Metabolism of the heart in health and disease. Part III

Review

Metabolism Part

of the heart

in health

and

disease.

Ill*

Lionel W. Opie, M.D. London, Englllnd

X. Pathological

C

conditions

normal level of high energy phosphates.““’ Another possible result of mechanical distortion is the early occurrence of mitochondrial damage, which would explain decreased rates of oxidative phosphorylation and a shift from aerobic to anaerobic metabolism in terminal heart failure.66,117 It would, therefore, be of major importance to study further the biophysical damage occurring in the contractile mechanism a11 d in the mitochondria, and to correlate such changes with biochemical lesions. Thyvotoxic heurt disuse. The relation between thyrotoxicosis and heart failure is not simple. Some clinical studies suggest that thyrotoxicosis only causes heart failure when another co-existing cardiovascular disease is preseut, but the detailed studies of Sandier and Wilson5o1 argue for pure thyrotosic heart disease. They studied 462 thyrotosic patients of whom 150 had significant cardiac involvement. The existence of a thyrotoxic cardionlegaly was

ongestive heart failure. The inlportance

of the abnormalities described in the processes of oxidative phosphorylation, high energy compound metabolisn~, calciunl metabolism, contractile proteins, protein synthesis, and catecholamine metabolism has already been evaluated. It is apparent that there is no general agreement ou the ahnorinalities fouud, uor auy unifying h!yothesis to explain divergent reports. A basic finding that has not been fulls appreciated is the distortion and destruction of sarcomere structure by undue stretching in congestive failure.“38 Extreme degrees of stretch must lead to spatial distortion with poor interaction between actin and myosin at the cross-bridges. The consequences could well include decreased ATPase activit~.,“8YJAo decreased contractility of isolated myofibrils,a”’ dec.reased usage of high energy phosphates, a11t1 heart failure with a normal or nearl~rnni

the M.R.C. Metabolic i’ngland. ‘I lie f~,lloming abbreviations .\Tl’ = .\I)P = = .\hlI’ l’i = = (‘yrlic .ihIl’

Reactions

Research

l.nit,

lkpartment

<,I Hiocl~emistry.

have been used: ;rdenosine-5’.tripllospllate .\‘.\l)P and adenrlsine-5’.diphospllate N.\DPH? adenosine-5’-monophosphate ininganic phosphate cyclic adcn,,sine-3’..5’-m,lni 1;1;.\ j~lN~SphCi~~~ (‘I 1’ = crcatinv 1A~x~spl~lte
LJol.

;;,

No.

3,

pp.

353-410

iuarch,

1969

American

Imperial

College,

I.S~ndutl,

S.\c’.i,

= oxidized and reduced forms of nicotinamide-adenine dinucleotide phosphate (formerly TPN and TPNI12) = free fatty acids or unesterified fat\ acids or nonesterified fntt, acids (NlZ1c.A) = triglxeride fatt, acids = Rlurl~se-h-pllospllutl.

1’9fnV iaae

Heart

ui thj-

Journal

.IOI K\.~I..

3x3

384

Opie

shown in 13 patients with conspicuous left ventricular enlargement (proved radiologicallq and confirmed electrocardiographically) but occurring in the absence of atria1 fibrillation, congestive heart failure, or other coincidental heart disease. Such cardiomegaly did not respond to radioiodine treatment in contrast to the good response of those with atria1 fibrillation and congestive failure. Necropsl studies in 3 patients also showed that hypertrophy of one or both ventricles could result from thyrotoxic heart disease. Summers and Surteesjo2 also found generalized or left ventricular cardiomegalJ solely due to thyrotoxicosis. The existence of “pure” thyrotoxic heart disease, as suggested by Likoff and Levine,“03 seems established and this conclusion is supported by the occurrence of cardiomegalq in hyperthyroid experimental animals.37F However, age and coexisting heart disease frequently contribute to the picture in man. Interaction with catecholamines has been thought to explain some features of thyrotoxic heart disease. Brewster and his co-workers504 abolished tachycardin and hypertension in thyrotoxic dogs suhjetted to a high spinal anesthetic, and showed that hyperthyroidism sensitized the body to the effects of reflexly released or administered catecholamines. Norepinephrine most closely simulated the physiological effects of hyperthyroidism, However, there are other reports that the cardiac response to norepinephrine in the dog is not affected by variations in the thyroid status. 505 Furthermore, the velocity of shortening and the rate of tension development of isolated cat papillary muscle are much increased in muscles from hyperthyroid cats, independent of the level of norepinephrine stores.5”6 Another contradiction lies in the catecholamine level of the hyperthyroid animal heart; in the guinea pig the level is up, in the rat the level is down,507 while in the cat it is unchanged.506 In man, too, the position is confused. The tachycardia induced by large doses of triidothyronine can be abolished by the simultaneous administration of a catecholamine antagonist, guanethidine.508 On the

