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1
Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor
Antagonists in Experimental Myocarditis
Lisa M. Godsel, Juan S. Leon and David M. Engman*
Departments of Pathology and Microbiology-Immunology, Northwestern University Feinberg
School of Medicine, Chicago, IL 60611, USA
Abstract: Myocarditis is a disease whose pathogenesis is not completely understood
and whose prevalence is likely underestimated. Individuals afflicted with this condition
may be treated with agents that relieve symptoms arising from inflammation and
concurrent cellular damage. One class of drugs commonly used in the treatment of
myocarditis includes the angiotensin converting enzyme inhibitors, such as captopril,
enalapril and lisinopril, and the angiotensin ΙΙ receptor antagonists, such as L-158,809
and losartan. The effects of these drugs on cardiomyopathy have been studied using a
variety of animal models of heart failure and hypertension. However, less research has
been done in the area of animal models of frank myocarditis. Here we review the use of angiotensin converting
enzyme inhibitors and angiotensin ΙΙ receptor antagonists in animal models of myocarditis. We extend the
implications of that published work by correlation with results from studies of other disease models and in
vitro experiments that highlight the immunomodulatory potential of these compounds. The literature strongly
suggests that aggressive therapy employing angiotensin converting enzyme inhibition and/or blockade of
angiotensin ΙΙ receptors is beneficial. Treatment is useful not only for reducing complications associated with
myocarditis, but also for downregulating the potential autoimmune component of disease—without
increasing the levels of the infectious agent that may initiate the myocarditis.
Key words: angiotensin converting enzyme, angiotensin II, renin-angiotensin system, immune modulation, myocarditis,
autoimmunity.
Trypanosoma cruzi infection is a major cause of myocarditis
in Central and South America [9].
MYOCARDITIS
Myocarditis, or inflammation of the heart, is formally
defined as mononuclear cell infiltration of cardiac tissue,
with or without myocyte necrosis, degeneration or fibrosis
[1]. There are many potential etiologies of myocarditis and
the prevalence of this group of diseases is probably
underestimated. For example, in a study of 176 individuals
with clinically suspected dilated cardiomyopathy, 14 were
given a clinical diagnosis of borderline myocarditis, while
67 were found to have cardiac mononuclear cell infiltration
upon biopsy [2,3]. A number of different cell types may
comprise the tissue infiltrate, including CD4+ and CD8+ T
lymphocytes, B lymphocytes, natural killer cells,
neutrophils and macrophages [4-6] and there are distinct
types of myocarditis in which one cell type is particularly
abundant, including those predominated by lymphocytes,
eosinophils, and giant cells [1]. It is estimated that 2,500
individuals develop myocarditis each year in the United
States, the majority being children [7], and myocarditis is a
major cause of sudden death in young persons [5]. There are
a number of agents that may cause myocarditis, including
bacteria, viruses and parasites, drugs and toxins among
many others [1,3,5,8]. Viral infection is the most common
cause of myocarditis in North America and Europe while
Treatments for myocarditis mainly involve management
of the associated disease complications, such as congestive
heart failure, cardiogenic shock, conduction abnormalities,
dysrhythmias and thromboembolism [10]. These typically
involve the administration of diuretics, digitalis, beta
blockers and vasodilators such as nitroglycerin, inotropic
drugs and angiotensin converting enzyme (ACE) inhibitors
[11]. In cases of diagnosed myocarditis, immunosuppressive
therapy may be warranted. However, the effectiveness of this
course of treatment is unpredictable and may be contraindicated, for example, in the setting of infection [5,12-20].
There is a wealth of literature comparing the relative efficacy
of ACE inhibition and angiotensin ΙΙ receptor (AIIR)
antagonism for the treatment of heart failure and
hypertension [21]. For this reason, we will restrict our
discussion to the comparatively small number of studies
involving animal models of myocarditis. Interestingly, these
reports suggest that ACE inhibitors and AIIR antagonists
may be helpful in treating disease even in the presence of
acute viral infection and, despite being potentially immunosuppressive, these agents do not increase the viral load.
ACE AND ACE INHIBITORS
*Address correspondence to this author at the Department of Pathology,
Ward 6-175, 303 E. Chicago Ave., Chicago, IL 60611; Tel: 312-503-1288;
Fax: 312-503-1265; E-mail: [email protected]
1381-6128/03 $35.00+.00
ACE is a bivalent dipeptidyl carboxyl metallopeptidase
present in soluble form in bodily fluids and as a membrane
© 2003 Bentham Science Publishers Ltd.
2 Current Pharmaceutical Design, 2003, Vol. 9, No. 3
bound form in endothelial, epithelial or neuroepithelial cells
of several organs—the heart being the focus of this
discussion. ACE is a key component of the reninangiotensin system in which angiotensinogen, synthesized
by the liver and released into the blood, is cleaved by renin
to generate the decapeptide angiotensin Ι (AI). ACE binds to
AΙ and cleaves its C-terminal dipeptide, His-Leu, creating
angiotensin ΙΙ (AΙΙ). ACE also cleaves the C-terminal
dipeptide Phe-Arg from bradykinin, thus regulating the
balance between the renin-angiotensin and kallikrein-kinin
systems [22]. Generation of the octapeptide AΙΙ initiates a
number of physiologic events associated with the reninangiotensin system, such as vasoconstriction. Although the
renin-angiotensin system is endocrine, a number of tissues,
including the heart, actually contain and synthesize
components of the system. An outstanding review by Dostal
and Baker discusses the evidence suggesting the presence of
a functional cardiac-specific renin-angiotensin system [23].
Recently, a second ACE (ACE2) was identified in the
vascular endothelial cells of the kidney and heart [24, 25].
