Cardiotoxicity

of lnterferon*

A Review of 44 Cases
Moshe

and Arnold

M.D.;

Sonnenblick,

Rosin,

MB.

complications
have occurred
in clinical
We review herein experience
to date of
cardiotoxicitywith
all types ofinterferons
in cancer
patients.
The most common
presentations
of cardiotoxicity
were
Cardiovascular

trials

of interferon.

cardiac

arrhythmia,

of ischemic
and sudden

dilated

cardiomyopathy,

and

symptoms

heart disease,
including
myocardial
infarction
death. The cardiac
effects were not related to

linical trials with interferon

have been carried
out
in recent
years in patients
with various
malignant
diseases,
but principally
in patients
with
advanced
nontreatable

cancer.

The

a flulike
syndrome.
ported
to be affected,

most

common

Various
systems
including
the

side
have
central

effect

following
in patients

that agent.
additional

there have
the possible

Since
reports

that report,
concerning

effects
of interferon.
Different
feron-induced
cardiotoxicity
some
of the patients
reaction
induced
by
was

also

suggested

been
renervous,

is to review

possibly

been
a few
cardiotoxic

manifestations
of interhave been
reported
in

cardiovascular

complications

describe
and

on interferon-related
the

to

associated

various
determine

with

effects

on

the

recombinant

There

have

induced

daily

the

The

15

reports

on

llible

cardiotoxicity.
and cumulative

the coexistence
Sex and

been

REPORTED

total

ofunderlying

CASES
44
the

heart

the

period

Doses

daily

in only

age

type

doses

high
not

between

correlation

cardiotoxicity

were

and

age

and

patients

related

0. 1 x 10

U/d

other

hand,

after

and

period

of

interferon-related

dose

Underlying

Heart

At least

the Department

Jerusalem,
Manuscript

Israel.
received

ofGeriatrics,

reported.

There

or sex (Fable

cardiotoxicity

May

31; revision

Shaare
accepted

Zedek

gamma

received

after

interferon

exceeded

effect
nor

and

x 10

U,

8,400

x 10

to the

day.

as

On the

oftoxicity

six

until

with

months,

one

of

as low

one

signs

in

duration

doses

ofonly
than

with
was

treated

ofinterferon

from

not show

more

administered

were

patient

after

U (Table

1).

evidence

ofpreexisting

the

Disease

12 ofthe

patients

all of those

myocardial

were

patients

a period
did

of

8,400

had

a few had known

some

coronary

heart

by interferon

had

of the
known

were

either

patients

with

previous

heart

However,

while

manifestations

the

disease

cardiotoxicity
none

disease.

heart

known

with

infarction,

induced

of interferon
of the

patients

interferon-induced

Doxorubicin

or

arrhythmia
cardiomyopathy

heart

disease

(Table

1).

Treatment

Previous

as

(Adriamycin)

well

period

had

was

1).

no

received

Medical
September

Center,
4.

the various

presented.

occurred
effect

various
duration

ways
ofthe

Most

a myocardial

suffered

the

in

ofinterferon

doxorubicin

patients.

five

None

effects

of

during

interferon-induced

suffered
or

patients.

the

In

direct

to the

single

from

death,

and

nine

patients

the

death.

oftheir
were

daily

arrhyth-

sudden

cause

cardiotoxicity

of the

of treatment,

in which

patients

not

dose,

related

or to the

to
total

of interferon.
the

Supraventricularand
most

common

ventricular
manifestations

in 25 patients.278116
arrhythmias
with

without

further
drugs.

did

not

Most
represent

arrhythmia
One

patient

while

cardiotoxicity,

had underlying

receiving

disease.

events.

continued

Three

treatment

treatment

ventricular

were

heart

life-threatening

had fatal

which

arrhythmias,

of

arrhythmia

supraventricular

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ofthe

infarction
was

manifestations

patients

rhythmic

eight

any evidence
ofcardiotoxic
therapy
(Table 1).

shown

2 summarizes

The

reported

in at least

of Toxicity

Ten

amount

with

treatment

concurrent

ofdoxorubicin

cardiotoxicity

mia.

as

reported

was

patients

Atrial

*Fmm

ten

treatment
of

cumulative

of

U/d)

ofthe

dose

disease;

X 10

while

sometimes

some

cumulative

were
with

patients

U/d). The cardiotoxic

to the total amount
of interferon
Toxic effects
were
documented

cardiomyopathy

of Interferon

Most

ofthe

interferon

(>36 x 1

Arrhythmia:

ll,pe

None

interferon

recombinant

Recombinant

of Treatment
(<9

patients,

treatment.