other hand, P-blockade I)>’ nethalide l)rt~duces no change in the cardiovascular of patients with spontaneous thyrotoxicosiPg; also, the hemodynanlic effects of cat+ cholamine infusions are no different itI euthyroid humans froul those render-cd hyperthyroid by triidoth~.ronine.510 Both thyroid and catecholamines mol)ilize FFA from adipose tissue, and increased FFA utilization by the hyperthyroid heart is associated with decreased glucose uptake and oxidation.268,511~512 These changes ;u-(* accompanied bl.increased ml.ocardial lcvcls of carnitine, acylcarnitines, and carnitiilc. acvltransferase.511 Such increased FF.4 ut iliza&on may contribute to the enhanc4 oxygen uptake of the thJ.rotoxic heart.‘e”J” Thyroid hormone may also act on osi(l;ltive phosphorylation. Thr-rotosic tissue+ have an increased concentration of mitochondria, in which the process of oxidative phosphorylation is less’ efficient.513-51Z This may be because th\rroxin can loosen 01 uncouple oxidative phosphorylation,:“” which would explain decreased ATP an(l CrP content of hearts from th>.rotoric rats and guinea pigs.“‘” The degree of this uncoupling is increased by calcium ions and decreased by deviations of the III~Knesium concentration from the optinlal.Z”“317 In man, there is only ver>. indirect evidence for uncoupling, consisting of l’i release across the th\-rotoxic he;trt.5’3 Other actions of thyroid hormones :11 :I molecular level include an effect on the structure and stabilit,of mitochondria (perhaps localized to the Initochondrial membrane), altered oxidation rates of hot h mitochondrial and extrainitochondrial SJ.Stents, and stimulation of RNA s~~nthesis.“‘” Some of these actions, including that OII oxidative phosphorylation, can onl! 1~ elicited by very high concentrations of thyroid hormones, probabl~~ greater tharl those found even in severe thyrotoxicosis. Tata51g suggests that physiological concentrations of thyroid hormones stimulate metabolism by a general increase in the cytoplasmic capacity to synthesize protein, which leads to increased activity of respiratory enzymes. Hence the I)hysiological action is anabolic. 111 toxic (-o11centrations, thyroid hormones cause u11coupling. In contrast to this view is tilts

.Iletabolism

tindillg of Hoch”15 that the dose of thyroxine required to alter mitochondrial respiratory control is 60 to 75 times less than the dose of triiodothyronine which influences protein synthesis in hypothyroid Irats. Yet another view relates the actions of t h?-roid hormones to increased enzyme iictivities. An enzyme of the glycerol-P c.ycle, mitochondrial glycerol-P oxidase, is increased in thyrotoxic heart tissue, which suggests an increased capacity for the gly-cerol-P cycle and therefore for glycolysis.28g~520 Because it has been supposed that there is a relatively minor role of the glycerol-P cycle in the heart (see cliscussion in Section VI), an increase of gll,cerol-P oxidase activitv is unlikely to he an important metabol;c factor in the genesis of thyrotoxic heart disease. \‘itamin deficiencies may contribute to thyrotoxic heart disease. Vitamins A, C, I), thiamine, nicotinamide, pyridoxine, pantothenic acid, and vitamin Blz are potentiallyor actually deficient in hyperth\roidism.“1~,j?1,5?2 Of these, thiamine deficjency is the best-documented, and the majorit)of patients with thyrotoxicosis may have thiamine deficiency as revealed t)>y decreased concentration of free thi;umine and diphosphothiamine in blood. The implication is that the heart disease of thiamine deficiency may complicate thg.rotoxic heart disease. In summar)-, it is convenient to think that thyroid hormone has both sympathomimetic and molecular actions on the heart. The sympathomimetic effect causes increased rate and force of contraction, and the latter may result from a direct effect on the contractile mechanism. However, the existence of a sympathomimetic effect does not necessarily mean that thyroid hormone and catecholamines have synergistic effects; rather, at present it appears that their effects are additive.“O” Molecular actions are both anabolic and catabolic. The anabolic effect stimulates protein synthesis, and this ma)- underlie thyrotoxic cardiomegalp. The occurrence of cardiomegal). would, however, probably depend on a complex interaction between the degree of thyrotoxicosis, the rate of secretion of other anabolic hormones such

