8 Carbohydrate Metabolism in Cardiovascular Disease L I O N E L H. O P I E W . A. S T U B B S
ACUTE MYOCARDIAL INFARCTION
Carbohydrate intolerance For many years there has been a controversy about the meaning of the carbohydrate intolerance seen with acute myocardial infarction. Is the diabetic state a temporary manifestation of myocardial infarction or does the infarct precipitate latent diabetes? In 1922 Levine linked coronary artery disease and diabetes, but in 1929 he pointed out that coronary thrombosis 'produces by itself a glycosuria that need not be indicative of diabetes', possibly because of 'the great pain and fear that accompanies it'. Myocardial infarction with glycosuria was reported in Britain in 1931 by Cruickshank, who failed to see how glycosuria could determine the onset of coronary thrombosis, but suggested that vascular degeneration was the common link between pancreatic and cardiac disease. Scherf in 1933 found that six of nine patients with myocardial infarction had transitory glycosuria and hyperglycaemia, and pointed out that the differential diagnosis of true diabetes from transitory hyperglycaemia could not always be made with certainty at the time of the acute attack. In 1936 Raab and Rabinowitz thought that abnormal glucose tolerance was a constant consequence of myocardial infarction, not dependent on latent diabetes and possibly related to disturbances in the 'vegetative centres' of the brain. These early workers, therefore, clearly understood the problems involved in the interpretation of hyperglycaemia during acute myocardial infarction. Goldberger took the problem further by studying patients during their convalescence and recovery (Goldberger, Alesio and Woll, 1945). He found that in some initially normal patients diabetic curves were only reached some months after a heart-attack, thus establishing that at least some of the patients had latent diabetes. The latter view was also taken by Sowton (1962) who followed-up patients for up to five years. Datey and Nanda (1967), however, found that myocardial infarction had only unmasked latent diabetes in 14 per cent of their series of 145 patients and ascribed the transient hyperglycaemia of the majority to unknown factors. Clinics in E n d o c r i n o l o g y a n d M e t a b o l i s m - - Vol. 5, No. 3, November 1976.
703
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LIONEL H, OPIE A N D W . A. STUBBS
In 1952 Ellenberg, Osserman and Pollack gave a new interpretation to hyperglycaemiain non-diabetic patients who had acute myocardial infarction: 'hyperglycaemia is a clinical manifestation of shock'. They, therefore, suggested that carbohydrate intolerance reflected severe myocardial infarction complicated by shock. Ellenberg, Osserman and Pollack (1952) also thought that hyperglycaemia was associated with a greater incidence of conduction defects and arrhythmias, and with a larger infarct size but unfortunately they did not give the exact figures. These workers only selected cases proven by autopsy thus denying themselves comparisons with the less severely ill surviving patients. MacKenzie et al (1964) confirmed that those patients with cardiogenic shock had blood sugar values over twice those found in the non-shocked patients (mean values, 14.7 mmol/1 (264 mg/100 ml) in shocked and 5.9 mmol/1 (107 mg/100 ml) in non-shocked patients). Both Taylor et al (1969) and Allison, Chamberlain and Hinton (1969) provided an explanation for the carbohydrate abnormalities of cardiogenic shock -failure of insulin secretion. Taylor et al (1969) showed that the secretion of insulin in response to intravenous tolbutamide was depressed in circulatory shock following myocardial infarction, probably as result of both reduced blood flow to the pancreas and the high level of circulating catecholamines; subjects improving clinically also had improved insulin secretion. Even in non-shocked patients the degree of glucose intolerance could be related to the prognosis because the trend for mortality for the diabetics studied by EckerstrSm (1951) exceeded that for hyperglycaemics which in turn exceeded that of normoglycaemics at four weeks, one year and four years after the onset (see Table 27, EckerstrSm, 1951). Allison, Chamberlain and Hinton (1969) suggested that the extent of changes in insulin secretion, basal glucose levels and in glucose tolerance could all be related to the severity of the illness. The similarity of the metabolic changes in acute myocardial infarction to other stress states such as thermal burns was pointed out by Ellenberg, Osserman and Pollack (1952) and supported by Allison, Chamberlain and Hinton (1969); the latter authors had found that metabolic changes in burned patients could be related to the burnt surface area (Allison, Hinton and Chamberlain, 1968). Opie (1971) also argued that the metabolic complications of acute myocardial infarction were similar to those found in other situations of acute physical or psychological stress, but emphasised the specific results of some complications of cardiac infarction: (a) acute left ventricular failure with increased catecholamine secretion rates, which would help to suppress insulin secretion (see Taylor et al, 1969); (b) cardiogenic shock with even higher catecholamine secretion rates and lactic acidosis (acidosis impairs glucose uptake in a variety of tissues) (Gevers and Dowdle, 1963; Delcher and Shipp, 1966). The failure of Datey and Nanda (1967) to show any differences between the normoglycaemic and hyperglycaemic groups in relation to the presence or absence of pain, shock, angina, hypotension or ECG abnormalities does not negate the hypothesis of Allison, Chamberlain and Hinton (1969) because the latter group studied their patients within 15 hours of the onset of symptoms of acute myocardial infarction, whereas Datey and Nanda (1967) studied patients up to 72 hours after the onset, and the hyperglycaemic
CARBOHYDRATE METABOLISM IN CARDIOVASCULAR DISEASE
705
response to infarction may be maximal only within the early hours. Vetter et al (1974) showed that hyperglycaemia took about 30 minutes to develop and returned to high normal values five hours after the onset; plasma insulin was initially low and then returned to the normal range one hour after the onset. Thus plasma insulin was low throughout the first five hours when compared with the high blood sugar. The other studies already cited suggest that glucose intolerance persists for much longer than the first five hours; the difference may lie in the severity of the clinical features which were not fully specified in the study of Vetter et al (1974). In view of the time-related and severity-related nature of the glucose abnormalities, it is not surprising that different workers have described different incidences of hyperglycaemia and glycosuria and have attributed different significances to their findings. In addition, different methods of assessment have been used. Oral ingestion of 100 g of glucose was used by Raab and Rabinowitz (1936), who found abnormal curves in all their patients. Datey and Nanda (1967) used a similar test and found initial hyperglycaemia in 65 per cent of patients but excluded those dying during the hospital stay - - probably the more severely ill patients. The oral two-dose test was used by Goldberger, Alesio and Woll (1945) who found that less than 50 per cent of patients were abnormal. An intravenous glucose tolerance test (Lundbaek, 1962) was used by Gupta et al (1969) who found a mean K value of 1.1 (borderline diabetic). Allison, Chamberlain and Hinton (1969) used a similar intravenous test and found diabetic values (less than one) in all patients. Taylor et al (1969) used basal plasma insulin values and the response to intravenous tolbutamide to show decreased basal insulin values and decreased insulin secretion in those patients with myocardial infarction complicated by shock or hypotension but not in uncomplicated infarctions. Abnormalities of carbohydrate metabolism, even in the absence of the diabetic state, are very frequent in acute myocardial infarction (see Tables 1 and 2). The exact incidence is difficult to define because of (a) the different tests used, (b) the evolving metabolic picture in acute infarction, and (c) the most severe disturbances are found in those with severest complications who are the most difficult to study.
