What is the difference between myocardial ischemia and myocardial infarction

Abstract

1. Introduction

In science, progress derives from discovery of facts; formulation of concepts follows. A theoretical physicist arrives at concepts by reasoning alone which may be confirmed by experimental evidence. However, in the life sciences, experiments precede concepts. We have attempted here to use the author's experience in documenting the translation of experimental data to new concepts, their dependence on techniques and methods, and their contribution to subsequent progress. What appears promising today may be forgotten tomorrow; what appears irrelevant today may be a giant step into the future. We have reviewed progress in substrate utilization by the infarcted heart in vivo and in vitro, presented evidence for the formation of nitric oxide (NO) and prostanoids by the infarcted heart, and have discussed their relationship to angiogenesis in myocardial infarction and cancer. We have also stressed the dependence of angiogenesis on inflammatory reactions. We have addressed ourselves to results which have an impact on future research and on the growth of new concepts. Both terms, ischemia and infarction, are used here. Ischemia denotes diminished volume of perfusion, while infarction is the cellular response to lack of perfusion. Some of the changes discussed here are the result of ischemia such as those involving myocardial substrate extraction. Others such as production of prostanoids and activation of inducible form of nitric oxide synthase (iNOS) result from inflammatory changes derived from cellular reactions, which are part of the infarction process.

2. Myocardial oxygen and substrate usage

In 1947, our group (Bing, Siegel, Vitale, Balboni and co-workers) began to study a new procedure, catheterization of the heart, to study hemodynamic changes in congenital heart disease. We noticed in some patients that blood drawn through the catheter was very dark with obviously very low oxygen saturation. It was then established that the catheter had entered the coronary sinus, which drains part of the heart muscle. This suggested the possibility of measuring the arterial–venous difference across the heart and also obtain the myocardial usage of substrates, by multiplying extraction of the substrate by the coronary flow, which was determined with the nitrous oxide method. With the approval of the chief of surgery at the Johns Hopkins Hospital, Alfred Blalock, and later at the University of Alabama, our group determined myocardial usage of glucose, pyruvate, lactate, amino acids, fatty acids and ketones, and calculated the contribution of these individual metabolites to the oxygen usage of the heart. Combining diagnostic catheterization with intubation of the coronary sinus, we could now measure myocardial usage of these substances in various cardiac pathologies, amongst them myocardial failure and myocardial ischemia. Changes in substrate utilization in congestive heart failure, hemorrhagic shock, cardiac arrhythmias, diabetes, hyper- and hypothermia were also reported [1]. The human heart in situ was shown to preferentially use fatty acids [1–4]. Later, in animal experiments producing myocardial ischemia by the injection of plastic microspheres into the coronary arteries, we noticed an immediate fall in cardiac output, coronary blood flow and myocardial oxygen consumption [4]. Potassium and inorganic phosphate appeared in increased amounts in coronary vein blood. Changes, or rather, failure of changes in substrate utilization in clinical conditions were also studied [1–4]. Significant metabolic changes were absent in the failing human heart [1]. This work carried out on patients was the first to relate myocardial metabolic changes to heart disease.

Evans had previously summarized the relationship between concentration of substrates in the blood and their cardiac utilization, and described myocardial usage of lactate acid uptake, and the effect of insulin as studied in the heart–lung preparation. He also described the relationship of oxygen consumption to heart rate and heart volume [5]. Evans also showed that the heart does not fail until oxygen lack is severe and demonstrated that anaerobiasis results in change-over to utilization of carbohydrates with production of lactic acid. He clearly foresaw the increase in glucose utilization by the ischemic heart: “In the mammalian heart glucose may be also removed from the blood (probably by glycolysis) in much larger amounts than normally” [5].

If these studies on the human heart appear primitive at a time when attention is focused on genetic controls of metabolic processes, our scientific successors will certainly look at today's research with the same degree of condescension. To appreciate past scientific accomplishments one must relate them to the times when the studies were performed; this not only applies to science but also to art. But there is a constant which remains unchanged: human nature, with its lasting search for truth and artistic expression.

If we return to the beginning of the 20th century, we find that early experiments on cardiac function were primarily related to myocardial usage of oxygen. In 1904, Winterstein examined the importance of myocardial oxygen usage in the perfused rabbit heart [6]. He quoted Alexander von Humboldt who showed that the working heart uses more oxygen than the resting organ. As early as the beginning of the 20th century, the question of aerobic versus anaerobic metabolism of the heart was widely discussed. Winterstein studied the effect of ‘Erstickung’ (suffocation) of the heart, extending his observation to the hypothermic organ [6]. He concluded that oxygen in the perfusate was essential in maintaining cardiac activity. On the other hand, Kronecker stated that oxygen was not essential for cardiac activity [7]. Many of these early experiments were carried out on the heart of cold-blooded animals where metabolic requirements were less than in the heart of warm-blooded species.

