Contribution and Risks of Left Ventricular

DOI: 10.1161/CIRCULATIONAHA.13.001414
Contribution and Risks of Left Ventricular
Endomyocardial Biopsy in Patients with Cardiomyopathies:
A Retrospective Study over a 28-Year Period
Running title: Chimenti et al.; Contribution and risks of left ventricular biopsy
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Cristina Chimenti, MD, PhD1,2; Andrea Frustaci, MD1-3
1
Cardiovascular,
Card
Ca
rdio
rd
iova
io
vascul
va
ulaar,
ul
ar Respiratory, Nefrologic and
nd
dG
Geriatric
eriatric Sciences D
Department,
epar
ep
a tment, La Sapienza
Un
niv
i ersity, Rome,
Roome,
me Italy;
Ital
It
aly;
y; 2IR
IRCCS
IRCC
CCS
CC
S Sa
San
n Ra
Raff
Raffaele
ffaeele
ff
l L
Laa Pisa
Pisana,
sanna,
sa
na, Ro
R
Rome,
me, It
Ital
Italy;
aly;
al
y 3IR
IRCCS
RCC
CCS
S L Sp
Spal
Spallanzani,
alla
lanz
la
nzan
nz
an
ni,
University,
Rome,
Rome,, It
Rome
Italy
tal
alyy
Address for Correspondence:
Andrea Frustaci, MD
Cardiovascular and Respiratory Sciences Department
La Sapienza University
Viale del Policlinico 155
00161 Rome, Italy
Tel: +390655170575
Fax: +390655170577
E-mail: [email protected]
Journal Subject Codes: Hypertension:[16] Myocardial cardiomyopathy disease, Diagnostic
testing:[33] Other diagnostic testing
1
DOI: 10.1161/CIRCULATIONAHA.13.001414
Abstract:
Background—Use of left ventricular (LV) endomyocardial biopsy (EMB) for investigation of
cardiomyopathies is currently discouraged as considered more risky and equally contributive
than right ventricular (RV) biopsy. Aim of our study is to report our experience on advantages
and disadvantages of this option.
Methods and Results—In our center from 1983 to 2010, 4221 patients underwent diagnostic
EMB. In particular 2396 (56.8%) underwent biventricular EMB, 1153 (27.3%) selective
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
LVEMB and 672 (15.9%) selective RVEMB. Rate of complications and histologic findings were
retrospectively
Periprocedural
major
rate (perforation
with or without
p
y analyzed.
y
p
j complications
p
(p
with
cardiac tamponade, embolization) was 0.33% for LVEMB and 0.45% for RVEMB,
RVEM
MB, w
itth a
significant
ignificant decrease in rate of major complication with time (from, respectively, 1.6% and 1.9%
in
both),
denoting
steep
n 1983-1988
198
9833-19988 too 0 an
and 0.
00.3%
3% inn 20
22007-2013,
077-22013,
3 pp<0.001
<00.0001
01 for bo
both
th), den
en
notin
ng a stee
ep le
llearning
arning
ng ccurve.
u ve.
ur
No
structural
functional
abnormalities
the
LV
N
o ppatient
atient died. When
Whenn tthe
he st
tru
ucturral aand
nd
d fun
nctionnall abn
bnor
orm
or
malitiees affected
mal
affeccteed
ed exclusively
exclu
l siive
vely
ly th
he L
V
the
he diagnostic
diag
di
agno
ag
nost
no
stic
st
ic yield
yie
ield
ld of
of LVEMB
LVEM
LV
EM
MB was
was 97.8%
977.8
.8%
8% compared
comp
co
mp
par
ared
e with
ed
wit
ithh 53%
53% of RVEMB.
RVE
VEMB
MB. Conversely,
MB
Conv
Co
nver
nv
erse
sely
se
ly,, when
ly
when
the
ventricular
he echocardiographic
echocard
dio
ogr
grap
aphi
ap
hicc presence
hi
p essen
pr
encce of
of increased
incrrease
in
easedd wall
wall thickness
thi
hick
c neess and/or
ck
and
nd/o
/ r local
/o
loca
lo
call or gglobal
ca
loba
lo
ball ve
ba
ven
ntricular
dilation and/or dysfunction involved also the RV, the diagnosis was reached in 98.1 % of
LVEMB and 96.5% of RVEMB. This discrepancy was particularly evident for myocarditis,
while in infiltrative and storage diseases the histologic abnormalities were always detectable in
both ventricles.
Conclusions—LVEMB is a safe procedure with very low transient complications comparable to
RVEMB. It appears diagnostically more contributive than RVEMB in patients with
cardiomyopathies and clinically preserved RV.
Key words: Biopsy; Diagnosis; Complications; Myocarditis; Cardiomyopathy
2
DOI: 10.1161/CIRCULATIONAHA.13.001414
Endomyocardial biopsy (EMB) of the right (RV) and of the left ventricle (LV) was introduced
into clinical practice in 1963 by Konno and Sakakibara1 and gradually became a recognized,
valuable diagnostic investigation for primary myocardial diseases.
Over the years the development of new techniques, such as immunohistochemistry, in
situ hybridization and polymerase chain reaction to detect a myocardial viral infection, improved
the diagnostic performance on endomyocardial biopsy tissue. On the other hand the development
of new therapies for specific myocardial diseases, administrable on the basis of histological and
molecular diagnosis, has given adjunctive value to the contribution of EMB.
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Despite the recognized diagnostic, prognostic and therapeutic value of this procedure,
ecently described in a joint scientific statement 2, the choice of the ventricular si
sit
site
te ooff EM
te
EMB
B iiss
recently
still
till a matter of question. Indeed , while the EMB of the RV, approached by right internal jugular
vein
veein
n or
or femo
ffemoral
emo
m ral ve
vein
vein,
in, is considered safe, the LV
V aapproach
pproach has no
not
ot yett gained
gaiined widespread
ga
acceptance
accceept
p ance bec
because
ecau
au
use ooff co
concerns
onc
nceern
erns
ns aabout
bout
bo
ut ppossible
ossib
ib
ble m
more
ore se
or
severe
evere
veree ccomplications.
om
mpllic
icat
atio
i ns.
ns.
Moreover,
Moore
reov
oveer, while
whiilee the
wh
th diagnostic
diag
gno
nosstic
sticc advantage
adv
dvaanta
tage
ta
ge of
of a biventicular
biv
iveenti
entiicu
c larr approach
appprooach
ap
h is
is widely
wiide
dely
ly
recognized
ecognized3 the
the ddiagnostic
iagn
ia
gnos
gn
osti
os
t c yi
yiel
yield
e d of
o L
LV
V ve
vers
versus
rsus
rs
us R
RV
V bi
biop
biopsy
o sy is
is still
s il
st
illl unclear.
uncl
un
c ea
cl
ear.
r
r.
In the present single-center study we report the experience of our group in a large
population of patients over a 28-year period, analyzing retrospectively the incidence of
complications and the diagnostic advantages of LV endomyocardial biopsy.
Methods
Patient population
In our center from 1983 to 2010, 4221 patients were submitted to non-invasive and invasive
cardiac studies including a diagnostic endomyocardial biopsy (EMB) because of clinically
3
DOI: 10.1161/CIRCULATIONAHA.13.001414
suspected myocarditis or non-ischemic cardiomyopathies. In particular 2396 (56.8%) underwent
a biventricular EMB, 1153 (27.3%) a selective LVEMB and 672 (15.9%) a selective RVEMB.
Thus, among the 4221 patients studied, 3549 (84%) received a LVEMB either selective (1153
patients) or associated with a RVEMB (2396 patients) and constituted our patient population.
Patients who received EMB to monitor heart transplantation were not included in the present
study.
Clinical indication of the EMB procedure was the evaluation of acute or chronic (> 3
months) unexplained LV and/or RV dysfunction (LVEF45%), unexplained ventricular
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arrhythmias, unexplained left ventricular hypertrophy, cardiac masses, cardiac involvement in
systemic
ystemic diseases, infiltrative or connective tissue disorders4. Furthermore 34% (n
(n=1435)
n=1
= 43
435)
5) ooff
patients had one, and 6% (n=253) 2 additional biopsies to monitor the evolution of the cardiac
disease
diiseeas
asee (i
(i.e
(i.e.
.e.
e. he
hhealing/healed
allin
ing/
g/healed or reactivation) and/
and/or
/or
o tthe
he response to
o a spe
specific
peecifi
cif c treatment (i.e.
immunosuppressive
mmunosuppre
mu
ress
sssiv
ve tr
treatment
reaatm
tmen
en
nt fo
forr vi
viru
virus-negative
russ-nnegaatiive iinflammatory
nflamm
mmat
mm
attorry ccardiomyopathy).
arrdio
rdiomy
myop
my
oppat
athhy).
hy).