CONCLUSION.
Carbohydrate intolerance as a reflection of general metabolic changes (Table 3) The above survey shows that it may be useful to view acute myocardial infarction as an example of an acute physical and emotional stress which may or may not precipitate overt glucose intolerance depending on the severity of the illness and the degree of pre-existing glucose intolerance, i.e. the inherited tendency towards diabetes. Owing to the extreme variability in the clinical picture of acute myocardial infarction, and the different propensities to diabetes in different populations and ethnic groups, generalisations about the incidence of carbohydrate abnormalities in acute infarction are probably not justified. On the other hand, interactions between the various metabolic abnormalities should help elucidate the mechanisms underlying glucose intolerance.
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CARBOHYDRATE METABOLISM IN CARDIOVASCULAR DISEASE Table 3. General metabolic and hormonal changes which may influence
carbohydrate metabolism in acute myocardial infarction
Authors Poor insulin secretion (shock)
Taylor et al
(1969)
An ti-glucose factors Catecholamine secretion Glucagon secretion Corticosteroid secretion Other hormones growth hormone prolactin? secretin? Starvation High circulation FFA concentrations
Vetter et al Laniado, Segal and Esrig Prakash et al
(1974) (1973) (1972)
Lebovitz et al Horrobin et al Henry, Flanagan and Buchanan Opie, Bruyneel and Kennelly Shipp, Opie and Challoner
(1969) (1973) (1975) (1975) (1961)
Other factors Antagonist of Vallance-Owen Latent diabetes mellitus
Stout and Vallance-Owen Datey and Nanda
(1969) (1967)
FREEFATTYACIDS.Plasma free fatty acids are elevated within 30 minutes of the onset of acute myocardial infarction (Vetter et al, 1974). The degree of elevation is related to the severity of the illness, as shown in Figure 1 by the response in 35 consecutive patients admitted to the Coronary Care Unit of the Hammersmith Hospital, London. About one-third of patients had serious complications such as left ventricular failure, congestive heart failure or cardiogenic shock (Group 2); those without such complications constituted Group 1. Mean FFA values in the more severely ill patients were higher throughout the first seven days in the more severely ill Group 2 patients (Gupta et al, 1969). Free fatty acids are liberated from adipose tissue and the rate of liberation is decreased by glucose and insulin. Hyperglycaemia and unchanged insulin secretion should at first sight act to lower free fatty acids, but free fatty acids are known to be elevated. In cardiogenic shock the explanation may be poor insulin secretion. A similar explanation may hold for infarction with hypotension (Taylor et al, 1969) and it is in cases with complications that the circulating free fatty acids are highest (Gupta et al, 1969). However, FFA concentrations are also elevated in non-complicated cases when there is an adequate insulin response~ although the concomitant hyperglycaemia shows that there is glucose intolerance (Taylor et al, 1969). The factors promoting glucose intolerance are generally the same as those elevating plasma FFA (Table 3), thereby showing the close links between glucose and free fatty acid metabolism in acute myocardial infarction, as in normal subjects. CATECHOLAMINES. Specific factors promoting high free fatty acids in myocardial infarction probably include an acute increase in plasma catecholamines and an acute fall in insulin (Vetter et al, 1974). The plasma catecholamine changes are reflected in increased urinary output of catecholamines (Figure 2). In an interesting study of myocardial infarction in dogs Russell, Crafoord and Harris (1961) showed that the damaged heart itself
710
LIONEL H. OPIE AND W. A. STUBBS
releases catecholamines. These might have a peripheral effect (Braunwald, Harrison and Chidsey, 1964) which could set up a vicious cycle with release of catecholamines, stimulation of lipolysis, further infarction and so on.
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CONCLUSION. Increased circulating concentrations of free fatty acids and of glucose are closely related changes reflecting alterations in the secretion rates of catecholamines, insulin and, very probably, glucagon, as well as of other hormones which modulate the rate of release of FFA from adipose tissue. The relation between the degree of carbohydrate intolerance and the severity of infarction is mirrored by a similar relation between the clinical severity and the rise of blood FFA and between severity and the urinary secretion of catecholamines (Gupta et al, 1969).
