Cardiotoxicity of lnterferon*

A Review of 44 Cases
Moshe Sonnenblick, M.D.; and Arnold Rosin, MB.

Cardiovascular complications have occurred in clinical the daily dose, cumulative total dose, or period of therapy.
trials of interferon.
We review herein experience to date of Some of the patients in whom interferon has caused
cardiotoxicitywith all types ofinterferons in cancer patients. cardiovascular sequelae have had a history of coronary
The most common presentations of cardiotoxicity were heart disease or have previously been given chemotherapy
cardiac arrhythmia, dilated cardiomyopathy, and symptoms with drugs known to be cardiotoxic. In most of the patients,
of ischemic heart disease, including myocardial infarction cardiac toxicity was reversible following the cessation of the
and sudden death. The cardiac effects were not related to drug therapy

C linical trials with interferon have been carried out recombinant

alpha-2 was
interferon
used by
alpha. The subtype
12 patients. Recombinant
recombinant
interferon
interferon
gamma
in recent years in patients with various malignant
was used by eight patients. None ofthe patients received interferon
diseases, but principally in patients with advanced
beta.
nontreatable cancer. The most common side effect is
a flulike syndrome. Various systems have been re- Doses and Duration of Treatment
ported to be affected, including the central nervous, Low daily doses (<9 X 10 U/d) of interferon were administered
gastrointestinal, hematopoietic, musculoskeletal, and in only seven patients, while ten of the patients were treated with
endocrine systems. Skin, adnexa and renal function high doses (>36 x 1 U/d). The cardiotoxic effect ofinterferon was
not related to the total amount of interferon nor to the duration of
are also affected. That interferon might be cardiotoxic
treatment. Toxic effects were documented from doses as low as
in humans was first suggested following four deaths 0. 1 x 10 U/d and sometimes after a period ofonly one day. On the
due to myocardial infarction in patients treated with other hand, some ofthe patients did not show signs oftoxicity until
that agent. Since that report, there have been a few after a period of treatment of more than six months, with a
additional reports concerning the possible cardiotoxic cumulative dose of 8,400 x 10 U, and in one patient after the
cumulative dose exceeded 8,400 x 10 U (Table 1).
effects of interferon. Different manifestations of inter-
feron-induced cardiotoxicity have been reported in Underlying Heart Disease
some of the patients and were related to the febrile At least 12 ofthe patients had some evidence ofpreexisting heart
reaction induced by first exposure to interferon. It disease; a few had known coronary heart disease. However, while
was also suggested that cardiovascular complications in almost all of those with known heart disease the manifestations
are superimposed on hearts with limited coronary or of interferon-induced cardiotoxicity were either arrhythmia or
myocardial infarction, none of the patients with cardiomyopathy
myocardial reserve. The purpose ofthe present report
induced by interferon had known previous heart disease (Table 1).
is to review the literature on interferon-related cardio-
toxicity, to describe the various manifestations of Doxorubicin Treatment

cardiotoxicity, and to determine the risk factors Previous as well as concurrent treatment with doxorubicin
possibly associated with interferon effects on the (Adriamycin) was reported in at least eight ofthe patients. None of

heart. these patients had shown any evidence ofcardiotoxic effects during
the period ofdoxorubicin therapy (Table 1).
DATA ON REPORTED CASES
Manifrstatione of Toxicity
There have been 15 reports on 44 patients with interferon-
Table 2 summarizes the various ways in which interferon-induced
induced cardiotoxicity. llible 1 summarizes the type of toxicity,
cardiotoxicity presented. Most ofthe patients suffered from arrhyth-
the daily and cumulative total dose, the period of treatment, and
mia. Ten suffered a myocardial infarction or sudden death, and
the coexistence ofunderlying heart disease.
cardiomyopathy occurred in five patients. In nine patients the

Sex and Age

cardiotoxic effect ofinterferon was the direct cause oftheir death.
The various manifestations of the cardiotoxicity were not related to
The sex and the age of 11 patients were reported. There was no the duration of treatment, to the single daily dose, or to the total
correlation between cardiotoxicity and age or sex (Fable 1). amount of interferon.
Arrhythmia: Supraventricularand ventricular arrhythmias, which
ll,pe of Interferon were the most common manifestations of cardiotoxicity, were
Most patients with interferon-related cardiotoxicity received reported in 25 patients.278116 Most had underlying heart disease.
Atrial arrhythmias did not represent life-threatening events. Three
*Fmm the Department ofGeriatrics, Shaare Zedek Medical Center, patients with supraventricular arrhythmia continued treatment

Jerusalem, Israel. without further arrhythmia while receiving treatment with antiar-
Manuscript received May 31; revision accepted September 4. rhythmic drugs. One patient had fatal ventricular fibrillation and

CHEST I 99 I 3 I MARCH, 1991 557

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 Table 1-Summary ofReported Cardiotaxicity of lnterferon*

