JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 77, NO.

2, 2021

ª 2021 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Prevalence and Outcomes of

Concomitant Aortic Stenosis and
Cardiac Amyloidosis
Christian Nitsche, MD,a Paul R. Scully, PHD,b,c Kush P. Patel, MBBS,b,d Andreas A. Kammerlander, MD, PHD,a
Matthias Koschutnik, MD,a Carolina Dona, MD,a Tim Wollenweber, MD,e Nida Ahmed, MBBS,b,d
George D. Thornton, MBBS,b,d Andrew D. Kelion, MD,f Nikant Sabharwal, MD,f James D. Newton, MD,f
Muhiddin Ozkor, MD,d Simon Kennon, MD,d Michael Mullen, MD,d Guy Lloyd, MD,b,d,g Marianna Fontana, PHD,h
Philip N. Hawkins, FMedSci,h Francesca Pugliese, MD,b,g Leon J. Menezes, MD,d,i James C. Moon, MD,b,d
Julia Mascherbauer, MD,a Thomas A. Treibel, PHDb,d

ABSTRACT

BACKGROUND Older patients with severe aortic stenosis (AS) are increasingly identified as having cardiac amyloidosis
(CA). It is unknown whether concomitant AS-CA has worse outcomes or results in futility of transcatheter aortic valve
replacement (TAVR).

OBJECTIVES This study identified clinical characteristics and outcomes of AS-CA compared with lone AS.

METHODS Patients who were referred for TAVR at 3 international sites underwent blinded research core laboratory
99m
technetium-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) bone scintigraphy (Perugini grade 0: negative; grades 1
to 3: increasingly positive) before intervention. Transthyretin-CA (ATTR) was diagnosed by DPD and absence of a clonal
immunoglobulin, and light-chain CA (AL) was diagnosed via tissue biopsy. National registries captured all-cause mortality.

RESULTS A total of 407 patients (age 83.4
6.5 years; 49.8% men) were recruited. DPD was positive in 48 patients
(11.8%; grade 1: 3.9% [n ¼ 16]; grade 2/3: 7.9% [n ¼ 32]). AL was diagnosed in 1 patient with grade 1. Patients with grade
2/3 had worse functional capacity, biomarkers (N-terminal pro-brain natriuretic peptide and/or high-sensitivity troponin
T), and biventricular remodeling. A clinical score (RAISE) that used left ventricular remodeling (hypertrophy/diastolic
dysfunction), age, injury (high-sensitivity troponin T), systemic involvement, and electrical abnormalities (right bundle
branch block/low voltages) was developed to predict the presence of AS-CA (area under the curve: 0.86; 95% confidence
interval: 0.78 to 0.94; p < 0.001). Decisions by the heart team (DPD-blinded) resulted in TAVR (333 [81.6%]), surgical
AVR (10 [2.5%]), or medical management (65 [15.9%]). After a median of 1.7 years, 23% of patients died. One-year
mortality was worse in all patients with AS-CA (grade: 1 to 3) than those with lone AS (24.5% vs. 13.9%; p ¼ 0.05). TAVR
improved survival versus medical management; AS-CA survival post-TAVR did not differ from lone AS (p ¼ 0.36).

CONCLUSIONS Concomitant pathology of AS-CA is common in older patients with AS and can be predicted clinically.
AS-CA has worse clinical presentation and a trend toward worse prognosis, unless treated. Therefore, TAVR should not
be withheld in AS-CA. (J Am Coll Cardiol 2021;77:128–39) © 2021 The Authors. Published by Elsevier on behalf of
the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Listen to this manuscript’s From the aDivision of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria; bInstitute of
audio summary by Cardiovascular Science, University College London, London, United Kingdom; cCardiology Department, Guy’s and St. Thomas’
Editor-in-Chief NHS Foundation Trust, London, United Kingdom; dBarts Heart Centre, St. Bartholomew’s Hospital, London, United Kingdom;
Dr. Valentin Fuster on e
Department of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; fJohn Radcliffe Hospital, Oxford, United
JACC.org. Kingdom; gQueen Mary University London, London, United Kingdom; hNational Amyloid Centre, London, United Kingdom; and
the iUCL/ULCH NIHR Biomedical Research Centre, London, United Kingdom.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received August 11, 2020; revised manuscript received October 26, 2020, accepted November 4, 2020.

ISSN 0735-1097 https://doi.org/10.1016/j.jacc.2020.11.006

JACC VOL. 77, NO. 2, 2021 Nitsche et al. 129
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D egenerative aortic stenosis (AS) affects >3% 6-min walk test, electrocardiography, and ABBREVIATIONS

of people aged 75 years or older (1). In se- transthoracic echocardiography with strain AND ACRONYMS

vere AS with symptoms or cardiac decom- analysis. All-cause mortality was selected as
AL = immunoglobulin light-
pensation, surgical aortic valve replacement (SAVR) the primary study endpoint, was determined chain cardiac amyloidosis
or transcatheter-based aortic valve replacement using national data via the U.K. National
AS = aortic stenosis
(TAVR) are indicated to improve outcome (2). Health Service (NHS Spine), and Austrian
AS-CA = aortic stenosis and
Morphologically, significant AS is characterized by Death Registry, and was 100% complete. Peri- cardiac amyloid pathology
hypertrophic myocardial remodeling, similar to car- procedural complications were defined using ATTR = transthyretin-related
diac amyloidosis (CA). CA is an infiltrative process the Valve Academic Research Consortium-2 cardiac amyloidosis

caused by myocardial deposition of amyloid fibrils. criteria. This study complied with the Decla- AUC = area under the curve
The 2 major amyloid proteins found in ventricular ration of Helsinki; relevant local ethics and CA = cardiac amyloidosis
myocardium are transthyretin (TTR), which predomi- site approvals were obtained, and all patients CI = confidence interval
nantly affects older adults, and immunoglobulin light- provided written informed consent.
DPD = 99m
technetium-3,3-
chain (AL), which occurs less frequently (3). The coex- LABORATORY AND ELECTROCARDIOGRAPHIC diphosphono-1,2-
istence of AS and CA in patients referred for TAVR ASSESSMENT. For detection of pathological
propanodicarboxylic acid

ranges from 9% to 16% (4–7). Increased diagnosis light-chains underlying AL-CA, laboratory HR = hazard ratio

of CA is driven by the sensitivity and specificity of testing included serum immunoglobins and hsTnT = high-sensitivity

bone scintigraphy ( 99mtechnetium-3,3-diphosphono- free light-chain quantification, as well as

troponin T

99m IQR = interquartile range

1,2-propanodicarboxylic acid [DPD], technetium- serum and/or urine immunofixation, which
99m
pyrophosphate, or technetium-hydroxymethylene was performed in all DPD-positive patients. LS = longitudinal strain

diphosphonate), in particular for ATTR. This is In addition, N-terminal probrain natriuretic LV = left ventricular

important because of the advent of novel CA therapies peptide (NT-proBNP) and high-sensitivity LVEF = left ventricular
(8). The survival implications of concurrent AS-CA troponin T (hs-TnT) serum levels were
ejection fraction

remain unclear. Three potentially underpowered determined in all patients. Electrocardio- NT-proBNP = N-terminal
proLbrain natriuretic peptide
studies recently reported no mortality difference of grams were recorded according to current
AS-CA compared with lone AS in cohorts of approxi- OR = odds ratio
recommendations (10). Voltage/mass ratio
mately 200 patients (4,6,9). Therefore, the present RAISE = remodeling, age,
was determined in patients without bundle
injury, system, and electrical
multicenter study was designed to evaluate the branch block, and paced rhythm was assessed
SAVR = surgical aortic valve
differential mortality hazard of AS-CA versus lone AS, by dividing the Sokolow-Lyon index by the replacement
as well as predictors of AS-CA beyond the existing left ventricular (LV) mass index on echocar- SV = stroke volume
diagnostic criteria. diography. The Sokolow-Lyon index was
TAVR = transcatheter aortic
calculated as the sum of pre-cordial voltage valve replacement
SEE PAGE 140
(S-wave in lead V1 plus R-wave in lead V 5 or
V6 [SV1 þ RV5 or V6 ]). Low-limb lead voltages were
METHODS
defined as all limb leads with an ampli-