LIONEL H. OPIE AND W. A. STUBBS
712
Local changes in carbohydrate metabolism (Table 4) Carbohydrate metabolism is also altered in those parts of the myocardium undergoing necrosis. According to the 'glucose hypothesis', increased utilisation of glucose by the ischaemic infarcting tissue can help to save at least some ceils from ultimate necrosis (Opie, 1970). There are substantial experimental data showing that the provision of glucose is beneficial to the survival of anoxic heart (Weissler et al, 1968; Hearse and Chain, 1972). In these experimental conditions, anoxia causes increased glycolytic flux by stimulation of glucose uptake, glycogen breakdown and phosphofructokinase activity; the rate of anaerobic ATP production then becomes crucial for survival of the heart, and peak rates of production are obtained in the presence both of hyperglycaemia and insulin. According to the 'glucosehypothesis' additional modes of action are an osmotic effect (Leaf, 1973), an electrophysiological effect (Cheneval et al, 1972; Prasad and MacCleod, 1969) and the ability to decrease blood FFA (Gupta et al, 1969). Table 4. Factors accelerating and inhibiting glycolysis in regional ischaemia (developing infarction) (see Opie, 1976) I. Glycolysis is increased by:
Anoxia/hypoxia with breakdown of high energy phosphate compounds activation of phosphofructokinase increased glucose transport increased glycogenbreakdown Increased provision of circulating glucose and insulin Decreased extraction of circulating free fatty acids by ischaemic zone Increased activity of pyruvate dehydrogenase Increased blood flow with increased deliveryof glucose and washout of products of anaerobic glycolysis II. Glycolysis is decreased by: Accumulation of protons and lactate inhibition of phosphofructokinase inhibition of triose phosphate dehydrogenase Decreased blood flow with decreased deliveryof glucose Residual oxidative metabolism with less anoxic/hypoxicstimulus
The position in developing infarction is, however, not as simple as in anoxia. A crucial feature of ischaemic underperfusion is the accumulation of protons, CO2 and lactate in the ischaemic tissue. Glycolytic flux is inhibited at the level of phosphofructokinase by intracellular acidosis (Opie, 1976) and at the level of triose phosphate dehydrogenase by lactate (Rovetto, Lamberton and Neely, 1975). The continued provision of oxygen to the infarcting zone, t a k e n as a whole, means that the predominant pattern of metabolism is aerobic and that anaerobic rates of ATP production are very low in relation to total requirement (Opie, 1976). Individual cells or parts of cells in the infarcting myocardium may vary considerably in the degree of oxygenation with some cells being totally ischaemic, receiving no 02 at all, and hence relying totally on glycogen for anaerobic energy. Other cells may be much
CARBOHYDRATE METABOLISM IN CARDIOVASCULAR DISEASE
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better perfused. Such variations probably reflect the heterogeneous nature of microsphere blood flow to small segments of the heart (Marcus et al, 1975) and give rise to the pathologically detectable heterogeneity of the ultimate infarct. Varying degrees of inhibition of contractile activity confer varying degrees of ATP demands in a system where ATP production rates greatly vary. In the above complex setting, it is not surprising that glucose effects on anaerobic ATP production in the infarcting zone should not be readily demonstrable. Nevertheless, glucose administered as glucose--insulin-potassium (GIK) to the infarcting dog or baboon heart can decrease metabolic and pathologic damage. The possible mechanisms are considered below. CONCLUSION.Patterns of regulation of glycolysis described in anoxia are not necessarily applicable to the much more complex situation in developing infarction when the ischaemic zone still receives oxygen from a collateral blood supply. Ischaemic changes may inhibit rather than stimulate glycolytic flux.
Local lipid changes The 'fatty acid hypothesis' of Kurien and Oliver (1970) suggests that increasing intracellular free fatty acids, derived either from the circulation or from intracellular lipid, could be 'toxic' to the ischaemic infarcting myocardium by causing arrhythmias and deleterious metabolic effects. Criticism of the FFA-arrhythmia hypothesis comes from the diverse results of various clinical studies, not all of which link high FFA levels to arrhythmias, and from conflicting animal data (Opie, 1975). Nevertheless, the arrhythmia hypothesis has received clinical support from an initial study linking decreased circulating FFA in patients to decreased arrhythmias (Rowe, Neilson and Oliver, 1975), but the numbers were small and the data inconclusive. At present emphasis has shifted to the possibility that FFA, especially when present at a high FFA:albumin molar ratio (when FFA exceeds the number of tight-binding sites on the albumin), can extend ischaemic damage and infarct size (de Leiris, Opie and Lubbe, 1975; Opie, 1975). Links between infarct size and arrhythmias have been found in patients (Roberts et al, 1975), hence the original FFA-arrhythmia hypothesis is not excluded from considerations of infarct size. The most clear-cut change in lipid metabolism in the infarcting myocardium is the accumulation of acyl CoA which is also known to be associated with impaired capacity of the mitochondrial translocase to transport ADP and Pi inwards and ATP outwards (Figure 3). A given amount of oxygen reduction should not only cause a proportional decrease in the rate of mitochondrial ATP production but in addition the residual ATP still produced is transferred to the cytoplasm with increased difficulty. Acyl CoA accumulation can occur within 30 minutes of acute coronary ligation and is associated with depressed respiratory activity of isolated mitochondria (Shug et al, 1975). It may be speculated that the administration of glucose could reduce the amount of acyl CoA present by increasing esterification. Continued uptake of free fatty acids, known to occur in
714
LIONEL H. OPIE AND W. A. STUBBS
r e g i o n a l i s c h a e m i a , m i g h t b e e x p e c t e d to l e a d to a n a c c u m u l a t i o n of acyl C o A a n d h e n c e to i n c r e a s e d lipid in the i n f a r c t z o n e . T h e r e is s o m e e x p e r i m e n t a l a n d p a t h o l o g i c a l e v i d e n c e for this s e q u e n c e of e v e n t s in t h a t i n c r e a s e d l i p i d h a s b e e n f o u n d in t h e i n f a r c t b o r d e r zones.
POSTULATED EFFECTS OF ISCHAEMIA] ON GLUCOSE AND FFA METABOLISM J
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Figure 3. Patterns of glycolysis in regional ischaemia (infarcting myocardium). Ischaemia after coronary arterial ligation causes a stimulation of the uptake of glucose (+) relative to that of free fatty acids (FFA) (--) and decreased uptake of oxygen. Absolute glucose uptake may be unchanged. Increased breakdown of triglyceride (lipolysis) is accompanied by increased formation of intracellular free fatty acid some of which is released into coronary venous blood and some of which is re-esterified with the help of alpha-glycerophosphate (aGP) derived from glycolysis. Both breakdown and formation of triglyceride appear to be accelerated, but absolute values are unchanged. Decreased uptake of oxygen is associated with decreased delivery of oxygen (1 in schema) to the rnitoehondria and decreased removal of acyl coenzyme A (CoA), formed from intracellular FFA (2 in schema). Acyl coenzyme A also accumulates because of decreased activity of the carnitine-dependent transferase which normally transfers acyl coenzyme A into the mitochondria. Acyl coenzyme A is thought to inhibit the translocase transferring of adenosine triphosphate (ATP) from mitochondria to the cytoplasmic contractile sites (3 in schema), thereby aggravating the ATP deficit in ischaemia. From Opie (1975) with kind permission of the editor of the American Journal of Cardiology.
CONCLUSION. L i p i d m e t a b o l i s m in t h e i s c h a e m i c m y o c a r d i u m is b e i n g r e - e x a m i n e d w i t h p a r t i c u l a r r e f e r e n c e to t h e p o s s i b l e role of a n a c c u m u l a t i o n of acyl C o A ( a c t i v a t e d l o n g - c h a i n fatty acids) in t h e i n h i b i t i o n of m i t o c h o n d r i a l m e t a b o l i s m in i s c h a e m i a .