The
EMB
was
various
The decision
d ci
de
cissioon
on to
to perform
per orrm an isolated
perf
isollatted right
rig
ght
h oorr le
lleft
ft vventricular
ft
entr
en
tric
icul
ic
ullarr E
MB w
MB
as or
ooriented
ieent
nted
ed bby
y va
arioous
ou
clinical and ttechnical
echn
ec
h ic
hn
ical
a cconsiderations
al
o siide
on
dera
rati
tion
ti
o s including:
on
in
ncl
c ud
udin
ing:
in
g 1) Elective
g:
Ele
l cttiv
ivee in
involvement
nvo
volv
lvem
lv
em
men
entt off a sspecific
peci
pe
cifi
ci
ficc ve
fi
vventricular
ntricular
chamber (i.e. RV in patients with suspected ARVD/C ); 2) Extreme thinning of the right or left
ventricular wall increasing the risk of perforation; 3) Older age with difficult approach of LV
because of atherosclerotic lesions as dolichomega-aorta and femoral arteries obstruction; 4) Very
tall patients (> 2 meters or 6.56 feet) where the long sheath and the bioptome length do not reach
the LV; 5) Presence of evident thrombotic apposition in the right or left ventricular chamber.
Cardiac studies
All patients included in the study underwent clinical examination, chest X-ray, routine laboratory
tests, including troponin, creatine phosphokinase (CPK) and CPKMB, and non-invasive cardiac
4
DOI: 10.1161/CIRCULATIONAHA.13.001414
studies (resting ECG, Holter monitoring, echocardiography and from 2000 cardiac magnetic
resonance). Invasive cardiac studies were performed after patient written informed consent and
approval by the Ethical Committee of our Institution and included cardiac catheterization,
selective coronary angiography, biventricular, LV or RV angiography and biventricular EMB,
LVEMB, or RVEMB. Coronary angiography preceded the first EMB in all patients. EMB was
performed in those patients without significant coronary stenosis or when the degree of cardiac
dysfunction was not explained by the extent of coronary artery disease or ischemic damage5.
Blood samples drawn at the time of cardiac catheterization were used for genetic, immunologic,
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
and molecular biology studies, and serological tests for the most common cardiotropic viruses6.
Endomyocardial biopsy
Endomyocardial biopsies were performed in the septal apical region of one or both ventricles,
approached
ap
ppr
proa
oaach
ched
ed with
withh a Ki
K
King’s
ng’s bioptome until 19907 aand
ndd afterwards byy BIP
BIPAL
PAL
AL biopsy forceps (Cordis
Corporation
C
orrporation
rp
430
430 Route
Rout
utte 22 East
Eas
astt Bridgewater,
Brrid
dgeewaterr, NJ
NJ 08807)
08807)
088
7) using
usiingg a 7F
F (5
(50
(501-613A
01-6
-613
133A Co
Cordis)
ord
dis
is)) lo
long
ong sh
sheet
hee
introduced
was
ntr
trod
oduc
od
u ed from
uc
from
rom a right
righ
ri
ghht and/or
a d/
an
d/oor
or left
lef
eftt femoral
f mora
fe
mora
rall access.
acce
cess
sss. The
The site
site off the
t e biopsy
th
biop
bi
opsy
op
sy w
as iidentified
as
d nti
de
ntifie
if ed on
on a
radiographic
adiographicc vview
ieew us
uusing
in
ng fl
flashing
las
a hi
h ng ooff ccontrast
onntrras
astt me
medi
medium.
d um
di
um.. Th
Thre
Three
reee to
o6R
RV
V an
and/
and/or
d/or
d/
or 3 tto
o 6 LV biopsies
(from 2 to 5 mm3) were drawn from each patient, according with the clinical condition and the
need of tissue samples Control echocardiography was performed few hours after the procedure to
detect asymptomatic pericardial effusion. Further technical description of catheter-based left and
right ventricular endomyocardial biopsy is reported in the supplemental material.
EMB procedures were limited to 2 experienced operators. LV endomyocardial biopsy
was performed from 1983 to 1990 under heparinization (intravenous infusion of 2.500 IE
heparin). Starting from 1990 the patients were pretreated with aspirin 800 mg bidie the day
preceding the exam and 800 mg before the procedure to reduce the thromboembolic risk, without
5
DOI: 10.1161/CIRCULATIONAHA.13.001414
the administration of i.v. heparin. In cases in which the execution of EMB was not programmed
and followed the evidence of normal coronary network, the EMB was preceded by i.v. infusion
of aspirin 1 gr8. Major complication included death, perforation with cardiac tamponade
requiring pericardiocentesis, pericardial effusion not requiring pericardiocentesis, brain
embolization with transient cerebral ischemia or stroke, pulmonary embolization, permanent
complete AV block. Minor complication included, transient conduction disturbances, transient
ventricular or supraventricular arrhythmias, transient chest pain, intramyocardial hematoma.
Local complications included vasovagal reaction, local nerve paresis, local hematoma, femoral
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
arterial-venous fistula.
Histopathologic and molecular analysis
Tissue specimens were fixed in 10% buffered formalin and embedded in paraffin wax; 5-mmthick
hicck sections
sect
ctio
tio
ions
nss were
wer
eree cut and stained with hematoxylin
hematox
ox
xyl
yliin and eosin, Mi
M
Miller’s
ller
err’ss eelastic
lastic van Gieson, and
Masson’s
Massson’s
ss
trichrome
trich
hro
ome and
andd examined
exa
xami
mine
mi
nedd by
by light
lig
ght microscopy.
microsscopyy. Additional
Addditi
tioonal
al staining,
staain
inin
ingg,
g, such
suc
uchh ass Congo
Conngo red,
red,
periodic
peri
pe
riod
ri
odic
od
i aacid-Schiff
ic
cidci
d-Sc
dSchhiff
hiff
f ,S
Sudan
udan bblack,
uda
laack
ck,, Pea
P
Pearl’s,
earl’
arl’
l’ss,
s, Z
Ziehl-Nielsen
ieehl
h -N
-Nie
i lsen
lsen aand
nd
dG
Giemsa
i ms
ie
msaa we
were
re pperformed
erfo
er
form
rmed
rm
d inn th
thee
suspi
pici
ciou
ci
o s of
ou
o specific
spe
p ciifi
f c diseases.
dis
isea
e se
ea
s s.. Additional
Add
ddit
ittio
iona
nall samples
na
saamp
mple
less were
le
were immediately
imm
mmed
mm
edia
ed
iate
ia
tely
te
ly frozen
fro
roze
zenn in
ze
i OCT
clinical suspicious
compound with isopentane cooled in liquid nitrogen and stored at -80°. For transmission electron
microscopy, myocardial samples were fixed in 2% glutaraldehyde in 0.1 m phosphate buffer (pH
7.3) and embedded in Epon resin. Ultrathin sections were stained with uranyl acetate and lead
hydroxide. Transmission electronmicroscopy was applied in the clinical suspicious of infiltrative
or storage disease and in the differential diagnosis of specific dilated cardiomyopathy (i.e. toxic
such as Adriamycin or hydroxyl-chloroquine cardiomyopathy). Idiopathic dilated
cardiomyopathy was diagnosed in the absence of a secondary cause of cardiac dilation and
dysfunction and in presence at histology of non-specific abnormal findings such as normally
6
DOI: 10.1161/CIRCULATIONAHA.13.001414
aligned myocardial fibers with nuclear evidence of hypertrophy and a normal or less than normal
diameter (attenuation), degenerative changes of cardiomyocytes, increased interstitial and
replacement fibrosis, endocardial thickening.
The diagnosis of myocarditis was performed according with Dallas criteria, confirmed
from 1990 by immunohistochemistry for the phenotypic characterization of the inflammatory
infiltrates6. In particular the presence of >14 infiltrating leukocytes/mm2 and/or the presence of
more than 2 CD3-positive lymphocytes per high-power field HPF (400-fold magnification),
often adherent to the contour of cardiomyocytes and focally associated with cell necrosis,
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
depicted by fraying of sarcolemmal membrane, were considered diagnostic for active
atie
ient
n w
nt
erre us
ere
used
ed
myocarditis. From 2000 two to four frozen myocardial specimens from each pat
patient
were
for polymerase chain reaction (PCR) and reverse transcriptase PCR analysis to detect
caard
dio
iotr
trop
tr
op
pic D
NA
A aand
nd RNA viruses (adenovirus,
s en
s,
nterovirus, cyto
to
omeega
gallovirus,
lo
parvovirus B19,
cardiotropic
DNA
enterovirus,
cytomegalovirus,
nfllue
u nza A an
nd B vi
iru
usees,
s hherpes
erpe
er
pess si
implex vviruses
irrusess 1 an
nd 2, hhuman
uman
uma
an hherpes
erppes
er
pes vi
iru
us 6, E
p tein
ps
tein
n-B
-Bar
Barrr
influenza
and
viruses,
simplex
and
virus
Epstein-Barr
viru
vi
ru
us, hepatitis
hep
epat
atit
at
itis
it
is C virus)
vir
irus
us)6. Re
Real
Real-Time
a -T
al
Tim
imee PC
PCR
CR w
was
ass no
nnott use
uused
sed
ed ffor
or any
ny ooff th
thee vviruses
irruse
rusees sc
sscreened.
reeen
ned
d.
virus,
In pre
presence
ese
senc
n e of
nc
o a hhypertrophied
ypper
ertr
trop
ophi
op
hied
hi
e heart,
ed
heaart
rt,, a diagnosis
d ag
di
agno
nosi
no
siss of hhypertrophic
yper
yp
ertrop
er
ophi
op
hicc ca
hi
card
cardiomyopathy
r io
rd
omy
myop
opat
op
a hy was
reached in presence of disarray of cardiomyocytes, consisting of short runs and interlacing
myocardial fibers, as well as severe cell hypertrophy, bizarre-shaped nuclei, often surrounded by
a clear zone (perinuclear halo) and increased myocardial fibrosis. Alternatively, the diagnosis of
infiltrative (i.e. amyloidosis) or storage (i.e. Fabry disease, glycogenosis) disease manifesting
with idiopathic left ventricular hypertrophy was obtained by means of additional stainings (i.e.