ACE2 is hypothesized to regulate blood pressure but is more
likely involved in heart function. Interestingly, ACE2 is
insensitive to classical ACE inhibitors, including captopril.
ACE inhibitors are drugs that inhibit the formation of
AΙΙ from AΙ, as well as the breakdown of bradykinin, by
binding to ACE via its peptide-binding pocket. A large
number of ACE inhibitors is commonly prescribed today,
including but not limited to captopril, enalaprilat, enalapril,
lisinopril, quinapril, ramipril, trandolapril and zofenopril.
AΙΙ is a potent vasoconstrictor, but may also be an important
immunumodulator in its own right. Some of the
immunomodulatory properties of AΙΙ are also briefly
discussed below in the context of ACE inhibition. ACE
inhibitors are commonly prescribed both as a first course of
and as continued treatment for myocarditis, including
autoimmune and infectious forms of the disease. While
many experimental animal studies have explored the
usefulness of modulating the renin-angiotensin system in
heart failure and hypertension [20], little has been done to
look at the effectiveness of the treatments in animal models
of myocarditis. The few studies published suggest that ACE
inhibitors are immunomodulatory drugs and their use in
myocarditis may aid in reducing disease morbidity, even in
the presence of viral or protozoan agents. These studies are
detailed in the sections below, together with a summary of
the research done to characterize the immunomodulatory
mechanisms of these commonly prescribed vasodilators.
AIIR AND THEIR ANTAGONISTS
There are two subtypes of AΙΙR in humans, AT1R and
AT 2 R [26] and, in rats, AT1 R has two subtypes, AT1A R
and AT1BR [27]. AIIR are seven-transmembrane G proteincoupled receptors which mediate the physiologic actions of
AΙΙ, such as vasoconstriction, hypertophy, proliferation of
cardiac fibroblasts and production of extracellular matrix
components [28]. Both AT1R and AT2R are expressed in the
heart; however, AT1 R is the receptor through which AΙΙ
exerts most of its effects by activating phospholipase C or
inactivating adenylate cyclase [29]. AΙΙR have been reported
to be increased in myocardial infarction [30], and models of
Engman et al.
cardiomyopathy [31-34], and hypertrophy [35-38]. Receptor
antagonists, such as losartan and PD123319, interact with
the transmembrane region of the receptor and inhibit the
binding of AΙΙ to AT1R or AT2R, respectively.
EXPERIMENTAL INFECTIOUS
IMMUNE MYOCARDITIS MODELS
AND
AUTO-
The most extensively studied models of myocarditis are
viral models utilizing the cardiotropic encephalomyocarditis
virus (EMCV) or coxsackievirus B3 (CB3). The diseases
have three phases—acute, subacute, and chronic. The acute
phase occurs within the first few days, during which death
due to viral infection can occur without the presence of frank
cardiac inflammation. The subacute phase occurs 4-14 days
post infection and, during this time, heart failure is
concurrent with inflammation and cardiac fibrosis.
Inflammatory cells observed in cardiac lesions first include
natural killer cells. By 7 days post infection macrophages
and lymphocytes are observed. The presence of the
lymphocytes correlates with the most severe cardiac damage.
In the chronic stage of the disease, virus cannot be cultured
from tissue; however, persistent cardiac damage is observed.
A variety of immunosuppressive agents have shown no
favorable effects and, in fact, led to increased damage
resulting from an increased viral titer [5,39].
Experimental autoimmune myocarditis (EAM) is induced
in susceptible strains of mice upon immunization with the
cardiac myosin α heavy chain [40]. This disease model is
useful in that anti-cardiac autoimmune responses can be
studied separately from those directed against an infectious
agent. Interestingly, immune responses against cardiac
antigens, cardiac myosin in particular, have been observed in
human inflammatory heart disease [41-47], making myosin a
relevant and effective antigen for disease induction in the
mouse model. Recent studies utilizing EAM have shown
that myosin-specific immunosuppression is possible and an
avenue worth pursuing [48,49]. EAM is histologically
similar to human myocarditis, with myocyte swelling and
necrosis accompanied by mononuclear cell infiltration and
fibrosis. Studies in animals have shown that EAM is a T
cell mediated disease, requiring both CD4+ and CD8+
subsets [50-54]. B cells are not vital for antigen presentation
in EAM and autoantibodies are not necessary for the
progression of myocarditis [55].
Another model of infectious myocarditis is that induced
in mice upon infection with the protozoan Trypanosoma
cruzi. T. cruzi is the agent of human Chagas heart disease, a
chronic, progressive, and fibrosing myocarditis of variable
degree. Upon infection and entry into the bloodstream, T.
cruzi invades cardiac myocytes, replicates in the cytoplasm,
and is released into the interstitium upon myocyte lysis. The
acute phase of Chagas heart disease is characterized by a
focal inflammation in the myocardium composed of
mononuclear cells (lymphocytes, macrophages, and plasma
cells), mast cells, and granulocytes. Intense tissue parasitosis
is typically found in both cardiac and skeletal muscle. The
acute myocarditis resolves after several weeks. Entry into the
chronic phase is characterized by development of a globose
heart with a rounded apex due to biventricular hypertrophy
ACE and Myocarditis
Current Pharmaceutical Design, 2003, Vol. 9, No. 3
and chamber dilatation. The exudate in chronic chagasic
myocarditis is mainly composed of lymphocytes and, to a
lesser degree, by macrophages, eosinophils, plasma cells,
neutrophils, and mast cells. T lymphocytes predominate,
with CD8+ T cells outnumbering CD4+ cells 3 to 1
(reviewed in [56]). In contrast to what is found in the acute
phase, parasites are often undetectable in the hearts during
the chronic phase. There is a variable degree of myofibrillar
destruction and replacement by connective tissue, leading to
progressive fibrosis.
