Cardiovascular Research 1999 43(1):25-31; doi:10.1016/S0008-6363(99)00074-7
© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
New look at myocardial infarction: toward a better aspirin
Richard J Bing*,
Tadahiko Yamamoto,
Masako Yamamoto,
Rani Kakar and
Anna Cohen
Department of Experimental Cardiology, Huntington Medical Research Institutes, Pasadena, CA, USA
* Corresponding author. Tel.: +1-626-397-5451; fax: +1-626-795-5774
Received 14 October 1998; accepted 22 January 1999
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Abstract
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The evidence for the formation of NO and of its oxidation products,
as well as of prostacyclin and thromboxane by the infarcted
heart muscle is reviewed. The importance of inflammatory cells,
primarily macrophages of cardiac origin is documented. Because
of its side effects on gastric mucosa and kidney by aspirin,
several modifications of aspirin are currently being developed.
These are based on eliminating their inflammatory effect by
selective inhibition of COX-2, or by attaching an NO-delivering
side chain to the aspirin molecule (NO–aspirin), or by
combining two preparations, an NO donor with aspirin. NO–aspirins
and the combination of an NO-donor with aspirin promise to be
beneficial in the early stages of myocardial infarction. Unfortunately,
the main beneficial effect of aspirin, that of inhibition of
thrombus formation, is also the cause for its most dreaded complication,
hemorrhagic stroke. None of the new aspirins is able to prevent
this complication.
KEYWORDS Myocardial infarction; Nitric oxide; Prostaglandin; Aspirin; NO donor
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1 Introduction
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Ever since the clinical description of myocardial infarction
by Herrick in 1912
[1], the primary emphasis has been on its
epidemiology and pathology. Interest in biochemical alterations
in infarcted heart muscle is of more recent date and is primarily
concerned with the diagnosis of myocardial infarction. This
includes the appearances of cardiac enzymes and of contractile
proteins in blood
[2,3]. The discovery of the formation of nitric
oxide (NO), prostacyclin (PGI
2), and thromboxane (TXA
2) in infarcted
heart muscle in situ has opened a new perspective
[4–6].
Myocardial infarction can now be considered a condition in which
pharmacologically active substances such as NO, prostacyclin,
and thromboxane are produced in ischemic heart muscle
[4–6].
Recently, it has been shown that aspirin, a nonsteroidal anti-inflammatory drug (NSAID), influences the production of NO and some prostaglandins in infarcted heart muscle [7]. Aspirin possesses toxic side effects to gastric mucosa and kidney. To overcome this, new aspirins are being developed [8,9]. While the role of new aspirins in the prevention of toxicity to the stomach and the kidney is undisputed, their value to patients with myocardial infarction has to be determined.
We review here work on the formation of pharmacologically active substances (NO and prostanoids) in heart muscle during the inflammatory phase of myocardial infarction with emphasis on the role of aspirin. Attempts to reduce side effects of aspirin by changes in its structure, by eliminating its inflammatory effect or by combining it with an NO donor, will be discussed.
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2 Myocardial origin of nitric oxide
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The production of NO in heart muscle has assumed considerable
importance because it favorably influences contractile and metabolic
functions of the infarcted heart
[10–12]. In addition,
it plays a role in the formation of prostanoids. The formation
of NO and prostanoids appears to be closely related
[13–17].
The success of new aspirins devoid of side effects depends on
the action of NO
[8,18]. The formation of prostanoids is also
of potential significance for the course of myocardial infarction.
For example, immunologically active cells, predominantly macrophages,
are involved in the synthesis of thromboxane (TXA
2). This alters
the electrical properties of heart muscle
[4] and initiates
dysrhythmias and is abolished by NO
[19]. Aspirin also causes
a decline in frequency of malignant dysrhythmias inducing a
decline in the production of thromboxane
[20]. The role of thromboxane
in initiating platelet aggregation is of primary importance.
The cardiac effects of NO, thromboxane, and prostacyclin are
shown in
Table 1.