Congo red for amyloidosis, Sudan black for Fabry disease, PAS for glycogenosis) and by
electron microscopy. For the differentiation of the amyloid subtypes, immunohistochemistry for
ț and Ȝ immunoglobulin light chain, transthyretin, serum amyloid A protein and apolipoprotein
7
DOI: 10.1161/CIRCULATIONAHA.13.001414
A-I was performed. Idiopathic restrictive cardiomyopathy was diagnosed in presence of an
hemodynamic restrictive pattern, with atrial enlargement and normally dimensioned ventricles
associated with non-specific histologic findings (i.e. cardiomyocyte hypertrophy, increased
fibrosis).
The histologic diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy
(ARVC/D) was performed on the basis of the International Task Force criteria9 and from 2010
on the revised criteria10.
Statistical analysis
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Normal distribution of variables was assessed with Kolmogorov–Smirnov test. Quantitative
measurements were expressed as mean ±SD. Categorical data were presented ass ab
aabsolute
bso
s lu
lute
te
frequencies and percent values. Bivariate comparisons were done by use of Mann-Whitney U
test
estt for
for non-normally
non
on-n
-n
norma
mall
ma
lly distributed continuous variables
varria
iabbles and one-w
one-way
way
a A
ANOVA
NOVA for normally
NO
ddistributed
dist
i tri
ributed variables.
vaari
riab
ablles.
ab
s The
The Chi-square
Chi
hi--squ
-squuar
aree ttest
esst an
and
nd Fishe
Fisher
her ex
he
exact
xact
act te
ttest
st w
were
ere us
used
sed
d ffor
or ccomparison
or
om
mpa
pari
risson off
ri
categorical
ca
ate
tego
gori
go
r ca
ri
call variables,
v ri
va
riaables,
les, when
when
hen appropriate
appr
ap
prrop
opri
r at
ri
atee (with
(wit
(w
ithh the
it
the latter
lattter
la
err uused
sedd wh
se
whe
when
en aan
en
n eexpected
xppect
pectted ccell
elll ccount
el
ouunt
unt was
waas
<5). A 2-taile
2-tailed
ledd P va
valu
value
l e <0
lu
<
<0.05
.055 wa
.0
wass co
considered
onssid
i er
ered
ed sstatistically
tattisstiica
c llly si
ssignificant.
gnif
gn
ific
if
ican
ic
nt.
t Computations
Com
ompu
p ta
pu
tati
tion
ti
onss we
on
w
were
re
performed with SPSS 20 (IBM, Armonk, NY, USA).
Results
Patient Characteristics
Baseline clinical and echocardiographic characteristics of the study patients are listed in Table 1.
In particular 2804 patients had an ejection fraction<50% and among them 757 (27%) suffered
from acute onset dilated cardiomyopathy and 2046 (73%) had a chronic form of cardiac
dysfunction (> 3 months).
8
DOI: 10.1161/CIRCULATIONAHA.13.001414
Complications of EMB
Rate of complication of LV vs RV EMB was determined comparing all patients of our
population receiving a LVEMB (n=3549) and all patients submitted to a RVEMB (n=3068): the
data are reported in Table 2.
In particular in all cases of LV perforation there was a thin LV wall (MWT=7.5±1.3mm)
with a LV dilation (72.5±8.7mm) and dysfunction (20.3±3.3%). Brain embolization with
transient cerebral ischemia, manifesting as visual and/or speech disturbances resolved
completely with mannitol and steroids administration. Importantly, most (n=5, 0.14%) of these
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
events occurred before the instauration of a pretreatment with aspirin. The 3 (0.08%) patients
were
who experienced a transient cerebral ischemia despite aspirin administration, we
ere aaffected
fffec
ecte
tedd by
te
by
Fabry disease.
Globally
0.33%
Glob
Gl
obal
ob
a ly
y tthe
he major complication rate forr LV
he
LVEMB was 0.33
33
3% an
andd for RVEMB was
the
EMB
(p=0.116).
The
00.45%,
.45
5%,
% without
ut ssignificant
ig
gniifi
f caant ddifferences
ifffere
if
fereenc
nces
es bbetween
etw
ween th
he twoo E
MB aapproaches
pprroac
roache
h s (p
he
p=0
=0.1
.116
1 ).
16
) T
hee ooverall
verrall
major
0.39%
procedures).
The
ma
ajo
jorr co
ccomplication
mpli
mp
lica
li
cati
tiionn rate
rate
ate in our
ouur
ur patient
pat
atie
ient
ie
nt population
pop
opul
ulattio
ul
ionn was
was 0.
0.39
39%
39
% (2
(266 ou
outt of
of 66617
6177 pr
61
proc
occed
edurress).
) T
hee
major complication
comp
pli
lica
cati
ca
t on rate
ti
rat
atee for
fo
or a biventricular
biive
vent
nttri
r cu
ulaar EMB
EMB was
was 0.66%
0..66
66%
% (16
(116 off 2396),
239
396)
6),, while
6)
w il
wh
i e was
was 0.54%
0 54% for
0.
univentricular EMB (10 of 1825) (p=0.172). Importantly, performance of the operators
significantly improved with the experience acquired over time. Indeed, a higher number of major
complications was recorded in the years, that significantly and progressively as experience
accumulated, denoting a steep learning curve. Specifically, major complications for LVEMB
went from 8 out of 496 (1.6%) in 1983-1988 to 1 out of 781 (0.1%) in 1989-1994, 3 out of 900
(0.3%) in 1995-2000, 0 out of 882 in 2001-2006, and 0 out of 481 in 2007-2013 (p<0.001).
Corresponding figures for RVEMB decreased from 8 out 420 (1.9%) to 3 out 692 (0.4%), 2 out
of 804 (0.2%), 0 out of 743, and 1 out of 389 (0.3%, p<0.001). Minor complications were
9
DOI: 10.1161/CIRCULATIONAHA.13.001414
comparable between RV and LVEMB (Table 2) while local complication such as vasovagal
reaction (1.3% in LV vs 0.78% in RV, p<0.05) and local hematoma (0.45% in LV vs 0.19% in
RV, p<0.05) were significantly more frequent in LV approach, even though transient and not
requiring surgical repair.
Histopathological diagnosis
The results of histopathology findings are reported in Table 3. Histopathology showed abnormal
changes compared with normal heart diagnostic or suggestive of a known disorder in 3448
patients (97.1%) (Table 3). Among them 1063 received an isolated LV biopsy (positive
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
pathologic diagnosis in 92.2%) and 2385 a biventricular biopsy (positive pathologic diagnosis in
patients
who
99.5%). Thus, positive diagnostic EMB results were obtained more often in pati
ien
ents
tss w
ho
received
eceived a biventricular EMB (p<0.001). This was mainly related to the reduced sampling error,
since
incce in the
the average,
avvera
raage,
ge 8.7±1.6 samples were takenn per
per patient in those
th
hos
o e who
who underwent
EMBs
samples
those
who
LVEMB
bbiventricular
iveentricular EM
MBs ccompared
ompa
om
paareed to 44.4±1.4
.4
4±1.44 sa
ampless iin
n tho
hose
ho
se w
h uunderwent
ho
nderw
nder
went sselective
went
elec
el
ecti
tiive L
VEMB
VE
MB
(p<0.001).
