Circulation Research
JUNE
VOL. 48
1981
NO. 6
Official •Journal of the American Heart Ansociation
BRIEF REVIEWS
Hormonal and Metabolic Reactions Evoked
by Acute Myocardial Infarction
LESZEK CEREMUZYNSKI
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RECOGNITION of the importance of humoral balance in the body originated in the work of Claude
Bernard (1855) and was developed later mainly by
Cannon (1915) and Selye (1950). Recent myocardial
infarction (MI) has been reported to elicit humoral
disturbances which, a little more than a decade ago,
were not considered of importance. The recognition
that they may influence the clinical course of the
disease came in recent years as a consequence of
better understanding of the complex character of
MI and the nature of its complications.
In this review I intend to show briefly the accumulated data on the pattern of humoral, mainly
hormonal, disorders accompanying MI which have
been relatively well elucidated. Their interrelations
and the mechanism of their possible influence on
the clinical course of the disease also will be outlined. The therapeutic implications of this knowledge will be discussed briefly and some areas which
require further research will be suggested.
Adrenergic Nervous System
The Adrenergic Response to Myocardial
Infarction and Its Effect on Cardiac Function
Following the preliminary reports by Forssman
et al. (1952), it has been well established both in
animals and in the clinic that MI is accompanied
by increased catecholamine content in blood (Forssman et al., 1952; Gazes et al., 1959; Ceremuzynski et
al., 1969; McDonald et al., 1969; Ceremuzynski,
1970; Siggers et al., 1971; Lukomsky and Organov,
1972; Christensen and Videbaek, 1974; Vetter et al.,
1974) and urine (Valori et al., 1967; Januszewicz et
al., 1968; Hayashi et al., 1969; Ceremuzynski, 1970;
Jequier and Perret, 1970; Lukomsky and Organov,
1972; Prakash et al., 1972; Januszewicz et al., 1974;
From the Department of Cardiology, Medical Center for Postgraduate
Education, Grochowski Hospital, Warsaw, Poland.
Address for reprints: L. Ceremuzynski, M.D., 04007 Warszawa, Poland,
Szpital Grochowski, ul. Grenadierow 51/59.
Ceremuzynski and Sandier, 1978). Numerous authors found an association between the catecholamine content in blood or urine and the severity of
MI (Valori et al., 1967; Januszewicz et al., 1968;
Ceremuzynski, 1970; Jequier and Perret, 1970; Prakash et al., 1972). This increased adrenergic activity
initially has thought to serve as a compensatory
mechanism for the diminished mechanical performance of ischemic and necrotic heart muscle. This
was contrary to the opinion best formulated in
Raab's work (1963) which considered that a pronounced adrenergic reaction was likely to cause
deterioration of ischemic heart disease and lead to
further myocardial infarction. Much evidence has
now been accumulated in favor of this viewpoint.
In some patients the increase of catecholamines
preceded the major complications of MI (Prakash
et al., 1972). A similar sequence of events was shown
in dogs subjected to coronary occlusion (Ceremuzynski et al., 1969). Arrhythmias did not occur
before the rise in catecholamines. However, within
a few minutes after catecholamine (mainly epinephrine) release, cardiac rhythm disturbances occurred,
often terminating in ventricular fibrillation. In those
experiments on dogs in which no increase of circulating catecholamines occurred, sinus rhythm usually was maintained despite the large area of infarction produced by subsequent occlusion of the second and sometimes even the third coronary artery.
Major arrhythmias were provoked easily in these
dogs by epinephrine administered in small doses
which did not disturb sinus rhythm when given
before coronary occlusion (Ceremuzynski et al.,
1969). This exaggerated response of ischemic heart
muscle to catecholamines confirmed the early observation by Maling and Moran (1957).
How Do Catecholamines Harm the Heart?
In recent years, numerous data have helped to
clarify the mechanisms whereby catecholamines
may exert their deleterious effects on heart muscle.
