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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

T, Ehlers

Reversibility

R, eds.

Kapur

Physiol

K, Zullo

of

with

Formanek

Radiol

1984;

MA,

Golstein

catecholamine-induced

pheochromocytoma.

Calcium

blockers:

Baltimore:

J

N EngI

mechanism

Urban

MA,

KS,

1982;

Cittadini

of action

and

Schwarzenherg,

RE,

Dhalla

heart BM,

Dani

J

cells.

Fleury

J

1981;

9 Schimke ment.

RN. HT,

Billingham

JJ,

JT,

Fenoglio

and

a classification.

Medicine,

AM,

Mol

TA,

Syndromes Med

M,

Role Can

Inesi

Cell

C,

Terranova

T

degenerative Cardiol

Roberts

WC.

curable

form

1982; Fatal

An

changes 13:265-79

catecholamine

of cardiac

arrest.

Am

102:930-32

Prog

11 Simons

NS.

cardiomyopath):

o)f calcium-induced

in pheochromocytoma:

Heart

Beamish

60:1390-97

A,

study

in dissociated crisis

N, Dhillon

in catecholamine-induced

Pharmacol

cholamine

Nuclear

Israel

DM,

cardiomyopath}:

Gautier

Jr.

applications.

PK,

10 Aretz

super-

abnormality

annual

Ilackshaw

in a child Zelis

8 McManus

en-

microscopy. A overload seems

Medicine

1977:243

Ilstrup

316:793-97

SF,

7 Russo

electron Ca

Clinical

SC,

endocrine

electrocardi-

in pheochromocytoma.

VJ,

J,

of free-radicals

removal of the by contraction

on histology

FA Davis,

Sheps

and

ED

clinical

6 Singal

type 3, a cateThis

Clinical

1982:25

difference

endocrine neoplasia, be accompanied by

contraction of sarcomeres on receptor-mediated intracellular to be

D’Souza

Vaughan

Med

indicating that lipoperoxisignificance in the necrotic with catecholamine over-

dilated

tity, at least partially pheochromocytoma, band

G,

ultrastructsiral

multiple rare, can

in

ed.

57:89-92

production. In conclusion although very

L,

Pheochromocytoma

DS,

a

JC,

Philadelphia: findings

cardiomyopathy

as

Rios

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

REFERENCES

structures,

blocks,

experimental

a late

impairment.

disor-

supramolecular

in various

shown

myocardial

metab-

mitochondria

anchoring

sequence. Finally, Ca tion of lipoperoxidative diffuse

are

energy

Ca may activate lysowhich may explain the

proteinaceous

microfilaments,

for

in mitochondria

impairing

damaged. The neutral proteases,

of

such has

only or

may

precipitates,

Genet

with

multiple

1979;

3:143-75

ME,

et al. Am

Donning cardiomyopathy

Edwards

Mvocarditis:

J SE.

WD,

gland

Factor

Pathol

Coronary

1986;

J

1985;

Fallon

definition 1:3-14

vaso)constriction Heart

involve-

SM,

a histopathologic

Cardiovasc Am

endocrine

and

cate-

109:297-304

1991

Medical School and the Joint Program in the Brigham and Women’s Hospital, The Children’s and the West Roxbury VA Medical Center. The course Place, Boston, April 22-25. For information: contact: Harvard

02117

(617:

432-1525).

CHEST

I 99 I 2 I FEBRUARY,

Downloaded from chestjournal.chestpubs.org by guest on July 10, 2011 © 1991 American College of Chest Physicians

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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