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Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths Esther Gonzalez-L opez 1,2,3, Christian Gagliardi4 , Fernando Dominguez1,3, Cristina Candida Quarta4 , F. Javier de Haro-del Moral5 , Agnese Milandri4 , Clara Sala

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Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths Esther Gonzalez-L opez 1,2,3, Christian Gagliardi4 , Fernando Dominguez1,3, Cristina Candida Quarta4 , F. Javier de Haro-del Moral5 , Agnese Milandri4 , Clara Salas3,6, Mario Cinelli4 , Marta Cobo-M...

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European Heart Journal (2017) 38, 1895–1904 CLINICAL RESEARCH
doi:10.1093/eurheartj/ehx043 Heart failure/cardiomyopathy

Clinical characteristics of wild-type transthyretin
cardiac amyloidosis: disproving myths
Esther Gonza pez1,2,3, Christian Gagliardi4, Fernando Dominguez1,3,
lez-Lo
Cristina Candida Quarta4, F. Javier de Haro-del Moral5, Agnese Milandri4,
Clara Salas3,6, Mario Cinelli4, Marta Cobo-Marcos1,3, Massimiliano Lorenzini4,

Downloaded from https://academic.oup.com/eurheartj/article/38/24/1895/3059372 by guest on 15 May 2024
Enrique Lara-Pezzi2,3, Serena Foffi4, Luis Alonso-Pulpon1,3, Claudio Rapezzi4, and
Pablo Garcia-Pavia1,3,7*
1
Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; 2Myocardial Biology Programme, Centro
Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; 3Centro de Investigaci
on Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV); 4Institute of
Cardiology, University of Bologna and S Orsola-Malpighi Hospital, Bologna, Italy; 5Department of Nuclear Medicine, Hospital Universitario Puerta de Hierro, Madrid, Spain;
6
Department of Pathology, Hospital Universitario Puerta de Hierro, Madrid, Spain; and 7Medical School, Francisco de Vitoria University, Madrid, Spain

Received 18 July 2016; revised 22 October 2016; editorial decision 20 January 2017; accepted 24 January 2017; online publish-ahead-of-print 1 March 2017

See page 1909 for the editorial comment on this article (doi: 10.1093/eurheartj/ehx210)

Aims Wild-type transthyretin amyloidosis (ATTRwt) is mostly considered a disease predominantly of elderly male, char-
acterized by concentric LV hypertrophy, preserved LVEF, and low QRS voltages. We sought to describe the char-
acteristics of a large cohort of ATTRwt patients to better define the disease.
...................................................................................................................................................................................................
Methods Clinical findings of consecutive ATTRwt patients diagnosed at 2 centres were reviewed. ATTRwt was diagnosed
and results histologically or non-invasively (LV hypertrophy >_12 mm, intense cardiac uptake at 99mTc-DPD scintigraphy and AL
exclusion). Mutations in TTR were excluded in all cases. The study cohort comprised 108 patients (78.6 ± 8 years);
67 (62%) diagnosed invasively and 41 (38%) non-invasively. Twenty patients (19%) were females. An asymmetric
hypertrophy pattern was observed in 25 (23%) patients. Mean LVEF was 52 ± 14%, with 39 patients (37%) showing
a LVEF < 50%. Atrial fibrillation (56%) and a pseudo-infarct pattern (63%) were the commonest ECG findings. Only
22 patients fulfilled QRS low-voltage criteria while 10 showed LV hypertrophy on ECG. Although heart failure was
the most frequent profile leading to diagnosis (68%), 7% of individuals presented with atrioventricular block and
11% were diagnosed incidentally. Almost one third (35; 32%) were previously misdiagnosed.
...................................................................................................................................................................................................
Conclusion The clinical spectrum of ATTRwt is heterogeneous and differs from the classic phenotype: women are affected in a
significant proportion; asymmetric LV hypertrophy and impaired LVEF are not rare and only a minority have low
QRS voltages. Clinicians should be aware of the broad clinical spectrum of ATTRwt to correctly identify an entity
for which a number of disease-modifying treatments are under investigation.
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Keywords Cardiac amyloidosis • Transthyretin • Wild-type • 99mTc-DPD • Scintigraphy