STUDY POPULATION. This prospective, multicenter

tude of #0.5 mV.

study enrolled consecutive adult patients with severe ECHOCARDIOGRAPHY. All patients underwent clin-
degenerative AS who were referred for TAVR at 3 ical transthoracic echocardiography, primarily for
tertiary referral centers: Barts Heart Centre, London, assessment of AS severity, any concomitant valve
United Kingdom (October 2016 to January 2019); John pathology, and ventricular function according to the
Radcliffe Hospital, Oxford, United Kingdom (January local protocols written in accordance with interna-
2018 to June 2019); and Vienna General Hospital, tional imaging guidelines (11–14). LV ejection fraction
Vienna, Austria (October 2017 to February 2019). This (LVEF) was calculated using Simpson’s biplane test
study included patients from 2 previous published where possible or otherwise quantified visually.
studies (4,6), which expanded the study cohort, Stroke volume (SV) was quantified using the LV
follow-up, and implementation of the blinded core outflow tract velocitytime integral and the LV
laboratory analysis of bone scintigraphy. outflow tract diameter and then indexed to body
To reduce selection bias, recruitment took place surface area. LV mass was calculated using the for-
after referral to AVR and before discussion by the mula from Devereux et al. (15). Strain analysis was
heart team. Therefore, we anticipated some crossover performed in the 4-, 3-, and 2-chamber apical views.
to medical therapy and to surgical valve replacement. Regional longitudinal strain (LS) was determined in
All patients underwent blinded DPD bone scintig- the 17 segments of the LV (16). Global LS was calcu-
raphy, as well as clinical and laboratory assessment, a lated as the average LS of these 17 segments. Relative
130 Nitsche et al. JACC VOL. 77, NO. 2, 2021

Outcome of Cardiac Amyloidosis and Aortic Stenosis JANUARY 19, 2021:128–39

scan speed of 10 cm/min using low-energy, high-res-

F I G U R E 1 Patient Population
olution collimators (18). Planar whole body images
were performed 3 h after tracer administration at all
Consecutive AS patients in evaluation for study sites. Additional single-photon emission
TAVR at 3 centers (N = 407): computed tomographycomputed tomography of the
- Vienna (N = 207) chest at 3 h was performed in London and/or Oxford.
- London (N = 170)
BLINDING PRE-PROCEDURE. DPD scans were re-
- Oxford (N = 30)
ported blinded to the clinical data by 2 readers from
each institution (C.N., T.V., P.S., L.M.) according to
99mTc-DPD bone scintigraphy (N = 407) the Perugini classification (19), where grade 0 repre-
sented no cardiac uptake with normal bone uptake
(i.e., negative) and grades 1 to 3 represented
increasing cardiac uptake with increasing bone
Aortic valve replacement attenuation and soft tissue uptake. In discrepant
(N = 342): Medical management cases (adjudication different to the previous local
- TAVR (N = 332) (N = 65) DPD grade; n ¼ 5), which occurred more often in
- SAVR (N = 10)
borderline cases who did not undergo single-photon
emission computed tomography, the adjudication
panel (C.N., T.V., P.S., L.M., T.A.T.) re-reviewed the
Follow-up after DPD scan: 700 ± 292 days scans and assigned the final diagnosis by consensus.

DIAGNOSIS OF CA. Referring to the different disease

Patient population. AS ¼ aortic stenosis; DPD ¼ 99m

technetium-3,3-diphosphono-1,2-
burden in Perugini grade 1 (subclinical amyloid
propanodicarboxylic acid; SAVR ¼ surgical aortic valve replacement; deposition) versus Perugini grade $2 (clinical
TAVR ¼ transcatheter aortic valve replacement. amyloidosis), these 2 conditions were defined as AS-
amyloid versus AS-amyloidosis, respectively. The
presence of ATTR was diagnosed in patients with
apical LS was calculated as average apical LS/(average cardiac tracer uptake on bone scintigraphy and un-
basal LS þ average mid-LS). The myocardial contrac- remarkable serum- and urine-free light-chain assess-
tion fraction, which indexes SV to the myocardial ment (8). AL was diagnosed if these were elevated
volume, was calculated as previously described (17). and there was endomyocardial or extracardiac biopsy
The classic low-flow, low gradient was defined as an amyloid of light-chain origin. AL amyloidosis was
2
aortic valve area of #1.0 cm , with an LVEF of <50%, considered possible in 3 cases (2 in grade 1 and 1 in
2
an indexed SV of <35 ml/m , a peak aortic valve ve- grade 2). In the first patient in grade 1, endomyo-
locity of <4 m/s, and a mean gradient of <40 mm Hg. cardial biopsy confirmed ATTR; the second patient in
In contrast, the paradoxical low-flow, low-gradient grade 1 died shortly after TAVR with an autopsy
was defined as an LVEF of $50% but an indexed SV diagnosis of AL (AL-kappa positive, TTR negative).
2
of <35 ml/m , peak velocity of <4 m/s, and a mean The patient in grade 2 had a monoclonal gammopathy
gradient of <40 mm Hg (14). When equivocal, AS of undetermined significance with an inconclusive
severity was adjudicated using low-dose dobutamine bone marrow biopsy; this patient declined further
stress echocardiography and the computed biopsy. However, because of the known coexistence
tomographyderived aortic valve calcium score. of ATTR and monoclonal protein without cardiac AL
amyloidosis (8) and the low percentage of AL with
DPD BONE SCINTIGRAPHY. Blinded, pre-TAVR DPD
Perugini uptake $2 (18), this patient was classified
bone scintigraphy was performed in all patients, who
as ATTR.
were scanned using Phillips Brightview single-photon
emission computed tomographycomputed tomog- STATISTICAL ANALYSIS. All statistical analyses were
raphy gamma camera (Philips Healthcare, Amster- computed using SPSS version 26 (IBM, Armonk, New
dam, the Netherlands), Siemens Symbia gamma York). Continuous data are expressed as mean
SD or
camera (Siemens Healthcare, Erlangen, Germany), as median (interquartile range [IQR]), and categorical
and/or Pulse CDC gamma camera (IS2, London, variables are presented as numbers and percentages.
United Kingdom), or the General Electric Infinia Differences between groups were analyzed with the
Hawkeye 4/GE Discovery 670 hybrid gamma camera chi-square and Kruskal Wallis tests, as appropriate.
(Vienna, Austria) following the administration of 700 Post hoc analyses were performed using Dunn-
MBq of DPD. Whole body images were acquired at a Bonferroni tests for continuous variables. The
JACC VOL. 77, NO. 2, 2021 Nitsche et al. 131
JANUARY 19, 2021:128–39 Outcome of Cardiac Amyloidosis and Aortic Stenosis