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It has been shown that catecholamines stimulate
the activity of adenylate cyclase in the myocardial
cell membrane with subsequent elevation of cyclic
adenosine 3',5'-monophosphate (cAMP) content
(Robinson et al., 1965; Drummond et al., 1966;
Wollenberger et al., 1967). An increase in plasma
cAMP, which may reflect intracellular changes, has
been found in humans with MI and is correlated
significantly and positively with plasma catecholamines. Patients with the worst prognosis have the
highest plasma concentrations of cAMP and catecholamines (Strange et al., 1974). An increased
cAMP content in ischemic regions has been found
to precede severe dysrhythmias in cats (Corr et al.,
1978) and ventricular fibrillation in baboons (Podzuweit et al., 1978). Accordingly, it has been established that the rise of cAMP in the heart tissue is
associated with a fall in the fibrillation threshold
(Lubbe et al., 1978). These findings are compatible
with the concept of an arrhythmogenic action of
catecholamines in MI. The evidence for a role of
enhanced adrenergic activity in triggering serious
arrhythmias in MI is reviewed by Wit et al. (1975)
and by Corr and Gillis (1978).
There also is considerable evidence that cAMP
influences Ca2+ influx channels, thus affecting the
contractile state and electrical activity of the heart
(Reuter, 1974; Tsien, 1973). The role of cyclic nucleotides in cardiac function recently has been reviewed by Drummond and Severson (1979). Increased entry of Ca2+, a consequence of catecholamine stimulation of the heart cell, is thought to be
an important factor in the production of ischemic
necrosis (Fleckenstein, 1971; Shen and Jennings,
1972). This is relevant to the observations that the
majority of patients who die with pheochromocytoma have diffuse patchy myocardial necrosis (Van
Vlier et al., 1966, Baroldi, 1974). It should be
stressed that the patients with complicated MI can
excrete amounts of catecholamines in the range
noted in proven pheochromocytomas (Valori et al.,
1967).
The increase in contractile force and in the heart
rate produced by the adrenergic response results
in augmented myocardial oxygen consumption
(MVO2) which is deleterious in MI. A rise of MVO2
may well be the common denominator of different
metabolic influences in MI. A contributing factor in
the case of catecholamines may be an oxygen wasting effect which results from mitochondrial uncoupling (Challoner and Steinberg, 1966; Sobel et al.,
1966). In a pioneering study, Raab (1963) stressed
the importance of augmented MVO2 as a reason for
catecholamine-induced myocardial ischemia in the
presence of impaired ability of the coronary arteries
to dilate. More recently, Iimura et al. (1974) designed an experimental model to imitate natural
conditions occurring in the arteriosclerotic human
heart. They found that a small amount of catecholamine infused into the dog with a moderately constricted (25-50%) coronary artery resulted in slight
VOL. 48, No. 6, JUNE
1981
adverse hemodynamic, metabolic, and electrocardiographic alterations. These changes were greatly
pronounced if more than 50% narrowing of the
vessel was produced.
Metabolic Abnormalities Associated with
Catecholamine Release
Herbaczyhska-Cedro (1970) found that, when
coronary occlusion in the dog was accompanied by
excessive release of epinephrine, the content of
several enzymes (succinic dehydrogenase and ATPase) in the healthy portion of the heart muscle was
considerably diminished; this was not the case if
the experimental MI did not produce excessive
release of catecholamines. This study is relevant to
that of Gudbjarnason (1971) who found a decrease
in the content of ATP and phosphocreatine in the
non-ischemic portion of the infarcted heart. More
recently, some experimental evidence has been obtained which suggests that the above metabolic
alterations observed in the myocardium may be
linked causally with the phenomenon of adrenergic
response evoked by MI. Infusion of epinephrine
into healthy dogs in a dose similar to that released
spontaneously after coronary occlusion resulted in
a marked decrease in myocardial ATPase and succinic dehydrogenase (SDH) activity (Ceremuzynski
et al., 1978). Ultrastructural changes in heart muscle
(predominantly in mitochondrial shape and structure) also have been found. Thus, catecholamines
by themselves may produce damage of the heart
muscle in both experiments on dogs and in patients
with pheochromocytoma. The dose of epinephrine
used in the canine experiments increased the level
of circulating epinephrine by a factor of 10-20. An
adrenergic reaction in this range is likely to occur
in humans with MI but also in various everyday
stresses such as automobile driving, public speaking, etc. (Taggart et al., 1972).