..
Introduction .. transthyretin amyloidosis (ATTRwt), also known as senile systemic
.. amyloidosis, is said to be present.3
..
Small amyloid deposits of structurally unstable transthyretin (TTR) fi- .. In contrast to other forms of amyloidosis, ATTRwt almost exclu-
brils have been found in autopsies of 14 to 25% of elderly individuals .. sively affects the heart, with the exception of carpal tunnel syndrome
..
depending on patient selection and amyloid detection methodology .. (CTS)3,4 and lumbar spinal canal stenosis.5 Patients affected by
employed.1,2 When wild-type TTR (TTRwt) is deposited in greater
.. ATTRwt can suffer from heart failure (HF), arrhythmias6 and other
..
amounts in the heart leading to clinical manifestation, wild-type . common cardiac manifestations including angina.3,4 The first series of

* Corresponding author. Tel: þ34 911917297, Fax: þ34 911917718, Email: pablogpavia@yahoo.es
Published on behalf of the European Society of Cardiology. All rights reserved. V
C The Author 2017. For permissions, please email: journals.permissions@oup.com.

, 1896 E. Gonzalez-L
opez et al.

..
ATTRwt with clinical manifestations was published in 1987.7 Since .. Data collection
then, however, studies describing the natural history and clinical char- .. Demographic and clinical characteristics were collected at admission or
..
acteristics of the condition have been few and included limited num- .. at presentation at the outpatient clinic. Age, date of ATTRwt diagnosis
ber of patients, from a small number of referral centres.8,9 .. and symptoms onset were obtained. The clinical profile leading to
.. ATTRwt diagnosis was recorded as well as the previous diagnosis. Data
Based on the available case series, ATTRwt has been traditionally ..
considered a remarkably sex-specific disease3,4 with a very strong .. regarding functional class according to New York Heart Association
.. (NYHA), heart failure signs, admissions due to cardiovascular causes,
male predominance affecting only patients over 60 years old.3,4 The ..
accepted ATTRwt clinical phenotype also includes concentric left .. blood pressure, and treatment at first evaluation were obtained.
.. Hypertension was defined based on clinical history or use of, at least,
ventricle (LV) hypertrophy, preserved left ventricular ejection frac- ..
tion (LVEF)3,4,9 and normal or low QRS voltages on ECG.3,4 .. one antihypertensive medication at presentation. Coronary artery dis-
.. ease (CAD) was defined by previous history of myocardial infarction or
Although the demonstration of TTR amyloid deposits on endo- .. by the presence of at least moderate coronary stenosis by angiography.
myocardial biopsy (EMB) plus the absence of mutations in the TTR ..
.. Left-sided valve disease was defined as the presence of moderate or se-
gene remains the gold standard for the diagnosis of ATTRwt,3,4 in re- ..

