Cardiovascular Research 51 (2001) 13–20

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Editorial

Myocardial ischemia and infarction: growth of ideas

Richard J. Bing*
Department of Experimental Cardiology, Huntington Medical Research Institutes, 99 North El Molino Avenue, Pasadena, CA 91101, USA

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Received 10 January 2001; accepted 15 February 2001

Abstract

This report reviews the author’s involvement in the growth of ideas and basic concepts in myocardial ischemia resulting in the
histological changes of myocardial infarction. Concepts arising from the study of myocardial substrate utilization, activation of the
inducible form of nitric oxide synthase and production of prostacyclin and thromboxane in the infarcted heart are presented. New
approaches are discussed dealing with the effects of nonsteroidal anti-inflammatory drugs on myocardial production of nitric oxide and
prostanoids, and with the relevance of the inducible form of cyclooxygenase. The review also records a number of significant similarities
between angiogenesis in the ischemic heart and some cancers. Angiogenesis in both instances originates from inflammatory reactions,
illustrating how different tissues and organs such as ischemic heart muscle and cancer react to similar pathological stimuli in an identical
manner. This multifocal approach opens new concepts on myocardial ischemia and cancer.  2001 Elsevier Science B.V. All rights
reserved.

Keywords: Angiogenesis; Coronary disease; Infarction; Macrophages; Prostaglandins

1. Introduction chemia denotes diminished volume of perfusion, while

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 attempt-
ed 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 contribu-
tion 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. Is-
*Tel.: 11-626-397-5860; fax: 11-626-795-5774.
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, catheteriza-
tion 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 estab-
lished 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

0008-6363 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved.
PII: S0008-6363( 01 )00250-4
14 R. J. Bing / Cardiovascular Research 51 (2001) 13 – 20
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 myocar-
dial 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 is-
chemia by the injection of plastic microspheres into the
coronary arteries, we noticed an immediate fall in cardiac
output, coronary blood flow and myocardial oxygen con-
sumption [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 be-
tween 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 relation-
ship 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 condes-
cension. 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 expres-
sion.
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 oxy-
gen 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
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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 bicar-
bonate. 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 in-
crease 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 phosphoryl-
ation, glycogen turnover, and by the reactions of the
glycolytic pathway [12].
Glucose utilization by the ischemic heart became par-
ticularly 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
 R. J. Bing / Cardiovascular Research 51 (2001) 13 – 20
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, ex-
ogenous 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 dis-
cordant increases in FDG activity relative to N-13 am-
monia. This discrepancy between the increased uptake of
glucose and the fall in coronary blood flow has been called
‘metabolism / perfusion mismatch’ [17]. Myocardial utiliza-
tion of glucose signifies viability; on the other hand, when
both coronary blood flow and myocardial glucose utiliza-
tion 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 ven-
tricular 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 per-
fused 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 respirato-
ry 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
15
phenotypically transformed fibroblasts-like cells, which
possess the ability to contract, as well as respond to
pharmacologically active compounds, aside from elaborat-
ing 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
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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 incon-
clusive. 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
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 (n54–9 for each group, POD5postoperative day).
NOS activity is higher in infarcted area on POD 1 (n56). Significant
differences are noted for POD 2 (n54) and groups POD 3–6 (n57) and
POD 7–14 (n59). Probability values denote the statistical significance for
infarcted versus noninfarcted area. Data are given as mean6S.E.M., n
indicates the number of different hearts (reproduced with permission).
16 R. J. Bing / Cardiovascular Research 51 (2001) 13 – 20
area of risk and the area of necrosis [26]. Myocardial
production of prostacyclin (PGI 2 ) and thromboxane
(TXA 2 ) also increases [27].
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, PGI 2 and TXA 2 ,
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].
2
Stuehr et al. explained
2
that the increase in nitrite (NO 2 )
and nitrate (NO 3 ) was caused by activated macrophages
2 2
and that NO 2 and NO 3 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 N=O 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 PGI 2 and TXA 2 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 primari-
ly by inflammatory cytokines [34].
It is known that NO counteracts TXA 2 by inhibiting
platelet aggregation, and by reducing myocardial contrac-
tility, attenuating inotropic responses [27]. NO also dilates
coronary arteries, suppresses ventricular fibrillation and
reduces infarct size [27]. PGI 2 inhibits platelet aggregation
and therefore possesses antithrombogenic properties, acts
as a vasodilator and decreases infarct size. TXA 2 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 nonsteroi-
dal 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 PGI 2 and
TXA 2 production in the infarcted heart [27,36]. Aspirin
(35 mg / kg / day) significantly diminishes production of
PGI 2 and TXA 2 but does not inhibit induction of iNOS
[37]. Celecoxib, a selective COX-2 inhibitor, lowers
myocardial PGI 2 production but fails to inhibit TXA 2 [38]
(Fig. 2); it does not interfere with the induction of iNOS
2
and 2therefore, fails to alter myocardial release of NO 2 and
NO 3 [38]. COX-2 is expressed by the ischemic myocar-
dium, since celecoxib, a specific COX-2 inhibitor, inhibits
formation of PGI 2 and TXA 2 [38]. The amount of PGI 2
produced by the infarcted heart after celecoxib is probably
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sufficient to inhibit platelet aggregation. Aspirin is con-
siderably more effective than celecoxib in reducing
myocardial PGI 2 synthesis and inhibiting myocardial
production of TXA 2 [38].
The significance of the relationship of NO, PGI 2 and
TXA 2 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 informa-
tive, because it shows that different cell populations react
in a similar manner by inflammatory changes with sub-
sequent initiation of angiogenesis. Much can be learned
about angiogenesis by studying it in solid tumors. Angio-
genesis in cancer supplements and amplifies our knowl-
edge 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]. Expo-
sure 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 vascu-
lar 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 sustain-
able new vessels [45].
In the infarcted heart as well as in solid tumors,
angiogenesis is accompanied by, if not dependent on,
 R. J. Bing / Cardiovascular Research 51 (2001) 13 – 20 17