Table

of toxicity,

of treatment,

disease.

of 11 patients

12 patients.

patients.

doses

seven

cardiotoxic

the

by

Duration

and

Low

interferon-

Age
sex and

caused

beta.

Manifrstatione

with

patients

1 summarizes
dose,

used

used by eight

was

alpha. The subtype

interferon
was

alpha-2

the
ON

of therapy.
has

sequelae
have had a history
of coronary
heart disease
or have previously
been given
chemotherapy
with drugs known to be cardiotoxic.
In most of the patients,
cardiac
toxicity was reversible
following
the cessation
of the
drug
therapy

these

heart.
DATA

or period
interferon

whom

cardio-

manifestations
of
the risk factors

interferon

total dose,
in

cardiovascular

in almost

on hearts
with limited
coronary
or
The purpose
ofthe
present
report

the literature

toxicity,
to
cardiotoxicity,

four deaths
treated
with

and were related

to the febrile
first exposure
to interferon.
It

that

are superimposed
myocardial
reserve.

cumulative
patients

is

gastrointestinal,
hematopoietic,
musculoskeletal,
and
endocrine
systems.
Skin,
adnexa
and renal
function
are also affected.
That interferon
might be cardiotoxic
in humans
was first suggested
due to myocardial
infarction

the daily dose,

Some
of the

with
fibrillation

I 99 I 3 I MARCH,

1991

antiar-

and
557

Table

1-Summary

ofReported

Cardiotaxicity

Previous
No.

of

Patients

Ref.
No.

(yr)

Sex/Age

of lnterferon*

Single

Cardiac

Type

of

Disease

Interferon

Total

Interferon
Dose

Interferon-

Interferon

(U)

Dose

induced

(Period)

Cardiotoxicity

Comments

ARRHY1HMIA

ND

ND

Ralpha

ND

and

Atrial

ND

Most-

ventricular

preexistent

arrhythmia

heart

disease

or doxorubicin
1

ND

None

NR alpha

15 x 10

75x10

FatalVF

ND

Arrhythmia

R alpha-2

ND

ND

Atrial

ND

None

R alpha

50

150 x 10/m2

VF

ND

None

Raipha

50x10

5OxR?

VPBs

11

F/67

Left

R alpha-2

30 x 10fm

150 x 10/m2

SVF

Doxorubicin

AF

Doxorubicin

(1 wk)
arrhythmia
10fm

(1 wk)
axis

(<lwk)
1

11

F/87

1#{176}-AVB

R alpha-2

1000 x

50 x 10fm

10/m

(<12
3

15

None

ND

Rgamma

0.6-20X10/m

wk)

ND

AFI
(<2

15

ND

1#{176}-AVB

Rgamma

ND

ND

and

VPBs

wk)
AFI

(2 wk)
1

16

ND

None

R gamma

0.1 x 10/m

ND

11

Ff64

AF

R alpha-2

30 x 10fm

300

APBs

10/m2

(<5
1

11

None

Mfll

R alpha-2

10 x 10fm

AF

Doxorubicin

AF

Doxorubicin

wk)

60 x 10/m4
(<2

wk)
ISCHEMIA

ND

ND

Alpha

ND

ND

Fatal

MI

ND

MI

Ralpha

ND

ND

Fatal

MI

ND

IHD

R alpha

50 x 10fm

50X10/m

Fatal

MI

(1 d)
1

ND

AP

Ralpha

50X10/m

50x10fm

MI

(1 d)
1

ND

IHD

R alpha-2

5 x 106/m2

65X10/m

MI

(8 wk)
1

16

ND

AP

Rgamma

1X1Ofm2

2 x 10/m

Ischemia

(2d)

CHF
COMPLICATION

M/56

None

NRalpha

3 x H?

