multiple endocrine neoplasia. A histologic,. Catecholamine-induced cardiomyopathy in http://chestjournal.chestpubs.org/content/99/2/382 can be found online ...
Catecholamine-induced cardiomyopathy in multiple endocrine neoplasia. A histologic, ultrastructural, and biochemical study. A Frustaci, F Loperfido, N Gentiloni, M Caldarulo, E Morgante and M A Russo Chest 1991;99;382-385 DOI 10.1378/chest.99.2.382 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/99/2/382
Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright1991by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692
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Catecholamine-induced in Multiple Endocrine A Histologic,
Cardiomyopathy Neoplasia*
Ultrastructural,
and Biochemical
Study Andrea Emanuela
A
M.D. , F.C.C.P; M.D.; Marina
Frustaci, Gentiloni,
Nicola
Morgante,
M.D.;
catecholamine-induced
ported
3. A histologic taken in cardiac
and
with
and
A. Russo,
endocrine
ultrastructural
M.D.
is re-
cardiomyopathy
multiple
neoplasia,
study
M.D.;
M.D.;
Matteo
dilated
in a patient
Loperfido,
Francesco
Caldarulo,
has
type
been
under-
ardiovascular overproduction,
include
manifestations as occurs
hypertension,
of catecholamine in pheochromocytoma,
possibly
with
flection and T-wave inversion’ ventricular tachyarrhythmyas condition occurs, LV hypertrophy ally,
patients
no study
biochemical The
(or both).
When
pheochromocytoma
deor
this
present
of dilated cardiomyopathy,3 when the tumor is removed.4
genesis of this there are only and
ST-segment
supraventricular
last
cardiomyopathy a few clinical exists
which
changes
with
pathogenesis
is poorly understood; reports in the literature, correlates
morphologic
myocardial
of the
with
clinical
damage
and damage.
induced
by
cell
sarcolemma nels; and
functions and (2) an
are
activated:
(1) the
sarcoplasmic reticulum increase of peroxidative
of
5Fmm
the
with an impairment in various experimental Institute
of Cardiology
and
of
Internal
cytosolic models Medicine,
chanlipope-
Ca and
impairment myocardial
report,
Ca
we
left
ventricular
homeostasis
have
studied type
overproduction.
tural observations, and determination
and a patient
and
Ca pattern
branes have been performed correlated with clinical features
on
then with
3, presenting with associated with cat-
Histologic
myocardial of the lipid
of the
LVEF
99:382-85)
as a result of pheochromocytoma. of Ca channels and the lipopeof membranes may explain the
endocrine neoplasia, dilated cardiomyopathy
echolamine
1991;
re-
weight
of cytosolic necrosis.
this
(Chest end-diastolic; dry
patients who died Both the opening roxidative damage
ultrastruc-
measurement, of cell mem-
biopsy samples to ascertain the
and path-
damage. CASE
A 33-year-old He
had
and
previous
was
slender,
in the localized rhythm
La
(SVI
the
+ RV5
mm)
T wave
revealed
enlargement
the
with
in leads
of the chambers.
left atrium
remarkable with
dilatation diffuse
reduction
(ST
A 2D
ECG and
ventricle
LV
Catecholamine-induced
Downloaded from chestjournal.chestpubs.org by guest on July 10, 2011 © 1991 American College of Chest Physicians
showed
asymmetric
chest
due
echocardiogram end-diastolic
left
a gallop
hypertrophy
V6). The
silhouette
(internal of
The
deflection
V, and
cardiac
of the
Hg.
ventricular
D 1 , aVL,
ofthe
mm)
strain
revealed
and lump
by murmurs.
mm
left
nodular
tongue
a thyroid
auscultation
160/110
and
in the
revealed
unaccompanied
was
left-sided
and
Cardiac
measured
85
=
lobe.
enzyme revealed
enlarged
present
neck
he
In the
hypertension,
examination
with were
of the
minute)
of 18 years,
converting
physical
effort.
stomach,
of a tumor.