CARBOHYDRATE METABOLISM IN CARDIOVASCULAR DISEASE
715
Glucose therapy in myocardial infarction (Table 5, Figure 4) The hypotheses that provision of glucose is beneficial and provision of FFA is harmful to the infarcting myocardium have, on the whole, been substantiated by animal experiments (Opie, 1975). The major mechanisms initially postulated have not yet been supported and alternate mechanisms should be considered. Increased anaerobic provision of ATP from glucose may seem an unlikely mechanism of action of the provision of glucose once it is accepted that the major fate of glucose in the early hours of infarction is oxidative metabolism. Increased oxidative metabolism of glucose has been achieved both by glucose--insulin--potassium and by dichloroacetate (which activates the enzyme pyruvate dehydrogenase); decreased myocardial ischaemic injury was evidenced by decreased epicardial ST-elevation and by improved metabolic parameters, such as increased tissue values of ATP and glycogen (Mj0s et al, 1976; Opie, 1976). Increased glycolytic ATP is also produced during increased glucose oxidation and may have a special electrophysiological role (Cheneval et al, 1972). Table 5. Possible modes of action of glucose--insulin or glucose--insulin--potassium
in developing myocardial infarction (see Opie, 1976) 'Repolarisation'; increased intracellular K qIncreased glycolytic ATP Increased tissue glycogen Increased tissue a-glycerophosphate for re-esterification of tissue FFA Decreased circulating free fatty acids 'Membrane' effects Hyperosmolar effects Increased oxidative metabolism of glucose Decreased lysosomal activity Accelerated wound healing
Why should increased oxidative metabolism of glucose have these effects? The change in P:O (phosphorylation:oxidation) ratio from complete glucose to complete FFA metabolism is from 3.15 to about 2.86 -- a saving of 02 of only 10 per cent; lesser changes possible in vivo would save smaller amounts of 02. Although the P:O with FFA utilisation in ischaemia could hypothetically fall lower (Bremer, 1976), experimental data are lacking. Another possibility is that entry of pyruvate into the citrate cycle is dependent on the pyruvate dehydrogenase complex which bypasses the acyl CoA-carnitine transferase mechanism. Accumulation of acyl CoA in ischaemia is likely to block the entry of FFA more than that of pyruvate. Thus provision of substrate for the citrate cycle is more likely to be rate-limiting with FFA as substrate than with glucose. Evidence showing that increased circulating FFA values can increase myocardial ischaemic damage has not yet been clear-cut, because elevation of FFA in vivo requires either the administration of triglyceride-heparin or of FFA-mobilising hormones such as isoprenaline. Direct addition of FFA by itself can be achieved in vivo by the very complex continuous flow centrifuge technique of Crespin, Greenough and Steinberg (1969). A much simpler system is the addition of FFA to the perfusate of the isolated working rat heart with left coronary ligation; de Leiris, Opie and Lubbe (1975) showed that the
716
LIONEL H. OPIE A N D W . A. STUBBS
EFFECTSON METABOLISM IN DEVELOPING INFARCTION
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Figure 4. A schema of glucose and fatty acid metabolism in developing myocardial infarction. For fuller details, see Opie (1975). There is still some residual oxygenuptake, dependent on the degree of collateral flow, and the overallpattern of metabolism is oxidativeeven in the infarcting zone, Glucose and glycogenform lactic acid (LA) which inhibits giycolysis at the level of the enzyme phosphofructokinase and there is now lactic acid output instead of uptake. Free fatty acids (FFA) are still taken up, although in diminished amount, and some may form triglyceride (TG). Some of the free fatty acid forms acyl CoA which inhibits ATP transfer from within the mitoehondria to the cytoplasm. An increased tissue FFA in regional ischaemia has not been clearly established. This schema also gives a representation of giucose--insulin--potassium (GIK) effects on the metabolic changes in developinginfarction (Opie et al, 1975). Increased extraction of glucose is accompanied by decreased extraction of free fatty acids and increased cardiac glycogen.The net metabolic effect is 'conservation' of oxygen. Epicardial ST-elevationis decreased.
rate of enzyme release was m u c h greater with F F A t h a n with glucose perfusions, a n d rates were reduced by the addition of glucose or glucose plus i n s u l i n to F F A . Initially K u r i e n a n d Oliver (1970) postulated a c c u m u l a t i o n of intracellular F F A , which was t h o u g h t to occur when F F A was t a k e n u p by ischaemic tissue. T h e a c c u m u l a t i o n of intracellular F F A was t h o u g h t to exert toxic effects on the cell m e m b r a n e a n d / o r the m i t o c h o n d r i a . I n contradiction of this, tissue F F A s were not increased in the studies of Regan, Oldewurtel a n d Ettinger (1972), a n d our p r e l i m i n a r y results (Lochner a n d Opie, 1976) show that m i t o c h o n d r i a l F F A are actually decreased i n regional ischaemia in the pig. However, a n o t h e r m e c h a n i s m of F F A 'toxicity' has come to light, n a m e l y the a c c u m u l a t i o n of acyl CoA in ischaemic tissue. Acyl CoA accumulates because the activity of acyl CoA-carnitine transferase is
717
CARBOHYDRATE METABOLISM 1N CARDIOVASCULAR DISEASE
depressed, in part by a direct effect of ischaemia on the enzyme (Wood et al, 1973), in part by ischaemic inhibition of mitochondrial metabolism and in part by substrate inhibition of the enzyme (i.e. accumulation of acyl CoA leads to even more accumulation of acyl CoA). The close interaction between the'metabolism of FFA and glucose found in non-ischaemic tissue also appears to apply to ischaemic tissue. Therefore, administration of glucose should decrease circulating FFAs (Figure 5) and FFA utilisation; and should divert acyl CoA to triglyceride formation. Administration of FFA-lowering agents should lead to increased glucose utilisation by the ischaemic tissue. Thus the 'glucose-benefits-ischaemia' and the 'FFA-harms-ischaemia' hypotheses are inevitably intimately linked and can be summarised as a 'Substrate--ischaemia' interaction. GIK both increases extraction of glucose and decreases that of FFA by the heart (Opie and Owen, 1976) while a beta-blocker, propranolol, decreases extraction of FFA and increases that of glucose (Opie and Thomas, 1976). p =
ACUTE MYOCARDIAL INFARCTION
Carbohydrate intolerance For many years there has been a controversy about the meaning of the carbohydrate intolerance seen with acute myocardial infarction. Is the diabetic state a temporary manifestation of myocardial infarction or does the infarct precipitate latent diabetes? In 1922 Levine linked coronary artery disease and diabetes, but in 1929 he pointed out that coronary thrombosis 'produces by itself a glycosuria that need not be indicative of diabetes', possibly because of 'the great pain and fear that accompanies it'. Myocardial infarction with glycosuria was reported in Britain in 1931 by Cruickshank, who failed to see how glycosuria could determine the onset of coronary thrombosis, but suggested that vascular degeneration was the common link between pancreatic and cardiac disease. Scherf in 1933 found that six of nine patients with myocardial infarction had transitory glycosuria and hyperglycaemia, and pointed out that the differential diagnosis of true diabetes from transitory hyperglycaemia could not always be made with certainty at the time of the acute attack. In 1936 Raab and Rabinowitz thought that abnormal glucose tolerance was a constant consequence of myocardial infarction, not dependent on latent diabetes and possibly related to disturbances in the 'vegetative centres' of the brain. These early workers, therefore, clearly understood the problems involved in the interpretation of hyperglycaemia during acute myocardial infarction. Goldberger took the problem further by studying patients during their convalescence and recovery (Goldberger, Alesio and Woll, 1945). He found that in some initially normal patients diabetic curves were only reached some months after a heart-attack, thus establishing that at least some of the patients had latent diabetes. The latter view was also taken by Sowton (1962) who followed-up patients for up to five years. Datey and Nanda (1967), however, found that myocardial infarction had only unmasked latent diabetes in 14 per cent of their series of 145 patients and ascribed the transient hyperglycaemia of the majority to unknown factors. Clinics in E n d o c r i n o l o g y a n d M e t a b o l i s m - - Vol. 5, No. 3, November 1976.