of the heart in health

and disease

38.5

as growth hormone, and the load placed on the heart by the hyperdynamic circulation. The catabolic effect may cause uncoupled respiration which would be expected to contribute to heart failure. Myxedenaa heart disense. Although the occurrence of a true myxedema heart disease has been questioned,jz3 the coexistence of a serum lactate dehydrogenase pattern indicating myocardial damage, together with electrocardiographic and radiological abnormalities, is strong evidence for this entity.524 Substrate metabolism of the myxedematous myocardium has been the subject of only a few studies. In the hypothyroid dog, there is bradycardia, reduced coronary blood flow, and a decreased left ventricular oxygen consumption.512~525 In contrast, a patient with hypothyroidism and Hashimoto’s thyroiditis had normJ values for cardiac output, coronary blood flow, and myocardial oxygen consumption.jJ6 However, glucose uptake was enough to account for more than all the oxygen uptake, perhaps suggesting storage of glucose as glycogen. This would agree with the increase in cardiac glycogen found in thyroidectomized rats.*49 The contractile mechanism may be altered in myxedema. Decreased contractility has been found in the isolated hearts from hypothyroid rats,527 and in papillar) muscle from hypothyroid cats506 The contractile response to added catecholamines is also held to be diminished,527 and the level of catecholamine in the hypothyroid guinea pig heart is decreased.528 However, there are also several reports of normal catecholamine metabolism in the hypothyroid heart.529J30 Thus, at present, the metabolism of the hypothyroid heart has not been sufficiently well characterized to present a clear picture. If, however, it is accepted that thyroid hormone has a direct stimulatory effect on the contractile mechanism, then decreased contractility would be expected in hypothyroidism. .4cromegalic heart disease. The development of giant hearts over 1,000 grams in weight stresses the possible extent of cardiac enlargement in acromegaly.531s5JZ However, the average heart weight is 160 per cent above normal, compared with 151

*Calculated tPatients rl’dtient

irorn the

data

of Brink

and

associates

543; Bing

and

cr>-workers”‘;

and

.I‘al,le

I\‘.

fasting. postprandial.

per cent for liver aud kidney, suggesting that in the “average” case of acromegal\. the heart merely shares in the general Hypertension is more splanchonnegaly. 531,533 frequent than usual and is said to occur ill the majority of patients with cardiotnegaly. The hypotensiou noted in some acronlegalics ma>. indicate past ml-ocardial iufarction or an advanced, burnt out stage of the disease with h~poI’ituitarisnl.~~.’ Heart failure is favored b)r hypertension and the increased heart \vork following splanchnontegaly-. The evidence for the existence of acromegalic cc~rdiovc~sc~~Itrv disease is, therefore, good. Radiologically demonstrable electrocardiographic cardiomegnl\:\11d damage call, however, occur in the absence of h!.l’ertellsioll”““-;‘“7 suggestiug the existence of a specific acromegalic cardiopathy. To qualify for the diagnosis of acromegalic heart disease, other coincident causes of cardiomcgal>~ specifically need exclusion, as iii the 3 patients described by Bricaire and colle;~gues.“~~8 I lowever. such patients are rare, aud their myocardial metabolism is as )-et ullstudietl. Beriberi he(lrt diseflsc. Impaired p>.ruvate metabolisiii is iiot the sole cause of beriberi heart disease, l~ca~~se such inlpairmeut also occurs ill other situations such AS diabetes mellitus and fasting” which are not associated with clinical signs of heart failure. Furthermore, myocardial p?ruvate uptake is normal in dogs with expermlental thiamine deficient>.,““” while, in man, tlcpressed uptake is evident only in severe beriberi (Table 1’). Depressed citrate cycle activity, resulting from decreased c~oxoglutarate decarboxylation (another step re-