On
the
basis
suspicion
diagnosis
was
mainly
p<0
<0.0
.001
001
0 ). O
n th
he ba
bas
sis of the
he iinitial
niti
ni
tial
ti
a cclinical
al
l ni
li
nica
call su
ca
susp
sppic
iciionn of ddisease
isea
is
ease
ea
see a ffailed
ailledd di
ai
iag
agno
n si
no
siss wa
as ma
m
inly
inly
preserved
observed in patients
pati
pa
tiien
nts with
witth suspected
susp
su
spec
sp
eccted myocarditis
myo
yoca
card
ca
rdit
rd
itis
it
iss in
in presence
pres
pr
esen
ence
en
ce ooff a pr
res
e er
erve
vedd cardiac
ve
c rd
ca
rdia
iacc function
ia
func
fu
n tion (77
out of 101, 76%) and occasionally in the suspicion of hypertrophic cardiomyopathy (5 pts, 5%),
idiopathic restrictive cardiomyopathy (5 pts, 5%), ARVD/C (5 pts, 5%), (endomyocardial
fibrosis (4 pts, 4%), amyloidosis (2 pts, 2%), tumor (2 pts, 2%), connective tissue disease (1 pt,
1%). Thus, some diagnoses may be missed in both ventricles.
Myocarditis was the most frequent diagnosis (49.4%). Myocardial inflammation with
either diffuse or focal signs of cardiomyocyte necrosis (i.e. active myocarditis) was detected in
88% of cases and without (borderline myocarditis) in 12% of patients. Most patients (95.5%)
were affected by a lymphocytic myocarditis (CD45RO+,CD3+, CD20-) while in 3,6% an
10
DOI: 10.1161/CIRCULATIONAHA.13.001414
eosinophilic inflammatory process, including necrotizing vasculitis (Churg-Strauss disease), drug
hypersensitivity and Loeffler disease, was detected. In the remaining 0.9% a granulomatous
(sarcoidosis) and a giant cell myocarditis was observed (figure 1). Among the 1752 (49.4%)
patients that globally received a diagnosis of myocarditis, 322 (18.4%) were diagnosed in the 7
years in which only Dallas criteria were adopted and 1430 (81.6%) in the 21 years after the
introduction of immunohistochemistry, with an average of 46 diagnosis of myocarditis/year
without IHC and 68 myocarditis/year with IHC, representing an overall 48%/year increase in the
rate of diagnosis. Regarding duration of symptoms, 30% (n=526) had a recent onset (< 3 months)
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
while 70% (n=1226) had a chronic disease (> 3 months).
Polymerase chain reaction analysis revealed the presence of a viral infection
infect
ctiion
ion inn 28%
28% of
of
patients consisting in Adenovirus (35%), EBV (30%), Enterovirus (16%), Influenza A virus
(5.2%),
PVB19
(3.3%),
combination
5.22%)
%),, PV
PVB1
B 9 (3
B1
(3.3
.3%), HHV6 (1.9%), Hepatitiss C virus (4.4%), an
aand
d co
com
mbination of viruses in
compared
with
recent
series
44.2%
.2%
% of cases,
s sshowing
howi
ho
wiing a ddifferent
iffe
if
fere
fe
rent
nt distribution
dis
istr
triibutiion off vviral
irall ggenomes
enom
en
omes
om
es co
omp
mpar
ared
ed w
ith re
ith
eceentt se
eriess
erie
-11-1
1-1
12
reported
some
German
centers
epo
port
rted
rt
e ffrom
ed
ro
om so
som
me G
me
errma
mann ce
cent
nter
nt
erss33-11-12
er
.
Mosst of ppatients
atie
at
i nt
ie
n s wi
with
th vir
irus
ir
u -n
us
neg
gat
ativ
ivee in
iv
infl
f am
fl
amma
m to
ma
ory ccardiomyopathy
ardi
ar
diom
di
omyo
om
yopa
yo
patthy aand
pa
nd E
F<45
F<
4 % were
Most
virus-negative
inflammatory
EF<45%
treated with a combination of steroids (prednisone 1 mg/Kg/die) and azathioprine (50 mg/bidie)
for at least six months and most (>80%) of them showed a significant improvement of LV
dimension and function paralleled by a resolution of the inflammatory process6. Resolution of
myocardial and vascular inflammation was usually obtained also in patients with giant cell13,
granulomatous myocarditis and Churg-Strauss disease14 following high dose steroids and
immunosuppressive agents (azathioprine, cyclophosphamide).
In 22% of patients the clinical and histological findings were suggestive of idiopathic
dilated cardiomyopathy. In 8.3% of cases dilated cardiomyopathy was associated with specific
11
DOI: 10.1161/CIRCULATIONAHA.13.001414
causes, such as alcohol abuse, hormonal imbalance (i.e. growth hormone deficiency, acromegaly,
hyper or hypotiroidism, pheochromocitoma, Cushing disease), drugs toxicity, (i.e. Cocaine,
Anagrelide, Adriamycin, Clozapine, Hydroxychloroquine), nutritional deficiency (selenium/zincdeficiency in intestinal malabsorption and celiac disease) or dystrophinopahies (Duchenne and
Becker diseases) and were defined as secondary dilated cardiomyopathies. From pathologic point
of view secondary dilated cardiomyopathy closely resembles idiopathic dilated cardiomyopathy
but prevalence of peculiar pathologic aspects could be in some cases detected. For instance cell
atrophy and extreme rarefying of contractile elements due to hyporegeneration (GH deficiency)
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
or to hyperdegradation (Cushing disease) was detected in hormonal imbalance dilated
cardiomyopathy. In hypothyroidism the interstitium was expanded by mucoid (PAS
(P
PAS positive)
pos
osit
itiv
it
ive)
iv
e)
infiltration.
nfiltration. At transmission elecronmicroscopy some forms of toxic dilated cardiomyopathy
showed
pathologic
anthracyclines
characterized
how
owed
ed sspecific
peci
pe
cificc pa
ci
path
thologic findings: anthracycli
liine
n s toxicity is cha
haaract
cter
eriized
er
iz by a grading of
lesions
cells),
esiions consisting
consissti
tinng mainly
mai
ainl
nlyy in loss
loss
oss of
of myofibrillar
myof
yofibrrilllar ccontent
onten
nt an
andd vac
vvacuolization
acuoli
oliza
zati
t on
on ((Adria
Adri
Ad
riaa ce
ellls),
distention
hydroxichloroquine
di
dist
sten
st
enti
en
tion
ti
on of
of sarcoplasmic
sarc
sa
rccoppla
lasm
smic
sm
ic reticulum
ret
etic
et
icul
ulum
ul
um and
and extensive
exteens
ex
n iv
ve diffuse
diiff
ffus
usee fibrosis;
us
fiibr
b osis
iss; hy
ydrrox
oxic
i hlor
ic
hlorroq
oqui
uinne
ne
cardiomyopathy
cardiomyop
patthy is
is ch
ccharacterized
a ac
ar
a teeriize
z d by the
thee ppresence
rese
re
senc
se
ncee of
nc
o iintracytoplasmic
n ra
nt
racy
cyto
cy
topl
to
plas
pl
asmi
as
micc vvacuoles,
mi
acuo
ac
uole
uo
l s, cconsisting
le
onsi
on
sist
si
s ing of
concentric lamellar figures in single membrane-bound vesicles and curvilinear bodies15; cocaine
cardiomyopathy is characterized by supercontraction with rupture of sarcomeres16.
Seven point six percent of patients received a histological diagnosis of hypertrophic
cardiomyopathy (figure 2). ARVD was diagnosed in 46 patients, all of them with a sporadic
form of the disease. Finally, other histologic diagnosis were reached in 301 patients, that
constituted the 8.5% of the global population.
Comparison of LVEMB with RVEMB
In order to understand the diagnostic value of LVEMB in comparison to RVEMB we concentrate
12
DOI: 10.1161/CIRCULATIONAHA.13.001414
on the 2396 patients who received a biventricular EMB (Table 4). In all patients the average
number of specimens drawn from LV and RV chamber was comparable (4.5±1.2 LV vs 4.2±1.6
RV, range 3-6 sample/chamber).
LVEMB showed diagnostic histopathologic findings in 96.3% of cases (2307 patients)
while RVEMB in 71.4% (1711 patients) (p<0.001).
To assess the diagnostic value of LVEMB versus RVEMB in relation to the evidence of a
structural and functional abnormality of the biopsied chamber, we retrospectively analyzed the
presence at echocardiography of increased wall thickness, local or global ventricular dilation and
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
local or global hypokinesia. The presence of at least one of these parameters was considered as
indicative
ndicative of chamber involvement by the pathologic process (Table 5).
Combining the histopathology results with the echocardiography dataa we observed that
when
exclusively
wh
en the
the structural
str
truuctu
ura
rall and/or functional abnormality
abnormalit
itty aaffected
ffected exclusi
siive
v ly oorr predominantly the LV
the
97.8
while
diagnostic
RVEMB
he diagnostic
diagnosticc yield
yie
i ld of
of LVEMB
LVEM
LV
EMB
EM
B raised
raaissed too 97
7.88 % wh
w
ilee the
the di
diag
agno
nost
stic
ic yyield
ieeld
d ooff RV
VEM
EMB
B
decreased
Thus,
LVEMB
would
have
decr
de
crea
cr
ease
ea
s d to 553%
se
3%
% ((p<0.001)
p 0.0001)
p<
001) ((figure
fiigu
gure
re 33).