T A B L E 1 Baseline Clinical Characteristics

DPD 0 (n ¼ 359; 88.2%) DPD 1 (n ¼ 16; 3.9%) DPD 2/3 (n ¼ 32; 7.9%) p Value

Age, yrs 83.6 (72.387.6) 85.4 (80.289.1) 86.6 (84.191.8)* 0.001

Male 48.2 50.0 65.6 0.167
BMI, kg/m2 26.4 (23.529.7) 27.6 (24.530.0) 25.7 (23.229.1) 0.429
EuroSCORE II 4.2 (3.75.1) 4.1 (3.64.6) 4.5 (3.95.2) 0.297
Systolic BP, mm Hg 134 (120148) 138 (118162) 126 (110150) 0.319
Diastolic BP, mm Hg 69 (6079) 80 (5891) 68 (6074) 0.244
Arterial hypertension 83.4 62.5†‡ 90.6 0.046
Pre-interventional PM 14.6 6.3 25.0 0.173
Diabetes 26.1 18.8 18.8 0.550
Atrial fibrillation 36.3 50.0 50.0 0.186
CAD 45.9 68.8 21.9*‡ 0.005
Previous MI 10.3 12.5 6.3 0.724
Previous PCI 22.8 37.5 3.1*‡ 0.011
PAD 11.5 0.0 0.0* 0.046
Cerebral OD 16.4 0.0 12.5 0.202
CTS 1.1 20.0† 18.8* <0.001
AS phenotype 0.176
D1: high gradient 67.2 53.3 43.8
D2: LFLG, LVEF $50% 16.4 26.7 28.1
D3: LFLG, LVEF <50% 16.4 20.0 28.1
Asymptomatic 7.7 6.7 6.3 0.948
Dyspnea 84.3 86.7 90.6 0.620
Angina 25.6 13.3 18.8 0.407
Syncope 19.1 6.7 12.5 0.324
Hs-TnT, ng/l 24 (1539) 25 (2332) 49 (3387)*‡ <0.001
NT-proBNP, pg/ml 1,606 (6403,843) 1,632 (9333,619) 4,855 (1,4127,494)* 0.003
Creatinine, mg/dl 1.1 (0.91.4) 1.3 (1.11.4) 1.1 (0.91.3) 0.230
eGFR, ml/min/1.73 m2 62.3 (46.477.9 52.5 (39.958.3) 61.4 (45.273.7) 0.213
Hemoglobin, mg/dl 11.9 (10.413.0) 13.3 (11.714.0) 11.8 (10.813.0) 0.097
Albumin, g/l 40.4 (32.640.0) 42.1 (41.944.5) 39.0 (35.642.0) 0.132
6-MWT, m 194 (82286) 260 (191369) 94 (50225)*‡ 0.034

Values are median (interquartile range) or %. *DPD grade 2/3 versus DPD grade 0: p # 0.05. †DPD grade 1 versus DPD grade 0: p # 0.05. ‡DPD grade 2/3 versus DPD grade 1:
p # 0.05.
6-MWT ¼6-min walk test; BMI ¼ body mass index; BP ¼ blood pressure; CAD ¼ coronary artery disease; CTS ¼ carpal tunnel syndrome; DPD ¼ 99mtechnetium-labeled 3,3-
diphosphono-1,2-propanodicarboxylic acid bone scintigraphy; eGFR ¼ estimated glomerular filtration rate; EuroSCORE II ¼ European System for Cardiac Operative Risk
Evaluation II; LFLG ¼ low-flow, low-gradient; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; NT-proBNP ¼ N-terminal prohormone of brain natriuretic
peptide; OD ¼ occlusive disease; PAD ¼ peripheral artery disease; PCI ¼ percutaneous coronary intervention; PM ¼ pacemaker.

discriminative power of the novel scoring system was SD. The proportional hazards assumption was tested
established using the receiver-operating character- with examination of Schoenfeld residuals. Kaplan-
istic curve analysis with area under the curve (AUC) Meier curves were used to evaluate the prognostic
and respective 95% confidence intervals (CIs). Uni- significance of CA and AVR. Univariate and multi-
variate and multivariate Cox regression analyses were variate binary logistic analyses were applied to eval-
performed for the overall and AVR cohort to evaluate uate the association of parameters with the presence
predictors of mortality (Supplemental Tables 1 to 3). of CA. A p value #0.05 was considered statisti-
All baseline parameters were proposed for univariate cally significant.
analysis. Multivariate analysis was performed using a
stepwise forward selection, with the univariate cutoff RESULTS
p value of #0.05 used to enter the multivariate model
for univariate testing and the p value of >0.1 used for PATIENT CHARACTERISTICS. A total of 407 patients
removal from multivariate testing. To allow better referred for TAVR (mean age: 83.4
6.5 years; 49.8%
comparison between continuous parameters within men) were recruited in 3 centers (Figure 1). All pa-
the multivariate model, scaled hazard ratios (HRs) (Z- tients underwent DPD bone scintigraphy performed
scores) were created by subtracting the mean from 16 days (IQR: 2 to 50 days) before AVR. Treatment
individual values and dividing them by the respective decisions were determined by the multidisciplinary
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Outcome of Cardiac Amyloidosis and Aortic Stenosis JANUARY 19, 2021:128–39

T A B L E 2 Baseline Echocardiographic and Electrocardiographic Characteristics

DPD 0 (n ¼ 359; 88.2%) DPD 1 (n ¼ 16; 3.9%) DPD 2/3 (n ¼ 32; 7.9%) p Value

Baseline echocardiographic parameters

LVEDD, mm 45.0 (40.0 to 50.0) 44.0 (39.0 to 50.0) 43.0 (38.0 to 49.0) 0.308
RVEDD, mm 36.0 (31.0 to 41.0) 36.0 (32.0 to 44.0) 38.0 (33.0 to 43.0) 0.158
IVS, mm 14.0 (12.0 to 16.0) 13.0 (12.0 to 14.0) 16.0 (14.0 to 19.0)*† 0.012
LA diameter, mm 51.0 (41.0 to 62.0) 55.0 (42.0 to 64.0) 56.0 (44.0 to 66.0) 0.405
AVA, cm2 0.7 (0.6 to 0.8) 0.7 (0.6 to 0.8) 0.7 (0.5 to 0.9) 0.814
AV Vmax, m/s 4.2 (3.9 to 4.6) 4.0 (3.4 to 4.7) 3.9 (3.2 to 4.6)* 0.017
AV-PPG, mm Hg 71.0 (60.0 to 84.0) 64.0 (45.0 to 87.0) 60.0 (42.0 to 86.0)* 0.018
AV-MPG, mm Hg 44.0 (35.0 to 53.0) 39.0 (27.0 to 49.0) 36.0 (25.0 to 48.0)* 0.017
SVi, ml/m2 40.1 (31.4 to 48.0) 33.2 (30.0 to 39.1)‡ 35.8 (27.4 to 44.0) 0.021
LVEF, % 58.0 (44.0 to 64.0) 55.0 (35.0 to 61.0) 51.0 (42.0 to 64.0) 0.371
LVEDV, ml 91.0 (68.0 to 117.0) 87.0 (77.0 to 107.0) 80.0 (61.0 to 99.0) 0.201
LVESV, ml 34.0 (22.0 to 51.0) 33.0 (24.0 to 65.0) 36.0 (22.0 to 43.0) 0.819
Peak TR velocity, m/s 3.0 (2.4 to 3.5) 3.2 (2.0 to 3.8) 3.4 (2.6 to 4.1) 0.074
sPAP, mm Hg 39.0 (27.0 to 50.0) 48.0 (18.0 to 53.0) 49.0 (32.0 to 61.0) 0.062
E-wave deceleration time, ms 217 (166 to 281) 229 (189 to 337) 196 (158 to 246) 0.143
E/A ratio§ 0.80 (0.68 to 1.20) 1.35 (0.64 to 3.09) 1.43 (0.88 to 2.43)* 0.010
TAPSE, mm 2.1 (1.6 to 2.5) 2.1 (1.6 to 2.2) 1.8 (1.3 to 2.3) 0.073
LV mass index, g/m2 127 (101 to 151) 120 (91 to 163) 150 (119 to 177)*† 0.017
MCF, % 33.6 (25.4 to 45.1) 34.8 (20.5 to 40.7) 24.5 (20.6 to 29.3)* 0.001
GLS, % 15.6 (19.3 to 10.2) 12.2 (18.0 to 8.6) 13.7 (17.3 to 10.2) 0.433
Apical LS, % 21.0 (26.6 to 13.2) 19.8 (26.1 to 5.8) 21.5 (25.2 to 16.0) 0.881
Midventricular LS, % 13.3 (17.5 to 8.8) 10.2 (18.7 to 7.2) 10.1 (13.8 to 7.3) 0.214
Basal LS, % 10.6 (13.6 to 6.5) 9.3 (12.0 to 5.6) 7.4 (10.8 to 3.0) 0.072
Apical/(mid þ basal) 0.84 (0.69 to 1.05) 0.87 (0.55 to 1.61) 1.10 (0.85 to 1.78)* 0.005
ECG parameters
Heart rate, beats/min 70 (62 to 79) 74 (68 to 83) 68 (60 to 77) 0.355
Sokolow-Lyon index, mV 2.25 (1.70 to 2.95) 1.25 (1.03 to 1.96)* 1.68 (1.33 to 2.35)* <0.001
VMR, mV/g/m2  10-2 1.84 (1.29 to 2.79) 1.18 (0.66 to 2.02)* 1.06 (0.83 to 1.85)* <0.001
Low voltage limb 3.2 0.0 3.1 0.783
QRS duration, ms 96 (86 to 118) 128 (106 to 141)‡ 107 (90 to 135) 0.005
LBBB 8.7 0.0 3.1 0.259
RBBB 8.7 33.3‡ 18.8 0.003