cluiring thianli~lc pyrophosphatc) would explain the decreased nlyocardial os>‘gell uptake of the beriberi heart (Table \r).z’l’J However, the extent of the depressioll of this decarbox\-latiou in acute experimental beriberi may not be sufficient to impair in)-ocardial functioll.z”n Other factors, indeficiencies, cluding associated vitanlin ina> also play a role.“‘” Catecholamines may accumulate in experinlclltal thiamine deficient>, aiicl ha\re cardiotosic effects.““,2’z Thus, the Iii)-owrdial necrosis iii esperimeiital thiaiiiine deficieiic>- could be cateYet another factor c-holailline-illducctl. contributing to beriberi failure, lnight IX leakage of cnz~~llles froiil the heart.:“” Depressecl c;lrl)oli~-tli-ate iiietat)olisiii iii Iwriberi Illa\. I)e caused liot ml>. b\: thiaInine-lack, Ijut I)\. enhanced l;FA oxidation (Table 17). A \iicious circle could be establishetl, \vhercb\ decreased carboh\-drate usage results iii iiicreased FE‘,4 usage, which iI1 turn further tlccreases carbohyclratc usag:e. If for ~1). reason FFL4 then becon~esunavailable to the heart, substrate tleficiellc!. could cause failure. For these t-KLso1ls, studies of lipid nletabolisul ill lwriberi hem-t diseasearc indicated. 11lcoholic kcclrt diwlse. Evidence has accumulated iii favor of n specific alcoholic distinct- froni beriberi ~ii).ocardiopatli).. or nutritional heart disease.s~Jim’~6 A consisteut a11t1n~arketl pathological change is ill traln?.ocardial trigl>.ceride accumulation. !“‘z~~A~‘~ Hccxuse the rate of utilization of ethatlol t,,. heart tissue is very 10w,~~*~~‘~ the triglyceride accumulation cannot result from changes in the intracellular NAD/NADH~ ratio as suggested for the

Iivcr. ‘1 direct toxic effect of alcohol on t-he conduction and contractile systems”“” could explain mechlunical deterioration of the heart exposed to ethanol, but does not ;m~ount for the ~~c.culllulatioil of triglycericle. Excess ii~yocardi~l triglyceritle ca11 result from (1) increased triglyceride synthesis from the uptake of circulating FFA4 or trigl\.ceritle fatt!, acid, especiall>. during osygeu lack Or utilization of alternate substrates; Or from (2) increased triglyccritle slmthesis fron1 non-lipid sources s~lch as glucose. I)uring a11 infusion of ;~lc~A~ol into the clog, at least part of the I~~\~ocartlial trigl>,ceritle acculnulation results froiil ;I greatI;. increased uptake of c:irculating triqlvcerltlc which occurs after 1 I :! to 3’ :! ho&sgO and it is consonant‘ with ,Ictival ioli of clearing-factor lipase tq ~tll;lllol.‘“’ The Other possibility, Of qxthesis Of ni~~ocai-dial triglJ.ceride from Ilou-li1)itl precursors. has 110t lxen inx~esti:cLtcd. Other pOssiMe Inechanislns Of damage to lhe heart tq. ethanol include leakage of (midative eiiqmes, iilitochc~utlrial damage, on the cell n~emtxaue, ,lllowing the uptake Of fatt L. acids (derived from circulating l+-lTLA Or TCF:lj to proceed at ;L rate esceeding their oxidation, with subsequent accuili ulatiou Of triglyceride n-ithin the heart. A+41ternativel>-, activation Of clearing-factor lipase may he the stinlulus to increased ul)talie of TX iFA. K~trsi~iovkor hetrvi disc~c~sc. The clitlical features of hear-t disease iI1 this form of infaitile pmtein rnaluutrition Illnq~ be retaletl to a re~lwetl niuscle t)ulk as ;I cmSNlueiict of ])I-otc’iil tlrtic-iclrc\..:::’