from our laboratory and others [57] have addressed the
effects of captopril in a non-infectious, purely autoimmune
murine model of the disease. The earliest studies focused on
the efficacy of captopril in treating an animal model of viral
myocarditis. Rezkalla et al. published work on the effect of
captopril on both early (6 days of treatment) and late (20 or
30 days of treatment) models of CB3 myocarditis [58]. In
the early treatment protocol, mice received captopril from
day 1 through day 6, while in the late model they did not
receive captopril until 10 days post infection. Mice treated in
both the early and late protocols had significant reduction in
heart weight and heart weight/body weight ratio compared to
control animals. Viral titers were the same in the captopril
treated and control animals. This indicates that any
immunosuppressive effect of captopril did not affect the
antiviral immune response. Hearts from animals given the
early protocol had less necrosis and calcification and
decreased inflammation; however, hearts from the late
protocol with treatment at either 20 or 30 days post infection
ACE INHIBITORS AND AIIR ANTAGONISTS IN
EXPERIMENTAL MYOCARDITIS
Captopril, enalapril and temocapril are the only ACE
inhibitors that have been studied in animal models of
myocarditis. The earliest work focused on CB3 and EMCV
myocarditides and is summarized in Table 1. Recent studies
Table 1.
Agent
CB3
EMCV
Use of ACE Inhibitors and AIIR Antagonists in Myocarditis Models
'Viral
Titer or
Parasitemia
Heart Wt
or Heart
Wt:Body
Wt Ratio
LV Wall
Thickness
and Cavity
Diameter
Myofibrillar
Diameter
Inflammation
Necrosis
Calcification
Fibrosis
Ref
Captopril treatment 1-6 days post
inoculation
nc
↓
nd
nd
↓
↓
↓
nd
[58]
Captopril treatment starting 10
days post inoculation
nc
↓
nd
nd
nc
nc
nc
nd
[58]
Captopril treatment 3 days post
inoculation
nd
↓
nd
nd
nc
↓
↓
nd
[59]
Captopril treatment 10-30 days
post inoculation
nd
↓
nc
↓
↓
↓
nc
↓
[64]
Captopril treatment 30-60 days
post inoculation
nd
nc
nc
nc
nc
nc
nc
nc
[64]
Captopril treatment from day of
inoculation
nd
↓
nd
nd
↓
↓
↓
nd
[60]
TCV116 (3 mg/kg dosage)
nc
↓
nd
nd
↓
↓
↓
nd
[66]
Captopril
nd
↓
↓
nd
↓
↓
nd
nd
[62]
Enalapril
nd
nc
nc
nd
nc
↓
nd
nd
[62]
Inoculation and Treatment
Protocols
3
Losartan
nd
↓
↓
nd
nc
nc
nd
nd
[62]
Captopril treatment from 4-16
weeks post inoculation
nd
↓
↓
↓
nd
nd
nd
↓
[63]
Losartan treatment from 4-16
weeks post inoculation
nd
↓
↓
↓
nd
nd
nd
nc
[63]
Captopril treatment 7-21 days
post inoculation
nd
↓
nd
↓
↓
↓
nd
nd
[65]
Enalapril treatment 7-21 days
post inoculation
nd
↓
nd
↓
nc
nc
nd
nd
[65]
L-158,809 treatment 7-21 days
post inoculation
nd
↓
nd
↓
↓
↓
nd
nd
[65]
Myosin in
CFA
Temocapril treatment from day of
immunization
na
↓
nd
nd
↓
nd
nd
nd
[57]
Myosin in
CFA
Temocapril treatment 15-21 days
post immunization
Na
nc
nd
nd
nc
nc
nd
nd
[57]
Myosin in
CFA
Captopril treatment from day of
immunization
na
↓
nd
nd
↓
↓
nd
↓
this
review
T. cruzi
Captopril treatment from day of
inoculation
nc
nc
nd
nd
↓
↓
nd
↓
this
review
na, not applicable; nc, no change from controls; nd, not determined; ↓ reduction compared to controls.
4 Current Pharmaceutical Design, 2003, Vol. 9, No. 3
were not statistically different in any of these three criteria.
The effects of captopril on virus-specific immunity were not
studied.
The same authors published on another short-term model
of CB3 myocarditis (9 days of infection) [59]. In that
model, captopril treatment was initiated 3 days after
infection and continued until the completion of the
experiment. The heart weights of the captopril treated
animals were different from those of the non-treated controls;
however, this difference was not addressed carefully by
determining the heart weight/body weight ratio. Myocyte
necrosis and calcification were also decreased upon captopril
treatment, although the degree of inflammation was
unchanged. These studies suggest that captopril treatment
can be beneficial in decreasing cardiac damage. Based on the
finding that captopril may decrease inflammation, it would
be useful to know whether the viral titer increased in the
captopril treated animals. Taken together, the results of these
papers seem to indicate that there is a narrow window in
which captopril treatment should be initiated early to have
the most beneficial effect on the inflammatory process,
although later treatment initiation is still of some utility.
Captopril and some other ACE inhibitors contain
sulfhydryl groups which have been hypothesized to be
involved in the drug’s effectiveness [60,61]. The EMCVinduced myocarditis model was used to compare the effects
of captopril and N ,2-mercapto-propionyl glycine, a
sulfhydryl-containing amino acid derivative without ACE
inhibiting properties [60]. In this paper the authors reported
that both drug treatments significantly increased survival and
decreased the amount of cellular infiltration, myocyte
necrosis and calcification in the hearts of the animals. Body
weights of the treated animals were significantly higher than
those of controls, as were the heart weight/body weight
ratios. The authors made the comparison between these two
drugs in an attempt to explore the effectiveness of the
sulfhydryl group in mediating captopril’s protective effects
beyond ACE inhibition. In autoimmune myocarditis,
administration of temocapril to myosin-immunized mice at
day 0, but not 21, post immunization, decreased heart
weight/body weight ratios, pericardial effusion, and
macroscopic and microscopic histologic scores [57]. The
authors suggested that this effect may be due to thioredoxin,
a protein involved in protecting cells from oxidative stress.