serum
patient
Palpation
age
a moderate and
nodules
there
negative of
developed
diuretics
hypotonic
per
pressure
At the
on
of the
because
of admission,
right
beats
rhythm;
dilatation L.
time
mucosa.
on
Blood
had by
and
(120
sinus
he
of dyspnea
dilatation
megaloureter.
neuromatous
labial
with
hemithyroidectomy
years,
multiple
because
childhood
controlled At the
REPORT
admitted
bilateral left
tWO)
which
was
since
undergone
lips;
in
man
suffered
megacolon, had
a tall,
Catholic
University, and the Department of Experimental Medicine, Sapienza University, Rome, Italy. Manuscript received April 18; revision accepted July 11. Reprint requests: Dr. Frustaci, institute of Cardio(ogia-UCSC, Agostino Gemelli 8, Rome, Italy 00168
382
abnormality
inhibitors.
roxidative metabolism.6 Secondly, early irreversible myocardial injury, described in detail as contraction band necrosis with the electron microscope,7 has been correlated homeostasis
main
ogenesis
opening Ca and
intracellular Ca overload as the sponsible for myocardial impairment.
left ventricular fraction; dw
be
could
receptor-mediated
=
We
supply
cate-
cholamine overproduction may be enlightened by two basic recent achievements. First, catecholamines are known to exert a receptor-mediated effect on myocardiocytes, which triggers a phosphorylation cascade dependent on inositol metabolites.5 Ultimately, two main
study.
or an a-adre-
coronary a
LVED ejection
the
membranes of
indicate
multiple a severe
which may The patho-
reduction
in
In
the echocardiogram usually shows with normal LV function.2 Occasion-
with
manifestations be reversed
and
of cellular
mediated
recognized
biopsy samples, together with determination ofmyocardial Ca and cellular membrane fatty acids. Contraction band necrosis of cardiocytes with supercontraction of sarcomeres progressing to myofibrolysis and increased levels of myocardial Ca have been found as morphologic and biochemical abnormalities, respectively.
C
No lipoperoxidation nergic
x-ray
showed diameter, (LVED
contractility
Cardiomyopathy
film
to prominence mild 44 mm)
diameter, (LVEF,
(Frustaci
68 0.30).
et a!)
Chemical
analysis
revealed
45 mI/mm),
while
levels
nemia
in the
normal
were
Analysis 76
of the
percent
test
well
hypertension (181
gland
the and
The
a 6
thyroid
medullarv
antigen
(3,800 to)tal-hodv
scan
metastatic
mm),
mg/24
on the
was
left
abnormal
mass
2 to 7 mg/24
ng/ml;
needle
dimethyl-mercapto-succinic
muscle
zation
and
and
were
(45/20
bio)psy,
processed
were
and
found
membrane
investigated LVED hg)
with
the
extraction
and
electron
fatty
acids,
a
evolution
serum.
failed
A
to show
neuromas
of the
gastrointestinal
carcinoma
o)f the
thyroid
diagnosis
of multiple
and
endocrine
with arteries
followed
microscop):
At
omr
patient tract,
bilateral neoplasia,
by
Ca
+ RV5
(50 mg
mm)
daily),
Dl,
of
2D strain
and
V5). The
diameter
(from
echocarcriteria
LV
aVL,
LVED
of LVEF
impairment
and of ECG
and
in leads
a reduced
recovery
ECGs
reduction
65
=
ST segment
partial
and therapy,
myocardial by
showed
registered
with
thyroid
tolerated
hydroccrtisone
16 months
follow-up
ofthe
0.30
of (mild
(from
2D 68 to
to 0.44).
Hg)
and
as some included
which
thickening
was
also)
cardiac
multiple
together
with 3, was
medullary made,
areas
of the
At transmission
the
contracture.
meres
(of
the
normally
and
progressive filament
FIGURE 1 . Catecholamine-induced dilated cardiomyopathy in multiple endocrine neoplasia, type 3. Contraction hand necrosis of mvocardio)cytes with foci ofinflammatory reaction (arrows) are seen (hematoxylin-eosin, original magnification X 250).