qmes such AS nmlic deh\.drogenase anti aldolase are lost from the heart.“18 In idiopathic mural endotllSocarcliol,ath~,, as fouutl iu South AAfrica, substrate metabolism at rest has a nori~ial osidative pnttern, hut during exercise there is a tencfas evieiiq’ for anaerobic n~et;~l~olisiii denced tq au alteration iii the redox state.“’ 1ii obstructive c.~irclioril!,ol)~ith!., there is ,ltso a tendenq. to lac.t;ite prmluctioi~ ait1 anaerobic n~etaholisn~ 1)~. the heart, which inay revert to norm~t after propanalol treatn~ent.“” ‘I’hus, the comn1on theme to cartliopathies is ;I tendeury to au anaerol~ic type Of energ>~ nietal)Olisni especially. on exercise. This is, of (xmrse, ;I rather nonspecific fiiiding. Diabetes nzellitus. The nlultiple metabolic almormalities found in hearts from alloxmdiabetic rats include defects iii glucose uptake, gl>xolysis, glycogen Iliet;it)olisni, gl>mride synthesis mtt lxxakclown, ;mtl Ix-otein qmthesis (see previous sections). The question arises as to why a dialwtic In>~ocardiopxt hy has not been found ill humans. One possibilit>~ is that it has not heeu searched for. Allother pOssihilit\. is that allos~tll-diabetes is a u~otlel of a ver1. coniplicated h!. severe diabetic state, lnarked ketosis and elevatecl circulating FFA levels; such a state does not corrcspond to the situation in most patients with diabetes nlellitus. It seems probable that streptozOtoc.in-tli~~l)etes is a better ;inini;il model Of the tli;tl)etic state.“” ;1;T?Iocurdid jibvo.si.s. Nstuitionctl jAmi.< ha been producetl ii1 rats fed a maize diet which is siulilar to that taken by Africans in South A4fric;l in whom myOcardiopath> cw develop.““” :\ 11.ocardial fibrosis also occurs in guinea pigs fed on a plaiitnin diet which resembles that taken lq, Iyga~lwho develop ellcloliig.ocardial cl au Africans filx-osis.5zfi Roth tqytophan deficiency a~~tl excess circulating S-h~dro~~tr~ptnminc have been implicated . in.._ the genesis Of the n1~~ocardial fil,rosis:J~‘~‘~.I~‘~ IHowever, castiron evidence for these niechnnisrns is lacking at prcseilt.

388

Up ie

valvular lesions is not clear. A prolonged serotonin infusion into the aorta of the dog produces fibrosis of the mitral, aortic, and tricuspid valves,55gwhich is a distribution not found in carcinoid heart disease. It is also difficult to relate the positive inotropic effect of 5-hydroxytryptamine56n to the cardiopathy. The similarity of the urinary loss of S-hydroxyindole acetic acid in cardiac and non-cardiac cases of carcinoid disease suggests that factors other than excess 5hydroxytryptamine may be involved.55* The diversion of tryptophan from protein and nicotinic acid synthesis raises the possibility of nutritional heart disease. That a combination of causes may be responsible for carcinoitl heart disease is suggested by the occurrence of endocardial and intimal fibrous proliferation in guinea pigs after a combination of hyperserotoninemia, tryptophan deficiency, and liver damage.561Hemodynamic factors may also contribute to the development of the fibrosis.562 Recent work has implicated the kinin peptides in the genesis of some of the clinical features of the carcinoid syndrome.j63 Kinins may play a part in carcinoid heart disease because the!, reduce peripheral vascular resistance and induce a high-output state.56’ Other metabolic causesof cardiac fibrosis include severe alcoholic heart disease,56j severe beriberi heart disease,5fi6and isoproterenol-induced myocardial necrosis.210 Myocardial infarction. L’irtuallv all studies 011 experimental myocardial -infarction have been carried out on the dog heart. Within 60 seconds of such infarction, myocardial cells fail to contract.567 As discussed in Section I, there is no obvious reason why the anoxic heart should stop beating so

soon.