This result may support the findings of other groups that
suggest that the sulfhydryl group of ACE inhibitors
ameliorate heart function through a redox mechanism.
Araki et al. then studied the effects of captopril and
enalapril in treating EMCV-induced myocarditis and
compared their effects to those of losartan, an AΙΙR
antagonist [62]. Heart weights and heart weight/body weight
ratios were reduced and left ventricular wall thickness and
cavity dimension were both decreased by captopril and
losartan treatment, but not by enalapril. Captopril reduced
cardiac inflammation and myocyte necrosis, while enalapril
only decreased myocyte necrosis. Losartan did not have any
effect on these two parameters, even though several doses
were tested. Therefore, these studies suggest that, while the
effect of captopril and enalapril on the renin-angiotensin
system is the same, there are some differences in the
Engman et al.
immune system regulation. These changes in the immune
system resulting from captopril treatment, at least in the
EMCV model, are not simply due to the lack of circulating
AΙΙ in the animals. In another study, losartan and captopril
treatment were compared in a long term model of EMCV
myocarditis [63]. Mice received the drugs from 4 weeks after
viral inoculation to the termination of the experiment at 16
weeks post infection. Losartan and captopril had similar
effects on all parameters tested—heart weight, left ventricular
thickness, left ventricular cavity dimension and myocardial
fiber diameter. The two drugs differed in their effect on
fibrosis. Only captopril lowered the degree of fibrosis, an
activity of this drug that has been explored by others in
myocarditis and other disease models.
Takada et al. used CB3 induced myocarditis as a model
to study the effect of captopril on fibrosis [64]. The authors
looked at both the inflammatory phase, with captopril being
administered on days 10 through 30 post infection, or the
fibrotic phase, with the drug administered on days 30
through 60 post infection. In the inflammatory phase,
survival was higher in the captopril treated group and
inflammation, necrosis and fibrin deposition were all
decreased. Furthermore, connective tissue architecture was
maintained, myocyte hypertrophy was decreased and the
shift of myosin isoforms from α to β was prevented. In this
case, calcification was not statistically different from that of
controls. The fact that inflammation is decreased contrasts
with results of Rezkalla et al., who observed decreased
inflammation and calcification only when captopril was
administered at the time of infection, and not when the drug
was administered 10 days post infection [58]. The disparity
may be explained by differences in the specific experimental
protocols, the mouse and/or virus strain, the number of
plaque-forming units of virus administered or the dosage of
drug. In the fibrotic phase of disease the only significant
difference in the results of Rezkalla et al. was that interstitial
reticulin fibers showed decreased thickening in treated
animals compared to controls. This indicated that captopril
afforded protection from virally mediated damage, even if
treatment was begun 10 days after the infection was
initiated.
Baba et al. published a study which addressed the effects
of the ACE inhibitors captopril and enalapril and the AΙΙR
antagonist L-158,809 on cardiac damage after EMCV
infection [65]. Mice were given the drugs for 14 days
starting 7 days post inoculation of virus. Heart weight/body
weight ratios and myofibrillar hypertrophy were significantly
decreased in the animals treated with any of the three agents
compared to untreated controls. Myocardial necrosis and
inflammation were reduced in the captopril and the L158,809 treated animals, but not in the enalapril treated
mice. The AΙΙR antagonist, but not either ACE inhibitor,
also reduced the amount of another potent vasoconstrictor,
endothelin-1. These findings illustrate that ACE inhibition
and AΙΙR blockade are not entirely interchangeable
approaches and that treatment regimens should be
individualized.
There are only four reports in the literature describing
AΙΙR blockade in myocarditis and three involving L-158,809
and losartan, which were mentioned above. Mice were
ACE and Myocarditis
treated with a variety of concentrations of the AIIR blocker
TCV-116 one day before or two days (1 or 10 mg/kg and
0.3 or 3 mg/kg, respectively) after EMCV inoculation [66].
3 mg/kg treatment resulted in a significantly lower heart
weight, myocyte necrosis, calcification and cellular
infiltration than in untreated control animals. However, the
drug at this concentration did not have any effect on viral
1sp titer. While the findings in this particular paper are
intriguing, it is difficult to compare the groups because of
the very different amount of the drug used. These data
correlate well with those in the EMCV model addressing the
effects of L-158,809 [65], but do differ from those for
losartan, in which there was no effect on inflammation or
necrosis [62]. As mentioned above for the CB3 papers, the
different results obtained in studies of AIIR blockade could
be due to variations in the experimental methods and
reagents used in each study.
It is noteworthy that, in the above experiments, treatment
with ACE inhibitors or AΙΙR antagonists did not lead to an
increase in viral load, as might be expected if the agents are
immunosuppressive. However, it is possible that the agents
have antiviral activity. The direct effects of the treatments on
the virus have not been examined in any detail. One in vitro
study examined the effects of captopril or losartan treatment
on herpes simplex virus type 2 infection of cardiac neonatal
myocytes. Losartan reduced cellular damage, as measured by
lactate dehydrogenase release into the medium, and viral
Current Pharmaceutical Design, 2003, Vol. 9, No. 3
5
release. However, the rate of viral replication was not
affected. Captopril had no effect on the same parameters, so
while this drug may not be as efficacious as losartan, it does
not increase the damage or viral load as compared to controls
[67].