The clinical relevance of these experimental findings has been substantiated recently by Mueller
and Ayres (1978). They showed a link between the
magnitude of the sympathetic response in humans
with MI, the heart muscle metabolism, and accompanying hemodynamic and clinical disorders. The
lowest content of blood catecholamines was found
in subjects with normal cardiac metabolism in
which the myocardium mainly utilizes carbohydrates. These patients displayed an uncomplicated
clinical course and undisturbed hemodynamic measurements. In patients who reacted to MI with
about a 6-fold increase in the catecholamine level,
a change in heart metabolism was observed with a
lowered extraction ratio of free fatty acids (FFA)
and pyruvates from the coronary circulation with
concurrent lactate production. Hemodynamic measurements were much altered; systemic vascular
resistance and pulmonary wedge pressure were increased, and stroke index and coronary blood flow
were found to be lowered. An intermediate catecholamine blood level was associated with a pre-
METABOLIC REACTIONS EVOKED BY MYOCARDIAL WFARCTIO^/Ceremuzyriski
dominant metabolism of FFA along with a considerable increase in MVO and deterioration of the
hemodynamic state.
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Catecholamin.es and Coronary Artery Spasm
Adrenergic overstimulation is likely to be involved in the chain of events resulting in coronary
artery spasm, a phenomenon which has received
much attention recently (Oliva et al., 1973; Maseri
et al., 1975). It has been suggested that the underlying mechanism here is a-adrenergic receptor stimulation (Yasue et al., 1974; Ricci et al., 1979) due to
either local (Cobb et al., 1976) or systemic (Yasue
et al., 1974) release of catecholamines. Phentolamine reversed spasm during coronary angiography, and administration of the long-acting a-blocking agent, phenoxybenzpmine, prevented the occurrence of the symptoms of variant angina during a
follow-up period of several months (Ricci et al.,
1979). Catecholamines also may increase the tendency of smooth muscle to contract by promoting
Ca2+ influx into the cell (Fleckenstein, 1971; Shen
and Jennings, 1972). Ellis et al. (1976) have suggested that repetitive severe vasospasm is likely to
produce endothelial damage, plaque hemorrhage,
and subsequent platelet aggregation and generation
of thromboxane A2 (TXA2). The release of this
potent vasoconstrictor and proaggregatory substance (Hamberg et al., 1975) thus may create a
vicious cycle. Catecholamines which are known to
induce platelet aggregation (O'Brien, 1963) may
further aggravate or possibly even initiate this chain
of events. Thromboxane A2 thus may be linked with
variant angina, myocardial infarction, and sudden
cardiac death (Needleman et al., 1976). Infusion of
TXA2 into a coronary artery resulted in myocardial
ischemia and necrosis in rabbits (Morooka et al.,
1977). The rate of production of TXA2 in patients
who survived MI is augmented (Szczeklik et al.,
1978). In patients with Prinzmetal's angina, the
plasma level of thromboxane B2, which is a TXA2
transformation product, was increased (Lewy et al.,
1979).
The Mechanism of Activation of the Adrenergic
System
Circulating epinephrine and norepinephrine in
MI are released from the adrenal medulla; epinephrine constitutes some 80% of catecholamine content
in this endocrine gland (Callingham, 1967). The
main sources of norepinephrine are postganglionic
sympathetic nerve endings and heart muscle (Wollenberger et al., 1967). Adrenal medullary secretion
which occurs within minutes after coronary occlusion in the dog (Staszewska-Barczak and Ceremuzyriski, 1968) is induced reflexly by stimulation of
cardiac receptors at the site and the boundary of
the infarct. The reflex involves vagal and extravagal pathways, and supraspinal structures (Staszewska-Barczak, 1971).
Malliani et al. (1969) have shown that increased
769
efferent sympathetic activity occurred almost immediately after coronary occlusion in the cat. In the
later stages of infarction, other non-reflex factors
may become important, such as circulatory disturbances due to cardiac insufficiency, the release of
humoral and chemical agents from the necrotic
myocardium or poorly perfused peripheral organs
(Staszewska-Barczak, 1971). Release of catecholamines from the adrenal medulla also may be directly stimulated by increases in [H + ] (Euler, 1967).
The mechanism of catecholamine release in humans is much more complex than in anesthetized
experimental animals. Psychological stimuli evoked
by pain and distress certainly play an important, if
not decisive, role in triggering sympathetic arousal.