FIGURE
lular
Ca
around process.
which
severely
injured to) cell
none
muscular
coat,
electron
Seven as is present
microscopy, samples
was
of disorganization, the
disorganization organization
2. Supercontraction overload and
was
also
seen
to and
(Fig
ofsarcomeres progressing focally
CHEST
study
half
of divided cells
on
the the
final
showed
severity
of
of the
sarco-
length
of
of M-lines, loss
of vectorial
3).
associated with to myofibrolysis
I 99 I 2 I FEBRUARY,
Downloaded from chestjournal.chestpubs.org by guest on July 10, 2011 © 1991 American College of Chest Physicians
or
walls.
2), disappearance
of Z-lines, were
were
reduction
shortening up
(Fig
arterioles
Myocardial
identifiable
maximum
was as well
in contracted
a complete done.
than
tissue,
luminal
depending
sarcomere)
rather
interstitium
normal had
of cells
myocardiocytes
necrosis, fibrous
of them
necrosis
inflammatory
of the
of connective
In particular,
contracted
a few
replacement.
specimens;
band
1). Only
Widening
to an increase
biopsy
degrees
contraction
(Fig
phenomenon
of fibrous
endomyocardial
mucosal
pheochromocytomas,
due in our
varying
of
localized
myocarditic
present
with
evident
a reactive
a primary
and
and
was
observed,
a LV endowere
hypertrophy
fibers
suggesting
also
cardiac
Study
myocardial and
later.
type
and
(SV1
histology,
appreciable
Material
of mvocardial in
catheteri-
(22 mm
found,
p.g daily),
well
substituting
of catecholamine-induced last
of residual
was
mg daily).
at 6, 12, The
60 mm),
for removal
intervention of hormonal
(150 (0.2
evaluated
Morphologic
as calcitonin
of five fragments
to he described
asso)ciation
pressure
coronary was
for determination
to) the
The
This
administration
thyroxine
hammocking
and
in the
by cardiac
were
Both
by
fludrocortisone
was
to surgery
glands.
of carcinoem-
acid
Catheterization
for histology available
mm
hvpokinesia.
no)rmal.
myocardial
was Increased
pressure
LV dilatation valves
followed
were
impairment
angiography
pulmonary
was and
submitted
LV hypertrophy
scan
adrenal
biops);
levels
0 to 5 ng/ml)
with
adrenal
echocardiogram by
normal,
right
was
of the
diograms.
one. Increased
0 to 100 pg/mI)
the
patient
of h), as
A CT
on
the and
specifically A
increase
5 to 60 mg/24
h; normal,
investigated
no)rlnal,
with
mm).
localization.
Ileart
Due
(23.5
was diagnosed.
(118.8
pg/mI;
an
h; no)rmal,
of a 4 x 4-cm
lump
creatini-
(776,000/cu
o)f a pheochromocytoma.
mass
carcinoma
bryonic
made
4-cm
and
(16,980/cu
revealed mg/24
presence
presence X
clearance,
BUN,
thrombocytosis
acid
the
(creatinine
leukocvtosis
and
for
suggesting
failure
electrolytes,
showed
catecholamines
confirmed
cell
blood
as vanillylmandelic
h),
renal
range.
neutrophils
screening urinary
mild o)f serum
1991
intracel(L).
383
a
in a patient with medullary thyroid mucosal neuromatosis of the tongue,
carcinoma stomach,
and and
colon (megacolon), which is the typical configuration of multiple endocrine neoplasia, type 3#{149}9 The major cardiovascular feature was a catecholamine-induced dilated cardiomyopathy, which is rare and has not been previously described in multiple endocrine neoplasia, type 3. At light microscopy, myocardial biopsy samples
showed
necrosis
of myocardiocytes
hypertrophy,
with and
tory reaction, mainly due blasts (Fig 1). This pattern
to macrophages does not meet
areas of fibrous replacement process, which also explains function,
even
ofviable
suggest a incomplete
the several
myocardium
months
must
sive; unfortunately, no ported in this article. The coronary network
FIGURE 3. Detail of contraction bands that suggests mechanism damage produced by supercontraction. Two hypercontracted misarcomeres delimited by arrows (Z-M 1)(Z-M2) are shown. tween them, initial mvofihrolysis is evident.