Therefore, the importance of oxygen for cardiac activity was established at the beginning of the 20th century, although isolated experiments pointed to the fact that the heart could maintain its activity with oxygen-free perfusate [7]. It is astonishing how long it took to establish the importance of oxygen in maintaining cardiac activity. Equally, exploration of myocardial substrate utilization extended over many years. Tigerstedt, the discoverer of renin production by the kidneys, quoted evidence of the importance of isotonicity of crystalloid solutions and of calcium and potassium for cardiac action first clearly outlined by Ringer [8]. Tigerstedt also ranks the efficiency of different perfusates for the isolated heart: on the top of the list is blood diluted with sodium chloride, followed by serum, then casein-free milk fortified with sodium bicarbonate. At the bottom are pure crystalloid solutions, which curiously became the preferred perfusate of isolated hearts.

Initially, the role of glycolysis in the ischemic heart received scant attention. In 1975, Neely et al. found an initial acceleration of glycolysis in the isolated rat heart due to more rapid rate of glycogenolysis [9]. They were particularly concerned with the difference between the ischemic and anoxic myocardium. They found that the degree of glycolytic inhibition was directly proportional to the severity of the restriction in coronary blood flow.

Opie noted that the rate of glycolysis in myocardial ischemia is primarily due to the rate of glucose delivery and subsequent transport into the cell [10,11]. They did not entirely exclude concomitant enzyme inhibition, but increase of glucose delivery appeared to be of greater importance. Enhanced myocardial glucose uptake and metabolism are controlled by the transmembrane glucose gradient, glucose transporters, rates of glucose phosphorylation, glycogen turnover, and by the reactions of the glycolytic pathway [12].

Glucose utilization by the ischemic heart became particularly relevant after the study of Sodi-Pallares et al. who presented treatment of patients with acute myocardial infarction with a mixture of potassium, glucose and insulin [13]. His rationale was to force potassium into the cell, thus restoring the normal resting potential and improving cardiac contractility. Numerous articles have appeared since then testifying to the value of glucose–insulin–potassium treatment in acute myocardial infarction. Results have been summarized by Opie [10,11] who described the reduction of 28% in mortality with 49 lives saved per thousand patients treated [11]. At the onset, very little attention was paid to the work of Sodi-Pallares because as Apstein and Taegtmeyer mentioned, “It was feared that the treatment might worsen myocardial acidosis; in addition, there was little gain for the pharmaceutical industry to market the glucose–potassium–insulin solution” [14].

An important contribution to the knowledge of glucose uptake in the infarcted heart muscle was made by the discovery of Sokoloff et al. who detected alterations in local cerebral glucose metabolism, with the use of (18-F) 2-deoxy-2-fluoro-T-glucose (18-F-FDG) [15]. Based on these findings, Marshall et al. were able to measure by means of positron computed tomography scanning, exogenous glucose utilization in the myocardium, while at the same time, determining myocardial perfusion by N-13 ammonia [16]. In a majority of patients with coronary heart disease, certain zones of myocardium showed discordant increases in FDG activity relative to N-13 ammonia. This discrepancy between the increased uptake of glucose and the fall in coronary blood flow has been called ‘metabolism/perfusion mismatch’ [17]. Myocardial utilization of glucose signifies viability; on the other hand, when both coronary blood flow and myocardial glucose utilization are diminished, the heart ceases to be viable.

Myocardial utilization of fatty acids has also gained clinical relevance. Elevation of free fatty acids in plasma after myocardial infarction is likely due to a surge of catecholamine activity, increasing the incidence of ventricular arrhythmias [18]. Increased glucose concentration reduces the myocardial uptake of fatty acids. In a series of papers, Opie has summarized the importance of fatty acids and glucose in myocardial ischemia [11]. Cardiac fatty acid uptake and transport have been thoroughly described by van der Vusse et al. [19]. Apparently, proteins are involved in the uptake and transport of long chain fatty acids. Membrane proteins are also important for transfer of fatty acids across endothelial and muscle cells membranes. Fatty acids themselves appear to be responsible for the protein interaction. Exogenous fatty acids can act also in cardiac transcriptional activity [20].