In the minutes immediately following experimental coronary occlusion by microspheres in dogs, there is myocardial output instead of uptake of glucose, pyruvate and lactate.’ This is associated with an acute reduction in coronary flow to the infarcted area, and probably reflects the effect of anaerobiosis in stimulating gl!‘cogen breakdown and glycolysis. WithIn minutes, an experimentall~~ infarcted area shows ultrastructural changes in that the

myofibrils relax and particulate glycoge~t decreases.“@ Within 1 to 2 hours, there is an earl!, swelling of mitochondria and the sarcoplasmic reticulum, followed b!. increased lipid droplets at~tl autoIysis.z6!’ Lipid formation in anosic heart tissue 11la~~ be related to increased tissue lipid formation from exogenous FFA during anaerobiosis8”~8” or from increased lipogenesis associated with an increased XADH2/_VAD ratio.“jj The amount a11t1rate of loss of myocardial K+ is similar to the gain of Naf, suggesting the replacement of intrkicellular K+ b\’ Na+.57D The K+ loss is progressive and severe; 24 hours after coronary- occlusion in the dog, 0111~.LO per cent of the myocardial K+ remains,z”’ K+ is released into venous blood and the ensuing high K+ may be associated \z.it h cctopic rl~ythn@1~580 especially- in the first hour after the infarct.“7” The infarcted area is almost immetliately depleted of CrP and within 15 minutes ATP virtually disappears.“73This ma). be in part related to altered oxidative phosphoqrlation in mitochonclria from infarcted areas; such mitochondria have decreased consumption of inorganic phosphorous, with depressed P/O ratios, butin the one study the oxl.gen uptake was increasedzi2 whereas in the other’” there was decreased oxpgen uptake alcl loss of abilitlr to increase oxygen uptake after ADP addition. The duration of anoxia required to produce irreversible damage appears to be in excessof 15 mirlutes573,574 and probabl!. about 30 to 60 minutes.“@ Over 60 millutes’ of oxygen-deprivation is required to depress Caf+ uptake by the sarcoplasmic reticulum.“‘” Catecholarnines are lost from the infarcted tissue, with 75 per cent disappearing within 24 hours.570There is, however, no direct evidence that catecholamines from this source cause the delayed ventricular tachycardias that may follow coronary ligation,570J71 nor is there indication for the routine use of p-blockade in the therapy of acute nlyocardial irlfarction.“‘j Within 4 hours of experimental infarction, there is a fall in protein synthesis as measured by l*C-glycine incorporation.2i”

Metabolism

Within 3 to 4 days there are supranormsl rates of resynthesis, occurring first in the nucleoli, then in mitochondria, and lastly in microsomes. Incorporation into the contractile protein subcellular fraction remains subnormal, for at least 10 days,576 and the myocardial myosin content takes al)out one month to return to normal.577 The incorporation of 14C-glycine into protein of infarcted tissue is increased b) treatment with insulin, growth hormone, anabolic steroids, and ascorbic acid; these qents stimulate fibroblastic proliferation.5gj [t is assumed, hut not proved, that studies ou dog heart infarction are relevant to the situation in human myocardial infarction. l‘kerapy of‘ myocardial infurction. If a ijotassium chloride-glucose-insulin (I’( ;I) solution is infused into dogs before and during the development of an experimental infarction, then mitochondria from the infarcted area maintain normal oxidative phosphorylation. I4 Similar treatment ma! improve the mortality rate of patients after m\rocardial infarction.“78~“7g The mode of .tction of the I’GI regime is not clear. In (logs with experimental infarction, the intracoronary administration of procaine amide or I’(;1 helps to prevent both K+ loss and ventricular arrhythmias.580 Similarly, it is suggested that the PGI solution may reduce the incidence of atrioventricular block in human myocardial infarction, by prevention of loss of intrncellular K+.57g Restoration of the m~‘ocardial K+ content may act either b>r

Table

Initial Oxygen Formation l’coz

1’1. Effect of fiH and and final uptake,

pII ~l/G~n.

wet wt.