Values are median (interquartile range) or %. *DPD grade 2/3 versus DPD grade 0: p # 0.05. †DPD grade 2/3 versus DPD grade 1: p#0.05. ‡DPD grade 1 versus DPD grade 0:
p # 0.05. §For patients in sinus rhythm at the time of echocardiography.
AV ¼ aortic valve; AVA ¼ aortic valve area; EDD ¼ end-diastolic diameter; EDV ¼ end-diastolic volume; EF ¼ ejection fraction; ESV ¼ end-systolic volume; GLS ¼ global
longitudinal strain; IVS ¼ interventricular septum; LA ¼ left atrial; LBBB ¼ left bundle branch block; LS ¼ longitudinal strain; LV ¼ left ventricular; MCF ¼ myocardial
contraction fraction; MPG ¼ mean pressure gradient; PPG ¼ peak pressure gradient; RBBB ¼ right bundle branch block; RV ¼ right ventricular; sPAP ¼ systolic pulmonary artery
pressure; SVi ¼ stroke volume index; TAPSE ¼ tricuspid annular plane systolic excursion; TR ¼ tricuspid regurgitation; Vmax ¼ peak velocity; VMR ¼ voltage/mass ratio; other
abbreviation as in Tale 1.

heart team. Of these 407 patients, 333 (81.6%) un- Independent predictors of presence of CA by
derwent TAVR; SAVR was performed in 10 (2.5%) multivariate linear regression analysis were a longer
patients, and conservative management or ongoing QRS duration (odds ratio [OR]: 2.51; 95% CI: 1.15 to
surveillance was pursued in 65 (15.9%) patients. 5.49; p ¼ 0.021), a lower voltage/mass ratio (OR: 0.37;
PREVALENCE, TYPE, AND PREDICTORS OF AS-CA. 95% CI: 0.16 to 0.87; p ¼ 0.022), and history of carpal
Cardiac tracer uptake on DPD bone scintigraphy was tunnel syndrome (OR: 1.55; 95% CI: 1.06 to 2.28;
present in 48 patients (11.8%). Distribution according p ¼ 0.024).
to the Perugini classification was as follows: 16 (3.9%) LONE AS VERSUS AS-AMYLOIDOSIS (GRADE 2/3
patients were in grade 1 (AS-amyloid), and 32 (7.9%) AS-CA). Patients with AS-amyloidosis (grade 2/3 AS-
patients were in grade 2/3 (AS-amyloidosis). ATTR CA; n ¼ 32) were 3 years older compared with pa-
was found in 47 patients (all wild-type confirmed by tients with lone AS (86.6 vs. 83.6 years; p < 0.001),
genotyping), and 1 patient had AL, as previ- with a trend toward higher percentage in men (men:
ously described. 65% vs. women: 48%; p ¼ 0.06) (Table 1); patients with
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JANUARY 19, 2021:128–39 Outcome of Cardiac Amyloidosis and Aortic Stenosis

F I G U R E 2 Scoring System for the Discrimination of Lone AS and Dual Pathology AS-CA

1.0
Parameter Points

0.8 CTS 3
RBBB 2
Sensitivity

0.6 Age ≥85 years 1

Hs-TnT >20 ng/l 1
0.4
IVS ≥18 mm 1
If in SR*: E/A ratio >1.4 1
0.2
If no BBB or PM: Sokolow index <1.9 mV 1
AUC 0.85 (0.79-0.91)
0.0 * AUC for AFib sub-cohort: 0.83
0.0 0.2 0.4 0.6 0.8 1.0
1-Specificity

Score Specificity Sensitivity

≥6 points 100% 14.9%
≥5 points 98.9% 23.4%
≥4 points 95.0% 42.6%
≥3 points 83.6% 72.3%
≥2 points 52.1% 93.6%
≥1 point 16.7% 97.9%

Scoring system for the discrimination of lone AS and dual pathology AS-CA. AFib ¼ atrial fibrillation; AS ¼ aortic stenosis; AUC ¼ area under
the curve; BBB ¼ bundle branch block; CA ¼ cardiac amyloidosis; CTS ¼ carpal tunnel syndrome; Hs-TnT ¼ high-sensitivity troponin T; IVS ¼
interventricular septum; PM ¼ pacemaker; RBBB ¼ right bundle branch block; SR ¼ sinus rhythm.