703
704
LIONEL H, OPIE A N D W . A. STUBBS
In 1952 Ellenberg, Osserman and Pollack gave a new interpretation to hyperglycaemiain non-diabetic patients who had acute myocardial infarction: 'hyperglycaemia is a clinical manifestation of shock'. They, therefore, suggested that carbohydrate intolerance reflected severe myocardial infarction complicated by shock. Ellenberg, Osserman and Pollack (1952) also thought that hyperglycaemia was associated with a greater incidence of conduction defects and arrhythmias, and with a larger infarct size but unfortunately they did not give the exact figures. These workers only selected cases proven by autopsy thus denying themselves comparisons with the less severely ill surviving patients. MacKenzie et al (1964) confirmed that those patients with cardiogenic shock had blood sugar values over twice those found in the non-shocked patients (mean values, 14.7 mmol/1 (264 mg/100 ml) in shocked and 5.9 mmol/1 (107 mg/100 ml) in non-shocked patients). Both Taylor et al (1969) and Allison, Chamberlain and Hinton (1969) provided an explanation for the carbohydrate abnormalities of cardiogenic shock -failure of insulin secretion. Taylor et al (1969) showed that the secretion of insulin in response to intravenous tolbutamide was depressed in circulatory shock following myocardial infarction, probably as result of both reduced blood flow to the pancreas and the high level of circulating catecholamines; subjects improving clinically also had improved insulin secretion. Even in non-shocked patients the degree of glucose intolerance could be related to the prognosis because the trend for mortality for the diabetics studied by EckerstrSm (1951) exceeded that for hyperglycaemics which in turn exceeded that of normoglycaemics at four weeks, one year and four years after the onset (see Table 27, EckerstrSm, 1951). Allison, Chamberlain and Hinton (1969) suggested that the extent of changes in insulin secretion, basal glucose levels and in glucose tolerance could all be related to the severity of the illness. The similarity of the metabolic changes in acute myocardial infarction to other stress states such as thermal burns was pointed out by Ellenberg, Osserman and Pollack (1952) and supported by Allison, Chamberlain and Hinton (1969); the latter authors had found that metabolic changes in burned patients could be related to the burnt surface area (Allison, Hinton and Chamberlain, 1968). Opie (1971) also argued that the metabolic complications of acute myocardial infarction were similar to those found in other situations of acute physical or psychological stress, but emphasised the specific results of some complications of cardiac infarction: (a) acute left ventricular failure with increased catecholamine secretion rates, which would help to suppress insulin secretion (see Taylor et al, 1969); (b) cardiogenic shock with even higher catecholamine secretion rates and lactic acidosis (acidosis impairs glucose uptake in a variety of tissues) (Gevers and Dowdle, 1963; Delcher and Shipp, 1966). The failure of Datey and Nanda (1967) to show any differences between the normoglycaemic and hyperglycaemic groups in relation to the presence or absence of pain, shock, angina, hypotension or ECG abnormalities does not negate the hypothesis of Allison, Chamberlain and Hinton (1969) because the latter group studied their patients within 15 hours of the onset of symptoms of acute myocardial infarction, whereas Datey and Nanda (1967) studied patients up to 72 hours after the onset, and the hyperglycaemic
CARBOHYDRATE METABOLISM IN CARDIOVASCULAR DISEASE
705
response to infarction may be maximal only within the early hours. Vetter et al (1974) showed that hyperglycaemia took about 30 minutes to develop and returned to high normal values five hours after the onset; plasma insulin was initially low and then returned to the normal range one hour after the onset. Thus plasma insulin was low throughout the first five hours when compared with the high blood sugar. The other studies already cited suggest that glucose intolerance persists for much longer than the first five hours; the difference may lie in the severity of the clinical features which were not fully specified in the study of Vetter et al (1974). In view of the time-related and severity-related nature of the glucose abnormalities, it is not surprising that different workers have described different incidences of hyperglycaemia and glycosuria and have attributed different significances to their findings. In addition, different methods of assessment have been used. Oral ingestion of 100 g of glucose was used by Raab and Rabinowitz (1936), who found abnormal curves in all their patients. Datey and Nanda (1967) used a similar test and found initial hyperglycaemia in 65 per cent of patients but excluded those dying during the hospital stay - - probably the more severely ill patients. The oral two-dose test was used by Goldberger, Alesio and Woll (1945) who found that less than 50 per cent of patients were abnormal. An intravenous glucose tolerance test (Lundbaek, 1962) was used by Gupta et al (1969) who found a mean K value of 1.1 (borderline diabetic). Allison, Chamberlain and Hinton (1969) used a similar intravenous test and found diabetic values (less than one) in all patients. Taylor et al (1969) used basal plasma insulin values and the response to intravenous tolbutamide to show decreased basal insulin values and decreased insulin secretion in those patients with myocardial infarction complicated by shock or hypotension but not in uncomplicated infarctions. Abnormalities of carbohydrate metabolism, even in the absence of the diabetic state, are very frequent in acute myocardial infarction (see Tables 1 and 2). The exact incidence is difficult to define because of (a) the different tests used, (b) the evolving metabolic picture in acute infarction, and (c) the most severe disturbances are found in those with severest complications who are the most difficult to study.