It is not surprising that most early studies on cardiac metabolism were concerned with substrate utilization, since the method requires only conventional analytical methods and experimental conditions in the isolated perfused heart can be rigidly controlled. This approach lasted for over 100 years, but it has limits. Organs are perfused with limited oxygen supply due to the absence of respiratory pigments and there is lack of colloid osmotic pressure in the perfusate. More sophisticated studies such as the relationship of gene regulation to metabolic events in the heart require new approaches [21].

The main emphasis in myocardial infarction has been on injured heart muscle. But the core of the ischemic regions turn into the infarct scar which is a dynamic tissue with its vascular blood supply. The infarct scar is composed of phenotypically transformed fibroblasts-like cells, which possess the ability to contract, as well as respond to pharmacologically active compounds, aside from elaborating fibrillar type I collagen [22].

3. Nitric oxide and prostanoids in myocardial infarction

The author's involvement in the relationship of NO production to the ischemic heart was the outcome of a long series of studies, commencing with an attempt to identify and characterize the endothelium relaxing factor (EDRF). Our initial research was frustrating, leading into many blind alleys. Kibira et al. initially devised a method to harvest large amounts of NO by attaching endothelial cells to microcarrier beads [23]. But attempts at identification of the relaxing factor by electron spin resonance was inconclusive. Thus, we missed a free ticket to Stockholm. But by focusing our goals, we were at last able to apply NO production to myocardial ischemia.

The pivotal finding was made in 1994, when our group discovered that NO production by the experimentally infarcted heart was markedly increased 2 days after ligation of a coronary artery, as shown by an increase in an oxidation products of NO in coronary sinus blood [24] (Fig. 1). Similar results were obtained in patients after onset of myocardial ischemia [25]. The increase in the inducible form of nitric oxide synthase (iNOS) activation by the infarcted heart coincides with the appearance of infiltrating macrophages located at the border between the area of risk and the area of necrosis [26]. Myocardial production of prostacyclin (PGI2) and thromboxane (TXA2) also increases [27].

Fig. 1

Nitric oxide synthase (NOS) activity expressed as production of l-citrulline (fmol/mg of protein/20 min) in myocardium, noninfarcted versus infarcted areas (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 (reproduced with permission).

This approach has led to interesting concepts concerning changes in myocardial infarction and in certain tumors. It has brought into focus the effects of NO, PGI2 and TXA2, and their relationship to angiogenesis. Pathologists have known for many years that in infarcted heart muscle, inflammatory cells, particularly macrophages, play an important role. In 1982, Wagner and Tannenbaum found an increase in nitrate synthesis during bacterial infection [28]. Stuehr et al. explained that the increase in nitrite (NO2−) and nitrate (NO3−) was caused by activated macrophages and that NO2− and NO3− were the pharmacologically active end-products of NO production [29]. Later, the role of NO as an intermediate of arginine oxidation was established. Hibbs et al. identified NO as a molecular effector of activated macrophages [30]. They synthesized NO from a terminal guanidino nitrogen atom of l-arginine which is converted to l-citrulline without loss of the guanidino carbon atom. Marletta et al. [31] also identified NO as an intermediate in the oxidation of l-arginine and found that NO formation is dependent on l-arginine and NADPH; their activity was found only in cytosol from activated cells.

The close relationship in time between activation of iNOS and production of PGI2 and TXA2 suggests an interaction between iNOS, the enzyme responsible for the production of NO, and cyclooxygenases (COX) activation [27,32,33]. COX isoenzymes produce prostanoids from arachidonic acid. COX exists in two isoforms, COX-1 is constitutively expressed, while COX-2 is induced primarily by inflammatory cytokines [34].

It is known that NO counteracts TXA2 by inhibiting platelet aggregation, and by reducing myocardial contractility, attenuating inotropic responses [27]. NO also dilates coronary arteries, suppresses ventricular fibrillation and reduces infarct size [27]. PGI2 inhibits platelet aggregation and therefore possesses antithrombogenic properties, acts as a vasodilator and decreases infarct size. TXA2 has opposite effects, promotes platelet aggregation, initiates ventricular arrhythmias and increases infarct size [27].