AS-amyloidosis had a higher prevalence of carpal On echocardiographic assessment (Table 2), pa-
tunnel syndrome (18.8% vs. 1.1%; p < 0.001) and had a tients with AS-amyloidosis had slightly lower gradi-
lower prevalence of coronary and peripheral artery ents (aortic valve Vmax 3.9 m/s vs. 4.2 m/s; aortic
disease (p < 0.05). Functional capacity was decreased valve peak/mean gradient 60/36 mm Hg vs.
significantly, as measured by a shorter 6-min walk 71/44 mm Hg; p < 0.05), although there was no
distance (94 m [IQR: 50 to 225 m] vs. 194 m [IQR: 82 to significant difference in absolute or indexed aortic
286 m]; p ¼ 0.038). Cardiac biomarkers were signifi- valve area (p ¼ 0.5 and p ¼ 0.3, respectively). Low-
cantly elevated: NT-proBNP: 4,855 ng/dl (IQR: 1,412 to flow, low-gradient AS (stage D2 or D3) was more
7,494 ng/dl) versus 1,606 ng/dl (IQR 640 to 3,843 ng/ prevalent among patients with AS-amyloidosis (56.2%
dl) in lone AS (p ¼ 0.001); and hsTnT: 49 ng/l (IQR: 33 vs. 32.9%; p ¼ 0.01) and was equally split between
to 87 ng/l) versus 24 ng/l (IQR: 15 to 39 ng/l) (p < 0.001; classical and paradoxical low-flow, low-gradient AS.
normal hsTnT: <14 ng/l). Moreover, patients with AS-amyloidosis exhibited
AS-amyloidosis was characterized by a lower worse cardiac remodeling with greater LV hypertro-
Sokolow-Lyon voltage (1.7 mV [IQR: 1.3 to 2.4 mV] vs. phy (LV mass index: 150 g/m 2 [IQR: 119 to 177 g/m 2]
2.3 mV [IQR: 1.7 to 3.0 mV]; p ¼ 0.007) and vs. 127 g/m 2 [IQR: 101 to 151 g/m 2]; p ¼ 0.006) and
2 2
voltage/mass ratio (1.1 mV/g/m  10 [IQR: 0.8 to worse diastolic dysfunction. LVEFs were not different
1.9 mV/g/m 2  10 2] vs. 1.8 mV/g/m 2  102 [IQR: 1.3 (p ¼ 0.39), whereas indexed SV trended to be lower
to 2.8 mV/g/m 2  10 2]; p ¼ 0.001). Higher right (35.8 ml/m 2 [IQR: 27.4 to 44.0 ml/m 2] vs. 40.1 ml/m 2
bundle branch block prevalence did not reach [IQR: 31.4 to 48.0 ml/m 2]; p ¼ 0.06). The myocardial
significance (18.8% vs. 8.7%; p ¼ 0.06). contraction fraction, the SV per myocardial volume,
134 Nitsche et al. JACC VOL. 77, NO. 2, 2021

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F I G U R E 3 1-Year Mortality for Lone AS and AS-CA

0.4
p = O.05

All-Cause Death 0.2

0.0

0 100 200 300 365

Time (Days)
No. at risk:
AS-CA 48 45 43 39 33
Lone AS 359 333 324 308 284

Patients with AS-CA experienced a trend toward higher all-cause mortality at 1 year in all patients referred for aortic valve replacement.
Abbreviations as in Figure 2.

was significantly worse (24.5% [IQR: 20.6% to 29.3%] REMODELING, AGE, INJURY, SYSTEM, AND ELECTRICAL
vs. 33.6% [IQR: 25.4% to 45.1%]; p < 0.001). Global LS SCORING SYSTEM FOR DISCRIMINATION OF LONE AS
was not different (13.7 [IQR: 17.3 to 10.2] vs. 15.6 VERSUS AS-CA. To aid clinical AS-amyloid and/or AS-
[IQR: 19.3 to 10.2]; p ¼ 0.3), but relative apical amyloidosis detection, a scoring system was created
sparing was more pronounced in AS-amyloidosis (1.1 across 5 domains: remodeling (LV hypertrophy
[IQR: 0.9 to 1.8] vs. 0.8 [IQR: 0.7 to 1.1]; p < 0.01). and/or diastolic dysfunction), age, injury (hsTnT),
LONE AS VERSUS AS-AMYLOID (GRADE 1 AS-CA). systemic (carpel tunnel syndrome), and electrical
Among patients with AS-amyloid (grade 1 AS-CA; (right bundle branch block or low voltages) (RAISE).
n ¼ 16), cardiovascular risk profiles were comparable The RAISE score captures systemic disease (carpal
with lone AS, except for a lower prevalence of arterial tunnel syndrome, 3 points), disproportionate elec-
hypertension. Carpal tunnel syndrome was more trical remodeling (right bundle branch block, 2
common (20.0% vs. 1.1%; p < 0.001). Cardiac markers points; low voltages or Sokolow-Lyon index <1.9 mV,
were the same. With the exception of a lower SV index 1 point), disproportionate myocardial remodeling
in patients with AS-amyloid (33 ml/m 2 [IQR: 30 to 39 (marked LV hypertrophy; septal wall thickness
ml/m 2] vs. 40 ml/m 2 [IQR: 31 to 48 ml/m 2]; p ¼ 0.033), $18 mm, 1 point; marked diastolic dysfunction, E/A
echocardiographic parameters did not differ, ratio >1.4, 1 point), chronic myocardial injury (hsTnT
including LV mass index, LVEF, myocardial contrac- >20 ng/l, 1 point), and age (85 years or older, 1 point).
tion fraction, E/A ratio, and strain values. On electro- The score was derived in the Vienna cohort with
cardiography, patients with AS-amyloid displayed strong discriminative power for the distinction of
longer QRS duration, mainly due to a higher preva- lone AS and AS-CA (AUC: 0.86; 95% CI: 0.78 to
lence of right bundle branch block (33.3% vs. 8.7%; 0.94; p < 0.001) and then validated in the London
p ¼ 0.002), and a lower Sokolow-Lyon voltage (1.3 mV cohort (AUC: 0.83; 95% CI: 0.75 to 0.92; p < 0.001).
[IQR: 1.0 to 2.0 mV] vs. 2.3 mV [IQR: 1.7 to 3.0 mV]; Scores of $2 and $3 points had high sensitivity
p ¼ 0.002) and voltage/mass ratio (1.2 mV/g/m 2  102 (93.6% and 72.3%), with adequate specificity
[IQR: 0.7 to 2.0 mV/g/m 2  10 2] vs. 1.8 mV/g/m 2  102 (52.1% and 83.6%) for the presence of AS-CA,
[IQR: 1.3 to 2.8 mV/g/m 2  10 2]; p ¼ 0.02). respectively (Figure 2). When excluding troponin,
JACC VOL. 77, NO. 2, 2021 Nitsche et al. 135
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F I G U R E 4 All-Cause Mortality in Lone AS Versus AS-CA Following Aortic Valve Replacement or With Medical Therapy

1.0

0.8
Medical
All-Cause Death

0.6

n.s. p = 0.001
0.4
p = 0.003
n.s.
0.2
AVR

0.0

0 1 2 3
Time (Years)
No. at risk:
AS-CA - Medical 11 4 0
Lone AS - Medical 54 35 13 0
AS-CA - AVR 37 29 13 6
Lone AS - AVR 305 249 85 30

Aortic valve replacement (AVR) improved outcomes for both lone AS and dual pathology AS-CA. Post-AVR survival of AS-CA was comparable
to lone AS. Abbreviations as in Figure 2.