CONCLUSION.
Carbohydrate intolerance as a reflection of general metabolic changes (Table 3) The above survey shows that it may be useful to view acute myocardial infarction as an example of an acute physical and emotional stress which may or may not precipitate overt glucose intolerance depending on the severity of the illness and the degree of pre-existing glucose intolerance, i.e. the inherited tendency towards diabetes. Owing to the extreme variability in the clinical picture of acute myocardial infarction, and the different propensities to diabetes in different populations and ethnic groups, generalisations about the incidence of carbohydrate abnormalities in acute infarction are probably not justified. On the other hand, interactions between the various metabolic abnormalities should help elucidate the mechanisms underlying glucose intolerance.
706
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CARBOHYDRATE METABOLISM IN CARDIOVASCULAR DISEASE Table 3. General metabolic and hormonal changes which may influence
carbohydrate metabolism in acute myocardial infarction
Authors Poor insulin secretion (shock)
Taylor et al
(1969)
An ti-glucose factors Catecholamine secretion Glucagon secretion Corticosteroid secretion Other hormones growth hormone prolactin? secretin? Starvation High circulation FFA concentrations
Vetter et al Laniado, Segal and Esrig Prakash et al
(1974) (1973) (1972)
Lebovitz et al Horrobin et al Henry, Flanagan and Buchanan Opie, Bruyneel and Kennelly Shipp, Opie and Challoner
(1969) (1973) (1975) (1975) (1961)
Other factors Antagonist of Vallance-Owen Latent diabetes mellitus
Stout and Vallance-Owen Datey and Nanda
(1969) (1967)
FREEFATTYACIDS.Plasma free fatty acids are elevated within 30 minutes of the onset of acute myocardial infarction (Vetter et al, 1974). The degree of elevation is related to the severity of the illness, as shown in Figure 1 by the response in 35 consecutive patients admitted to the Coronary Care Unit of the Hammersmith Hospital, London. About one-third of patients had serious complications such as left ventricular failure, congestive heart failure or cardiogenic shock (Group 2); those without such complications constituted Group 1. Mean FFA values in the more severely ill patients were higher throughout the first seven days in the more severely ill Group 2 patients (Gupta et al, 1969). Free fatty acids are liberated from adipose tissue and the rate of liberation is decreased by glucose and insulin. Hyperglycaemia and unchanged insulin secretion should at first sight act to lower free fatty acids, but free fatty acids are known to be elevated. In cardiogenic shock the explanation may be poor insulin secretion. A similar explanation may hold for infarction with hypotension (Taylor et al, 1969) and it is in cases with complications that the circulating free fatty acids are highest (Gupta et al, 1969). However, FFA concentrations are also elevated in non-complicated cases when there is an adequate insulin response~ although the concomitant hyperglycaemia shows that there is glucose intolerance (Taylor et al, 1969). The factors promoting glucose intolerance are generally the same as those elevating plasma FFA (Table 3), thereby showing the close links between glucose and free fatty acid metabolism in acute myocardial infarction, as in normal subjects. CATECHOLAMINES. Specific factors promoting high free fatty acids in myocardial infarction probably include an acute increase in plasma catecholamines and an acute fall in insulin (Vetter et al, 1974). The plasma catecholamine changes are reflected in increased urinary output of catecholamines (Figure 2). In an interesting study of myocardial infarction in dogs Russell, Crafoord and Harris (1961) showed that the damaged heart itself
710
LIONEL H. OPIE AND W. A. STUBBS
releases catecholamines. These might have a peripheral effect (Braunwald, Harrison and Chidsey, 1964) which could set up a vicious cycle with release of catecholamines, stimulation of lipolysis, further infarction and so on.
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Figure 2. Measurements of urine catecholamines in the same two groups of patients show higher values, especially of adrenaline, in the more seriously ill patients. F r o m G u p t a et al (1969) with kind permission of the author and the editor of Lancet.
CONCLUSION. Increased circulating concentrations of free fatty acids and of glucose are closely related changes reflecting alterations in the secretion rates of catecholamines, insulin and, very probably, glucagon, as well as of other hormones which modulate the rate of release of FFA from adipose tissue. The relation between the degree of carbohydrate intolerance and the severity of infarction is mirrored by a similar relation between the clinical severity and the rise of blood FFA and between severity and the urinary secretion of catecholamines (Gupta et al, 1969).