Work from our laboratory strongly suggests that
captopril is useful for the prevention of autoimmune
myocarditis, as well as for myocarditis resulting from
infection with the cardiopathogenic protozoan parasite
Trypanosoma cruzi. A/J and BALB/cJ strains of mice
immunized with syngeneic cardiac myosin develop a severe,
diffuse inflammatory disease specifically localized to the
cardiac tissue and absent from skeletal muscle and smooth
muscle. Captopril prevented development of increased heart
weight, heart weight/body weight ratio, cardiac
inflammation and cardiac fibrosis (Fig. (1)). The captopril
treated animals also failed to develop myosin-specific
cellular immunity in response to myosin-immunization as
measured by delayed-type hypersensitivity. Further
experiments indicate that this immunosuppression was not
cardiac specific, since ovalbumin-specific cellular immune
responses were also decreased in ovalbumin-immunized
animals treated with captopril (data not shown).
Therefore, it appears that both ACE inhibitors and AIIR
antagonists may be beneficial when myocarditis is
suspected, since they seem to suppress the complications
Fig. (1). Captopril reduces myocardial inflammation and fibrosis in A/J mice immunized with cardiac myosin or phosphate-buffered
saline (PBS) in complete Freund’s adjuvant. Representative cardiac sections of captopril treated (75 mg/L in the drinking water
beginning at first immunization) and untreated mice at 28 days post treatment. Sections are at 40X and are stained with Masson’s
trichrome or hemotoxylin and eosin.
6 Current Pharmaceutical Design, 2003, Vol. 9, No. 3
Engman et al.
associated with myocarditis without increasing disease
severity. They have the added advantage of decreasing
cardiac-specific inflammation without promoting increased
replication of the infectious agent. From the work cited in
this section, it is clear that critical information on the use of
these agents in myocarditis is lacking and that there are
many aspects of both ACE inhibition and AIIR blockade
that should be investigated more extensively. The remainder
of this review will focus on studies of the
immunomodulatory effects of both ACE inhibitors and AIIR
antagonists on immune cell function and correlate those
findings with the results described above.
ACE INHIBITORS IN CHAGAS HEART DISEASE
ACE inhibitors are also used to treat another prevelant
cardiomyopathy, Chagas heart disease (CHD), caused by
infection with the parasite Trypanosoma cruzi. CHD is a
common cause of cardiac death in Latin America and may
manifest as congestive heart failure, cardiac dysrhythmia or
thromboembolism. Once heart failure develops in CHD
patients, life expectancy is reduced to a few years and sudden
death occurs in approximately 40% of patients [68].
Management of clinical CHD is based on the treatment of
other cardiomyopathies. CHD patients with congestive heart
failure respond to routine management, including sodium
restriction and treatment with diuretics, digitalis, and ACE
inhibitors.
Despite the routine administration of ACE inhibitors to
patients with CHD, only a few pilot studies have been
conducted to test their potential benefits. These studies are
summarized in Table 2. Captopril and enalapril, two ACE
inhibitors, seem to improve cardiac function and are well
tolerated by Chagas patients; at least 90% of patients do not
develop side effects [69,70]. Patients with cardiomyopathy,
including CHD patients, were given captopril (75 mg/day)
for 12 weeks and these individuals exhibited a significant
decrease in heart rate and objective improvement of cardiac
function in 98 (85.2%) patients [69]. However, no
conclusions can be drawn about the CHD patients since the
results of their treatment were not presented separately.
ACE inhibitors may improve cardiac function in CHD
patients by interfering with the renin-angiotensin system.
While ACE is probably the main target of these inhibitors,
Table 2.
ACE activity levels were not measured in any of these
studies. ACE inhibitors can also affect renin levels, though
they are believed to operate downstream of the renin
biosynthetic pathway. Renin levels have been observed to be
higher in CHD patients with heart failure than in those with
asymptomatic CHD [71]. One study of CHD patients
reported an increase in plasma renin levels upon
administration of captopril for 6 weeks [70], while a second
study reported decreased renin levels upon administration of
enalapril over 96 hours [72]. The change in renin levels
induced by ACE inhibitors probably influences AΙΙ levels
and cardiac function. Interestingly, one study reported that
the ACE inhibitor captopril enhanced T. cruzi invasion of
host cells in vitro and therefore may affect cardiac function
in the host [73]. Captopril blocks the degradation of
bradykinin, which was shown to increase infection of host
cells by T. cruzi. However, there are no published reports of
ACE inhibitors affecting the parasite burden of CHD
patients. Lastly, these ACE inhibitors may affect cardiac
function through the parasympathetic and sympathetic
systems, since the levels of neurohormones such as
norepinephrine were affected.
In conclusion, preliminary reports suggest that cardiac
function in individuals with CHD may be improved by
ACE inhibitor therapy. The mechanisms by which ACE
inhibitors may provide this benefit are unknown but may
include modulation of the renin-angiotensin system and the
parasympathetic/sympathetic systems. Large scale controlled
studies on morbidity and long term survival of CHD
patients treated with ACE inhibitors are necessary to confirm
the benefits of ACE inhibitors in CHD and to identify
specific populations best suited to receive such therapy.
CAPTOPRIL IN EXPERIMENTAL CHAGAS HEART
DISEASE
Preliminary evidence in our laboratory suggests that
captopril treatment also reduced myocarditis in an
experimental model of acute Chagas heart disease. Captopril
treatment of A/J mice infected with T. cruzi resulted in a
decrease in cardiac inflammation and cardiac fibrosis (Fig.
