© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
New look at myocardial infarction: toward a better aspirin
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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 Top Abstract 1 Introduction2 Myocardial origin of...3 NO formation by...4 Nitrite and nitrate5 Production of PGI2...6 Relationship between NO...7 New aspirin8 Selective inhibitors of...9 NO-aspirins10 NO-donor plus aspirin11 ConclusionReferences |
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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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TopAbstract1 Introduction2 Myocardial origin of...3 NO formation by...4 Nitrite and nitrate5 Production of PGI2...6 Relationship between NO...7 New aspirin8 Selective inhibitors of...9 NO-aspirins10 NO-donor plus aspirin11 ConclusionReferences |
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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 (PGI2), and thromboxane (TXA2) 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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TopAbstract1 Introduction2 Myocardial origin of...3 NO formation by...4 Nitrite and nitrate5 Production of PGI2...6 Relationship between NO...7 New aspirin8 Selective inhibitors of...9 NO-aspirins10 NO-donor plus aspirin11 ConclusionReferences |
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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 (TXA2). 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.
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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]. |
3 NO formation by macrophages |
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TopAbstract1 Introduction2 Myocardial origin of...3 NO formation by...4 Nitrite and nitrate5 Production of PGI2...6 Relationship between NO...7 New aspirin8 Selective inhibitors of...9 NO-aspirins10 NO-donor plus aspirin11 ConclusionReferences |
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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 NO3– diet showed increased NO3– synthesis during bacterial infection [28]. This observation led to the discovery by Stuehr et al., that activated macrophages are the source of NO2–/NO3–. They recognized that NO2– (nitrite) and NO3– (nitrate) are the inactive end-products and that reactive NO causes the immune response which originates during the metabolism of L-arginine to NO2–/NO3– [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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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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TopAbstract1 Introduction2 Myocardial origin of...3 NO formation by...4 Nitrite and nitrate5 Production of PGI2...6 Relationship between NO...7 New aspirin8 Selective inhibitors of...9 NO-aspirins10 NO-donor plus aspirin11 ConclusionReferences |
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Increased NO production in infarcted heart is reflected by an increased concentration of its oxidation products, nitrite (NO2–) and nitrate (NO3–), in coronary sinus blood and by a widening of their coronary arterial–venous difference [31,32] (the sum of NO2– and NO3– 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 NO2– and NO3– 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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TopAbstract1 Introduction2 Myocardial origin of...3 NO formation by...4 Nitrite and nitrate5 Production of PGI2...6 Relationship between NO...7 New aspirin8 Selective inhibitors of...9 NO-aspirins10 NO-donor plus aspirin11 ConclusionReferences |
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PGI2 and TXA2 are produced in infarcted heart muscle, PGI2 by endothelial cells and TXA2 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-PGF1
(stable products of PGI2) 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-PGF1: 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 TXB2, the stable products of TXA2: 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 PGI2 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 PGI2 and TXA2 on infarcted heart muscle is shown in Table 1. |
6 Relationship between NO and COX |
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TopAbstract1 Introduction2 Myocardial origin of...3 NO formation by...4 Nitrite and nitrate5 Production of PGI2...6 Relationship between NO...7 New aspirin8 Selective inhibitors of...9 NO-aspirins10 NO-donor plus aspirin11 ConclusionReferences |
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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 PGE2 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]. PGE2 downregulates and PGI2 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 PGE2 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 PGI2 and TXA2, 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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TopAbstract1 Introduction2 Myocardial origin of...3 NO formation by...4 Nitrite and nitrate5 Production of PGI2...6 Relationship between NO...7 New aspirin8 Selective inhibitors of...9 NO-aspirins10 NO-donor plus aspirin11 ConclusionReferences |
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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 A2, 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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TopAbstract1 Introduction2 Myocardial origin of...3 NO formation by...4 Nitrite and nitrate5 Production of PGI2...6 Relationship between NO...7 New aspirin8 Selective inhibitors of...9 NO-aspirins10 NO-donor plus aspirin11 ConclusionReferences |
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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 G2, 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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9 NO–aspirins |
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TopAbstract1 Introduction2 Myocardial origin of...3 NO formation by...4 Nitrite and nitrate5 Production of PGI2...6 Relationship between NO...7 New aspirin8 Selective inhibitors of...9 NO-aspirins10 NO-donor plus aspirin11 ConclusionReferences |
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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. |
10 NO-donor plus aspirin |
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TopAbstract1 Introduction2 Myocardial origin of...3 NO formation by...4 Nitrite and nitrate5 Production of PGI2...6 Relationship between NO...7 New aspirin8 Selective inhibitors of...9 NO-aspirins10 NO-donor plus aspirin11 ConclusionReferences |
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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 PGI2. NO together with PGI2 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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TopAbstract1 Introduction2 Myocardial origin of...3 NO formation by...4 Nitrite and nitrate5 Production of PGI2...6 Relationship between NO...7 New aspirin8 Selective inhibitors of...9 NO-aspirins10 NO-donor plus aspirin11 ConclusionReferences |
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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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TopAbstract1 Introduction2 Myocardial origin of...3 NO formation by...4 Nitrite and nitrate5 Production of PGI2...6 Relationship between NO...7 New aspirin8 Selective inhibitors of...9 NO-aspirins10 NO-donor plus aspirin11 ConclusionReferences |
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