LIONEL H. OPIE AND W. A. STUBBS
712
Local changes in carbohydrate metabolism (Table 4) Carbohydrate metabolism is also altered in those parts of the myocardium undergoing necrosis. According to the 'glucose hypothesis', increased utilisation of glucose by the ischaemic infarcting tissue can help to save at least some ceils from ultimate necrosis (Opie, 1970). There are substantial experimental data showing that the provision of glucose is beneficial to the survival of anoxic heart (Weissler et al, 1968; Hearse and Chain, 1972). In these experimental conditions, anoxia causes increased glycolytic flux by stimulation of glucose uptake, glycogen breakdown and phosphofructokinase activity; the rate of anaerobic ATP production then becomes crucial for survival of the heart, and peak rates of production are obtained in the presence both of hyperglycaemia and insulin. According to the 'glucosehypothesis' additional modes of action are an osmotic effect (Leaf, 1973), an electrophysiological effect (Cheneval et al, 1972; Prasad and MacCleod, 1969) and the ability to decrease blood FFA (Gupta et al, 1969). Table 4. Factors accelerating and inhibiting glycolysis in regional ischaemia (developing infarction) (see Opie, 1976) I. Glycolysis is increased by:
Anoxia/hypoxia with breakdown of high energy phosphate compounds activation of phosphofructokinase increased glucose transport increased glycogenbreakdown Increased provision of circulating glucose and insulin Decreased extraction of circulating free fatty acids by ischaemic zone Increased activity of pyruvate dehydrogenase Increased blood flow with increased deliveryof glucose and washout of products of anaerobic glycolysis II. Glycolysis is decreased by: Accumulation of protons and lactate inhibition of phosphofructokinase inhibition of triose phosphate dehydrogenase Decreased blood flow with decreased deliveryof glucose Residual oxidative metabolism with less anoxic/hypoxicstimulus
The position in developing infarction is, however, not as simple as in anoxia. A crucial feature of ischaemic underperfusion is the accumulation of protons, CO2 and lactate in the ischaemic tissue. Glycolytic flux is inhibited at the level of phosphofructokinase by intracellular acidosis (Opie, 1976) and at the level of triose phosphate dehydrogenase by lactate (Rovetto, Lamberton and Neely, 1975). The continued provision of oxygen to the infarcting zone, t a k e n as a whole, means that the predominant pattern of metabolism is aerobic and that anaerobic rates of ATP production are very low in relation to total requirement (Opie, 1976). Individual cells or parts of cells in the infarcting myocardium may vary considerably in the degree of oxygenation with some cells being totally ischaemic, receiving no 02 at all, and hence relying totally on glycogen for anaerobic energy. Other cells may be much
CARBOHYDRATE METABOLISM IN CARDIOVASCULAR DISEASE
713
better perfused. Such variations probably reflect the heterogeneous nature of microsphere blood flow to small segments of the heart (Marcus et al, 1975) and give rise to the pathologically detectable heterogeneity of the ultimate infarct. Varying degrees of inhibition of contractile activity confer varying degrees of ATP demands in a system where ATP production rates greatly vary. In the above complex setting, it is not surprising that glucose effects on anaerobic ATP production in the infarcting zone should not be readily demonstrable. Nevertheless, glucose administered as glucose--insulin-potassium (GIK) to the infarcting dog or baboon heart can decrease metabolic and pathologic damage. The possible mechanisms are considered below. CONCLUSION.Patterns of regulation of glycolysis described in anoxia are not necessarily applicable to the much more complex situation in developing infarction when the ischaemic zone still receives oxygen from a collateral blood supply. Ischaemic changes may inhibit rather than stimulate glycolytic flux.
Local lipid changes The 'fatty acid hypothesis' of Kurien and Oliver (1970) suggests that increasing intracellular free fatty acids, derived either from the circulation or from intracellular lipid, could be 'toxic' to the ischaemic infarcting myocardium by causing arrhythmias and deleterious metabolic effects. Criticism of the FFA-arrhythmia hypothesis comes from the diverse results of various clinical studies, not all of which link high FFA levels to arrhythmias, and from conflicting animal data (Opie, 1975). Nevertheless, the arrhythmia hypothesis has received clinical support from an initial study linking decreased circulating FFA in patients to decreased arrhythmias (Rowe, Neilson and Oliver, 1975), but the numbers were small and the data inconclusive. At present emphasis has shifted to the possibility that FFA, especially when present at a high FFA:albumin molar ratio (when FFA exceeds the number of tight-binding sites on the albumin), can extend ischaemic damage and infarct size (de Leiris, Opie and Lubbe, 1975; Opie, 1975). Links between infarct size and arrhythmias have been found in patients (Roberts et al, 1975), hence the original FFA-arrhythmia hypothesis is not excluded from considerations of infarct size. The most clear-cut change in lipid metabolism in the infarcting myocardium is the accumulation of acyl CoA which is also known to be associated with impaired capacity of the mitochondrial translocase to transport ADP and Pi inwards and ATP outwards (Figure 3). A given amount of oxygen reduction should not only cause a proportional decrease in the rate of mitochondrial ATP production but in addition the residual ATP still produced is transferred to the cytoplasm with increased difficulty. Acyl CoA accumulation can occur within 30 minutes of acute coronary ligation and is associated with depressed respiratory activity of isolated mitochondria (Shug et al, 1975). It may be speculated that the administration of glucose could reduce the amount of acyl CoA present by increasing esterification. Continued uptake of free fatty acids, known to occur in
714
LIONEL H. OPIE AND W. A. STUBBS
r e g i o n a l i s c h a e m i a , m i g h t b e e x p e c t e d to l e a d to a n a c c u m u l a t i o n of acyl C o A a n d h e n c e to i n c r e a s e d lipid in the i n f a r c t z o n e . T h e r e is s o m e e x p e r i m e n t a l a n d p a t h o l o g i c a l e v i d e n c e for this s e q u e n c e of e v e n t s in t h a t i n c r e a s e d l i p i d h a s b e e n f o u n d in t h e i n f a r c t b o r d e r zones.
POSTULATED EFFECTS OF ISCHAEMIA] ON GLUCOSE AND FFA METABOLISM J
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Figure 3. Patterns of glycolysis in regional ischaemia (infarcting myocardium). Ischaemia after coronary arterial ligation causes a stimulation of the uptake of glucose (+) relative to that of free fatty acids (FFA) (--) and decreased uptake of oxygen. Absolute glucose uptake may be unchanged. Increased breakdown of triglyceride (lipolysis) is accompanied by increased formation of intracellular free fatty acid some of which is released into coronary venous blood and some of which is re-esterified with the help of alpha-glycerophosphate (aGP) derived from glycolysis. Both breakdown and formation of triglyceride appear to be accelerated, but absolute values are unchanged. Decreased uptake of oxygen is associated with decreased delivery of oxygen (1 in schema) to the rnitoehondria and decreased removal of acyl coenzyme A (CoA), formed from intracellular FFA (2 in schema). Acyl coenzyme A also accumulates because of decreased activity of the carnitine-dependent transferase which normally transfers acyl coenzyme A into the mitochondria. Acyl coenzyme A is thought to inhibit the translocase transferring of adenosine triphosphate (ATP) from mitochondria to the cytoplasmic contractile sites (3 in schema), thereby aggravating the ATP deficit in ischaemia. From Opie (1975) with kind permission of the editor of the American Journal of Cardiology.
CONCLUSION. L i p i d m e t a b o l i s m in t h e i s c h a e m i c m y o c a r d i u m is b e i n g r e - e x a m i n e d w i t h p a r t i c u l a r r e f e r e n c e to t h e p o s s i b l e role of a n a c c u m u l a t i o n of acyl C o A ( a c t i v a t e d l o n g - c h a i n fatty acids) in t h e i n h i b i t i o n of m i t o c h o n d r i a l m e t a b o l i s m in i s c h a e m i a .