Catecholamines are eliminated mainly in urine
as inactive metabolites (methoxycatecholamines
and vanillylmandelic acid) after enzymatic breakdown. It is interesting to note that in MI complicated by serious dysrhythmias, heart failure, or
hypotension, there was an increase of the catecholamine:metabolite ratio, as compared to that in uncomplicated MI, suggesting that impaired catecholamine inactivation may be present when the disease
has a serious clinical course (Ceremuzyriski, 1970;
Jequier and Perret, 1970; Januszewicz et al., 1974;
Ceremuzynski and Sandier, 1978). It is not clear at
present whether there is a causal relationship between catecholamine metabolism and the clinical
picture of MI, although it seems very probable. The
underlying mechanism of the decreased activity of
the catecholamine-inactivating enzymes also remains to be elucidated.
Thyroid Hormones
An interest in possible thyroid involvement in
MI originated in the study of Hamolsky et al. (1957),
who found that in a considerable fraction of patients
the uptake of triiodothyronine (125I-T3) by erythrocytes was enhanced markedly. Later it was found
that, in severe MI, red cell T3 uptake and PBI both
are increased (Ceremuzynski, 1970). Increased
levels of circulating free thyroxine (T4) also were
noted in single cases of MI (Bernstein and Oppenheimer, 1966). Others obtained opposite results:
serial measurement of PBI (Volpe et al., 1969) and
T4-secretion rate (Harland et al., 1972) were found
to be normal.
In recent years it has become apparent that T 3
plays a more important role than T4 in the maintenance of metabolic rate by the thyroid gland. Our
early study revealed that, unexpectedly, the serum
level of this hormone was below the normal range
in complicated cases of MI. This was in contrast to
mild infarcts, in which T3 was normal (Nauman et
al., 1975). Low T 3 values in MI also were reported
by other authors (Larty et al., 1975; Westgren et al.,
1977). This phenomenon also has been found in
other non-thyroidal illnesses such as cerebrovascular accident (Larty et al., 1975), infective diseases
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CIRCULATION RESEARCH
(Chopra et al., 1975), and after major surgery (Burr
et al., 1975).
Low T3 Syndrome
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Obviously, the low-T3 syndrome, as it is now
called, is a nonspecific phenomenon which may be
considered as a part of a general stress reaction. Is
this phenomenon involved in mechanisms leading
to complications or, on the contrary, does it depict
a favorable compensatory reaction? This important
question remains unsolved. Westgren et al. (1977)
suggest that the low T3 syndrome is a favorable
response; they found that it is accompanied by an
elevation of reverse-T3 which is the metabolically
inactive product of thyroxine. Hence the authors
concluded that in MI, thyroxine is converted preferably to reverse-T3 with a subsequent decrease in
T 3 resulting in an attenuation of the metabolic rate.
This is a beneficial effect. The weak point of this
assumption is that the clinical symptoms of increased, instead of lowered, metabolism are commonly found in MI. In MI with a serious clinical
course which is most frequently accompanied by
the low T 3 syndrome, nitrogen balance remained
negative for several days (Ceremuzyriski, 1970).
This phenomenon was much less pronounced and
transient when MI followed a mild clinical course.
Another doubt stems from the fact that if increased reverse T3 and low T3 levels reflected a
beneficial, compensatory mechanism, this pattern
should be found predominantly in uncomplicated
MI. This was not the case, at least with the low T3
syndromes observed in our study. On the contrary,
the lowest values of T 3 in our study were found in
the most serious cases with cardiogenic shock or
before fatal ventricular fibrillation (Ceremuzyriski
et al., 1978). The same observation of rapidly decreasing or almost undetectable values of T 3 in
patients dying from stroke or MI was reported by
Larty et al. (1975).
Alterations in T3 Receptors
On the basis of preliminary experimental results,
it may be suggested that the low T 3 syndrome can
also be produced by another mechanism. Under
physiological conditions, approximately 40-50% of
all the available nuclear receptor binding sites for
T 3 are occupied by the hormone (Oppenheimer and
Dillmann, 1978). In dogs with acute coronary occlusion, occupancy of nuclear receptor binding sites
was found to be increased to 63%, indicating more
T 3 bound to the receptors (Nauman et al. 1976).