I‘ris

bldfer

oj the heart in henith

and diseaw

389

maintenance of normal cardiac action potential,581 or by restoration of the normal rates of oxidative phosphorylation.” It may be noted that Ii+ is required for optimal rates of respiration of isolated brain and liver mitochondria.582*5Y3 Acidosis and myocardiczl infarction. The acidosis associated with myocardial infarction may contribute to the high mortalitv , rates.584 Because a high pH is associated with increased phosphofructokinase activity55 and accelerated glycolysis in the isolated rat heart,51-52Ait appears to be theoretically desirable to induce alkalosis to nchieve the maximal glycolytic rate to aid the survival of the anaerobic and infarcted tissues.“*” Although the induction of alkalosis I-)). Tris (THAiJI) accelerates glycolysis in rat heart slices, it also depresses oxldative metabolism at pH 7.7 to 8.0 (Table VI). This does not contradict the finding of Delcher and Shippj? that a Tris buffer at pH 7.8 did not depress the oxidative metabolism of the isolated rat heart, because in their study the final pH of the buffer was only 7.5. If these results are at all applicable to the human heart, then correction of acidosis to normality or to mild alkalosis. rather than induction of severe alkalosis (pH exceeding 7.7)) woulrl be the aim during the use of Tris. Conclusions

The topics that have been discussed include substrate utilization by the heart,

on glucose

metabolism

of rat heart slices 7.7

8.0

6.8 (8) 736 =t 45

7 1 (5) 790 * 95

7.4 (12) 662 * 56

520 *

13*0,1 3.2 * 0.2 0.2 * 0.01

1.6 * 0.2 4.9 * 0.8 0.2 * 0.06

1.2 * 0.1 6.2 * 0.4 0.3 f 0.04

0.9 + 0.1 6.8 f 0.3 0.5 * 0.04

(8)

(8)

56

452 *

71

01:

lactate pyruvate Lactate/pyruvate ratio:

2.1 f

3

20 f

3

19 *

2

15 *

1

0.7 * 0.1 8 0 f 0.9 0.5 * 0.01 16=‘= 1

Glucose-U-T, 10 mM. Buffer contained ‘I‘&, 25 mM.; ions (mEq./L.): X\‘a+, 140; K+, 5.1; Ca+‘, 5.5; Mg’-+, 2.6; Cl-, 148; SO,--, 2.6. “CO*, lactate and pyruvate formation expressed as p moles glucose equivalent per gram wet wt./60 min. Unpublished data of Muller and Opie.

nlitocholldrial metabolisnl, protein s).tithesis, calciun~ :ind the c-ontrxtile nlechmiism, and the role of c~~~techolalnincs. The metabolic cha~qqs fou11t1 ilI various cardiopathies and iI1 nl~mxrdial infarctiolr are also reviewed. The importance of carbohydrate (glucose and lactate) as fuel for m~~ocardial energy metabolism has recently been overlooked because studies in human and animal hearts selected conditions undd\favoring lipid utilization. The control (;f gl)xol!Gs is much better understood thml that of FF,I oxidation. Iii pxticular, the points ;It which l-I;A oxitlatioll inhibit gl!-col\-sis arc well-tleiiued md this has give11 rise to the collccpt that FFrl oxidation nornlall~~ restricts glvcol>-sis, while the rate of 1;FL4 oxidation -is in turn controlled b!- the ;~vailabilitq. of fatt!. acid to the heart mtl herlce l)>- the circulating FFA concelltration; the latter is ~IIO\YI~ to be influenced b>. the rate of lipolysis in adipose tissue. This sequence Inakes the heart a11 organ devoid of intrinsic control of its substrate metabolisn~. However, the rate of FFA osidatioii iii;r~. be controlled within the heart b\r the carnitine qstem ancl 1))~ the avnilabilit~~ of alternative substrates. ‘IY;FA niid ketone bodies are riot important fuels for the hunIan heart, except perhaps in pathological conditions. As yet, little is li~ion~ii about protein nietabolisii~ and the factors involved in the ml-ocardiJ response to ;III increasetl work load. The control of ;m~illoxid uptake mld protein qmthrsis 1)~. insulin cud growth hormone 111a!‘ lx directl,. relev;lnt to the underst;trlding of cardisc hypertrophy-. ATP pla)x a prime role in the control of myocardial metabolisnl, as emphasizctl by the importance of .ATl’ in the con tractile process and in maintaining ion gradients across cell and nlitochondrial membranes. ,i\TP makes a major contribution to the control of glycolysis b>- inhibiting phosphofructokinase. By )-ielding AMP and c>.cIic-.L\i\,I 1’ during arioxia aiifl c~itechol;~iIiiiir stiiIliIl;itioII, A’I‘I’ iIltlii.ec.tl\7 ;l(.ti\‘;tttTZ ~JllO~~JlIOfl~ll~~tOliill~lS~ ;lll(l [JllOS~~lIor-\~l;~s~. ;i’i‘l’ ~~I-ol~;~l~l!~ ;rlso regul:~tcs tlIc> ;i(.ti\‘it> of the citrate c,\.c.le, ;iii(l helrc,e the rate of oxidation of ;Jl Iii),ocardial sulk-