Previous Single Total Interferon-

No. of Ref. Cardiac Type of Interferon Interferon induced
Patients No. Sex/Age (yr) Disease Interferon Dose (U) Dose (Period) Cardiotoxicity Comments

ARRHY1HMIA
9 1 ND ND Ralpha ND ND Atrial and Most-
ventricular preexistent
arrhythmia heart disease
or doxorubicin
1 5 ND None NR alpha 15 x 10 75x10 FatalVF
(1 wk)
2 7 ND Arrhythmia R alpha-2 ND ND Atrial
arrhythmia
1 8 ND None R alpha 50 X 10fm 150 x 10/m2 VF
(1 wk)
2 8 ND None Raipha 50x10 5OxR? VPBs
1 11 F/67 Left axis R alpha-2 30 x 10fm 150 x 10/m2 SVF Doxorubicin
(<lwk)
1 11 F/87 1#{176}-AVB R alpha-2 50 x 10fm 1000 x 10/m AF Doxorubicin
(<12 wk)
3 15 ND None Rgamma 0.6-20X10/m ND AFI and VPBs
(<2 wk)
1 15 ND 1#{176}-AVB Rgamma ND ND AFI
(2 wk)
1 16 ND None R gamma 0.1 x 10/m ND APBs
1 11 Ff64 AF R alpha-2 30 x 10fm 300 x 10/m2 AF Doxorubicin
(<5 wk)
1 11 Mfll None R alpha-2 10 x 10fm 60 x 10/m4 AF Doxorubicin
(<2 wk)
ISCHEMIA
4 2 ND ND Alpha ND ND Fatal MI
1 3 ND MI Ralpha ND ND Fatal MI
1 6 ND IHD R alpha 50 x 10fm 50X10/m Fatal MI
(1 d)
1 8 ND AP Ralpha 50x10fm 50X10/m MI
(1 d)
1 9 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
1 4 M/56 None NRalpha 3x10 3 x H? Cardiac
(1 d) arrest
1 9 ND None R alpha-2 lOx 10fm ND Left heart Concurrent
failure doxorubicin
therapy
1 9 ND LVH R alpha-2 1 x 10fm 6 x 10/m Sudden
(3.5 wk) death
2 10 ND ND Rgamma ND ND 1#{176}-AVB
1 11 M/58 R alpha-2 30 x 10fm 300X10/m HR168/m Doxorubicin
None (<5 wk)
CARDIOMYOP-
ATHY
1 12 Ff62 None R alpha-2 3-9 x 10 27 x 10 Cardiomyopathy
1 13 M/42 None Ralpha 3-35x10 5,500 x 10 Cardiomyopathy
(57 wk)
1 13 Mi35 None Ralpha 35x10 2,700 x 106 Cardiomyopathy
(<llwk)
1 13 M/37 None Ralpha 11.8x10 8,400 x 10 Cardiomyopathy
(102 wk)
1 14 Mfl4 None Ralpha-2 3x10 540 x 10 Cardiomyopathy

#{149}Ref reference; ND no data R recombinant; NR nonrecombinant; VF ventricular fibrillation; VPBs = ventricular premature beats;
Svr= supraventricular taehycardia 1#{176}-AVB 1st-degree atrioventricular block; AF=atrial fibrillation; AF1=atrial flutter; APBsatrial
premature beats; MI myocardial infarction; AP=angina pectoris; IHD ischemic heart disease; CHF=congestive heart failure; LVH =left
ventricular hypertrophy; HR= heart rate.

558 Cardiotocity of Interferon (Sonnenblick, Rosin)

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 Table 2-Various Piesentstions of that they were related to the flulike reaction.
lnterferon-induced Cardiotoxicity Predisposing factors for interferon-related cardio-