). T
).
hus, oomitting
hu
mi tin
mitt
i g LV
LVEM
EMB
EM
B in
n tthese
hese
he
se ppatients
atie
at
ient
ie
n s wo
nt
w
ulld ha
hav
ve
ve
resulted
RV
also
esulted in missing
miss
mi
ssin
ss
i g 47%
in
47% off diagnosis
dia
i gn
gnos
o is (figure
os
(fi
figu
gure
gu
re 33).
) Conversely,
).
Conv
Co
n er
nv
erse
sely
se
ly,, if tthe
ly
hee R
V wa
wass al
lso structurally
str
truc
u turally
uc
and/or functionally involved by the disease the diagnosis was reached in 98.1% of LVEMB and
96.5% of RVEMB, so that omitting the LVEMB in this group would have resulted in missing
only 3.5% of diagnoses.
Discussion
This study represents the largest contribute on procedural safety and diagnostic value of LVEMB
in patients with cardiomyopathies. Four thousand two-hundred twenty-two patients were
biopsied in a 28-year period in a single center and among them 3549 received a LVEMB, either
13
DOI: 10.1161/CIRCULATIONAHA.13.001414
selective or associated with a RVEMB.
Safety of LVEMB
In our experience, the incidence of major complications following LVEMB was very low
(0.33%) and comparable with that of RVEMB (0.45%), suggesting a biopsy in the LV is as safe
as in the RV. Remarkably, no patient died. These results are at variance with a recent report by
Yilmaz et al3 and are likely related to a greater operator experience obtained in a longer period of
time.
In particular, LVEMB showed a lower incidence of cardiac perforation compared with
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
RVEMB (p=0.046), most likely due to the thinner RV wall. Indeed, in all LV perforation there
was a thin LV wall associated with remarkable ventricular dilation.
The second major complication of LVEMB was brain embolization (0.24%). Importantly
Importantly,
hiss complication
com
ompl
plic
pl
icat
ic
a io
at
on was
was associated with transient cerebral
cereebral ischemiaa an
ce
aand
d no ppermanent
ermanent damage and
this
wass si
ssignificantly
gnifican
ntlly rreduced
edu
duce
du
ceed pret
ppretreating
ret
etrrea
eati
tinng
ti
ng tthe
hee pat
tieents w
ith
h hhigh
ighh dose
ig
dosee aaspirin.
sppir
irin
i . No
otaabl
bly,
y tthe
y,
he 3 ccases
asees
as
was
patients
with
Notably,
epo
port
rtin
rt
ingg cerebral
in
cere
ce
rebr
braal ischemia
isc
schhem
hemia
mia despite
desppit
desp
itee this
thiis pretreatment
th
pre
rettre
treat
atm
ment
men
nt were
wer
eree affected
affe
af
fect
fe
ctted
d by
by Fabry
Faabr
bryy di
dise
seas
asee w
as
heere
ere
reporting
disease
where
at ex
expo
posi
po
siiti
t on
o iin
n ad
addi
diti
di
t on tto
ti
o a re
eco
cogn
gniz
gn
ized
iz
ed pplatelet
late
la
teele
lett hy
hype
p rpe
r-ac
acti
ac
tivi
ti
vity
vi
ty ccould
ould
ou
ld hhave
a e
av
endocardial fa
fat
exposition
addition
recognized
hyper-activity
overcome aspirin effect. No heparin infusion was adopted during the procedure, except in case
of thromboembolic events.
The low rate of complication in our study may also be related to the high level of
experience of few operators dedicated to the execution of EMB in our center. A higher rate of
complication from EMB was reported in previous studies17-18 where the procedure was
performed in more than one center and/or from a high number of operators, while an even lower
incidence of EMB complications was present when only a small number of interventional
cardiologist with extensive EMB procedure experience (> 100 EMB procedure per year) was
14
DOI: 10.1161/CIRCULATIONAHA.13.001414
operating19. In the present study, the two operators’ ability significantly improved with
experience and a steep learning curve was clearly identified with a rate of complications in the
first seven year 2.5 fold higher than in the following 10 years and 17 times higher than in last
decade.
Diagnostic impact of LVEMB
EMB showed abnormal changes diagnostic or compatible with a known disorder in a high
number of patients and biventricular EMB showed a major diagnostic yield than isolated
LVEMB (99.5% and 92.2% respectively). This confirms the results of a recent study by Yilmaz
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
et al3, being mainly related to the reduced sampling error due to the higher number of specimens
available. Indeed, the lack of a histopathologic diagnosis in 7.8% of patients who
ho
o rec
received
e eive
ec
eive
vedd an
isolated
solated LVEMB was mainly related to an inadequate amount of tissue available (1-2 samples of
small
mal
alll dimensions
dime
di
mens
me
n ions
ns
nss i.e.
i.e
.e. less than 2 mm3). Thus, a biventricular
biv
iveentricular approach
appro
roachh is generally advisable,
ro
even
ev
ven
n because it
it does
d es not
do
nott increase
inc
ncre
reaase
re
ase the
the overall
overalll periprocedural
ove
perippro
proceedu
edura
ural
al risks
ris
iskks (0.5%
(0.
0 5% for
for biventricular
biven
iven
ntr
t ic
icul
ularr EMB
ul
EMB
and
EMB).
Att va
variance
with
Yilmaz
study
showed
an
nd 0.44%
0 44
0.
4 % for
for univentricular
un
niv
ven
enttric
iccul
ularr E
MB).
MB
) A
).
vari
rian
ri
nce
c w
i h Yi
it
Yilm
lmazz sseries
lm
eriees (3)
erie
(3
3) our
our st
stud
u y sh
ud
show
wed
ed a
higher rate off diagnostic
dia
i gn
gnos
o ti
os
t c biopsies
biiop
opsi
sies
es (9
(99.5%
99.
9 5% biventricular
biv
iven
entr
en
trric
icul
ullar
a diagnostic
dia
iagn
gnos
gn
osti
os
ticc yield
ti
yie
ield
ld compared
com
ompa
paareed with
with 79.3% inn
Yilmaz series). This can be related to a more extensive indication to EMB for patients with
idiopathic left ventricular hypertrophy, where the diagnostic yield of EMB in differentiating
hypertrophic cardiomyopathy from secondary forms of left ventricular hypertrophy (i.e.
infiltrative and storage diseases) is almost 100%. In addition , being a tertial referral center for
the diagnosis of myocarditis, many patients with high pretest probability for myocardial
inflammation (i.e. clinical history, positive CMR) were sent to our department for a definite
diagnosis and a personalized treatment, and this can explain the high diagnostic rate for
myocarditis. Finally, compared with Yilmaz article, our study reports a larger population
15
DOI: 10.1161/CIRCULATIONAHA.13.001414
biopsied in a longer period, emphasized the safety and the diagnostic yield of EMB.
When the patient clinical condition requires reducing the length of the procedure, it is
important for the operator to make a correct decision regarding which ventricular approach might
reach more likely a histological diagnosis.
For this reason we compared the diagnostic accuracy of LVEMB and RVEMB in patients
who received a biventricular EMB, and demonstrated that the overall diagnostic yield of
LVEMB was higher than that of RVEMB, being 96.3% and 71.4% respectively (p<0.001).
This discrepancy was even more evident when structural and/or functional
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
echocardiographic abnormalities affected exclusively the LV, being the diagnostic yield of
LVEMB raised to 97.8 % while the diagnostic yield of RVEMB decreased to 53%.
533%.
%. Thus,
Thu
hus,
s,
omitting LVEMB in these patients would have resulted in missing 47% of histological
diagnoses.
di
iag
agno
nosses.
no
se s.
Indeed,
Indeed
d, LV was
was the
the only
onl
nlyy chamber
chaambe
ch
ambeer involved
in
nvo
olveed at
at imaging
imagi
magi
gingg in
in 66.5%
66 5% of our
66.5
our
ur cases.
cassess.
Myocarditis
associated
with
echocardiographic
94.2%
Myoc
My
ocar
oc
ardditiis wa
wass as
asso
oci
c at
ated
ed w
itth ec
ech
hoca
card
ca
rd
dio
ogr
g ap
aphi
hicc LV iinvolvement
hi
nvvol
o veement
ment iin
n 94
4.22% off ccases,
assess,
with
26.9%.
patients
with
isolated
LV
alone in 67%,
67%
%, an
andd in
n aassociation
sssoccia
iati
tion
ti
nw
itth RV iin
n 26
26.9
.9
9%.
% IIn
n pa
pati
tien
ti
ents
en
ts w
itth is
isol
o at
ol
ated
ed L
V
echocardiographic involvement, the histological and immunohistochemical diagnosis of
myocardial inflammation was present in 95.7% of LVEMB and in 54.2% of RVEMB, while in
patients with associated echocardiographic RV involvement the LVEMB was diagnostic in
96.6% of cases and the RVEMB was diagnostic in 96.1%. Thus, in the clinical suspicion of
myocarditis, when both ventricles show echocardiographic abnormalities the EMB can be
performed indifferently in LV or RV, while in presence of a selective LV involvement a
LVEMB is advisable.