;j,,

!,li’

I,‘,,,,

‘I

‘a(/

strates. ‘Thus, \\-hen :j’I‘l’ is ~~tili~:c~l, .I’ dui-iilg the imposition of ;I \vork 10~~41 (iis the heart, there x-e c~olllpelmttor! IIICY-II,Iliisiiis for erihaiic~ecl ,gl!.cml! sis ;i11(1 sril~stratc 0sid;itioll. i’i

SeUJlld

Ill~\jOl~

I~Cg:Lil;LtOI~

Of

iII~~~~~~~Ll~(li~ll

Illetabolism is the calciullr ioIl, Lvhich I\I,I\ Ixlrticilxite in collti-actioii either b\- forillilig ;I c.hel;itiilg link between ac;ili ;irr(l Ill~Yxdll, or I)!, overcoiiiiiig the .~l’I‘f’-irrhil)i(ioii of ;ictoili\.osiiI coiltrx~tion. F,I(,tot-s ~overiiiiig the flux of c~:Jciuili ioll xross 1he cell mid riiitoc~hof~tlrial l11el11lniiles ;~iid iti ;iiitl out of the sarcol)lminic~ reticulunl ;ire therefore tlirectll. relev;~lrt 10 the control of c;lr(li;l(. c.olltr;tc‘tilitJ A

thirtl

Iiiajor

riietalmlislli is ilnportaiit c.ontr;lctilit).. on

regulator

of

iII~~ocx-tli~~l

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toward the understmldirlg of endocrirltl :~ntl nutritioml c;lrtliopathies at ;L molec~ular level. The nlet;tboIic chmges in ischernic, heart disease are cluite \vcll defined, bt1 t it is Ilot known xvhich f;lc-tort; restrain ;InaerotJic gl\.col!-sis froill illaxitnal r;ltes \vliich uxild p-haps c.ontril~u tt to tllc kmerg?’

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;irguments for the iisr of tlic I’otassiulii-SlIIcose-irlsulin solutioli in ni\~ocarclial infarction, Ixit full clinical evaluation is still incomplete. It is IloteworthJ. that IIKLI~~~ of the receipt atlvances

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hexts of experinlental ;minlaIs &isol~~te~l hearts or subcellul~~r preparations. It w~ultl Ix ideal to h:tve methods of obtail1in.q IIUII~;UI tissue iii-t’ Ihiis f.~iiII ;l~J[J;lwlll tabolisIIi iii

for silIIilar st utlics, ft.\\ Iliajor 51m.ies ltJ(* I);tltcI-IIb of tIt7ii.t ;ui(l tlisv;ksc.

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15. I .Ippreciate the support and encouragement of f’rofesmr FL. B. Chain. F.R.S., and the financial ;wkt;mce d the British Ileart Foundation and the \\‘cil~nne ‘frust. The following criticized the manw wripr : Dr. Iloward E. Rlorgan, Dr. Joseph C. Shipp, I jr. Eric Niewsholme, l)r. \\‘ieland Gcvers, Professor \. J. Brink. and ;\lr. K. R. IA. 1Ianbford. Sections were c.ritirized by Dr. I>. S. Robinson and Dr. Carl rt. I lonig. 1 k. Steven illayer, Professor A. \\‘ollcnberger, and l’rofe+or $1‘. Lochner provided manw \crlpts of papers 111 the press. The help of thebe collwgues has been invaluable.

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