3.1. Nonsteroidal anti-inflammatory drugs

It was only a step from the study of NO and prostanoids in infarcted heart muscle to that of the effect of nonsteroidal anti-inflammatory drugs (NSAIDs). These studies are relevant because NO and prostanoids influence coronary flow and myocardial contractility as well as angiogenesis. In addition, COX-2, the inducible form of cyclooxygenase, has received considerable attention, because nonselective NSAIDs, such as aspirin, can cause erosion of gastric mucosa, which can be overcome by ‘a safer aspirin’ [35]. Yamamoto and co-workers reported effects of NSAIDs which shed some light on the significance of PGI2 and TXA2 production in the infarcted heart [27,36]. Aspirin (35 mg/kg/day) significantly diminishes production of PGI2 and TXA2 but does not inhibit induction of iNOS [37]. Celecoxib, a selective COX-2 inhibitor, lowers myocardial PGI2 production but fails to inhibit TXA2[38] (Fig. 2); it does not interfere with the induction of iNOS and therefore, fails to alter myocardial release of NO2− and NO3−[38]. COX-2 is expressed by the ischemic myocardium, since celecoxib, a specific COX-2 inhibitor, inhibits formation of PGI2 and TXA2[38]. The amount of PGI2 produced by the infarcted heart after celecoxib is probably sufficient to inhibit platelet aggregation. Aspirin is considerably more effective than celecoxib in reducing myocardial PGI2 synthesis and inhibiting myocardial production of TXA2[38].

The significance of the relationship of NO, PGI2 and TXA2 to myocardial infarction lies in the potential for stimulating growth of new blood vessels and in affecting cardiac motility and coronary flow [27]. This makes it unlikely that nonspecific NSAIDs have any therapeutic value in the preservation of the ischemic myocardium.

4. Angiogenesis in ischemic heart and cancer: similarities and differences

It seems strange to include in a report on the heart some observations on cancer. But such an inclusion is informative, because it shows that different cell populations react in a similar manner by inflammatory changes with subsequent initiation of angiogenesis. Much can be learned about angiogenesis by studying it in solid tumors. Angiogenesis in cancer supplements and amplifies our knowledge on angiogenesis in the infarcted heart. They are the two sides of a coin. The importance of angiogenesis in the progression of solid tumors has been recognized for many years [39]. In contrast, because of the potential therapeutic effects of promoting angiogenesis, its study in the infarcted heart is more recent [40–43]. Efforts have been made to induce angiogenesis in infarcted heart muscle by gene transfer. Several methods have been attempted [41]. Exposure to unmodified naked DNA, coupling of DNA with lipophilic/hydrophobic agents, viral vectors, retroviral vectors, adenoviral vectors have been used [41]. Recently, Lee et al. reported that high level expression of vascular endothelial growth factor (VEGF) led to growth of vascular tumors in mice and resulted in heart failure [44]. This illustrates the difficulty in the use of VEGF as a treatment of myocardial ischemia [45]. Of importance is whether the growth of capillaries or arteriogenesis is the goal; both of them are required for reoxygenation. It is apparent that angiogenic therapy should aim at functional and sustainable new vessels [45].

In the infarcted heart as well as in solid tumors, angiogenesis is accompanied by, if not dependent on, inflammation with upregulation of inflammatory cytokines [46]. In both instances, the inflammatory response is characterized by the presence of blood-derived macrophages. Activated macrophages release NO, PGI2 and TXA2, which have been shown to play an important role in the development of angiogenesis [27] (Fig. 3). This finding does not exclude the possible role of cardiac myocytes or tumor cells in the formation of angiogenic factors. Growth factors such as fibroblast, vascular endothelial, platelet-derived endothelial cell, and epidermal growth factors, their receptors and inhibitors play an important role in myocardial infarction and solid tumors [47,48]. Monocytes/macrophages also produce angiogenic growth factors when adequately stimulated [47]. Apparently during ischemia, probably because of the activity of activated inflammatory cells, the production of growth factor is upregulated. Li showed that a macrophage-derived peptide, PR39, inhibits the ubiquitin–proteosome dependent degradation of an hypoxia-inducible factor-1 α protein [49].

Fig. 2

(A) Effects of aspirin, celecoxib and NCX 4016 on 6-keto-prostaglandin F1α (PGF1α) production in the infarcted and non-infarcted myocardium. Celecoxib, like NCX 4016, significantly lowered myocardial 6-keto-PGF1α production; however, the effect of aspirin was more pronounced. In the non-infarcted portion, only the effect of aspirin was significant (reproduced with permission). (B) Comparative effects of aspirin, celecoxib and NCX 4016 on myocardial thromboxane B2 (TXB2) production. Only the effect of aspirin was significant. In the non-infarcted portion, none of the compounds caused any changes in myocardial TXB2 production (reproduced with permission).