This was accompanied by a considerable diminution of T3 levels in the blood. The same effect was
observed in intact dogs infused with adrenaline in
a dose comparable to that released spontaneously
after coronary occlusion. In this study, the number
of receptor-binding sites and the affinity of the
hormone to the receptor both were unchanged. It
may be expected that increased saturation of the
VOL. 48, No. 6, JUNE
1981
receptors with T3 results in augmentation of the
metabolic rate, since the metabolic action of the
hormone is initiated by its accumulation at the
nuclear receptor sites. Indeed, Oppenheimer et al.
(1976) have shown that the biological effect of T3,
as measured by the rate synthesis of malic enzyme,
was almost doubled when receptor saturation increased by 10%. If such an augmentation in metabolic rate, resulting from increased tissue uptake of
T3 and reflected by low serum T3, occurs in patients
with acute MI, it should be considered as detrimental. Some hints favoring such an interpretation of
the low T3 syndrome were earlier expressed by
Chopra et al. (1975).
Summing up, it may be stated that the involvement of thyroid hormones in the reaction elicited
by MI is likely, although more data are needed to
substantiate both operating mechanisms and clinical significance of this phenomenon.
Insulin
Disturbed carbohydrate metabolism in MI has
been recognized for a long time. In the majority of
patients, an increase in the blood glucose level or
impaired glucose tolerance has been found; occasionally the occurrence of ketone bodies was reported, even in individuals who were apparently
healthy before the onset of MI. Some clarification
of the underlying mechanism has been possible
since the introduction of a reliable radioimmunoassay for insulin. In the first hours after MI there is
a decrease in immunoreactive insulin (Ceremuzyriski, 1970; Vetter et al., 1974) or an impaired response of the hormone to a glucose or tolbutamide
stimulus (Allison et al., 1969; Taylor et al., 1969).
These reactions occur more frequently in severely
ill patients. The majority of patients who displayed
a suppressed insulin response in the first days of MI
had a normal insulin-glucose balance a few weeks
later (Boden, 1971).
Insulin Deficiency
The mechanism underlying this transient, although sometimes very profound, impairment of
insulin release is related predominantly to the sympathetic nervous system which plays an important
role in the regulation of insulin secretion in humans.
Evidence for this has accumulated from studies on
animals both in vitro (Coore and Randle, 1964) and
in vivo (Kris et al., 1966) and on man (Porte et al.,
1966). Stimulation of a-receptors by catecholamines
or /^-blockade suppressed insulin release whereas
the yS-receptor agonist, isoproterenol, or a-receptor
blockade with phentolamine potentiated the secretion of this hormone (Porte, 1969; Majid et al.,
1970). Impairment of insulin release in MI is obviously a nonspecific phenomenon because similar
disorders have been reported in congestive heart
failure (Majid et al., 1970) and with low cardiac
output states after open-heart surgery (Majid et al.,
METABOLIC REACTIONS EVOKED BY MYOCARDIAL INFARCTION/Ceran«iyrtsA:j
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1971). In a fraction of patients with MI, glucose
intolerance is not accompanied by lowered insulin
activity; this indicates the presence of insulin antagonism which is likely to be due to increased
cortisol and growth hormone levels and to an elevated content of FFA (Boden, 1971).
As mentioned earlier, suppression of insulin
release was shown during adrenaline or noradrenaline infusion both in animals and in healthy subjects. The same mechanism seems to operate in
humans with MI accompanied by increased catecholamine secretion (Ceremuzyriski, 1970; Christensen and Videbaeck, 1974).
The antagonistic effects of thyroid hormones and
insulin have also long been recognized. In experimental hyperthyroidism, glucose-induced insulin
secretion from the isolated pancreas is inhibited
due to a diminution of pancreatic islet volume (Lenzen and Kloppel, 1978).
The phenomenon of insulin deficiency in MI gave
further support to the concept of potassium-glucose-insulin therapy in MI. This question and the
problem of carbohydrate metabolism in MI in general, have been reviewed by Opie (1975).