(2)). However, the reduction in inflammation and fibrosis
was not associated with a decrease in heart weight or heart
weight/body weight ratio compared to infected controls that
did not receive captopril. Interestingly, infected mice treated
Use of ACE Inhibitors and AIIR Antagonists in Clinical Chagas Disease
Ace Inhibitor
Type
Size
Dose mg/day
Length
Effects/Comments
Ref
Captopril
Single blind,
cross-over
18
150
12 weeks (6
weeks
treatment)
↓Heart rate, ↓Ventricular couplets (ns), ↓Nonventricular
tachycardia (ns),↑Plasma renin, ↓Urinary, norepinephrine,
Systolic/Arterial blood pressure (nc)
[70]
Enalapril/
Captopril
Prospective
Cohort
56
“conventional
doses”
2 years
No association with mortality (ns)
[139]
Enalapril
Intervention
13
5
96 hours
↓Functional Class, ↓Weight, ↓Plasma Norepinephrine,
↓Aldosterone, ↓Renin, Systolic/Arterial blood pressure
(ns)
[72]
Enalapril
Intervention
20
5-10
8 weeks
↓ E/A relationship (improved diastolic function)
[140]
nc, no change from controls; ns, not significant; ↓ reduction compared to controls.
ACE and Myocarditis
Current Pharmaceutical Design, 2003, Vol. 9, No. 3
7
Fig. (2). Captopril reduces myocardial inflammation and fibrosis in A/J mice acutely infected with T. cruzi. Representative cardiac
sections of captopril treated (75 mg/L in the drinking water beginning at infection) and untreated mice at 28 days post treatment.
Sections are at 40X and are stained with Masson’s trichrome or hemotoxylin and eosin. Arrowheads indicate T. cruzi pseudocysts.
with increasing amounts of captopril had higher mortality.
In addition, captopril treated mice exhibited reduced anti-T.
cruzi cellular immune responses as measured by delayed
type hypersensitivity, similar to the immunosuppresive
effect observed in captopril-treated, myosin-immunized
mice. These results suggest that, while captopril treatment
reduces inflammation in T. cruzi induced myocarditis,
captopril may also enhance T. cruzi - induced mortality.
ACE INHIBITORS IN OTHER AUTOIMMUNE AND
INFECTIOUS DISEASE MODELS
A number of other disease models, both infectious and
autoimmune, have yielded more information regarding the
effects of ACE inhibitors on the immune response. In an
animal model of multiple sclerosis, experimental
autoimmune encephalomyelitis, captopril treatment resulted
in decreased clinical disease severity and a suppressed and
shortened duration of the disease. In vitro studies showed
that lymphocytes from treated animals had a diminished
response to myelin basic protein and to the mitogen
concanavalin A (Con A) [74].
Several papers describe the use of captopril in a number
of granulomatous inflammation models. The drug reduced
the size of liver granulomas in murine schistosomiasis [75],
but not the size of hypersensitivity granulomas induced by
bovine serum albumin-coated sepharose beads. Since the
latter granulomas contained no ACE, the paper suggested
that the immunomodulatory effects of captopril may be due,
at least in part, to the inhibition of ACE. In another study,
captopril was used to decrease lung inflammation and
splenomegaly in Bacille Calmette Guerin-induced granuloma
[76]. In vitro the drug did not affect the macrophage
migration nor did it change the chemotactic activity of
isolated granulomas. In yet another paper the granulomatous
response to Histoplasma capsulatum was modulated by
administration of captopril with different findings from any
of those reported above. With ACE inhibition present during
the early stages of the infection, the clinical severity of
infection and the histopathologic changes in mice were
significantly worsened and the growth of the yeast in livers
and spleens was increased [77]. If captopril was first
administered later during the resolution phase of the
infection, there was no effect on the healing of the
granulomas, but the drug did not cause a relapse of
infection. Some in vitro experiments demonstrated that
captopril treatment of normal animals did not result in
suppression of splenocyte responses to the mitogens Con A
or phytohemagglutinin in vitro or delayed type
hypersensitivity. The somewhat contradictory results of
8 Current Pharmaceutical Design, 2003, Vol. 9, No. 3
Engman et al.
these in vitro experiments may be due to differences in the
specific ACE inhibitor employed, or to differences in the
dosage and treatment regimen used both in the animals and
in the culture dish. The presence of AΙΙ during the course of
infection may therefore affect the outcome, depending on the
type of infection involved, and a decrease in AΙΙ may be the
method through which ACE inhibition decreases the size of
the granulomas.
The protective effects of AΙΙ against infection are
presented in a paper studying bacterial peritonitis in which
treatment of rats treated with AII inhibitors resulted in a
decreased abscess size and an increase in host resistance [78].
These data were correlated with in vitro experiments
showing that AΙΙ treatment increased respiratory burst of rat
peritoneal macrophages and increased phagocytosis of rat
macrophages and human peripheral blood mononuclear cells.
Thus, the presence of AΙΙ can increase the activation of the
immune response against an infectious agent, while the
inhibition of AΙΙ production via ACE inhibition or AΙΙR
antagonism may decrease the activation of immune cells.
Information is available regarding the effects of captopril and
other ACE inhibitors and AΙΙR antagonists that differ
enough from each other to suggest that not all of the effects
mediated by ACE inhibitors can be explained simply by a
lack of AΙΙ in the circulation or resident in tissues. The
section below strives to summarize the research on a variety
of indicators of normal inflammatory cell function.
IMMUNOMODULATORY EFFECTS OF
INHIBITORS AND AIIR ANTAGONISTS
ACE
There are a number of ways that ACE inhibitors and
AΙΙR antagonists may modulate the immune response.