Nitric oxide in infarcted heart muscle is released mainly through
the enzymatic action of the inducible form of NO synthase (iNOS)
by activated macrophages
[5,6]. In 1987, Hibbs et al. demonstrated
that an
L-arginine-dependent pathway in macrophage monolayers
synthesized
L-citrulline and nitrite, which when coupled to
an effector mechanism, inhibited DNA synthesis and mitochondrial
respiration
[21]. Later, several isoforms of the enzyme responsible
for NO synthesis were found which are homologous and divided
into constitutive isoforms produced by endothelial cells and
transcriptionally regulated NO synthase, produced by activated
specific cytokines
[22,23]. Nitric oxide is connected with specific
molecular targets; by binding to the iron in heme group of guanylate
cyclase, it produces cyclic guanosine monophosphate (cGMP),
which activates a cascade of cellular processes
[24]. Both the
inducible and the constitutive forms of nitric oxide synthases
are present in the myocardium and are inhibited by dexamethasone
and by arginine analogs such as N-monomethyl-arginine (
L-NMMA)
and by other specific inhibitors
[25–27]. Under physiological
conditions, the activity of the inducible form of NOS is relatively
low, but is increased by endotoxin as well as tumor necrosis
factor (TNF-
) and interleukin (IL-1β)
[25].
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3 NO formation by macrophages
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An important finding which led the way to discovery of the role
of macrophages was the finding of Wagner et al. in 1982 that
human subjects on a low NO
3– diet showed increased NO
3– synthesis during bacterial infection
[28]. This observation
led to the discovery by Stuehr et al., that activated macrophages
are the source of NO
2–/NO
3–. They recognized that
NO
2– (nitrite) and NO
3– (nitrate) are the inactive
end-products and that reactive NO causes the immune response
which originates during the metabolism of
L-arginine to NO
2–/NO
3– [29]. Later, the role of NO as an intermediate of arginine oxidation
was established
[30]. It was found that NO is produced in infarcted
heart muscle, reaching its peak 2 days after onset of ischemia;
at the same time concentration of oxidation products of NO in
coronary sinus blood are increased (
Fig. 1)
[5]. Activation
of iNOS in myocardial infarction is the result of ischemia,
in contrast to NO formation by endotoxins which occurs with
bacterial invasion.
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Fig. 1 Serial changes in nitric oxide synthase activity in infarcted and non-infarcted muscle (n=4–9 for each group, POD=postoperative day). NOS activity is higher in infarcted area on POD 1 (n=6). Significant differences are noted for POD 2 (n=4) and groups POD 3–6 (n=7) and POD 7–14 (n=9). Probability values denote the statistical significance for infarcted versus noninfarcted area. Data are given as mean±S.E.M., n indicates the number of different hearts (from Dudek et al., Biochem Biophys Res Commun, 205 (1994).
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After ligation of a branch of left circumflex coronary artery
of rabbits, inducible nitric oxide synthase (iNOS) activity
is elevated in the infarcted area of the left ventricle
[5,6].
On the second post-operative day, the differences between the
infarcted and noninfarcted areas become significant. Twenty-one
days after surgery, iNOS activity disappears
[5,6] (
Fig. 1).
The highest number of infiltrating macrophages are located in
a relatively narrow zone at the border between the area of risk
and the area of necrosis.
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4 Nitrite and nitrate
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Increased NO production in infarcted heart is reflected by an
increased concentration of its oxidation products, nitrite (NO
2–)
and nitrate (NO
3–), in coronary sinus blood and by a widening
of their coronary arterial–venous difference
[31,32] (the
sum of NO
2– and NO
3– is referred to as NOx). Under
controlled conditions as in the coronary care units or in the
experimental animal, the elevation of NOx in peripheral blood
is related to the length and severity of the inflammatory process.
Both NO
2– and NO
3– are pharmacologically inactive
[33]. Since nutrition as well as renal factors influence concentrations
of NOx in peripheral plasma, the concentration of NOx in peripheral
blood is not specifically related to cardiac disease. On the
other hand, an elevation of the coronary arterial–venous
difference of NOx denotes an increase in cardiac formation of
NO. In animals with experimental myocardial infarction, a causal
relationship exists between NO production by the heart and elevated
plasma levels of NOx
[31]. In patients with acute anterior myocardial
infarction, the coronary arterial–venous differences are
significantly greater when compared to their control or to the
systemic arterial–venous NOx differences, demonstrating
a cardiac origin for these oxidation products
[32].