While in the infarcted heart angiogenesis is therapeutically desirable, it leads in solid tumors to spread and metastasis. Weidner et al. have shown that spread of tumors is dependent on angiogenesis; in some tumors, this is related to the activity of COX, particularly COX-2 [50]. In myocardial infarction, COX-2 leads to the production of prostaglandins, which are angiogenic. COX-2 plays an even larger role in colon cancer. A large series of reports have been published on the relationship between COX-2 expression and colorectal cancer [51–59]. Sheehan et al. found that not all colon cancers express COX-2 and that the extent of COX-2 expression was related to survival [60]. The effect of NSAIDs on reducing colon cancer has also been known for a number of years [61]. More recently, treatment and prevention by selective inhibition of this isoenzyme has been attempted [56,57]. The therapeutic effects of the COX-2 inhibitor, celecoxib, has also been repeatedly observed [58,62]. On the basis of these findings, a search for COX-2 expression in cardiomyocytes or macrophages in the infarcted heart muscle may be rewarding.

Fig. 3

Comparisons of the inducible form of nitric oxide synthase (iNOS), 6-keto prostaglandin F1a (PGF1a) and thromboxane B2 (TXB2) in infarcted and noninfarcted heart muscle, and in colon and breast cancers. The increase of iNOS activation in infarcted heart muscle is noted. Both the infarcted heart and colon cancer present with an increase in iNOS activation, and in myocardial concentration of PGF1a and TXB2. In contrast, iNOS activation, PGF1a and TXB2 concentrations are reduced in breast cancer.

Another similarity between myocardial infarction and solid tumors is NO production. Gallo et al. documented a strong correlation between the activity of iNOS pathways, angiogenesis and metastatic behavior in head and neck cancer [63]. Despite the evidence that assessment of microvessel counts correlates with prognosis in several solid tumors, the assessment of vascular density does not give information about the biochemical pathway involved in tumor angiogenesis [63]. In colon cancer, iNOS mRNA and protein are overexpressed [64,65]. Overproduction of NO in tumor cells leads to cytotoxicity, with enhanced cell replication [66]. Increased production of NO can act as a molecular ‘signal’ in the angiogenic response to basic fibroblast growth factor [67]. However, recent studies could find no correlation between iNOS expression and PGI2 and TXA2 production in colon cancer, although the mean values of iNOS expression were markedly increased.

Therefore, in both myocardial infarction and colon cancer, induction of iNOS, and formation of PGI2 and TXA2 are increased, probably as the result of inflammatory processes. Ischemia plays a predominant role in initiating these reactions. In infarcted heart muscle as well as in solid tumors, angiogenesis depends on the activation and interrelationship of growth factors, NO, PGI2 and TXA2. Heart muscle responds to ischemia in a predictable manner, because of the homogeneity of the myocardium. In contrast, great differences in responses of tumors even of the same type are seen because of the inhomogeneity of cancer cells. For this reason, considerable scatter of iNOS activation and production of PGI2 and TXA2 are observed in individual colon cancers.

5. Final comments

We have reviewed progress in substrate utilization by the infarcted heart in vivo and in vitro, presented evidence for the formation of NO and prostanoids by the infarcted heart, and have discussed their relationship to angiogenesis in myocardial infarction and cancer. We have also stressed the dependence of angiogenesis on inflammatory reactions. We have addressed ourselves to results which have an impact on future research and on the growth of new concepts.

Many years ago in 1936 when the author was at the Rockefeller Institute, his teacher, Alexis Carrel, a Nobel prize winner, advised him to pursue only subjects of general importance which had a good chance of success. If this advice had been followed, Gregor Mendel would not have discovered the fundamentals of genetics working on the sweet pea and Hubble would not have found the red shift in the universe. The usefulness of ‘useless science’ cannot be disputed. Discoveries of fundamental processes in the heart are now found under the general heading of ‘cardiac metabolism’. This is a broad topic which includes cardiac energetics, formation of prostanoids, angiogenesis and gene regulation as related to metabolic effects. But definitions matter little. What counts is to explore cardiac functions and relate them to basic events. If we look at the different facets of ‘cardiac metabolism’ with special reference to ischemia, we see a large variety of possibilities for discovery. All of us working in the field are intrigued and attracted by possible clinical applications. This is because we all are aware that we too may be in need of receiving the bonuses of fundamental studies. This is all to the good, because through the study of the abnormal, we become aware of those mechanisms which are given to us to preserve the equilibrium which is life.

Acknowledgements

I thank Dr. Masaru Miyataka, Nicholas Hanson, Thomas Lester and Jinny Suh for technical help.

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Copyright © 2000, European Society of Cardiology

Copyright © 2000, European Society of Cardiology

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