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Fig. 2. (A) Effects of aspirin, celecoxib and NCX 4016 on 6-keto-prostaglandin F 1a (PGF 1a ) production in the infarcted and non-infarcted myocardium.
Celecoxib, like NCX 4016, significantly lowered myocardial 6-keto-PGF 1a 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 TXB 2 production (reproduced with permission).
18 R. J. Bing / Cardiovascular Research 51 (2001) 13 – 20
inflammation with upregulation of inflammatory cytokines
[46]. In both instances, the inflammatory response is
characterized by the presence of blood-derived macro-
phages. Activated macrophages release NO, PGI 2 and
TXA 2 , 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]. Mono-
cytes / macrophages also produce angiogenic growth factors
when adequately stimulated [47]. Apparently during is-
chemia, 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 degra-
dation of an hypoxia-inducible factor-1 a protein [49].
While in the infarcted heart angiogenesis is therapeu-
tically 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 thera-
Fig. 3. Comparisons of the inducible form of nitric oxide synthase
(iNOS), 6-keto prostaglandin F1a (PGF 1a ) and thromboxane B 2 (TXB 2 )
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 PGF 1a and TXB 2 .
In contrast, iNOS activation, PGF 1a and TXB 2 concentrations are reduced
in breast cancer.
peutic 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.
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
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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
PGI 2 and TXA 2 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 PGI 2 and
TXA 2 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 interre-
lationship of growth factors, NO, PGI 2 and TXA 2 . Heart
muscle responds to ischemia in a predictable manner,
because of the homogeneity of the myocardium. In con-
trast, 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 activa-
tion and production of PGI 2 and TXA 2 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
 R. J. Bing / Cardiovascular Research 51 (2001) 13 – 20
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 possi-
bilities 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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