Comparative
histologic
fragments ventricular
showed
mostly
and
The
Their
o)f the
patient
with
and
arterio)les
three
the
histology
of
after
thickening was
X
at the
24.5p,
multiple
fibers,
endocrine
observed
nuclear
vs
60.9p.
of
neoplasia.
in co)ntrol
samples
were
Biochemical
Analysis
Myocardial
Ca
1 .8 mg w/w
‘
has
‘
by atomic
been
at 90#{176}C, acid
extraction
LaCl3.
As a control,
five samples
surgery
for
SD
in
SD
=
tetralogy
in the
control
52. 1/mg
Analysis obtained
of
compared lipid
fatty
w/w
three
extraction
and
The
addition
weight value
dw)
of 1 percent
were
taken
during
of myocardial
was
higher
of
overnight
calcium
than
the
(mean±SD=39.8±8/mg of
cardiac
biopsy
cell
sample
surgical This by
multiple
mg of protein;
control
method BF3.
secnd
dw;
2nd
membranes
0.363
0. 140 ± 0.005
nmol/mg
has
been
by gas chromatography samples
included
Fatty
endocrine
palmitate,
(stearate,
0.360±0.010
Fallot.
fragment after
from tissue
by chlorophormium-methanol
transesterification
controls
HNO3),
ofsimilar
(82 nM/mg
acids
mg
with
from
(iN
group
of Fallot.
sample
in a biopsy
spectrophotometry
dw).
in 2.2
tetralogy
of
patient
our
determined
absorption
drying
observed
acids neoplasia
nmollmg nmol/mg
and
a patient
with
homogenization, (2: 1), filtration,
were
not
different
(stearate, of protein) of
and in
0. 134 compared
protein;
the
nmoll with
palmitate,
animal
been
pheochromocytomas
evaluated
been
observed
re-
through
which
ascribe
coronary
a major
role
constriction”
to ain
the
of the
coronary intramural
in the which
smooth muscle should have arterioles a hypertrophic
induced reaction,
This suggests that may have a minor of catecholamine-
associated myocardial damage in man. At electron microscopy, most of myocardiocytes showed
all stages
of supercontraction
(Fig 2 and 3), previously diocytes and induced Such changes to irreversible death, most
of sarcomeres
described in isolated by high cytosolic Ca
are considered disorganization
sequential and
myocarlevels.7
events myocardial
and many experimental evidences suggest of the steps are dependent on cytosolic
and energy physiologic
supply, contraction.
cium when
in biopsy compared
gical
samples
ever,
have
exten-
were
pathogenesis of catecholamine cardiomyopathy. In particular, such a long-term stimulation
there
dependent
tissue with of
a key
associated
384
studies mediated
suggests
of pro)tein). DISCUSSION
Bilateral
has
less
studies
is totally lacking in our patient. reduction in coronary blood flow role, if any, in the pathogenesis
unremarkable.
been
morphologic
tumor
recovery has the substitu-
document abnormalities of the main coronaries, as well as thickening of intimal and medial layers of intramyocardial arterioles. This seems in contrast with adrenergic
control
have
reparative recovery
coronary angiography and light microscopy of intramyocardial arterioles. Although a direct measurement of coronary blood flow was not obtained, we failed to
some
right
myocardial
average
o)f 400
with from
hypertrophied
magmficatio)n
interstitium
surgically
undertaken.
alignment.
with
myocardiocytes The
were
studies
drawn
moderately
in regular
level
morphometric
of Fallot,
o)utflOW,
samples
and
tetralogy
O)f
of heBe-
and fibromorpho-
the
removal; however, a case of complete been recently reported,4 indicating that tion
band inflamma-
for myocarditis, as recently defined . ofinterstitial fibrous tissue as well as the
logic criteria The increase
of cardiac
contraction
a moderate
with
role
that
are similar Determination
sample normal
tetralogy of Ca
function
of
Fallot.