the AUC was 0.81 (95% CI: 0.73 to 0.88; p < 0.001) between CA and AVR was identified (p ¼ 0.94). One-
(Supplemental Figure 1). year mortality was 10.8 (AVR) versus 31.5% (medi-
OUTCOME IN AS-CA VERSUS LONE AS. After a me- cal) for the lone AS cohort and 16.2% versus 54.5% for
dian of 1.7 years (IQR: 1.3 to 2.6 years), 97 (24%) of 407 the AS-CA cohort; this persisted out to 2 years. ATTR-
patients referred for TAVR died. In this overall cohort, targeting therapy (tafamidis only) was used in a mi-
there was a trend toward higher 1-year mortality in nority of patients with AS-CA (all after AVR, 14.9%;
patients with AS-CA versus patients with lone AS n ¼ 7 of 47) and was not associated with a mortality
(25.0% vs. 13.9%; log-rank p ¼ 0.05) (Figure 3). When difference (log-rank; p ¼ 0.40).
excluding the AL case, unadjusted all-cause mortality PREDICTORS OF OUTCOME. By multivariate Cox
of AS-CA was higher (196 deaths per 1,000 patient- regression analysis, AVR (HR: 0.62; 95% CI: 0.53 to
years) compared with lone AS (137 deaths per 1,000 0.73; p < 0.001), serum albumin (HR: 0.70; 95% CI:
patient years; p ¼ 0.001), with even those in grade 1 0.57 to 0.85; p ¼ 0.001), NT-proBNP (HR: 1.40;
having significantly higher unadjusted all-cause 95% CI: 1.12 to 1.76; p ¼ 0.003), creatinine (HR: 1.20;
mortality than those with lone AS (p < 0.001). AVR 95% CI: 1.04 to 1.38; p ¼ 0.015), and body mass index
improved survival in patients with lone AS and AS-CA (HR: 0.77; 95% CI: 0.61 to 0.97; p ¼ 0.018) were in-
compared with medical management (p < 0.001 and dependent predictors of mortality for the overall
0.003, respectively) (Figure 4). Results remained the cohort (Table 3, Supplemental Table 1). In the inter-
same when surgically managed patients were vention subgroup, independent mortality predictors
excluded (p < 0.001 and 0.017, respectively) were peri-procedural stroke (HR: 1.43; 95% CI: 1.25 to
(Supplemental Figure 2). There was a trend toward 1.63; p < 0.001), hematocrit (HR: 0.64; 95% CI: 0.48 to
higher levels of intervention in the lone AS cohort 0.84; p ¼ 0.001), serum albumin (HR: 0.73; 95% CI:
(85.0% vs. 72.7% for lone AS vs. AS-CA; p ¼ 0.07). 0.58 to 0.92; p ¼ 0.008), peak aortic jet velocity (HR:
Post-AVR, survival was comparable between lone AS 0.73; 95% CI: 0.56 to 0.95; p ¼ 0.018), left atrial
and AS-CA (log-rank; p ¼ 0.36). No interaction diameter (HR: 1.34; 95% CI: 1.03 to 1.74; p ¼ 0.032),
136 Nitsche et al. JACC VOL. 77, NO. 2, 2021

Outcome of Cardiac Amyloidosis and Aortic Stenosis JANUARY 19, 2021:128–39

We also confirmed that AS-CA was common and

T A B L E 3 Multivariate Cox regression Analysis Assessing the Association of Parameters
With Mortality in the Overall Cohort
affected 1 in 8 patients referred for TAVR, either those
with amyloid deposition (grade 1) or those with clin-
Univariate Analysis Multivariate Analysis
ical amyloidosis (grade 2/3). The presence of occult
Baseline Clinical Parameters HR (95% CI) p Value HR (95% CI) p Value
ATTR in AS was first described in patients who un-
Aortic valve replacement 0.621 (0.5320.725) <0.001 0.617 (0.5260.723) <0.001
derwent SAVR in 2016 (21). Since then, data from
Albumin 0.605 (0.5510.804) <0.001 0.699 (0.5720.854) 0.001
multiple retrospective and prospective studies were
NT-proBNP* 1.555 (1.2601.918) <0.001 1.401 (1.1181.755) 0.003
Creatinine 1.249 (1.0981.422) <0.001 1.196 (1.0351.383) 0.015
reported, (4–7,22,23), most of which were solely
BMI 0.721 (0.5740.905) 0.005 0.765 (0.6130.965) 0.018 dedicated to ATTR. This study added to the existing
Troponin T 1.354 (1.2041.522) <0.001 data on the prevalence of AS-CA (4–7); data from our
Hematocrit 0.741 (0.6040.909) 0.004 study and other studies was 10 times higher than that
Dual AS-CA 1.145 (0.9701.352) 0.100 in unselected populations, in which prevalence in the
AV-Vmax 0.673 (0.5510.823) <0.001
older adults was <1% in those aged 80 years or older
AV-MPG 0.666 (0.5320.834) 0.001
(24). CA in AS is predominantly of the ATTR-type, but
LVEF 0.825 (0.6840.995) 0.045
AL-amyloidosis needs to be excluded by concomitant
LVESV 1.270 (1.0771.498) 0.004
GLS 1.263 (1.0491.521) 0.014 screening for plasma cell dyscrasia (25). Although
Apical LS 1.260 (1.0541.505) 0.011 most of the patients with CA in the present series had
Mid-ventricular LS 1.237 (1.0301.486) 0.023 ATTR, 1 case of AL was identified. Although inter-
pretation of light-chain results is challenging and re-
Bold values indicate statistical significance in multivariate testing. *NT-proBNP was graded into quartiles for this
analysis. quires multidisciplinary decision-making processes,
AS-CA ¼ dual aortic stenosis and cardiac amyloid pathology; CI ¼ confidence interval; HR ¼ hazard ratio; other AL screening is essential in case of suspicion for CA,
abbreviations as in Tables 1 and 2.
because it usually requires urgent specific treatment
(26).
The perception of futility of aortic valve interven-
and body mass index (HR: 0.73; 95% CI: 0.54 to 0.98; tion in AS-CA (27) originated from limited data in
p ¼ 0.033) (Supplemental Table 2). small observational studies. In our data, we clearly
PERI-PROCEDURAL COMPLICATIONS. In patients showed that TAVR improved outcome in patients
who underwent TAVR, major adverse events accord- with AS-CA, and that on the basis of these data, TAVR
ing to Valve Academic Research Consortium-2 should not be withheld from patients with dual pa-
occurred at the same rate in those with lone AS and thology AS-CA. The clinical picture in AS-amyloidosis
AS-CA: stroke (2.7% vs. 2.9%); vascular complication (grade 2/3), with lower functional capacity, elevated
(4.7% vs. 2.9%); acute kidney injury (7.5% vs. 6.1%); biomarkers, and impaired biventricular function,
and pacemaker implantation (6.4% vs. 14.7%) (p for highlighted a more decompensated clinical state that
all >0.05). would likely affect outcome; although in our cohort,
there was no statistical outcome difference in those
DISCUSSION patients who underwent TAVR. Patients with AS-
amyloid (grade 1) also had worse outcomes, despite
In this international multicenter study of older pa- only mild remodeling (with a lower SV index) and a
tients with severe AS referred for TAVR, we showed lower prevalence of electrical disturbances; there-
that dual pathology of severe AS-CA conferred overall fore, AS-amyloid could not be considered as clinically
worse disease by functional capacity, cardiac remod- irrelevant or benign. Larger prospective studies and
eling and biomarkers, and could be predicted by a registry data are warranted to understand the
simple clinical score. Despite blinding clinicians importance of grade 1 AS-amyloid.
before heart team decisions, fewer patients with AS- Routine screening of older adult patients with se-
CA underwent TAVR and had overall worse out- vere AS or AS-CA using bone scintigraphy is not
comes. However, if patients with AS-CA were selected feasible in routine clinical practice. However, patients
for and received TAVR, their outcomes were indis- with AS-CA have distinct clinical risk profiles,
tinguishable from patients with lone AS. Medically including older age, a history of carpal tunnel syn-
managed patients (both patients with lone AS or AS- drome, elevated troponin levels, increased septal
CA) had poor survival in line with previously pub- thickness and E/A ratio on echocardiography, and
lished data (e.g., PARTNER 1B trial [20]) (Central right bundle branch block and lower Sokolow criteria
Illustration). Therefore, we concluded that a diag- on electrocardiography. Those parameters were in-
nosis of AS-CA should not preclude patients from tegrated into a simple clinical scoring system that
TAVR. helped to identify patients with AS with a high
JACC VOL. 77, NO. 2, 2021 Nitsche et al. 137
JANUARY 19, 2021:128–39 Outcome of Cardiac Amyloidosis and Aortic Stenosis

C ENTR AL I LL U STRA T I O N Concomitant Pathology Aortic Stenosis-Cardiac Amyloidosis

Nitsche, C. et al. J Am Coll Cardiol. 2021;77(2):128–39.

