment data were recorded.
Discussion
Outcomes and follow-up
Follow-up began at the time of decision for AS management and was To the best of our knowledge, our study provides for the first time a
based on medical examination or telephone interviews. clinical description of the combination of AS and TTR-CA. This
study suggests that TTR-CA should be suspected in elderly patients
Statistical analysis with severe AS and low-flow low gradients, especially in the pres-
Continuous variables were described as mean + SD or median ence of carpal tunnel syndrome, excessive cardiac ‘hypertrophic
(25th;75th inter-quartile range) and dichotomous as percentage. Statis- remodelling’, and signs of HF.
tical analyses were performed using SPSS software.
Diagnosing cardiac amyloidosis in aortic
stenosis
Results In elderly patients with AS, CA should be suspected in presence of
carpal tunnel syndrome, severe dyspnoea (NYHA III –IV), markedly
Clinical and biological characteristics of increase of NT-proBNP or troponins and/or TTE with altered
patients with aortic stenosis/transthyretin LV-LS and/or diffuse cardiac MRI-LGE. In this population, with ad-
cardiac amyloidosis combination vanced age, non-invasive tools such as, BS should be performed
Sixteen patients with the combination of AS and TTR-CA were to screen TTR-CA. If the BS shows cardiac fixation, TTR-CA diag-
analysed (Table 1). All of them were referred for AS management nosis needs then to be confirmed by biopsy (extracardiac/cardiac)
or for persistent dyspnoea after surgical AVR with an associated and a TTR genetic testing should be done. Recognition of TTR-CA
diagnosis of CA. is crucial, as several specific therapeutic trials are in progress.
Transthyretin cardiac amyloidosis in aortic stenosis Page 3 of 7

Figure 1 Patient number 10 (Table 1). Transcatheter aortic valve implantation was performed after the first echocardiography; (A) parasternal Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 2, 2016
view of TTE. Note the increased left ventricular wall thickness, aortic stenosis and the pericardial effusion; (B) transaortic flow using continuous
Doppler showing low gradient; aortic surface area 1.08 cm2; SVi:25 ml/m2; (C) global left ventricular longitudinal strain showing severe decrease of
left ventricular contractility. (A ′ , B ′ , C ′ ) Same views 33 months after showing improvement of the aortic gradient (mean gradient: 5 mmHg) and
decrease in contractility. Of note, the left ventricular thickness the pericardial effusion continued to increase; (D) HMDP bone Scintigrpahy show-
ing a Perugini’s visual score of 3; (E): SPECT scan showing high cardiac uptake.

Aortic stenosis and transthyretin cardiac association is due to chance. There is increasing data in the literature
amyloidosis: more than a simple supporting a central role of oxidative stress, inflammation, and
extracellular remodelling in the TTR amyloidogenic process.2,7
epiphenomenon These mechanisms are also part of the pathophysiology of AS.8,9
It is unclear if there is a causative link between AS and TTR-CA. Both It is conceivable that amyloid deposits could be induced or acceler-
are observed in the elderly and the one may argue that their ated in AS. Interestingly, similar echocardiographic features are seen
 Page 4 of 7
Table 1 Clinical and biological characteristics, diagnosis and prognosis of aortic stenosis/cardiac amyloidosis patients

Clinical and biological characteristics Baseline echocardiographic characteristics of the patients