also
in
that of the of total cal-
This
further
myocardiopathy
overproduction;
agreement that
that Ca
showed a net increase myocardium from sur-
catecholamine
is no
to
leading cell
on
what
is responsible
Catecholamine-induced
Downloaded from chestjournal.chestpubs.org by guest on July 10, 2011 © 1991 American College of Chest Physicians
how-
is the for cell
Cardiomyopathy
Ca disor-
(Frustaci
et a!)
ganization.
Calcium
as fluffy, olism;
dense but
ganized somes
or
injury
as
branes;
accumulate
occasionally
however,
been
to be
membrane
cytosolic
Ca
have
studied
from
biopsy
control, tetralogy
which
homeostasis. pattern
of Fallot.
failed
between the two samples, dation also is of minor disorganization associated
to
1986;
any
cholamine-induced
necrosis
the
1987;
5 Flaim and
with
cardiomyopathy.
reversible after is characterized
of cardiocytes
main
biochemical
and
J
This Nuclear
Hospital,
15th
responsible
Dana-Farber
course at
Beth
is offered
Cancer
will be held at the Westin Harvard Med-CME, P0
Hotel, Box
by
Hospital,
Institute, Copley
825,
Boston
BT,
Tajik
AJ.
J Cardiol
Am Glass
TA,
J
Br
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catecholamine-induced
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Calcium
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N EngI
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MA,
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Cittadini
of action
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Dani
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Fleury
J
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9 Schimke ment.
RN. HT,
Billingham
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JT,
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a classification.
Medicine,
AM,
Mol
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C,
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curable
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An
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Am
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o)f calcium-induced
in pheochromocytoma:
Heart
Beamish
60:1390-97
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in catecholamine-induced
Pharmacol
cholamine
Nuclear
Israel
DM,
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Jr.
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PK,
10 Aretz
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abnormality
annual
Ilackshaw
in a child Zelis
8 McManus
en-
microscopy. A overload seems
Medicine
1977:243
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316:793-97
SF,
7 Russo
electron Ca
Clinical
SC,
endocrine
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removal of the by contraction
on histology
FA Davis,
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ED
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endocrine neoplasia, be accompanied by
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D’Souza
Vaughan
Med
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dilated
tity, at least partially pheochromocytoma, band
G,
ultrastructsiral
multiple rare, can
in
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57:89-92
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L,
Pheochromocytoma
DS,
a
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as
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57:971-75
AG.
we
and,
Electrocardiogram
In:
Ct,eto-Garcia
4 Imperato-McGinley
the
a patient
find
C,
3 Velasquez
activarise to a
ML.
disorders.
Echocardiographic
isolated
patient
Mangiardi
correlations.
2 Shub
this
possibility,
from
B,
metabolic
ographic
impairs
this
our
samples We
a strong giving
in membranes
from
surgical
and
disorganizing
further
To test
lipid
1 Surawjcz
mem-
or
models,
in the
may trigger metabolism,
specimens
from
event
damage
the
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1991
385
Catecholamine-induced cardiomyopathy in multiple endocrine neoplasia. A histologic, ultrastructural, and biochemical study. A Frustaci, F Loperfido, N Gentiloni, M Caldarulo, E Morgante and M A Russo Chest 1991;99; 382-385 DOI 10.1378/chest.99.2.382 This information is current as of July 10, 2011 Updated Information & Services Updated Information and services can be found at: http://chestjournal.chestpubs.org/content/99/2/382 Cited Bys This article has been cited by 4 HighWire-hosted articles: http://chestjournal.chestpubs.org/content/99/2/382#related-urls Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.chestpubs.org/site/misc/reprints.xhtml Reprints Information about ordering reprints can be found online: http://www.chestpubs.org/site/misc/reprints.xhtml Citation Alerts Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to the right of the online article. Images in PowerPoint format Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online figure for directions.
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