Concomitant pathology aortic stenosis-cardiac amyloidosis. PARTNER 1B data adapted from Kapadia et al. (20). AS ¼ aortic stenosis;
99m
AVR ¼ aortic valve replacement; CA ¼ cardiac amyloidosis; DPD ¼ technetium-3,3-diphosphono-1,2-propanodicarboxylic acid;
RBBB ¼ right bundle branch block; TAVR ¼ transcatheter aortic valve replacement.

likelihood of coexisting CA and guide referral for bone limited data on amyloid prevalence in the aging
scintigraphy and exclusion of plasma cell dyscrasia. general population, ATTR has a lower prevalence in
We proposed a stepwise screening process for CA in noncardiac patients (<1%) and predominantly af-
older adult patients with severe AS. The proposed fects older adult men (24). AS-CA appears to be
algorithm would allow high-volume TAVR centers to different, with not only a 10 times higher general
detect CA with high sensitivity, without overstraining prevalence, but also near equal sex distribution and
local resources. Based on the data presented (see predilection for grade 2/3 tracer uptake in AS (rather
Figure 2), scores of $2 points would instigate further than an equal distribution between grades). These
screening by bone scintigraphy and light-chain observations point toward a causal relationship be-
assessment. TAVR should not be delayed for AS-CA tween AS and amyloid. The increased LV afterload
workup without evidence of plasma cell dyscrasia posed by AS was hypothesized to prime the LV for
because TAVR improves survival. An alternative deposition of amyloid fibrils (6,29). This might be
approach would be screening by obtaining the extra- driven by increased extracellular matrix turnover,
cellular volume fraction from pre-procedural TAVR low grade inflammation, chronic subendocardial
cardiac computed tomography (28); the use of routine ischemia, and resultant cell death because both
cardiac magnetic resonance is not feasible in all TAVR fibrosis and amyloid deposition occur with an
patients. endocardial to epicardial gradient. In particular, the
Underlying pathophysiological aspects of AS-CA significant shear stresses in AS could cause an
are still incompletely understood. Despite the increased TTR deposition through a mechano-
138 Nitsche et al. JACC VOL. 77, NO. 2, 2021

Outcome of Cardiac Amyloidosis and Aortic Stenosis JANUARY 19, 2021:128–39

enzymatic cleavage process (30). Valve intervention, LS was comparable between groups. This should be
per se, might stabilize ATTR by reducing the shear  was
re-evaluated in future studies. Mitral annular S
stresses and thereby the aforementioned mechano- not available for the derivation cohort (Vienna);
enzymatic cleavage process (30), like AVR im- therefore, respective data were not presented. Single-
proves gastrointestinal bleeding in Heyde syndrome photon emission computed tomography/computed
by reducing activation of acquired type-2A von tomography was not performed in the Vienna cohort;
Willebrand factor (31). Alternatively, common up- however, blinded core laboratory adjudication
stream pathways might affect both amyloidosis and ensured that the diagnosis was as accurate as
valve stenosis progression; for example, higher possible. Cause of mortality was not ascertained.
levels of systemic inflammation might accelerate
aortic valve calcification and drive greater cardiac CONCLUSIONS
deposition of amyloidogenic proteins (32). Further
research is warranted to strengthen our under- Dual pathology of AS-CA is common in older patients
standing of underlying mechanisms of AS-CA, with AS referred for possible TAVR. We presented a
especially with respect to amenability to novel simple clinical scoring system to help identify those
TTR therapeutics. Whether patients with AS-CA in whom bone scintigraphy is indicated. Patients with
post-AVR (i.e., afterload is treated) will benefit AS-CA had worse functional capacity, cardiac
from novel therapies that stabilize the TTR tetramer remodeling pre-procedure, and a trend toward worse
(tafamidis) (33) or reduce TTR serum levels (AG10, prognosis if not treated by TAVR. However, mortality
inotersen, patisiran) (34–36) is unclear. In our study, was the same if TAVR was performed. Based on these
7 of 47 patients with ATTR-CA received tafamidis data, TAVR should not be withheld in AS-CA.
after AVR (on a named patient program in Austria).
AUTHOR DISCLOSURES
Survival of the 40 therapy-naïve patients with ATTR
was similar to lone AS and parallel to findings in
The authors have reported that they have no relationships relevant to
other studies (6,9). Multicenter registries (e.g., the the contents of this paper to disclose.
Aortic Stenosis & Amyloidosis Registry) and larger
studies of patients with CA post-AVR are required ADDRESS FOR CORRESPONDENCE: Dr. Thomas
to elucidate the benefit of ATTR therapy in this Treibel, Barts Heart Centre, St. Bartholomew’s Hos-
patient cohort, ideally in a randomized controlled pital, West Smithfield, London EC1A 7BE, United
trial (patients with AS were excluded from previous Kingdom. E-mail: Thomas.Treibel@nhs.net. Twitter:
randomized controlled trials in this area). @ThomasTreibel.

STUDY LIMITATIONS. Despite the recruitment of pa-

tients before heart team recommendations, there PERSPECTIVES
might still be a selection bias of those patients who
were actually referred to recruiting centers. Blinding
COMPETENCY IN PATIENT CARE AND PROCE-
pre-procedure was broken for 2 reasons: 7 patients
DURAL SKILLS: Concomitant CA occurs in 1 of 8
had plasma cell dyscrasia that necessitated unblind-
patients with severe AS referred for TAVR and is
ing, as per protocol. Austrian and U.K. centers used
associated with more severe functional incapacity,
echocardiographic strain software from different
cardiac remodeling, and adverse prognosis. Following
vendors, which might have affected comparability of
TAVR, the outcomes of patients with concomitant CA
respective data. Dual pathology AS-CA is much rarer
were not significantly different from those with AS
in younger patients (21), and at middle age, would be
without CA.
affected by a different valve etiology (likely bicuspid)
and amyloid type (AL or hereditary ATTR). These
TRANSLATIONAL OUTLOOK: Future studies
were not investigated in the present study; therefore,
should determine whether ATTR-specific treatment
prognosis and management strategies were not
improves survival in patients with AS and ATTR-CA
generalizable to this younger group. As opposed to
following aortic valve replacement.
previous findings (7), relative apical sparing was more
pronounced in patients with AS-CA, whereas global
JACC VOL. 77, NO. 2, 2021 Nitsche et al. 139
JANUARY 19, 2021:128–39 Outcome of Cardiac Amyloidosis and Aortic Stenosis