................................................................................................................................. ....................................................................................................
Sex M/F Age (years) CT NYHA III –IV AF NTproBNP/ Troponin ASA MG CO SVi LG AS LVEF IVST GLS (%)
BNP (pg/mL) (cm2) (mmHg) (l/min) (ml/m2) (%) mm
.............................................................................................................................................................................................................................................
1 + 90 2 NA 2 264a NA 1.17 15 4.1 32 Moderate 41 21 23
2 + 89 2 + + 7846 + 0.67 33 3.0 25 + 52 13 NA
3 + 84 + 2 2 2425 + 0.86 27 4.2 17 + 55 22 NA
4 + 84 2 2 2 4730 + 0.9 20 3.6 22 + 36 21 24.5
5 + 81 2 + + NA NA 1.2 10 3.2 34 Moderate 58 18 NA
6 + 79 2 + 2 4382 + 0.49 34 3.1 24 + 35 17 27.8
7 + 79 2 + 2 NA NA 0.69 38 2.4 24 + 35 20 NA
8 + 75 + + + 4478 + 0.76 34 4.3 23 + 35 17 25,4
9 + 75 + + + NA NA NA 39 5.9 41 + 60 24 NA
10 + 74 + + + 5347 + 1.08 15 4.0 25 + 37 27 24.2
11 + 73 2 + 2 1740 + 0.4 39 3.0 20 + 45 15 NA
12 + 70 + 2 + 124a + 0.8 35 2 NA + 70 12 NA
13 + 70 2 2 + NA NA 0.85 82 3.7 23 2 69 13 NA
14 2 82 2 2 2 1932 2 0.4 108 4.7 27 2 56 13 215.8
15b 2 79 2 2 + 2799 + 0.81 27 4.8 40 + 69 14 28.5
16 2 78 2 + + 959a + 0.93 24 4.7 28 + 50 16 23
13/16 (81%) 79 + 6 5/16 (31%) 9/15 (60%) 9/16 (56%) 4382 (2425; 4730) 10 (91%) 0.80 + 0.25 33 + 23 3.8 + 0.7 27 + 7 12/14 (86%) 50 + 13 18 + 4 27 + 0.7
.............................................................................................................................................................................................................................................
CA diagnosis Management and prognosis
........................................................................ .......................................................
c
MRI-LGE BS uptake Cardiac biopsy TTR mutation Team decision Follow-up Death
.............................................................................................................................................................................................................................................
1 + + NA 2 Medical 16 +
2 + + NA 2 TAVI 2 +
3 + + NA NA Medical 8 2
4 + + + 2 Medical 10 2
5 NA + NA 2 Medical 10 +
6 + + + 2 Surgery 4 +
7 + + NA 2 Surgery 78 +
8 + + NA 2 Surgery 24 2
9 + + NA 2 Surgery 65 2
10 + + NA 2 TAVI 41 2
11 + NA + 2 Surgery 78 2
12 + NA + 2 Surgery 28 +
+

A. Galat et al.
13 NA NA 2 Surgery 164 2

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Transthyretin cardiac amyloidosis in aortic stenosis Page 5 of 7

in CA and AS: CA is known to induce basal LS abnormalities with

ventricular ejection fraction; GLS, global longitudinal strain; IVST, interventricular septum thickness; MRI, magnetic resonance imaging; BS, cardiac uptake at bone scintigraphy; Surgery, surgical aortic valve replacement; TAVI, trans-aortic valve
Values are n (percentage) or median (Q1;Q4). CT, carpal tunnel syndrome; AF, atrial fibrillation; ASA, aortic surface area; MG, mean gradient; CO, cardiac output; SVi, indexed stroke volume; LG AS, low-gradient aortic stenosis; LVEF, left
a relative apical sparing related to amyloid deposits.10 Similar
abnormalities have been observed in severe AS and were attributed
mainly to myocardial fibrosis.11 It may be possible that basal LS
impairment in some patients with AS is, in fact, due to amyloid infil-
tration. This is supported by Allen et al. who found a prevalence of
10% of TTR amyloid deposits on septal myectomy during surgical
AVR for AS.12

Aortic stenosis and transthyretin cardiac

amyloidosis: the chicken or the egg?
The question of whether CA is a cause or a consequence of AS is
unknown. On one hand, the amyloid deposits could induce or wor-
sen AS as shown by Kristen et al. who reported a high prevalence of
amyloid deposits in surgically removed heart valves, mainly in AS
(74% of aortic valves);13 on the other hand, pressure overload pro-
duced by AS could have deleterious effects on myocardial remodel-

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ling and so may induce or worsen TTR amyloid deposits. We report
here few cases identified retrospectively. Only severe cases or un-
usual presentation of AS were suspected and investigated for CA.
Thus, the association of these two diseases might be more frequent
than thought.
An ongoing prospective and consecutive multicenter study
was designed to determine the prevalence of TTR-CA in AS
(NCT02260466).
7/16 (44%)

Consequences of Aortic stenosis/

2
2
+

transthyretin cardiac amyloidosis

combination on clinical management
Management of AS and TTR-CA patients is challenging. Once diag-
26 (10;61)

BNP (values in bold). They were not included in the calculation of the median reported in the bottom line.

nosed, b-blockers should be avoided and pacemaker implant

Positive biopsy means positive Congo-red staining and positive immunolabeling with anti-TTR antibodies.

discussed depending on conduction disorder. Aortic valve replace-

16
33
57

ment option needs to be discussed individually as it is too early to

define the best strategy. Improvement after AVR might be limited in
terms of survival and symptoms. Furthermore, these patients are at
Surgery
Surgery
Surgery

high risk of having operative and post-operative complications.14,15

Transcatheter aortic valve implantation which is generally indicated
for high-risk patients may not be optimal in this particular popula-
tion with risk of left ventricular rupture and complete atrio-
1/13 (8%)
Val122Ile

ventricular block leading both to death in per or post-TAVI

procedure.16,17 Moreover, autopsy data in patients who had previ-
NA
NA

ously undergone TAVI revealed myocardial amyloid deposits in

nearly one-third of examined cases, which may contribute to
poor outcomes.18 Thus, diagnosis workup of TTR-CA should be
12/12 (100%) 13/13 (100%) 6/6 (100%)

performed before referring a patient with suspected TTR-CA

NA

for surgical AVR or TAVI in severe AS.