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5 Production of PGI2 and TXA2 in infarcted heart muscle
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PGI
2 and TXA
2 are produced in infarcted heart muscle, PGI
2 by
endothelial cells and TXA
2 by macrophages and other immunologically
reactive cells
[4]. Prostanoids are also increased in coronary
sinus blood after myocardial infarction
[34]. Both prostanoids
are produced by the infarcted rabbit heart muscle in situ
[35] and by microsomes obtained from infarcted dog hearts
[4]. According
to McCluskey et al. the production of 6-keto-PGF
1 (stable products
of PGI
2) increased by 126% from 31.7 to 71.7 pmol/mg per hour
(
P<0.05). The activity of thromboxane synthetase in the tissue
was also significantly increased by 144% from 30.7 to 73.7 pmol/mg
per hour
[4]. Similar findings were obtained by Yamamoto et
al. in the infarcted rabbit heart in situ (6-keto-PGF
1: 101.4±12.4
pg/mg in infarcted portion versus 33.8±5.7 pg/mg in non-infarcted
portion of the left ventricle, and TXB
2, the stable products
of TXA
2: 47.0±8.0 pg/mg in infarcted portion as compared
to 7.4±2.9 pg/mg in non-infarcted region)
[35]. In these
experiments a branch of the circumflex coronary artery was ligated.
Two days later, the concentrations of prostacyclin and thromboxane
were determined in separate specimens obtained from infarcted
and non-infarcted portion of left and right ventricle using
enzyme immunoassay. Further confirmation of the production of
PGI
2 in heart muscle has come from the study of Isakson et al.
[36] and deDeckere et al.
[37]. The rate of prostanoids in the
heart was found to be increased by ischemia
[38]. The role of
PGI
2 and TXA
2 on infarcted heart muscle is shown in
Table 1.
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6 Relationship between NO and COX
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Both iNOS and prostacyclin and thromboxane are found in the
infarcted heart muscle
[4,5,35]. NO counteracts the effect of
thromboxane (
Table 1)
[39]. The connection between iNOS and
cyclooxygenase (COX) activation is documented by the fact that
an NO donor increased PGE
2 formation in hypothalamic fragments,
and that released NO stimulated the synthesis of a series of
prostanoids
[40]. NOS and COX pathways also interact in mesangial
cells
[14]. PGE
2 downregulates and PGI
2 stimulates iNOS induction
[14]. Salvemini et al. distinguished between a synergistic effect
(NO production and activation of COX), and the interaction at
the level of the enzymes
[41]. COX is potential target for NO
because it contains an iron-heme center at its active sites
[42]. In cell cultures NO plays an important role in release
of prostanoids by direct activation of COX; inhibitors of NO
attenuate PGE
2 release
[41]. Similarly, Davidge et al.
[15] described that NO produced by endothelial cells increased the
production of eicosanoids through the activation of COX synthesis.
On the other hand, Yamamoto et al. have shown that in the infarcted
heart in situ, low doses of aspirin inhibit PGI
2 and TXA
2, while
failing to interfere with the production of NO
[35]. In general,
it is likely that the activation of iNOS and COX are related.
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7 New aspirin
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Aspirin (acetylsalicylic acid) is one of the most widely prescribed
agents to treat inflammation. In myocardial infarction, it has
been shown to be effective in the long-term prevention of arterial
occlusion and reocclusion
[43]. In low doses, aspirin possesses
a selectivity for the inhibition of platelet thromboxane formation
[44]. After inhibition with aspirin, platelets cannot reproduce
thromboxane A
2, for the rest of their existence in the circulation
because of the irreversible inhibition of COX-1
[45]. For these
reasons the value of aspirin in myocardial infarction is undisputed.
Aspirin, however, has undesirable side effects on the gastric
mucosa and the kidney which detract from its usefulness.
Whether aspirin has beneficial effects directly on the infarcted heart is not clear. In chronically infarcted rats, low doses of aspirin as used in the prevention of thrombosis with favorable hemodynamic effects [46], affect collagen deposition in non-infarcted myocardium as part of the remodeling process [47]. Bonow et al. [48] failed to demonstrate a beneficial effect of aspirin on infarct size. Möbert et al. believe that inhibition of COX causes shunting of arachidonic acid toward nonenzymatic oxidation products with thromboxane-like activity, such as isoprostanes [49]. These compounds are vasoconstrictive, acting on the heart through TXA2 receptors. This might explain the impairment of ventricular recovery of hearts treated with aspirin or indomethacin [49].