Free Fatty Acids
Since the early papers by Kurien and Oliver
(1966) and Oliver et al. (1968) which generated
attention for the possible detrimental effects of
elevated FFA in MI, numerous investigators have
worked on the subject. However, results obtained
so far have been conflicting. Clinical observations
showed that patients with the highest concentration
of FFA in the blood displayed serious arrhythmias
and other major complications more frequently
(Oliver et al., 1968; Gupta et al., 1969; Prakas et al.,
1972), but other authors did not confirm these findings (Rutenberg et al., 1969; Nelson, 1970).
The results of experimental studies also were
inconsistent. Elevation of circulating FFA in the
dog with occluded coronary arteries resulted in a
burst of ventricular ectopic activity (Kurien et al.,
1971) that was not observed in experiments performed by another group which used a slightly
different protocol (Opie et al., 1971). A suggestion
has been advanced that the concentration of FFA
in blood is in itself less important than the FFA :
albumin ratio. If the latter is higher, it is more
probable that "an excess" of FFA, not bound to
albumin binding sites, will be transferred to the
heart muscle (Evans, 1964). Nevertheless, Kostis et
al. (1973) produced a high FFA: albumin ratio in
dogs with and without coronary occlusion and failed
to observe a decrease in the ventricular fibrillation
threshold. Thus, no conclusive data have been provided on the postulated detrimental role of FFA in
humans with MI or in experimental models. However, there still is evidence suggesting adverse effects of FFA in ischemic myocardium.
It has been shown that FFA stimulate nonphos-
771
phorylating types of metabolism (Challoner and
Steiberg, 1966) and also increase myocardial oxygen
consumption (MV02) (Mj0s, 1971). In the situation
of limited oxygen supply this depresses contractility
and also widens the ischemic area (Kjekshus and
Mj0s, 1972). When lipolysis is inhibited, the extent
and severity of myocardial ischemic injury both are
lessened (Kjekshus and Mj0s, 1973).
There also is evidence pointing to the deleterious
effects of intermediates of FFA metabolism which
accumulate in the heart subsequent to impaired
oxidation. These are long chain acyl-CoA esters
which have profound effects on energy metabolism
of the heart by inhibiting the transport of ADP and
ATP across the inner mitochondrial membrane
(Shung et al., 1975). In fact, an excess of FFA caused
a significant decline in aortic pressure and left ventricular work, together with an increase in myocardial oxygen consumption in perfused working swine
heart (Liedtke et al., 1978). An excess of FFA during
ischemia resulted in even greater deterioration of
hemodynamic function. In these cases tissue contents of acyl-CoA and acyl carnitine derivatives
were increased greatly, compared to those found in
nonischemic hearts. The data on the role of FFA in
metabolic disorders evoked by MI were reviewed
by Opie several years ago (Opie, 1975).
More recent investigations cast some doubt as to
whether certain of the experimental findings are in
fact relevant to human pathology. Rogers et al.
(1977) reported that acute elevation of FFA to
pathophysiological levels after heparin-induced lipolysis had no effect on MV0 2 in patients. The
authors concluded that the excess of FFA is stored
as triglyrides instead of being oxidized. Simmonsen
and Kjekshus (1978) found that the actual FFA
concentration was not of primary importance in
determining MV02, unless there has a concomitant
catecholamine stimulation. This is consistent with
the suggestion of Opie et al. (1971) that catecholamine activity may "sensitize" the heart to the effects of FFA and is relevant to the results of Mueller
and Ayres (1978) vide supra.
At this stage, then, it is safe to state that an
elevated FFA in MI predominantly reflects profound disturbances of both the autonomic nervous
system and the hormonal balance. Augmented adrenergic stimulation "sensitizes" the heart to FFA;
i.e., these substances become a major fuel for energy
production which is not economical in terms of
oxygen consumption and presumably may increase
the imbalance between O2 supply and demand. Intermediate toxic products also may provide a significant contribution here. The role of FFA in MI
seemed at one time to be crucial. This inclined
many groups to focus their attention on metabolic
aspects of ischemic heart disease. Although the
suspected key role of FFA has not been ultimately
confirmed, our knowledge about the complexity of
homeostatic disturbances in MI has been advanced
considerably.