REFERENCES

1. Coffey S, Cox B, Williams MJ. The prevalence, 13. Nagueh SF, Smiseth OA, Appleton CP, et al. 24. Longhi S, Guidalotti PL, Quarta CC, et al.
incidence, progression, and risks of aortic valve Recommendations for the evaluation of left ven- Identification of TTR-related subclinical amyloid-
sclerosis: a systematic review and meta-analysis. tricular diastolic function by echocardiography: an osis with 99mTc-DPD scintigraphy. J Am Coll
J Am Coll Cardiol 2014;63:2852–61. update from the American Society of Echocardi- Cardiol Img 2014;7:531–2.
2. Schwarz F, Baumann P, Manthey J, et al. The ography and the European Association of Cardio-
25. Maurer MS, Bokhari S, Damy T, et al. Expert
effect of aortic valve replacement on survival. vascular Imaging. J Am Soc Echocardiogr 2016;29:
consensus recommendations for the suspicion and
Circulation 1982;66:1105–10. 277–314.
diagnosis of transthyretin cardiac amyloidosis. Circ
3. Gertz MA, Dispenzieri A, Sher T. Pathophysi- 14. Baumgartner H, Hung J, Bermejo J, et al. Heart Fail 2019;12:e006075.
ology and treatment of cardiac amyloidosis. Nat Recommendations on the echocardiographic 26. Gertz MA. Immunoglobulin light chain
Rev Cardiol 2015;12:91–102. assessment of aortic valve stenosis: a focused amyloidosis: 2018 update on diagnosis, prognosis,
4. Nitsche C, Aschauer S, Kammerlander AA, update from the European Association of Cardio- and treatment. Am J Hematol 2018;93:1169–80.
et al. Light-chain and transthyretin cardiac vascular Imaging and the American Society of
Echocardiography. J Am Soc Echocardiogr 2017; 27. Ternacle J, Krapf L, Mohty D, et al. Aortic
amyloidosis in severe aortic stenosis: preva-
30:372–92. stenosis and cardiac amyloidosis: JACC review
lence, screening possibilities, and outcome. Eur
topic of the week. J Am Coll Cardiol 2019;74:
J Heart Fail 2020 Feb 20 [Epub ahead of 15. Devereux RB, Alonso DR, Lutas EM, et al. 2638–51.
print]. Echocardiographic assessment of left ventricular
28. Scully PRP KP, Saberwal B. Identifying cardiac
hypertrophy: comparison to necropsy findings. Am
5. Scully PR, Treibel TA, Fontana M, et al. Preva- amyloid in aortic stenosis - ECV quantification by
J Cardiol 1986;57:450–8.
lence of cardiac amyloidosis in patients referred cardiac CT in TAVR patients. J Am Coll Cardiol Img
for transcatheter aortic valve replacement. J Am 16. Lang RM, Badano LP, Mor-Avi V, et al. Rec- 2020;13:2177–89.
Coll Cardiol 2018;71:463–4. ommendations for cardiac chamber quantification
29. Galat A, Guellich A, Bodez D, et al. Aortic
by echocardiography in adults: an update from the
6. Scully PR, Patel KP, Treibel TA, et al. Prevalence stenosis and transthyretin cardiac amyloidosis: the
American Society of Echocardiography and the
and outcome of dual aortic stenosis and cardiac chicken or the egg? Eur Heart J 2016;37:3525–31.
European Association of Cardiovascular Imaging.
amyloid pathology in patients referred for trans- 30. Marcoux J, Mangione PP, Porcari R, et al.
Eur Heart J Cardiovasc Imaging 2015;16:233–70.
catheter aortic valve implantation. Eur Heart J A novel mechano-enzymatic cleavage mechanism
2020;41:2759–67. 17. King DL, El-Khoury Coffin L, Maurer MS.
underlies transthyretin amyloidogenesis. EMBO
Myocardial contraction fraction: a volumetric in-
7. Castano A, Narotsky DL, Hamid N, et al. Mol Med 2015;7:1337–49.
dex of myocardial shortening by freehand three-
Unveiling transthyretin cardiac amyloidosis and its 31. Godino C, Lauretta L, Pavon AG, et al. Heyde’s
dimensional echocardiography. J Am Coll Cardiol
predictors among elderly patients with severe syndrome incidence and outcome in patients un-
2002;40:325–9.
aortic stenosis undergoing transcatheter aortic dergoing transcatheter aortic valve implantation.
valve replacement. Eur Heart J 2017;38:2879–87. 18. Hutt DF, Quigley AM, Page J, et al. Utility
J Am Coll Cardiol 2013;61:687–9.
and limitations of 3,3-diphosphono-1,2-
8. Gillmore JD, Maurer MS, Falk RH, et al. Non- 32. Bois JP, Crowson CS, Khullar T, Achenbach SJ,
propanodicarboxylic acid scintigraphy in systemic
biopsy diagnosis of cardiac transthyretin Krause ML, Mankad R. Progression rate of
amyloidosis. Eur Heart J Cardiovasc Imaging 2014;
amyloidosis. Circulation 2016;133:2404–12. severity of aortic stenosis in patients with rheu-
15:1289–98.
9. Rosenblum H, Masri A, Narotsky DL, et al. matoid arthritis. Echocardiography 2017;34:
19. Perugini E, Guidalotti PL, Salvi F, et al. 1410–6.
Unveiling outcomes in coexisting severe aortic
Noninvasive etiologic diagnosis of cardiac
stenosis and transthyretin cardiac amyloidosis. Eur 33. Maurer MS, Sultan MB, Rapezzi C. Tafamidis
amyloidosis using 99mTc-3,3-diphosphono-1,2-
J Heart Fail 2020 Jul 30 [Epub ahead of print]. for transthyretin amyloid cardiomyopathy. N Engl
propanodicarboxylic acid scintigraphy. J Am Coll
J Med 2019;380:196–7.
10. Kligfield P, Gettes LS, Bailey JJ, et al. Rec- Cardiol 2005;46:1076–84.
ommendations for the standardization and inter- 34. Benson MD, Waddington-Cruz M, Berk JL,
20. Kapadia SR, Leon MB, Makkar RR, et al. 5-year
pretation of the electrocardiogram: part I: the et al. Inotersen treatment for patients with he-
outcomes of transcatheter aortic valve replace-
electrocardiogram and its technology a scientific reditary transthyretin amyloidosis. N Engl J Med
ment compared with standard treatment for pa-
statement from the American Heart Association 2018;379:22–31.
tients with inoperable aortic stenosis (PARTNER
Electrocardiography and Arrhythmias Committee,
1): a randomised controlled trial. Lancet 2015;385: 35. Judge DP, Heitner SB, Falk RH, et al. Trans-
Council on Clinical Cardiology; the American Col-
2485–91. thyretin stabilization by AG10 in symptomatic
lege of Cardiology Foundation; and the Heart
transthyretin amyloid cardiomyopathy. J Am Coll
Rhythm Society endorsed by the International 21. Treibel TA, Fontana M, Gilbertson JA, et al.
Cardiol 2019;74:285–95.
Society for Computerized Electrocardiology. J Am Occult transthyretin cardiac amyloid in severe
Coll Cardiol 2007;49:1109–27. calcific aortic stenosis: prevalence and prognosis 36. Adams D, Gonzalez-Duarte A, O’Riordan WD,
in patients undergoing surgical aortic valve et al. Patisiran, an RNAi therapeutic, for hereditary
11. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/
replacement. Circ Cardiovasc Imaging 2016;9: transthyretin amyloidosis. N Engl J Med 2018;379:
EACTS guidelines for the management of valvular
e005066. 11–21.
heart disease. Rev Esp Cardiol (Engl Ed) 2018;71:
110. 22. Cavalcante JL, Rijal S, Abdelkarim I, et al.
Cardiac amyloidosis is prevalent in older patients
12. Nishimura RA, Otto CM, Bonow RO, et al. 2017 KEY WORDS aortic stenosis, cardiac
with aortic stenosis and carries worse prognosis.
AHA/ACC focused update of the 2014 AHA/ACC amyloidosis, TAVR
J Cardiovasc Magn Reson 2017;19:98.
guideline for the management of patients with
valvular heart disease: a report of the American 23. Longhi S, Lorenzini M, Gagliardi C, et al.
College of Cardiology/American Heart Association Coexistence of degenerative aortic stenosis and A PP END IX For supplemental tables and
Task Force on Clinical Practice Guidelines. J Am wild-type transthyretin-related cardiac amyloid- figures, please see the online version of this
Coll Cardiol 2017;70:252–89. osis. J Am Coll Cardiol Img 2016;9:325–7. paper.