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8 Selective inhibitors of COX-2
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The first attempt to arrive at aspirins free from side effects
was based on selective inhibition of COX-2 (
Fig. 2). Aspirin
inhibits the enzyme responsible for formation of prostanoids,
cyclooxygenase (COX), also referred to as prostaglandin synthase-1
(PGHS-1) (
Fig. 2). This enzyme exists in two isoforms, COX-1
and COX-2. COX-1, the constitutive form is responsible for the
formation of prostacyclin which is anti-thrombotic and has cytoprotective
action on the gastric mucosa (
Fig. 2). COX-1 also synthesizes
thromboxane (
Fig. 2). Endothelial cells synthesize COX-1 de
novo within a few hours
[50]. PGI2 and PGE modulate renal blood
flow and influence salt and water excretion. COX-2, the inducible
form on the other hand originates mainly in macrophages and
leukocytes by inflammatory stimuli and cytokines
[45] and participates
further in inflammatory processes (
Fig. 2). COX oxidizes arachidonic
acid to prostaglandin G
2, and then peroxidizes it to prostaglandin
H2 (
Fig. 2). It is therefore apparent that an ideal nonsteroidal
aspirin-like drug should primarily inhibit COX-2. Aspirin is
10–100 times as potent against COX-1 compared to COX-2
[51]. Since the unwanted side-effects of aspirin are due to
the inhibition of COX-1, it would be advantageous to diminish
them by a compound that selectively inhibits COX-2. Several
aspirin-like molecules have been designed which irreversibly
inactivate COX-2. The most potent of these is
o-(acetoxy-phenyl)hept-2-ynyl
sulfide (APHS) (
Fig. 3)
[51]. This compound is 60 times as reactive
against COX-2 and 100 times as selective in its inhibition
[51].
The development of COX-2 inhibitors has been popularized by
the media and has been actively pursued by the pharmaceutical
industry.
Fig. 3 shows an aspirin-like molecule that covalently
inactivates cyclooxygenase-2. This and other molecules alter
the selectivity of aspirin for the two different cyclooxygenases
by varying the length of the acyl group attached to the salicylate
moiety, but the compounds retain COX-1 selectivity (
Fig. 3)
[51].
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Fig. 3 Chemical structures of selective COX-2 inhibitor: o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS) and of NO–aspirins: NCX 4215 (2 acetoxybenzoate 2-(2-nitroxy)-butyl ester) and NCX 4016 (2 acetoxy-benzoate 2-(2-nitroxy-methyl)-phenyl ester), from Minuz et al. Cardiovasc Drug Rev, 16 (1998) with permission from NAVA Press, and from Marnett et al. Science, 280 (1998).
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9 NO–aspirins
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The second promising approach toward the development of a new
aspirin devoid of side effects on stomach, kidney, and of potential
benefit to the infarcted heart is to design derivatives of the
aspirin molecule with a side chain containing a moiety able
to release NO
[9]. Examples of two NO–aspirin molecules
with an NO releasing side chain are shown in
Fig. 3. NCX4215
is a 2-aceto-benzoate-2 (2-nitroxy)-butylester; NCX4016 is a
2-aceto-benzoate-2 (2-nitroxy-methyl)-phenylester. NCX4016 possesses
a second benzol ring to which the lateral chain containing the
NO carrying group is bound (
Fig. 3)
[9]. These NO–aspirins
also exhibit anti-platelet activity because of the release of
NO
[9]. NO–aspirins inhibit both COX-1 and COX-2, but
the release of NO counteracts the loss of prostacyclin, protects
the gastric mucosa by preserving blood flow, and increases the
synthesis of gastric mucus
[9]. Release of NO is also advantageous
to the infarcted heart (
Table 1). Endogenous NO favorably influences
contractile and metabolic functions of the infarcted heart
[12] and counteracts the effect of thromboxane
[39]. Node et al.
showed that NO formed in the infarcted heart improves cardiac
function by reducing myocardial contractility and by attenuating
positive inotropic responses
[12]. This is in part based on
the finding of Ljusegren and Axelsson, who found that cyclic
guanylate monophosphate (cGMP) originating from NO, reduces
lactate accumulation (
Table 1)
[52]. Apparently, the beneficial
effect of NO donors on the heart are attributable to a myocardial
energy sparing effect and to coronary vasodilatation (
Table 1)
[12]. In the rat model, acetylcholine stimulates protective
mechanisms during ischemia, effects which are mediated through
production of NO
[53]. In the reperfused heart, Pabla and Curtis
detected that NO prevented ventricular fibrillation after 60
min of ischemia (
Table 1)
[19]. NO infusion also provides myocardial
protection after ischemia and reperfusion
[10]. On the other
hand, Schulz et al.