+

Limitations
implantation; NA, not available.

There are several limitations. First, this is a retrospective study.

Patient 15 refused surgery.
NA
+
+

Thus, it is not possible to calculate the prevalence of TTR-CA in

AS. Furthermore, we can suppose that the diagnosis of TTR-CA
was made in this specific group of AS patients because they were
referred initially to surgery with a suggestive phenotype of TTR-CA,
NA

NA
15b +

i.e. important increase in LV wall thickness, altered LV-LS, increased

NT-proBNP, and persistent dyspnoea after AVR. Cardiac biopsy
14

16

b
c
a

was not possible to obtain from all the patients, thus scintigraphy
Page 6 of 7 A. Galat et al.

Table 2 Comparisons of the baseline characteristics of the patients depending on their vital status (alive or dead)

N Alive (9) Dead (7) P

...............................................................................................................................................................................
Clinical and biological characteristics
Gender male, n (%) 7 (78) 6 (86) 0.60
Age (years) 75 (74; 83) 79 (78; 89) 0.35
Height (cm) 176 (164; 178) 169 (158; 172) 0.14
Weight (kg) 77 (65; 84) 66 (64; 73) 0.14
Carpal tunnel syndrome, n (%) 4 (44) 1 (14) 0.23
Atrial fibrillation, n (%) 5 (56) 4 (57) 0.67
NYHA III– IV vs. I– II, n (%) 4 (44) 5 (83) 0.17
Systolic blood pressure (mmHg) 127 (115; 128) 117 (111– 121) 0.21
Diastolic blood pressure (mmHg) 72 (67; 78) 67 (57; 71) 0.17
Heart rate (bpm) 80 (70; 100) 73 (69; 88) 0.46
NT-proBNP (pg/ml) 2799 (1932; 4730) 4382– 6114a 0.33
...............................................................................................................................................................................
Baseline echocardiographic and bone scintigraphy characteristics of the patients

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ASA (cm2) 0.83 (0.79; 0.89) 0.80 (0.67; 11.17) 0.69
MG (mmHg) 33 (15; 35) 34 (24; 41) 0.30
CO (l/min) 4.2 (3.7; 4.7) 3.2 (2.9; 4.3) 0.11
SVi (ml/m2) 23 (22; 34) 27 (24; 33) 0.33
Low gradient vs. high-gradient AS, n (%)b 7 (78) 5 (100) 0.40
LVEF, n (%) 55 (37; 65) 50 (35; 58) 0.68
IVST (mm) 17 (14; 23) 17 (13; 20) 0.47
GLS (%) 25.4 (212.2; 24.4) 25.4 27.8a 0.57
...............................................................................................................................................................................
Bone scintigraphy visual score, n (%)
2 4 (57) 1 (33) 0.70
3 3 (43) 2 (67)
...............................................................................................................................................................................
Treatment
Medical, n (%) 3 (33) 2 (29) 0.97
TAVI, n (%) 1 (11) 1 (14)
Surgery, n (%) 5 (56) 4 (57)

Values are n (percentage) or median (Q1;Q4). CT, carpal tunnel syndrome; AF, atrial fibrillation; ASA, aortic surface area; MG, mean gradient; CO, cardiac output; SVi, indexed
stroke volume; LVEF, left ventricular ejection fraction; GLS, global longitudinal strain; IVST, interventricular septum thickness; BS, cardiac uptake at bone scintigraphy; Surgery,
surgical aortic valve replacement; TAVI, trans-aortic valve implantation.
Proportions were compared using x 2 test or the Fisher’s exact test when the number of patients was less than five in a group.
a
Only two patients had data available in the dead group.
b
Only including the 15 patients with severe aortic stenosis; only 10 of 13 patients with bone scintigraphy had visual score estimated.

was used to make the diagnosis. All patients had visual score . 2 Authors’ contributions
at hydroxy methylene diphosphonate (HMDP) scintigrpahy which
as we have reported is 100% specific.19 It is to note that amyloid de- A.G., T.D., and E.A. performed statistical analysis. T.D. handled funding
posits could be focal, thus a negative cardiac biopsy could not ex- and supervision. A.G., M.S., M.D., D.M., O.M., D.A., J.L.M. acquired the
clude amyloidosis. data. A.G., A.G., D.B., and T.D. conceived and designed the research.
Nevertheless, this study brings some insights of the clinical A.G., A.G., T.D. drafted the manuscript. J.L.D.R., D.M., J.L.M. made
feature of TTR-CA in AS. Our prospective study (NCT02260466) critical revision of the manuscript for key intellectual content.
is aimed at determining the prevalence, phenotype, and outcomes
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