CARBOHYDRATE METABOLISM IN CARDIOVASCULAR DISEASE
715
Glucose therapy in myocardial infarction (Table 5, Figure 4) The hypotheses that provision of glucose is beneficial and provision of FFA is harmful to the infarcting myocardium have, on the whole, been substantiated by animal experiments (Opie, 1975). The major mechanisms initially postulated have not yet been supported and alternate mechanisms should be considered. Increased anaerobic provision of ATP from glucose may seem an unlikely mechanism of action of the provision of glucose once it is accepted that the major fate of glucose in the early hours of infarction is oxidative metabolism. Increased oxidative metabolism of glucose has been achieved both by glucose--insulin--potassium and by dichloroacetate (which activates the enzyme pyruvate dehydrogenase); decreased myocardial ischaemic injury was evidenced by decreased epicardial ST-elevation and by improved metabolic parameters, such as increased tissue values of ATP and glycogen (Mj0s et al, 1976; Opie, 1976). Increased glycolytic ATP is also produced during increased glucose oxidation and may have a special electrophysiological role (Cheneval et al, 1972). Table 5. Possible modes of action of glucose--insulin or glucose--insulin--potassium
in developing myocardial infarction (see Opie, 1976) 'Repolarisation'; increased intracellular K qIncreased glycolytic ATP Increased tissue glycogen Increased tissue a-glycerophosphate for re-esterification of tissue FFA Decreased circulating free fatty acids 'Membrane' effects Hyperosmolar effects Increased oxidative metabolism of glucose Decreased lysosomal activity Accelerated wound healing
Why should increased oxidative metabolism of glucose have these effects? The change in P:O (phosphorylation:oxidation) ratio from complete glucose to complete FFA metabolism is from 3.15 to about 2.86 -- a saving of 02 of only 10 per cent; lesser changes possible in vivo would save smaller amounts of 02. Although the P:O with FFA utilisation in ischaemia could hypothetically fall lower (Bremer, 1976), experimental data are lacking. Another possibility is that entry of pyruvate into the citrate cycle is dependent on the pyruvate dehydrogenase complex which bypasses the acyl CoA-carnitine transferase mechanism. Accumulation of acyl CoA in ischaemia is likely to block the entry of FFA more than that of pyruvate. Thus provision of substrate for the citrate cycle is more likely to be rate-limiting with FFA as substrate than with glucose. Evidence showing that increased circulating FFA values can increase myocardial ischaemic damage has not yet been clear-cut, because elevation of FFA in vivo requires either the administration of triglyceride-heparin or of FFA-mobilising hormones such as isoprenaline. Direct addition of FFA by itself can be achieved in vivo by the very complex continuous flow centrifuge technique of Crespin, Greenough and Steinberg (1969). A much simpler system is the addition of FFA to the perfusate of the isolated working rat heart with left coronary ligation; de Leiris, Opie and Lubbe (1975) showed that the
716
LIONEL H. OPIE A N D W . A. STUBBS
EFFECTSON METABOLISM IN DEVELOPING INFARCTION
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Figure 4. A schema of glucose and fatty acid metabolism in developing myocardial infarction. For fuller details, see Opie (1975). There is still some residual oxygenuptake, dependent on the degree of collateral flow, and the overallpattern of metabolism is oxidativeeven in the infarcting zone, Glucose and glycogenform lactic acid (LA) which inhibits giycolysis at the level of the enzyme phosphofructokinase and there is now lactic acid output instead of uptake. Free fatty acids (FFA) are still taken up, although in diminished amount, and some may form triglyceride (TG). Some of the free fatty acid forms acyl CoA which inhibits ATP transfer from within the mitoehondria to the cytoplasm. An increased tissue FFA in regional ischaemia has not been clearly established. This schema also gives a representation of giucose--insulin--potassium (GIK) effects on the metabolic changes in developinginfarction (Opie et al, 1975). Increased extraction of glucose is accompanied by decreased extraction of free fatty acids and increased cardiac glycogen.The net metabolic effect is 'conservation' of oxygen. Epicardial ST-elevationis decreased.
rate of enzyme release was m u c h greater with F F A t h a n with glucose perfusions, a n d rates were reduced by the addition of glucose or glucose plus i n s u l i n to F F A . Initially K u r i e n a n d Oliver (1970) postulated a c c u m u l a t i o n of intracellular F F A , which was t h o u g h t to occur when F F A was t a k e n u p by ischaemic tissue. T h e a c c u m u l a t i o n of intracellular F F A was t h o u g h t to exert toxic effects on the cell m e m b r a n e a n d / o r the m i t o c h o n d r i a . I n contradiction of this, tissue F F A s were not increased in the studies of Regan, Oldewurtel a n d Ettinger (1972), a n d our p r e l i m i n a r y results (Lochner a n d Opie, 1976) show that m i t o c h o n d r i a l F F A are actually decreased i n regional ischaemia in the pig. However, a n o t h e r m e c h a n i s m of F F A 'toxicity' has come to light, n a m e l y the a c c u m u l a t i o n of acyl CoA in ischaemic tissue. Acyl CoA accumulates because the activity of acyl CoA-carnitine transferase is
717
CARBOHYDRATE METABOLISM 1N CARDIOVASCULAR DISEASE
depressed, in part by a direct effect of ischaemia on the enzyme (Wood et al, 1973), in part by ischaemic inhibition of mitochondrial metabolism and in part by substrate inhibition of the enzyme (i.e. accumulation of acyl CoA leads to even more accumulation of acyl CoA). The close interaction between the'metabolism of FFA and glucose found in non-ischaemic tissue also appears to apply to ischaemic tissue. Therefore, administration of glucose should decrease circulating FFAs (Figure 5) and FFA utilisation; and should divert acyl CoA to triglyceride formation. Administration of FFA-lowering agents should lead to increased glucose utilisation by the ischaemic tissue. Thus the 'glucose-benefits-ischaemia' and the 'FFA-harms-ischaemia' hypotheses are inevitably intimately linked and can be summarised as a 'Substrate--ischaemia' interaction. GIK both increases extraction of glucose and decreases that of FFA by the heart (Opie and Owen, 1976) while a beta-blocker, propranolol, decreases extraction of FFA and increases that of glucose (Opie and Thomas, 1976). p =