[54] found that NO induced in heart muscle
by cytokines IL-1β and TNF
is a cardiac depressant; this
may, however, result in a desirable reduction in energy demands.
Others found that inhibition of NO synthesis by the arginine
equivalent
L-nitroarginine methylester (
L-NAME) reduced infarct
size after coronary occlusion and reperfusion
[11]. Similarly,
in the heart in situ, inhibition of iNOS by
L-NAME reduced the
ratio of infarcted/risk areas after ischemia and reperfusion
[55]. The release of NO from NO–aspirin, has been shown
to inhibit platelet activation by mechanisms which differ from
that causing inhibition by COX-1.
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10 NO-donor plus aspirin
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The final approach to create new aspirins devoid of side effects
is to combine two different preparations, an NO-donor with aspirin.
Several NO-donors have been described in the literature. Glyceryl
trinitrate (GTN) and possible sodium nitroprusside (SNP) need
activation by vascular smooth muscle GTN
[56,57]; others release
NO spontaneously like SIN-1 (Linsidomine)
[58] or mesoionic
3-aryl substituted (GEA-3162) oxatriazole-5-imine derivatives
[59]. SNP is equipotent with GTN in arteries and veins but SIN-1
is 10-fold less potent then GTN in vitro and 100-fold less potent
in vivo
[58]. Szekeres et al. showed that the NO-donor (GEA-3162)
can reduce the impairment of mechanical functions of the isolated
heart in post-ischemic reperfusion
[60]. These NO-donors activate
COX leading to the release of PGI
2. NO together with PGI
2 contribute
to the anti-platelet effect
[39]. SIN-1 has been used as intracoronary
bolus injection for its antispastic vasodilatory effects, which
may be responsible for its hypotensive action
[61]. The difficulty
with NO-donors with the exception of GTN is that they must be
given intravenously and that their onset is rapid as measured
by a decline in blood pressure; their effect does not extend
beyond the period of infusion. Additionally, oral NO-compounds
have to be taken at regular intervals and may produce hemodynamic
effects.
The question arises as to the value of these new aspirins in the treatment of myocardial infarction. As far as gastric and renal toxicity is concerned, COX-2 inhibitors preserve the protective function of PGI2 on gastric mucosa and renal circulation. However, they fail to prevent the formation of thromboxane, and thus do not prevent platelet aggregation [51].
NO–aspirins are also effective in preventing toxicity to gastric mucosa, because NO is recognized as a critical mediator in the defense mechanism of the gastrointestinal mucosa [18]. NO–aspirins may also be beneficial in myocardial infarction particularly in its early phase. Since NO has not yet been produced by the inflammatory cells in the myocardium on day-1 following the onset of myocardial ischemia, NO donors could supply the heart with NO at a critical time when some patients develop life threatening complications [62]. Both the American Heart Association and the American College of Cardiology recommend nitroglycerine 24 to 48 h after hospitalization [63]. NO also improves cardiac function and causes coronary vasodilatation which reduces the infarct size and prevents cardiac arrythymias (Table 1) [64].
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11 Conclusion
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In summary, the evidence for the formation of NO and of its
oxidation products, as well as of prostacyclin and thromboxane
by the infarcted heart muscle is reviewed. The importance of
inflammatory cells, primarily macrophages of cardiac origin
is documented. Several reports have mentioned the relationship
between inducible nitric oxide synthase and prostanoids. Because
of its side effects on gastric mucosa and kidney by aspirin,
several modifications of aspirin are currently being developed.
These are based on eliminating their inflammatory effect by
selective inhibition of COX-2, or by attaching an NO-delivering
side chain to the aspirin molecule (NO–aspirin), or by
combining two preparations, an NO donor with aspirin. NO–aspirins
and the combination of an NO-donor with aspirin promise to be
beneficial in the early stages of myocardial infarction. Unfortunately,
the main beneficial effect of aspirin, that of inhibition of
thrombus formation, is also the cause for its most dreaded complication,
hemorrhagic stroke. None of the new aspirins is able to prevent
this complication. For this reason, the risk benefits of aspirin
therapy should be evaluated in light of each patient’s
individual risk profile for cardiovascular events
[65].
Time for primary review 27 days.
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Acknowledgements
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We acknowledge the support of the Charles S. & Carmen DeMora
Hale Foundation, Pasadena, California, and an unrestricted grant
from Pfizer, New York. We also thank Kelly Cho for secretarial
help.
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Abstract
1 Introduction