In idiopathic dilated cardiomyopathy the LV was always involved by the disease at
16
DOI: 10.1161/CIRCULATIONAHA.13.001414
echocardiography (100%), while the RV was affected in 29.5% of patients. Histology showed
pathologic changes in 100% of LVEMB and in 48.3% of RVEMB (p<0.001) when the RV was
not involved at imaging. The percentage rose to 98.8% when RV showed echocardiographic
abnormalities. Although the histological findings are nonspecific, EMB diagnosis of idiopathic
dilated cardiomyopathy may be valuable in the workup of heart failure to exclude specific
diseases including myocarditis. The distinction between these two pathologic entities is crucial
since a diagnosis of idiopathic dilated cardiomyopathy can orientate the clinician to a more
radical therapeutic option (i.e. heart transplantation) while in case of myocarditis a specific
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
etiologic treatment can be taken under consideration. On the other hand, recent studies showed
that
presenting
hat cardiac MRI is unsatisfactory
r to guide clinical management of patients prese
seent
ntin
i g wi
in
with
th
chronic heart failure20.
Prog
Pr
ogreesssiv
og
ivee heart
h art failure can be caused also
he
also
s by secondaryy forms
f rm
fo
ms of
of dilated
Progressive
ca
cardiomyopathy
ard
dio
i myopatthy (such
(ssuch
ch as
as alcoholic,
alccoh
al
coholi
holic,
c, hormonal
horm
monnal imbalance,
imbbal
balannce,
e, dystrophinopathies
dysstr
troophino
hinoppatthie
thiees toxic
toxiic and
toxi
a nd
nutr
nu
nutritional
trit
tr
ittio
iona
nall de
defi
deficiency).
fici
ciien
ncy
y). E
Even
venn in tthis
ve
hiss setting
hi
sett
se
t in
tt
ng LV appears
appe
ppears
rs clinically
cli
linnica
call
ca
llyy an
andd hhistologically
isstol
stolog
o ic
og
i allly m
more
ore
ore
compromisedd than
than
n RV
RV and
a d the
an
th
he tissue
tiss
ti
s ue obtainable
ss
obt
b ai
aina
nabl
na
b e from
bl
from LV
LV biopsy
biop
bi
opsy
op
sy can
an be
be used
used
e for
for research
res
e ea
e rch
porposes to assess myocardial trace elements21, enzyme activity15 and to recognize the effects of
hormonal imbalances susceptible of recovery22.
Thus, in our experience LV seems the preferential site where to perform an EMB in the
clinical suspicion of idiopathic or secondary dilated cardiomyopathy while RV should be
considered as an alternative option whenever it would be dilated and/or hypokinetic.
Use of LVEMB in patients with unexplained LV hypertrophy is still controversial and it
is generally recommended in the suspicion of an infiltrative or storage disease, when noninvasive
tests are inconclusive2. Indeed, clinical presentation of some infiltrative diseases can be
17
DOI: 10.1161/CIRCULATIONAHA.13.001414
misleading because of normal QRS voltages or presence of left ventricular branch block at ECG,
while some storage diseases like Fabry and Danon disease or mutation of PRKAG2 gene,
particularly in sporadic form, may inextricably mimic an obstructive, non obstructive and even
apical HCM. Gene analysis can be diagnostic but also expensive and time consuming while it
can miss new or unknown gene mutations. In this situation, EMB can be extremely useful. In our
experience in up to 18% of HCM clinical diagnoses, EMB unexpectedly allowed to reclassify
patients as affected by infiltrative or storage myocardial disease23. In patients with true HCM,
LVEMB can be specifically useful in analysing the cause of cardiac deterioration24, in showing
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
the histological changes of the disease that are unreliable in the highly trabeculated RV
myocardium, and in providing myocardial tissue for research purposes.
Conclusions
Con
Co
nclusi
nclu
sion
ion
onss
LVEMB
LVE
EMB is a ssafe
afee ddiagnostic
af
iag
ag
gno
ost
stiic
ic pprocedure
roce
ro
ceedur
d ur e w
with
ithh vvery
ery lo
low,
ow, tr
transient
ran
anssient
ent co
comp
complications
mpli
licaati
li
tioons
ons co
comp
comparable
mpar
mp
arab
able
ab
le tto
o
those
RVEMB
whenever
hos
osee of
o RVEMB.
RVE
VEMB
MB
B. It seems
see
eems
ms diagnostically
dia
i gn
gnos
osttica
os
ticaallly more
more
re contributive
con
ontr
t ibut
ibut
utiv
ivee than
iv
than
nR
VEM
VE
MB w
MB
hene
he
neeve
ver a
cardiomyopathy
cardiomyop
patthy iiss as
aassociated
s ci
so
c atted w
with
i h no
it
nnormal
rm
mal oorr po
poor
poorly
o ly ccompromised
or
om
mpr
prom
omis
om
ised
is
e R
RV.
V.
Funding Sources: The study has been supported by the Grant RF-2009-1511346, by the Grant
RBFR081CCS and by the Grant MRAR08Y012 from the Italian Ministry of Health.
Conflict of Interest Disclosures: None.
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Table 1. Baseline characteristics of patients submitted to a biventricular, isolated left ventricular
(LV) and isolated right ventricular (RV) endomyocardial biopsy (EMB).
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Demographic
Age, year
Male patients
Symptoms
Dyspnea
Palpitation
Chest pain
Symptom onset>3months
Echocardiography
LV maximal wall thickness (mm)
LV
V end
end diastolic
dia
i st
stol
o icc diameter
dia
iameter (mm)
LV
VEF
LVEF
L
LVE
LVEF<45%
VEF<45%
%
Biventricular EMB
(n=2396)
n° (%)
LVEMB
(n=1153)
n° (%)
RVEMB
(n=672)
n° (%)
P value
45.7±15.4
1592 (66)
46.2±14.4
747 (65)
53.4±18.8
466 (69)
<0.001
0.13
2037 (85)
359 (15)
264 (11)
1863 (78)
1006 (87)
165 (14)
115 (10)
888 (77)
564 (84)
114 (17)
54 (8))
514 ((76)
76)
76)
0.09
0.3
00.07
.077
.0
00.4
0.
4
11.3±5.0
64.2±11.6
64.2±
±11
1.6
.
31.1±
±14
1 .6
31.1±14.6
2014
20
14 (84)
(844)
11.4±4.9
63.3±12.3
63.3±122.33
31.9
9±1
± 4.
4.66
31.9±14.6
967 (8
96
(85)
5)
11.0±3.7
63.3±11.5
31.4±14.8
55
555
55 (83)
(83)
0.2
0.12
0.3
0.6
0.6
21
DOI: 10.1161/CIRCULATIONAHA.13.001414
Table 2. Complications of left ventricular (LV) vs right ventricular (RV) endomyocardial biopsy
(EMB).
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Major complication
Perforation with cardiac
tamponade
Pericardial effusion without
pericardiocentesis
Brain embolization with transient
cerebral ischemia
Pulmonary embolization
Permanent AV block
Death
Overall
Minor complication
Ventricular or supraventricular
ransient arrhythmias
transient
Transient heart block
Transient
chest
Tran
ansi
sien
en
nt ch
hes
e t pa
pain
in
Intramyocardial
ntr
tram
amyo
am
y ca
card
rdiall he
rd
hhematoma
ema
m toma
Local
L
Loc
ocal
ca comp
complication
pli
lica
ca
ati
tionn
Vasovagal
V
asovagal reaction
reactiion
n
Lo
oca
call he
hema
maato
toma
maa
Local
hematoma
Femoral
Femo
mora
rall ar
arte
arterial
t riiall ven
venous
enou
ous fi
fist
fistula
s ul
ulaa
LVEMB (n=3549)
n° (%)
RVEMB (n=3068)
n° (%)
P value
3 (0.08)
9 (0.29)
0.033
1 (0.028)
5 (0.16)
0.069
8 (0.22)
0
0.007
0
0
0
12 (0.33)
0
0
0
14 (0.45)
1.0
1.0
1.0
0.116
6 (0.17)
4 (0.13)
0.23
0.
2311
23
0.231
0
(0.19)
7 (0.19
199)
1 ((0.028)
0.02
02
28))
2 (0.06)
6 (0.19)
(0
0.1
.19)
9
0
0.215
0.218
0.536
447
7 (1.3
(1.3)
3)
116
6 (0
((0.45)
.445))
1 (0.0
((0.028)
0.0
028
28))
223
3 (0
(0.78)
0.778))
6 ((0.19)
0.199)
0.
0
0.0077
0.
.03
035
5
0.035
00.536
0.53
.53
536
6
22
DOI: 10.1161/CIRCULATIONAHA.13.001414
Table 3. Spectrum of left ventricular biopsy diagnoses in 3549 patients submitted to a left
ventricular endomyocardial biopsy (LVEMB).