3x10

Cardiac

(1 d)
1

ND

None

R alpha-2

lOx

10fm

arrest

ND

Left

heart

Concurrent
doxorubicin

failure

therapy
1

ND

LVH

R alpha-2

1 x 10fm

6 x 10/m

10

ND

ND

Rgamma

ND

ND

11

M/58

R alpha-2

30 x 10fm

300X10/m

(3.5

None

Sudden

wk)

death
1#{176}-AVB

(<5

Doxorubicin

HR168/m

wk)
CARDIOMYOPATHY

12

Ff62

None

R alpha-2

3-9 x 10

27 x 10

13

M/42

None

Ralpha

3-35x10

5,500 x

Cardiomyopathy
Cardiomyopathy

10

(57 wk)
1

13

Mi35

None

Ralpha

2,700

35x10

106

Cardiomyopathy

(<llwk)
1

M/37

13

None

Ralpha

8,400

11.8x10

x 10

(102
1

14

#{149}Ref reference;

Svr=

Mfl4
ND

supraventricular

premature

beats;

ventricular

hypertrophy;

MI

None

no data

taehycardia
myocardial
HR=

recombinant;

Ralpha-2
NR

1#{176}-AVB 1st-degree
infarction;

heart

AP=angina

540 x 10

3x10

nonrecombinant;

VF

atrioventricular
pectoris;

IHD

Cardiomyopathy

wk)

ventricular

block;
ischemic

AF=atrial
heart

Cardiomyopathy
fibrillation;

VPBs

fibrillation;

disease;

ventricular

AF1=atrial

CHF=congestive

premature
flutter;

heart

failure;

beats;

APBsatrial
LVH

=left

rate.

558

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Cardiotocity

of Interferon

(Sonnenblick,

Rosin)

Table

2-Various

Piesentstions
Cardiotoxicity

lnterferon-induced

of

that

No. of
Type

ofToxicity

Patients
25

Arrhythmia

infarction/ischemia

Myocardial

they

were

related

Predisposing

toxicity
cases,

to the

factors

for

flulike

are not clear.

It appears
toxicity
was not necessarily

Of those
occurred
cardiotoxicity

within

Sudden

in patients

2
1

patients
patients

receiving
accumulating
died of a cardiac
event

heart

istration

of a very

block

Atrioventricular
Congestive

heart

failure5

with

patient

ischemia

had,

in addition,

congestive

failure.

another

experienced

of heart
dose

ventricular

disease.

The

of interferon

was

lschemia:

tachycardia,

ventricular

without

both

tachycardia

infarction

was

of

died..3.6

One

additional

development

ofchest

pain associated

with

ST segment

whom
that

who

indeed

underlying

five

had

experienced

therapy.6856

the single
toxicity.

dose

myopathy
with

been
significantly

suspended.

All

period,

but

the

average

four.

Two

of the

but

interferon

the

was

restarted

first

in one

without

by Cohen

described

four

the

on

edema.

All

heart

disease.
within

et

in another
In four

of the

improved
patients
daily

five

after

were
dose

patients

four

Three

of the

two

days of

patient

appeared

were

patients,

did not demonstrate

different

a change

in the ejection

types

In most

of

fraction

of the

sequelae
been reported:
heart disease,

cases,

the cardio-

consisted
primarily
of arhowever,
20 patients
receiving

recombinant

interferon

DNA

gene

for cardiac

for cardiotoxicity
in 12 ofthe

rhythm

were

prospectively

disturbances;

is that

none

no signffi-

nant

at baseline
that even
of inter-

from 15 phase 1 trials

most of whom
were

given
recombinant
interferon
alpham
or interferon
gamma,
and a few interferon
beta,313
no significant
cardiotoxic
adverse
effects
of interferon
were
reported.
In some
of these
studies,
however,
acute
effects

of

interferon

in

the

consisted
mainly
of tachycardia,
distal cyanosis.
Since these side
during

the first exposure

cardiovascular

system

hypertension,
and
effects were described

to interferon,

it was suggested

toxic

might

factor

for

in

of the
admin-

within

one

to

disease,
finding

cardiomyopathy

of doxorubi-

speculate

that

some

cardiotoxicity
was ascribed

of

were
to the

interferon-induced

some

ofthe

adverse

might
similar.

cardio-

effects

cardiotoxicity
alpha

ofthe

different

differ from one another,

Most
of the patients
or

received

they
with

recombi-

recombinant

interferon

jority of trials with

with the recombinant
this is the reason
related
cardiotoxicity

interferon
therapy
were carried
out
alpha type, we have to assume
that
that most
reports
on interferonwere
from
patients
who
had
recombinant

treated

The

with

various

presentations

as shown

interferon

alpha.

of interferon-related

in the

present

car-

review

indicate

more than one mechanism.