No. of
toxicity are not clear. It appears that in most of the
Type ofToxicity Patients cases, toxicity was not necessarily related to a long
period of interferon therapy. Of those on whom data
Arrhythmia 25
were available, cardiotoxicity occurred in 18 of 24
Myocardial infarction/ischemia 9
Cardiomyopathy 5 within five weeks. Similarly, cardiotoxicity occurred
Sudden death 2 in patients receiving low and high daily doses and in
Atrioventricular block 2 patients receiving accumulating doses. Some of the
Congestive heart failure5 1
patients died of a cardiac event following the admin-
patient with ischemia had, in addition, congestive heart istration of a very low total dose and within one to
failure. seven days of initiating the drug treatment. Toxicity
another experienced ventricular tachycardia, both without a history was also not related to age. The only possible risk
of heart disease. The ventricular tachycardia resolved after the factor for cardiotoxicity was previous cardiac disease,
dose of interferon was reduced.
as reported in 12 ofthe patients. An interesting finding
lschemia: Myocardial infarction was reported in eight pa-
is that none of the patients with toxic cardiomyopathy
tients,23689 of whom died..3.6 One additional patient had
development ofchest pain associated with ST segment elevation on had known previous heart disease. It seems, therefore,
electrocardiogram that was complicated by pulmonary edema. All that the presence of underlying heart disease can be
five patients who were questioned concerning previous heart disease considered a risk factor for interferon-induced ar-
indeed had underlying coronary artery disease. Three of the
rhythmia or ischemic manifestations. The importance
five experienced the ischemic event within the first two days of
of previous or concurrent administration of doxorubi-
interferon therapy.6856 Therapy was restarted in one patient after
the single dose was reduced significantly, without further cardiac cm is also not clear. One might speculate that some of
toxicity. the cases of interferon-induced cardiotoxicity were
Cardionuppathy: The first case of interferon-induced cardiomy- not reported because the toxicity was ascribed to the
opathy was reported in 1988 by Cohen et al.52 Since then cardio-
administration of doxorubicin. More data on cardio-
myopathy has been described in another four patients who were
toxicity in patients receiving treatment with interferon
treated with interferon.34 In four of the five patients, myocardial
dysfunction significantly improved after interferon therapy was who had been previously treated with doxorubicin
suspended. All four patients were treated for a relatively long might clarify the importance of doxorubicin as a
period, but the average daily dose appeared to be high in only one contributing risk factor for interferon-induced cardio-
of the four. Two of the patients were retreated with lower doses of
toxicity.
interferon but did not demonstrate a change in the ejection fraction
Although some ofthe adverse effects ofthe different
during the rechallenge.
types ofinterferon might differ from one another, they
DISCUSSION
are, in general, similar. Most of the patients with
Three different types of cardiovascular sequelae interferon-related cardiotoxicity received recombi-
attributed to interferon treatment have been reported: nant interferon alpha or recombinant interferon
arrhythmia, manifestations of ischemic heart disease, alpha-2. A few received recombinant interferon gamma,
and cardiomyopathy. In most of the cases, the cardio- while none received interferon beta. Since a great ma-
toxic effect of interferon consisted primarily of ar- jority of trials with interferon therapy were carried out
rhythmias. In one study, however, 20 patients receiving with the recombinant alpha type, we have to assume that
recombinant DNA gene interferon were prospectively this is the reason that most reports on interferon-
assessed for cardiac rhythm disturbances; no signffi- related cardiotoxicity were from patients who had
cant changes in average heart rate and in the frequency been treated with recombinant interferon alpha.
of ventricular or supraventricular ectopic beats were The various presentations of interferon-related car-
documented when comparing monitoring at baseline diotoxicity as shown in the present review indicate
and during ra7 It seems, therefore, that even more than one mechanism. The most common dose-
arrhythmia is a very uncommon side effect of inter- limiting toxicity of interferon is a flulike syndrome.
feron administration. Moreover, from 15 phase 1 trials Febrile responses are generally noted in all patients
involving a total of 432 patients, most of whom were and always most severely after the first dose Increased .

given recombinant interferon alpham or interferon oxygen demand caused by fever, chills, and tachycar-
gamma, and a few interferon beta,313 no significant dia may therefore precipitate infarction or arrhythmia
cardiotoxic adverse effects of interferon were re- in compromised myocardium. Another possibility is
ported. In some of these studies, however, acute that interferon induced coronary spasm in these
effects of interferon in the cardiovascular system patients. It seems, therefore, that the cardiotoxic effect
consisted mainly of tachycardia, hypertension, and may be principally due to peripheral vascular effects
distal cyanosis. Since these side effects were described ofinterferon which reflexly stress the heart. A different
during the first exposure to interferon, it was suggested mechanism has to be considered to explain the revers-

CHEST I 99 I 3 I MARCH, 1991 559

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 ible cardiomyopathy that occurred in patients with no occur, must be treated symptomatically, the interferon
known previous ischemic heart disease . Since three treatment may be continued, usually without risk.
of the patients with interferon-induced myocardial Awareness of the possibility of cardiomyopathy, even
depression were patients with acquired immunodefi- in patients without previous cardiac disease, should
ciency syndrome, it was suggested that cardiomyopa- focus attention on the cardiovascular tolerance of a
thy resulted from a synergy between human immu- patient receiving prolonged interferon treatment. If
nodeficiency virus infection and interferon. However, symptoms develop, tests of myocardial function and
a recent report in interferon-induced reversible car- ejection fraction should be carried out. In older
diomyopathy in a patient with hairy cell leukemia subjects, a routine electrocardiogram should be done
points to a different mechanism . A complex of before commencing treatment. The present review
interferon and cardiac tissue stimulating an autoim- emphasizes the importance of recognizing the differ-
mune or inflammatory reaction is a possibility. How- ent adverse cardiotoxic consequences of interferon,
ever, an endomyocardial biopsy carried out in a patient especially in view ofreported evidence ofthe potential
with reversible cardiomyopathy did not demonstrate reversibility following the discontinuation of the drug
the characteristics of myocardial damage such as therapy.
myofibrillar loss, sacrotubular swelling, interstitial
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