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Adrenal Cortical Function
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Glucocorticoids
An early study by Forssman et al. (1952) showed
that in many patients with MI, the hormone output
from the adrenal cortex is increased. This was assumed on the basis of measurement of 11-oxysteroid
and 17-ketosteroid in urine. Other authors confirmed these results. In addition, it was found that
urinary excretion of hydrocortisone (Bailey et al.,
1967) and of its metabolites (Ceremuzyriski, 1967)
might be augmented in the first days of MI. Serum
levels of cortisol also were reported to be increased
(Oka, 1956; Klein and Palmer, 1963; Logan and
Murdoch, 1966; Bailey et al., 1967; Prakash et al.,
1972) in some cases to the range found in Cushing's
disease (Logan and Murdoch, 1966).
It also was revealed that adrenal cortical activity
occurring in the first days of MI is much more
pronounced in complicated cases than in subjects
with a mild clinical course (Klein and Palmer, 1963;
Ceremuzyriski, 1967; Prakash et al., 1972). The
causal relationship of these findings remains uncertain. Klein suggested that a blood concentration of
circulating cortisol may be harmful if it exceeded
20 ng% (Klein and Palmer, 1963). At this level of
the hormone, transcortin, the hormone-carrying
protein, becomes saturated and an excess of cortisol
blocks cellular oxidative processes. Serial determinations of the indices of adrenal cortical activity
revealed that in complicated cases the cortisol level
remained elevated until death (Prakas et al., 1972).
Other authors reported that in some patients the
excretion of glucocorticoid metabolites fails to increase (Forssman et al., 1952) or may even be below
the normal range at about the second week of
complicated MI (Ceremuzyriski, 1967). Thus the
suggestion has been advanced that this may represent poor adrenal reserve or adrenal exhaustion,
which may correspond to an exhaustion phase of
the general adaptation syndrome described by Selye (1950). Therefore it is tempting to speculate
that inadequate secretion might actually contribute
to the occurrence of adverse clinical symptoms. In
fact, a considerable deterioration of heart muscle
function has been found after adrenalectomy (Lefer
et al., 1968). The deterioration was reversed after
supplementation with cortisol.
Aldosterone
There also are limited data concerning aldosterone in MI. Wolff et al. (1956) reported an increase
in the urinary excretion of the hormone, predominantly in severe MI. Other authors interested in
this field obtained similar results (Arora, 1965; Ceremuzyriski, 1970). Recently, these early findings
have been confirmed by radioimmunoassay in studies of large groups of patients with MI (Wedler et
al., 1979). Aldosterone in serum was much raised in
the presence of major complications (multiple ven-
VOL. 48, No. 6, JUNE
1981
triclar extrasysoles, conduction disturbance, pulmonary edema). A causal relationship between clinical symptoms and the hormone level is postulated
in view of the early findings of Arora and Somani
(1962) who established that administration of aldosterone to the dog with coronary occlusion provoked ventricular arrhythmias. This probably was
due to an aldosterone-induced increase in Na+:K+
ratio in the ischemic area and, in particular, to the
rise of intracellular content of Na+ (Levitin and San
Roman, 1977). This results in alterations of the
action potential. It also should be noted that cardiac
rhythm disturbances provoked by aldosterone in
dogs with coronary occlusion were prevented by the
aldosterone antagonist, spironolactone (Arora and
Somani, 1962). This agent was shown earlier by
Selye (1966) to protect against cardiac necrosis
induced by mineralocorticoids.
Summing up, it may be suggested that, in the
early period after MI, an inadequate secretion of
cortisol and an excess of aldosterone are likely to
occur in patients with severe disease. This pattern
of reaction should be considered deleterious and if
this postulate ultimately is confirmed, it may indicate some therapeutic approaches.
Hormonal Interrelations
The humoral disturbances outlined above are
interrelated. Catecholamines have been shown to
stimulate the uptake and incorporation in organic
compounds of iodine and hormonal biosynthesis in
isolated cells of calf thyroid. Moreover, the induction of secretion by the thyroid gland and an enhancement of peripheral turnover of thyroid hormones were observed. This area of research has
been reviewed recently by Mellander (1977).
It also is recognized that increased adrenergic as
well as thyroid activity suppresses insulin secretion,
as mentioned above. This pattern of hormonal disturbances stimulates lipoprotein lipase activity
which results in an increase of FFA concentration
in blood.