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Myocarditis
Idiopathic DCM*
Secondary DCM
Alcoholic DCM
Hormonal imbalance DCM
Dystrophinopathy
Toxic DCM
Nutritional deficiency DCM
Hypertrophic CM†
ARVD/C‡
Other diagnoses
Amyloidosis
Fabry disease CM
Glyc
Gl
ycog
yc
ogen
og
enos
en
osis
os
i
Glycogenosis
Idio
Id
Idiopathic
opa
pathic
ic R
Restrictive
estr
tric
icti
tivee C
CM
M
Coonn
n ective ttissue
isssu
s e di
dis
seas
asee
Connective
disease
Hemo
He
m chroma
m to
osi
siss/heemosiiderrosi
ss
Hemochromatosis/hemosiderosis
Endo
En
domy
do
myoc
my
occar
ardi
diaal fibrosis
fib
ibrrossis
si s
Endomyocardial
Tuumo
mor
Tumor
Non-diagnoost
stic
ic§§
ic
Non-diagnostic§
Patients with
All patients with
Patients with
LVEMB
selective LVEMB biventricular EMB
(n=2396)
(n=1153)
(n=3549)
n° (%)
n° (%)
n° (%)
1752 (49.4)
564 (48.9)
1188 (49.6)
781 (22.0)
178 (15.4)
603 (25.2)
297 (8.3)
80 (6.9)
217 (9)
75 (2.1)
21 (1.8)
54 (2.3)
118 (3.3)
36 (3.1)
82 (3.4)
43 (1.2)
6 (0.5)
37 (1.5)
29 (0.8)
10 (0.9)
19 (0.8)
32 (0.9)
7 (0.6)
25 (1.0)
271 (7.6)
141 (12.2)
130 (5.4)
0 (0.0)
4 ((1.9)
46
1.9)
1.
9)
46 (1.3)
100 (8.7)
2201
20
011 (8
(8.4
.4
4)
301 (8.5)
(8.4)
102
0 (4.3)
(4.
4 3))
143 (4.0)
41 (3.6)
102
63 (1.8)
21 (1.8)
42 (1.8)
10 (0.3)
3)
3 (0.3))
7 (0.3)
12 ((0.3)
0 3))
0.
4 (0.3)
( .3
(0
3)
8 (0.4)
(0
38
8 ((1.1)
1 1))
1.
115
5 (1
.3)
.3
3)
23 ((1.0)
1.0)
1.
0)
(1.3)
133 ((0.4)
0.4))
4 ((0.3)
0.3)
(0
0.4)
9 (0.4)
(0.
0 4)
(0
0.4
.4))
(0.4)
0.4))
15 (0.4)
5 (0.4)
100 (0.4)
(0.22)
(0
(0.66)
(0
(0.00)
(0
7 (0.2)
7 (0.6)
0 (0.0)
101 (2.8)
(2.8
(2
.8))
.8
(7.
7.8)
8)
1 (0.5)
11
101
90 (7.8)
* DCM=Dilated
DCM
DC
M Di
Dillattedd ca
cardiomyopathy.
rdi
diomyopath
thy † CM
CM= C
Cardiomyopathy;
ardi
diomyopath
thy; ‡‡Arrhythmogenic
Arrh
hyth
thmogeniic ri
right
ight
ht vent
ventricular
triicular
l
dysplasia/cardiomyopathy. § Non-diagnostic LVEMB was related either to an inadequate amount of tissue or normal
findings.
23
DOI: 10.1161/CIRCULATIONAHA.13.001414
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Table 4. Comparison of diagnostic performance of left ventricular (LV) and right ventricular (RV) endomyocardial biopsy (EMB) in patients
submitted to a biventricular EMB (n=2396).
Myocarditis
Idiopathic DCM†
Secondary
dary DCM
Alcoholic
holic
Hormonal
monal imbalance
Dystrophinopathy
rophinopathy
Toxicc
Nutritional
itional deficiency
Hypertrophic
CM‡
troph
phic
ic C
M‡
ARVD/C§
/C
C§
Other di
diagnoses
d
agno
gn ses
Amyloidosis
yloido
l do
d sis
Fabry
disease
ry di
dise
s ase CM
Glycogenosis
cogenos
no is
Idiopathic
Restrictive
CM
path
thic
hic R
est
stric
tric
icti
tive
ti
ve C
M
Connective
nectiv
ive tissue ddisease
i ea
is
ase
s
Hemochromatosis/hemosiderosis
ochromatosis/hem
em
mos
o id
i erros
osis
is
Endomyocardial
myo
yoca
card
rdia
iall fibrosis
fibr
fi
bros
osis
is
Non-diagnostic
Biventricular EMB
n° (%)
1188 (49.6)
603 (25.2)
217 (9.0)
54 (2.3)
82 (3.4)
37 (1.5)
19 (0.8)
25 (1.0)
130 (5.4)
46 (1.9)
(8.4)
201
20
1 (8
(8.4
.4))
.4
102
102 (4.3)
10
( .3)
(4
42 ((1.7)
1 7)
1.
7
7 (0.3)
(0.3
(0
0 3)
(0.3)
8 (0
(0.3
.3))
.3
23 ((0.9)
0.9)
9)
9 (0
(0.4)
0.44)
10 ((0.4)
0.4)
0.
4)
11 (0.5)
LVEMB
n° (%)
1136 (47.4)
603 (25.2)
217 (9.0)
54(2.3)
82 (3.4)
37 (1.5)
19 (0.8)
25 (1.0)
130 (5.4)
20 (0.8)
201
(8.4)
201 (8
(8.4
.4)
.4
102
02 (4.3)
(44.3)
3)
42 ((1.7)
1 7))
1.
(0.3)
7 (0
.3)
.3
(0.3)
8 (0
.3)
.3
3)
23 ((0.9)
0 9)
0.
(0.4)
9 (0
(0.4
. )
.4
10 ((0.4)
0.4)
0.
4)
89 (3.7)
RVEMB
n° (%)
799 (33.3)
424 (17.7)
184 (7.7)
38 (1.6))
72 (3.0))
37 (1.5)
15 (0.6)
22 (0.9)
74 (3.0)
46 (1.9)
184
18
84 (7.7)
(7.7
(7
.7))
.7
102
1002 (4.3)
(4.3
(4
.3))
42 ((1.7)
42
1 7)
1.
7
(0.3)
7 (0.3
0.3
. )
3 (0
(0.1)
(0.1
.1))
15 ((0.6)
0 6)
0.
(0.4)
9 (0
(0.4
.44)
(0.2)
6 (0
(0.2
.2))
685 (28.6)
p value*
<0.001
<0.001
<0.001
<0
<0.001
<0.0
<0
. 01
<0.001
<
<0
.001
.0
0
NS
0.05
NS
<0.001
<0.001§
<0.001
<0.001
< .0
<0
. 01
NS
N
N
NS
N
NS
<0.05
<0.0
<0
0.005
0.001
0.00
001
1
NS
<0.05
<0
0.0
.05
5
<0.001
* Comparison between LV and RV diagnostic value.† DCM=Dilated cardiomyopathy. ‡ CM=Cardiomyopathy. § ARVD/C=Arrhythmogenic right ventricular
dysplasia/cardiomyopathy. Only in this pathology RV biopsy has a significantly higher diagnostic value than LV biopsy.
24
DOI: 10.1161/CIRCULATIONAHA.13.001414
Table 5. Comparison of diagnostic performance of left ventricular (LV) vs right ventricular (RV) endomyocardial biopsy (EMB) in
patients submitted to a biventricular EMB (n=2396) related to the echocardiographic ventricular chamber involvement.