Downloaded from https://academic.oup.com/eurheartj/article/38/24/1895/3059372 by guest on 15 May 2024
vere regurgitation or stenosis by echocardiography according to current
cent years, cardiac magnetic resonance (CMR) has been shown to be ..
.. guidelines. The history of monoclonal gammopathy of undetermined sig-
helpful in the work-up for cardiac amyloidosis10 and scintigraphy with .. nificance (MGUS) or CTS was also collected.
diphosphonate agents has been proven very useful in identifying pa-
.. Blood test parameters were collected from the first blood test avail-
..
tients with cardiac amyloidosis.10,11 Furthermore, non-invasive diag- .. able. Creatinine clearance was calculated using CKD-EPI formula and
nostic criteria for cardiac ATTR amyloidosis based on technetium-
.. NT-proBNP was obtained when available.
..
labelled bone scintigraphy and absence of a monoclonal protein in .. Follow-up started at the time of diagnosis of ATTRwt. Information on
serum or urine have been proposed very recently.12
.. patient’s final status was obtained from medical records or from the pri-
..
Although the true prevalence of ATTRwt in the general population .. mary care physicians. Overall mortality was defined as mortality due to
.. any cause during follow-up. Cardiovascular mortality was considered if
remains unknown,4 we are witnessing a significant increase in the ..
.. death was caused by heart failure, myocardial infarction or stroke. A com-
number of referred patients with the suspicion of ATTRwt and sev-
.. mittee formed by two physicians adjudicated these events. A third phys-
eral recent reports suggest that ATTRwt could be the most frequent .. ician resolved discrepancies.
form of cardiac amyloidosis.4,13,14 ..
..
The need for a better delineation of ATTRwt clinical characteris- .. ECG
tics is stressed by the fact that diagnosing this disease should lead clin- ..
.. ECG measures were based on standard definitions using the first ECG
icians to avoid certain drugs and to screen patients for possible .. available when the diagnosis of ATTRwt was made. Low voltage was as-
complications such as atrial arrhythmias and conduction disorders.3,4 ..
.. sessed by limb or precordial criteria (QRS amplitude <_0.5 mV in all limb
Furthermore, several new therapies are under development for this .. leads or <_1 mV in all precordial leads)3,10 and Sokolow index (<_1.5
condition,4,15,16 some of which have shown promising preliminary .. mV).19,20 Electrocardiograhic LV hypertrophy was evaluated according to
..
results.16,17 .. Sokolow criteria and voltage-to-mass ratio was calculated as peripheral
In the context that ATTRwt diagnosis has clinical implications and .. QRS score divided by indexed LV mass. Ventricular-paced QRS com-
..
that ATTRwt could soon be treatable, cardiologists should be familiar .. plexes were excluded.
with the broad clinical spectrum of the disease in order to correctly ..
..
identify it. .. Echocardiography
The purpose of this study was to describe the main clinical charac-
.. Chamber and LVEF quantification was based on standard recommenda-
..
teristics of a large cohort of patients with ATTRwt to better define .. tions.21 Patterns of hypertrophy were defined as previously described.22
the disease.
.. LV mass was evaluated by M-mode and myocardial contraction fraction
.. (MCF) was calculated.23
..
..
.. 99m
Tc-DPD-scintigraphy
Methods ..
.. 99m
Tc-DPD-scintigraphy studies were performed and evaluated as
.. described elsewhere.14,18 The scan was considered positive when it re-
We conducted a descriptive study at two tertiary university hospitals in ..
Bologna (Italy) and Madrid (Spain). Information from prospective local .. vealed a moderate to severe 99mTc-DPD uptake (Perugini score 2–3) in
databases and clinical charts of all patients diagnosed with ATTRwt at
.. both ventricles.18
..
both centres over a 16-year period (Bologna) and a 6-year period ..
(Madrid) were reviewed. .. Genotyping
..
.. All patients underwent genetic analysis for mutations in TTR gene. The
.. coding regions of the TTR gene were amplified by polymerase chain reac-
Study patients ..
ATTRwt was diagnosed in the presence of (1) cardiac involvement and .. tion and amplified DNA fragments were directly sequenced.
..
TTR deposits on tissue biopsy or (2) non-invasively, in the presence of: ..
cardiac involvement defined as maximal left ventricular wall thickness .. Histology
>_12 mm, intense biventricular uptake (Perugini Score 2–3) on 99mTc-
.. Patients underwent cardiac, abdominal fat or salivary gland biopsies if con-
..
DPD scintigraphy18 and AL exclusion by serum and urine protein electro- .. sidered by their treating physicians. Sections from formalin-fixed, paraffin-
phoresis by immunofixation electrophoresis plus serum free light chain .. embedded biopsy specimens were stained with Haematoxylin-Eosin and
assay.4,12 In all cases, genetic testing confirmed the absence of mutations
..
.. Congo Red. Immunostaining was performed using the following antibodies:
in the TTR gene. . monoclonal antibody directed against AA amyloid, TTR, k-light chain, and

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Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths Esther Gonzalez-L opez 1,2,3, Christian Gagliardi4 , Fernando Dominguez1,3, Cristina Candida Quarta4 , F. Javier de Haro-del Moral5 , Agnese Milandri4 , Clara Sala

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