Several of the processes that may be affected include
chemotaxis, motility and adhesion, differentiation,
activation and cytokine/chemokine production. There is also
a large base of research demonstrating an involvement of AΙΙ
in basic immunity, suggesting potential utility for ACE
inhibitors and AΙ Ι R antagonists in modulating
inflammation. Much of the research has focused on cellular
adhesion and chemotaxis and how ACE inhibitors and AΙΙR
antagonists modulate these processes. For example, both
types of agent may inhibit mononuclear cell infiltration,
either because of drug-induced decrease in expression of
adhesion molecules on the mononuclear, endothelial or
interstitial cells or because of decreased chemokine
production.
A variety of in vivo and in vitro studies have
demonstrated that AII is involved in the chemotaxis and
adhesion of monocytes and macrophages. Angiotensin
knockout animals have decreased production of MCP-1 [79]
AIII is an AII processing product that also increased MCP-1
[80]. ACE inhibition resulted in decreased MCP-1 levels in
a model of atherosclerosis [81,82] as well as in patients
suffering myocardial infarction, which correlated with a
decreased accumulation of macrophages in heart tissue [83].
In addition, AΙΙ has been shown to induce monocyte
migration [84], leukocyte rolling, adhesion and extravasation
while AΙΙR antagonists inhibit these processes [85]. AΙΙ
induced leukocyte-endothelial cell interactions in vivo [86].
AΙΙR antagonists and ACE inhibitors reduced the amount
of neutrophil [87,88] and macrophage [89] recruitment and
decreased neutrophil [90], polymorphonuclear cell [91,92]
and leukocyte [93] adhesion. Enalapril decreased ICAM-1,
VCAM-1, MCP-1 levels in circulating adhesion molecules
in serum of patients [94]. In some of the studies, differences
among the results of AΙΙR antagonism and ACE inhibition
were highlighted. For example, study of the effects of
captopril on neutrophils showed that treatment did not affect
neutrophil adherence [90] and, in fact, actually might
enhance neutrophil migration [95] and activation [96], in
contrast to the results detailed above. In another study,
treatment decreased the activated circulating and
endothelium-adherent monocytes [97]. AIIR antagonists
prevented increased expression of ICAM-1 and VCAM-1,
which correlated with a decrease in macrophage infiltration
[98,99]. Other studies did not support this conclusion,
however, possibly because a different agent was employed
[100,101].
A ΙΙ therefore may upregulate chemotactic factors
important for attracting immune cells to the affected tissue,
and may induced expression of molecules that enable the
cells to adhere to endothelium. Administration of ACE
inhibitors or AΙΙR antagonists decreases the amount of
circulating and tissue AΙΙ and may decrease inflammation in
this manner. Another way that ACE inhibitors and AΙΙR
antagonists may modulate the immune response is via their
effects on immune cell proliferation and differentiation. AΙΙ
has been shown to act through AT1 R to stimulate the
proliferation of splenic lymphocytes [102,103].
Interestingly, ACE activity, AΙΙ release, and AT1 R and
AT 2R expression all increased when the human leukemia
cell line THP-1 is induced to differentiate into a macrophage
[104].
The majority of the ACE inhibition studies that focus on
cell proliferation and differentiation utilized captopril, while
a small number utilized enalapril and enalaprilat.
Unfortunately, many of the results are contradictory.
Captopril inhibited the proliferation of hematopoietic stem
cells and progenitors [105] and also reduced proliferation of
the stem cells in vivo [106]. In contrast, the drug stimulated
the proliferation of both human [107] and rat [108]
lymphocytes in vitro, but proliferation of lymphocytes
derived from captopril treated rats was inhibited. In a mouse
model of lupus, captopril was used to inhibit T cell
stimulation, but enalapril did not have this effect [109].
However, in another study, captopril increased Con Astimulated T cell proliferation while enalapril and enalaprilat
inhibited the proliferation [110]. Finally, T cells were
stimulated when cocultured with a low concentration of
serum from patients treated with either captopril or enalapril,
but were inhibited when the serum concentration was high
[111]. Because AΙΙ stimulates lymphocyte proliferation, it
follows that ACE inhibitors would decrease proliferation of
immune cells through reduction of AΙΙ. There is a
suggestion that all these effects are directed at least in part at
macrophages and there may be some effects of the drugs that
are independent of AΙΙ.
Another way that ACE inhibitors and AT1R and AT2R
antagonists might modulate the immune response is via
ACE and Myocarditis
alteration of cytokine release. AΙΙ induces transcriptional
activation of a number of cytokine genes. ACE inhibitors
and AT1 R and AT2 R antagonists might therefore inhibit
cytokine secretion by decreasing the amount or antagonizing
the effects of AΙΙ. AΙΙ increases the transcription of IL-6 in
macrophages, which can be inhibited by AT1R antagonists
[112,113]. This decrease in IL-6 production has also been
observed in vivo in a model of chronic heart failure and
myocardial infarction [114,115]. Quinapril treatment in a
model of myocardial infarction reduced expression of IL-1β,
IL-5, IL-6, and TNF-α. Captopril suppressed IL-1β induced
production of IL1-α and TNF-α in peripheral blood [116].
Interestingly, captopril even increased production of IL-1Rα
[113]. ACE inhibition was also shown to decrease the
amount of IL-2, IL-12 and IFN-γ produced by T cells [117,
118]. In contrast, murine T cells secreted higher levels of IL2 upon captopril treatment after Con A stimulation [119].
Peripheral blood monocytes release TNF-α in response to
AII treatment—an effect blocked by AT1R antagonism and
ACE inhibition [113,116,120,121]. However, not every
ACE inhibitor was able to block TNF-α expression by the
same cell populations [116]. ACE inhibitors were also
shown to be more efficient at decreasing the plasma
concentration of TNF-α than are AΙΙR antagonists [122].