The most common
doselimiting
toxicity
of interferon
is a flulike
syndrome.
Febrile
responses
are generally
noted
in all patients
and always most
oxygen
demand
dia may therefore

severely
after the first dose
Increased
caused
by fever, chills, and tachycarprecipitate
infarction
or arrhythmia
.

in compromised
myocardium.
Another
possibility
is
that interferon
induced
coronary
spasm
in these
patients.
It seems,
therefore,
that the cardiotoxic
effect
may be principally
ofinterferon
which
mechanism

due to peripheral
vascular
effects
reflexly
stress the heart. A different

has to be considered
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and

alpha-2.
A few received
recombinant
interferon
gamma,
while none received
interferon
beta. Since a great ma-

diotoxicity

feron administration.
Moreover,
involving
a total of 432 patients,

and

administration

One

risk

interferon

when
comparing
monitoring
ra7
It seems,
therefore,
effect

with

or concurrent

interferon-related

documented
and during

side

dose

was previous
cardiac
patients.
An interesting

patients

not clear.

Although

been

uncommon

Some
the

toxicity.

in average
heart rate and in the frequency
or supraventricular
ectopic
beats were

is a very

of the

of previous

cant changes
of ventricular

arrhythmia

doses.
following

had known
previous
heart disease.
It seems,
therefore,
that the presence
of underlying
heart disease
can be
considered
a risk factor
for interferon-induced
arrhythmia
or ischemic
manifestations.
The importance

types ofinterferon
are, in general,

of cardiovascular

doses

contributing

doses

toxic
effect
of interferon
rhythmias.
In one study,
assessed

total

occurred

daily

one

was

in only

lower

high

long

myocardial

a relatively

with

to interferon
treatment
have
manifestations
of ischemic

and cardiomyopathy.

low

and

data
of 24

administration
of doxorubicin.
More
data on cardiotoxicity
in patients
receiving
treatment
with interferon
who had been
previously
treated
with doxorubicin
might
clarify
the importance
of doxorubicin
as a

were

therapy

to be high

retreated

cardio-

who

DISCUSSION

Three

low

the cases
of interferon-induced
not reported
because
the toxicity

rechallenge.

attributed
arrhythmia,

factor

cm is also

cardiomy-

patients

for

after
cardiac

then

interferon

treated

disease

further

Since

al.52

pahad

elevation

case of interferon-induced

first

in 1988

of the
during

artery

eight

patient

previous

significantly,

interferon.34

dysfunction

in

by pulmonary

event

Therapy

The

has

treated

coronary

reported

reported

concerning

ischemic

was reduced

Cardionuppathy:
was

complicated

questioned

the

interferon

opathy

was

were

Similarly,

as reported

Myocardial

five patients

the

reduced.

tients,23689
electrocardiogram

after

weeks.
receiving

on whom
in 18

seven
days of initiating
the drug treatment.
Toxicity
was also not related
to age. The only possible
risk

a history

resolved

five

cardio-

that in most of the

related
to a long

period
of interferon
therapy.
were
available,
cardiotoxicity

Cardiomyopathy
death

reaction.

interferon-related

to explain
I 99

I 3 I MARCH,

the revers1991

559

ible

that occurred

cardiomyopathy

known

previous
of the patients
depression
were
ciency

syndrome,

thy resulted
nodeficiency
a recent

it was

from
virus

report

diomyopathy
points
to

infection

reversible

hairy

an endomyocardial
biopsy
reversible
cardiomyopathy

effect

The
of the

car-

were

cells.

Another

some
tile function.

eventual
impairment
However,
another

out to
cells.

2 Dickson

interferon-induced

by a direct
in functional
feron
Since

myocardial

effect or is indirectly
cellular
elements

interferon

introduced

principally

tions. Patients
with documented
disease
may show aggravation
Therefore,
interferon
should

human

ofunstable

feron

ischemic

observation
until

angina.

the

Patients

events

should

following
cessation

of the

the

with

effort

first

flulike

advisable
to commence
treatment
with
and increase
them gradually.
Arrhythmias,

dose

K.A,

small
doses
should they

560

Downloaded From: http://journal.publications.chestnet.org/ on 07/18/2014

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42

angina

be under

malignancy.

Mitchell

or symptomatic
heart
of ischemic
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not be given
in the

interferon

effects

I trial

8 Grunberg

to
some
been

halts

Bukowski

Phase

recombinant

overlooked.
From the cases ofcardiotoxicity
reviewed,
one can point to several
possible
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condi-

cardiac

CT,

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