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Diagnosis
Myocarditis
LVEMB+
RVEMB+
Idiopatic DCM*
LVEMB+
RVEMB+
MB+
ry DCM
Secondary
Alcoholic
ic DCM
LVEMB+
MB+
RVEMB+
MB+
al imbalance DCM
Hormonal
MB+
+
LVEMB+
MB
B+
RVEMB+
Dystrophinopathy
hin
i op
opathy
p h
LVEMB+
M +
MB
RVEMB+
M +
MB
Toxic DCM
CM
LVEMB+
MB+
MB
B+
RVEMB+
MB+
MB
+
Nutritional
nal deficiency
defi
de
f ciency
fi
cyy DCM
CM
LVEMB+
MB+
RVEMB+
MB+
Hypertrophic cardiomyopathy
LVEMB+
RVEMB+
ARVD/C†
LVEMB+
RVEMB+
Other diagnoses
Amyloidosis
LVEMB+
RVEMB+
Isolated LV involvement
n°tot
n°
%
706
676
95.7%
382
54.1%
424
424
100%
205
48.3%
34
p value*
<0.001
<0.001
Isolated RV involvement p value* Biventricular involvement p value*
n° tot
n°
%
n° tot
n°
%
43
<0.001
439
NS
27
62.8%
424
96.6%
40
93.0%
422
96.1%
0
179
0.001
0
0
179
100%
0
0
170
95.0%
1770
95.0
95
.0%
%
<0.001
34
18
100%
52.9%
48
38
100%
79.1%
133
133
100%
00%
100%
100
0
<0.001
48
13
100%
100%
0
55.5%
55.5
55
5%
11
1
8
100%
100%
772.7%
72
.7%
7%
75
26
100%
34.6%
0
0
0
0
0
0
NS
6
6
0
0
0
0
0
0
0
0
25
34
34
100%
100%
24
2
244
100%
100%
100%
100%
%
NS
NS
0
0
0
0
4
27
14.8%
100%
0
0
0
0
NS
10
1
10
100%
100%
%
100%
100%
14
14
1
100%
100%
55
48
100%
83.7%
16
19
84.2%
100%
96
96
100%
100%
NS
14
14
<0.05
55
<0.001
0
100%
100%
100%
100%
10
10
27
6
20
20
24
24
0
0
NS
34
0
<0.001
75
0
0
0
NS
11
0
0
0
<0.05
<0.05
9
5
0
0
0
NS
9
20
19
NS
96
NS
DOI: 10.1161/CIRCULATIONAHA.13.001414
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Fabry disease CM‡
LVEMB+
RVEMB+
Glycogenosis
LVEMB+
RVEMB+
Idiopathic restrictive CM‡
LVEMB+
RVEMB+
Connective tissue disease
LVEMB+
MB+
RVEMB+
MB+
Hemochromatosis
romatosis
LVEMB+
MB+
RVEMB+
MB+
Endomyocardial
ocardial fibrosis
LVEMB+
MB+
RVEMB+
MB
B+
Non-diagnostic§
agno
ag
n st
stic
ic§
LVEMB+
MB+
MB
B
RVEMB+
M +
MB
12
NS
12
12
100%
100%
1
1
100%
100%
6
1
100%
16.7%
12
4
100%
33.3%
3
3
100%
100%
5
1
100%
100%
5
1
100%
100%
%
100%
1 0%
10
0
1
0
NS
6
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
100%
100%
2
2
100%
100%
11
11
1
100%
%
100%
100%
6
6
100%
100%
100%
5
5
100%
100%
5
5
100%
1000%
100%
1 0%
10
%
NS
NS
NS
NS
6
5
0
0
5
6
6
11
0
5
100%
100%
2
0
NS
NS
30
30
6
0
<0.001
3
0
0
0
<0.05
12
30
0
0
NS
5
NS
* DCM=Dilated
Dila
Di
i ted
ed cardiomyopathy. † AR
A
ARVD/C=
VD/C
D/ = Arrh
Arrhythmogenic
rhyt
y hm
h oggenic
i rright
i ht
ig
h vventricular
e tricul
en
cu ar
a dyspl
dysplasia/cardiomyopathy.
p as
asia/car
ardi
diom
di
om
myo
y pa
pathy.. ‡ CM=Cardiomyopathy.
CM=Cardio
a i my
yopathy.
p
§ Non-diagnostic
N nNo
n diagno
i n stic LVEMB
LVE
V M was
related either
inadequate
findings.
her
e too an inadequa
atee aamount
moun
ountt of ttissue
issue
is
ue or nnormal
orma
mal
al find
ings
ngs
g.
26
DOI: 10.1161/CIRCULATIONAHA.13.001414
Figure Legends:
Figure 1. Prevalence of different forms of myocarditis (A=lymphocytic, B=eosinophilic,
C=giant cell and sarcoid) in left ventricular endomyocardial biopsy. A=immunoperoxidase
for CD45RO, 200x. B=H&E, 250x. C= H&E, 200x. D=H&E, 200x.
Figure 2. Prevalence of specific causes of unexplained left ventricular hypertrophy
(A=hypertrophic cardiomyopathy, B=Fabry disease, C=myocardial glycogenosis,
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
D=amyloidosis) by left ventricular endomyocardial biopsy. A, B,C= H&E, 200x, in
squa e t a s ss o eelecronmicroscopy.
ec o
c oscopy. D=Congo
Co go red
ed staining,
sta
g, 100x,
00 , in
square=transmission
square=transmission elecronmicroscopy.
Figu
Fi
g ree 33.. Ec
cho
hoca
c rdiographic (A=diastole, B=s
systtole in four cham
am
mbeer ap
apic
i al view) and
Figure
Echocardiographic
B=systole
chamber
apical
h stologiccal (C=left
hi
(C=le
lefft ventricle,
vent
ntri
ricl
ri
cle,
cl
e, D=right
D=rig
=rig
ghtt ventricle,
ven
ntrricle,, H&E,
H&E,
E, 200x)
200x)
x) ccomparison
ompari
om
riso
son
n off L
V an
nd RV
V
histological
LV
and
invo
in
v lv
vo
lvem
emen
em
entt in
n a ppatient
atie
at
i nt
ie
n with
wit
ith
h heart
heaart
he
art failure.
fail
fail
ilur
uree. IItt sshows
ur
hows L
how
V dilation
dilaati
di
tion
on
n aand
nd ddysfunction
ysfu
ys
func
ncti
nc
tiion
o ddue
ue to
ue
o acti
aactive
ctiv
ve
ve
involvement
LV
myocardi
diti
tiss an
ti
nd a no
norm
mal
a R
V.
myocarditis
and
normal
RV.
27
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Figure 1
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Figure 2
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Figure 3
Contribution and Risks of Left Ventricular Endomyocardial Biopsy in Patients with
Cardiomyopathies: A Retrospective Study over a 28-Year Period
Cristina Chimenti and Andrea Frustaci
Circulation. published online September 4, 2013;
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Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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http://circ.ahajournals.org/content/early/2013/09/04/CIRCULATIONAHA.13.001414
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http://circ.ahajournals.org/content/suppl/2013/09/04/CIRCULATIONAHA.13.001414.DC1
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SUPPLEMENTAL MATERIAL
Description of catheter-based left and right ventricular endomyocardial biopsy
Endomyocardial biopsies (EMB) were performed in the left, right or both ventricles, approached
with a King’s bioptome until 1990 and afterwards by BIPAL biopsy forceps (Cordis Corporation
430 Route 22 East Bridgewater, NJ 08807) using a 7F (501-613A Cordis Corporation 430 Route 22
East Bridgewater, NJ 08807) long sheet introduced from a right and/or left femoral access. A long
sheath with angulated tip was introduced through the femoral vein and used for right ventricular
EMB while a long sheath with straight tip was introduced through the femoral artery and used for
left ventricular EMB. Biopsy specimens were taken using a disposable dedicated cardiac bioptome.
The cardiac biopsy forceps used has a PTFE-covered shaft with a length of 104 cm for curving the
distal section of the forceps into the desired shape and to direct it easily towards the ventricular wall
and two stainless steel symmetrical hinged cutting jaws able to drawn a 5.2 mm3 of tissue sample.
The BIPAL biopsy forceps has a great operational flexibility having at its proximal end a 3-pull
ring handle with spring so that samples can be held easily while being removed and the central ring
of the handle rotates to accommodate any hand position.
The left ventricular EMB procedure starts with a 7F pigtail guiding catheter that is introduced into
the long sheath and then passed retrogradely through the aortic valve into the left ventricle using a
standard J tip guide wire. Once the sheath is positioned near to the segment of the left ventricle
where the biopsy should be performed the guiding catheter is withdrawn through the sheath. Before
insertion the bioptome is bent smoothly in its distal part to enhance flexibility and to decrease the
risk of perforation. Then the bioptome is advanced through the guiding sheath into the left ventricle
under biplane fluoroscopic control (30° RAO and 60° LAO) which helps to guide the tip of the
catheter to the target area. The site of the biopsy is identified on a radiographic view using flashing
of contrast medium. Care is taken that the jaws of the bioptome are opened within the left
ventricular cavity before close wall contact is reached. A series of ventricular premature beats
usually denote the contact with the ventricular wall. Then a soft pressure is exerted and the biopsy
specimen is taken from the wall region of interest. After each biopsy, aspiration of blood from the
sheat and rinsing with heparinised saline solution is performed to prevent clotting.
For right ventricular biopsy, a 7F pigtail guiding catheter inserted into the sheath with angulated tip
is advanced over a J tip guide wire into the right ventricle. Under fluoroscopic control at 30° RAO
the tip of the guiding catheter is positioned in the septal position. Then the guiding catheter is
withdrawn through the sheath, the bioptome is advanced and the biopsies are taken from the
septum. In addition to using the preshaped sheath the bioptome is usually manually bend in the
distal part by 30°-45°, so that the jaws can be orientated more directly toward the septum.
Both the procedures were performed after intravenous infusion of 2.500 IE heparin from 1983 to
1990 but later heparin was only used in the washing saline solution since the patients were
pretreated with aspirin 800 mg bidie the day preceding the exam and 800 mg before the procedure.

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