Adrenaline acts as a stimulus for cortisol production in humans, but glucocorticoids have been found
to depress the activity of the epinephrine-forming
enzyme, phenyl-ethanolamine-TV-methyl transferase (Wurtman et al., 1967), thus attenuating adrenergic strain. This may constitute a major adaptive
mechanism.
Thyroid hormones also stimulate cortisol secretion and greatly enhance cortisol turnover (Gallagher et al., 1972). As in the adrenergic system, a
negative feedback operates; the administration of
hydrocortisone is accompanied by an acute suppression of both the thyroidal iodine release and
serum TSH values (Nicoloff et al., 1970).
The effects of catecholamines on the heart, such
as an increase in cardiac rate and the force of
contraction, are greatly attenuated by insulin. This
hormone also possesses its own inotropic action
METABOLIC REACTIONS EVOKED BY MYOCARDIAL INFARCTION/ Ceremuzyriski
which is not dependent on the external glucose
concentration (Lee and Downing, 1976). The patterns of major humoral disturbances in MI have
recently received much attention and their proven
and/or probable interrelations are shown in Figure
1.
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Promising Areas of Future Research
The evidence accumulated so far indicates that
MI evokes a generalized metabolic reaction which
presumably constitutes a nonspecific response to
injury or stress. In a fraction of patients, this response is pronounced and accompanied by serious
complications and a high mortality rate. There is a
considerable body of evidence that a causal relationship does exist here; at least it is justified to say
that metabolic alterations per se aggravate the clinical course of MI. This is why the elucidation of the
mechanisms involved is a matter of importance.
A key problem seems to be whether and how
much the heart muscle and total body oxygen demands are increased in MI by metabolic inefficiency. This review suggests such a possibility,
pointing also to some probable underlying mechanisms. An adrenergic "storm" should be considered
the most important mechanism in this respect because it influences body and heart metabolism by
itself and presumably also acts as a trigger for a
variety of metabolic changes. Of these, the suggested catecholamine-induced enhancement of T3
uptake by specific nuclear receptors seems to be of
ACIH -
1 CORTISOL-.
• * RENIN
platelet aqqreqationi
It
PROGRESSION
|
j
considerable importance. This phenomenon deserves further research as it may constitute the
crucial mechanism accounting for the increase in
metabolic rate observed in MI as well as in other
acute diseases. Kinetic studies of T3 combined with
measurements of MVO2 and heart muscle function
might cast some light on the nature and clinical
significance of the puzzling low T3 syndrome. If the
above assumption is true and the condition proves
to be detrimental, some measures aimed at preventing the enhanced T3 uptake in MI should be
devised.
The nature of the adrenergic response remains
mysterious. In particular, it is not known why this
response is large in one individual and only moderate in another. There are suggestions that the
inactivation rate of catecholamines in MI may be
variable. Kinetic studies would help to trace the
fate of catecholamines in MI, their turnover and
uptake. Attention should be focused also on the
important link between the adrenergic reaction and
the thromboxane A2-prostacyclin system and related consequences.
The place of aldosterone in promoting adverse
symptoms in MI is unclear, although the role of the
hormone could be considerable. Spironolactone
might be effective here and might be added to the
list of so-called metabolic interventions in MI. The
actual needs for cortisol in MI are undefined, and
it is not clear whether they are adequately supplied
in older patients or in those with chronic diseases.
We have no data on the turnover rate of the hormone in the various clinical responses to MI. Nevertheless cortisol presumably is increased greatly in
the individuals displaying a marked stress reaction.
Finally, the metabolic reaction in MI which has
been discussed is nonspecific. Thus, every research
achievement in this field will enrich the knowledge
of the mechanism of clinical symptoms in several
acute illnesses, enabling the introduction of more
rational therapeutic approaches.
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I ALDOSTERONE
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thromboxone A ;
773
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toss
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lot 1SCHEM1C DAMAGE I
FIGURE 1 Interrelations of humoral and metabolic
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hemodynamic disturbances, ischemic area of the heart;
—» = stimulatory effect; - - - • = suppressive effect.
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Circ Res. 1981;48:767-776
doi: 10.1161/01.RES.48.6.767
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