These results raise the point that the activities of ACE
inhibitors are not all directly related to their effects on AΙΙ.
Caution must be taken when analyzing the effects of these
agents. In some cases, a large amount of drug is needed to
obtain a decrease in cytokine production and the observed in
vitro responses may therefore not be physiologically relevant
[113,116,123]. TGF-β is a cytokine that is regulated by AΙΙ
and is decreased by ACE inhibition and AIIR antagonism
[124-127]. While cytokines are markers of cellular
activation, there are other important markers of activation
that have also been analyzed. For example, AΙΙ has been
shown to increase macrophage phagocytosis [128] and the
adherence of peripheral blood monocytes to endothelial cell
monolayers [120]. AΙΙ increased cytosolic calcium in
peripheral blood mononuclear cells, which could be blocked
by the AT1R antagonist losartan [130]. Along these lines,
treatment of hypertensive rats with the ACE inhibitor
captopril significantly lowered the intracellular calcium in
thymocytes, which correlated with a decrease in blood
pressure [130].
The studies mentioned above support the hypothesis that
ACE inhibition and AΙΙR antagonism are involved in the
downregulation of the immune response. This
downregulation may be mediated in part by the simple fact
that AΙΙ is not produced, as in the case of ACE inhibition,
or its activity is inhibited, as in the case with receptor
antagonism. However, there are differences in the way that
ACE inhibitors function compared to receptor antagonists
and even how drugs within the same class effect immune
cell function. Some papers even showed that the activities of
some types of immune cells are actually enhanced by
treatment with ACE inhibitors. ACE inhibitors have also
been shown to increase the activation of neutrophils and
mast cells as demonstrated by myeloperoxidase, lysozyme
and histamine release [96,131,132]. These results indicate
that the actions of these drugs are more complex than simply
to reduce AΙΙ production and suggest that each drug needs to
be analyzed individually. Certainly one must be aware that
Current Pharmaceutical Design, 2003, Vol. 9, No. 3
9
an effect observed for one inhibitor or antagonist cannot be
assumed to be the same for other agents.
Underlying all of the data in the above reports is the
possibility that ACE inhibitors and the receptor antagonists
modify the immune response via cell signaling pathways.
Certainly there are results suggesting that AΙΙ is involved in
cell signaling and, in the most obvious scenario, ACE
inhibitors and AT1R and AT2R antagonists could modulate
the immune response by decreasing the concentration of AΙΙ
available for signaling. AΙΙ-mediated degradation of IκB and
activation of NFκB increased transcription and translation of
VCAM-1 and ICAM-1, which are important for recruitment
of leukocytes to inflamed tissues [1-3]. This upregulation
may be due, at least in part, to the AΙΙ-induced production of
endothelin-1 [133-135]. Angiotensin III, a product of AΙΙ
cleavage, increases the production of MCP-1 via NFκB
activation [80]. AΙΙ has also been shown to augment tyrosine
kinase activity [136]. Interestingly, captopril treatment has
been shown to inhibit pp60c-src tyrosine phosphorylation in
human mesanglial cells in vitro [137]. Studies using ACE
inhibitors and an AT1 R antagonist make the case for cell
signaling even stronger as NFκB activation of macrophages
and vascular smooth muscle cells is decreased upon
treatment with these agents [81,82]. ACE inhibition with
captopril, idapril, fosinopril, and losartan all reduced the
expression of tissue factor in monocytes via the inhibition of
NFκB translocation to the tissue factor promoter [138].
CONCLUSIONS
ACE inhibitors and AΙΙR antagonists are extremely
useful in the management of heart disease. However, little
has been done to study the effects of these drugs in
myocarditis specifically. There is a concern that use of these
agents will decrease the immune response against an
infectious agent that has induced the heart damage and/or
that has precipitated the inflammation against self proteins
(autoimmunity). There is cause for concern, since
contradictory information regarding the effects of AΙΙ and its
inhibitors on the immune response continues to be
generated. However, the general theme arising from the
papers on this topic suggests that these drugs may not
increase the proliferation of an infectious agent and can
decrease the morbidity of the inflammatory heart disease.
The amount and type of ACE inhibitor or AΙΙR
antagonist used may make a difference in the effects
observed on the immune system. Certainly there are
differences between the ACE inhibitors and the AΙΙ receptor
antagonists and between drugs within either category,
suggesting that each has its own specific effects on the
immune system beyond inhibition of AΙΙ activity by
decreasing the amount of AΙΙ or by blocking its effects.
Some of the effects include chemotaxis and motility, the
production of cytokines important in activation and
proliferation, the accumulation of bradykinin and
prostaglandin production and the deposition of extracellular
matrix. With so many effects attributed to such widely
administered medications, further research is necessary to
fully understand the impact of these agents.
10 Current Pharmaceutical Design, 2003, Vol. 9, No. 3
ACKNOWLEDGEMENTS
Research in our laboratory was supported by grants and
fellowships from the National Institutes of Health and the
American Heart Association. We thank Drs. William Ward,
Agostino Molteni and Carl Waltenbaugh for helpful advice
and assistance.
Engman et al.
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ABBREVIATIONS
ACE
=
Angiotensin converting enzyme
AI
=
Angiotensin I
AII
=
Angiotensin II
AIII
=
Angiotensin III
AIIR
=
Angiotensin II receptor
AT1R
=
Angiotensin II receptor 1
AT2R
=
Angiotensin II receptor 2
CHD
=
Chagas heart disease
CHF
=
Congestive heart failure
CB3
=
Coxsackievirus B3
Con A
=
Concanavalin A
EAM
=
Experimental autoimmune myocarditis
EMCV
=
Encephalomyocarditis virus
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