dichloroacetate as metabolic therapy for myocardial ischemia and failure

Basic Concepts

Dichloroacetate as metabolic therapy for myocardial ischemia and failure Robert M. Bersin, MD, and Peter W. Stacpoole, PhD, ?,~3 Charlotte, N.C, and GainesviUe, Fla.

This article critically reviews the pharmacologic effects of the investigational drug dichloroacetate (DCA), which activates the mitochondrial pyruvate dehydrogenase enzyme complex in cardiac tissue and thus preferentially facilitates aerobic oxidation of carbohydrate over fatty acids. The pharmacologic effects of DCA are compared with other interventions, such as glucose plus insulin, inhibitors of long chain fatty acid oxidation and adenosine, that are also thought to exert their therapeutic effects by altering myocardial energy metabolism. Short-term clinical and laboratory experiments demonstrate that intravenous DCA rapidly stimulates pyruvate dehydrogenase enzyme complex activity and, therefore, aerobic glucose oxidation in myocardial cells. Typically these effects are associated with suppression of myocardial long chain fatty acid metabolism and increased left ventricular stroke work and cardiac output without changes in coronary blood flow or myocardial oxygen consumpiion. Although long-term studies are lacking, short-term parenteral administration of DCA appears to be safe and capable of significantly improving myocardial function in conditions of limited oxygen availability by increasing the effi- cient conversion of myocardial substrate fuels into energy. (Am Heart J 1997; 134:841-55.)

The search for newer inotropes and cardioprotective agents is gradually moving deeper within the myocardial cell. The evolution of this quest has progressed from drugs that alter neurotransmitter release to those that act at the extracellular surface of the sarcolemma to stimulate or antagonize hon'none receptors or ion transport mechanisms. A more recent strategy has been to design chemicals capable of entering myocardial cells and inter- acting with intracellular enzymes integral to various processes of signal transduction and contraction, a,2

Coincidentally, however, drags have also been developed that stimulate cardiac contractility, not by directly altering the function of surface receptors or the contractile process, but by influencing basic pathways of inter- mediary metabolism and thus modulating the efficiency by which myocytes convert substrate fuels into energy. This article reviews progress in the investigation of one such compound, sodium dichloroacetate (DCA), as a possible treatment for ischemic heart disease and congestive heart failure. An understanding of the pharmacologic

From the Sanger Clinic and the Departments of Medicine and Biochemistry and Molecular Bbbgy, University of Florida College of Medicine. Supported in part by Clinical Research Center grant RRO0082 from the National Institutes of Health. Submitted Dec. 5, 1996; accepted April 4, 199Z Reprint requests: Peter W. Stacpoole, MD, Box 100226, University of Florida College of Medicine, Gainesville, FL 32610. Copyright �9 1997 by Mosby- Year Baolc, Inc. 0002-8703/97/$5.00 + 0 4/I/82560

characteristics of DCA is predicated on the following fun- damental principles of myocardial energy metabolism.

Normal Myocardial Metabolism Under conditions of rest or normal work loads, the

mammalian heart uses unesterified long chain fatty acids (LCFA) as its predominant source of energy. 3,4 iMitochondrial LCFA oxidation generates reducing equivalents, in the form of nicotine adenine dinucleotide (reduced) (NADH) and ravine adenine dinucleotide (reduced) (FADH2) , for the multiple enzyme complexes of the respiratory chain and also provides substrate for the tric.arboxylic acid (TCA) cycle in the form of acetyl coenzyme A (CoA) (Fig. 1). Additional reducing equivalents are produced by the action of various dehydrogenases of the TCA cycle. Thus LCFA metabolism raises the intracellular ratios of NADH/NAD and acetyl CoMfree CoA. Flux of electrons through the respiratory chain allows specific complexes to function as proton pumps that create an electrochemical gradient across the mitochondrial inner membrane. 5-8 This gradient drives a membrane-associated adenosine triphosphate (ATP) synthase, the terminal component of the respiratory chain, to produce ATE Complete combustion of one molecule of a typical LCFA, such as palmitate, to carbon dioxide and water requires the consumption of 46 mop ecules of oxygen and yields, at most, 2.8 mol ATP/atom of oxygen, or 129 mol ATP/mol palmitate.

842 Bersin and Stacpoole

Figure 1

Pyruvate [C~" NAD+ .~ -"'~NADH + H + - ~ . . .

Acetyl CoA ",, %

J. ", Anabolic Catabolic \ \ ( pathway pathway _~_. ~,

B~ogn~he~c (NADH+H+.~Oxa/oace"~te Citrate ".,, \ v NAD+ 7.....~r ~ ~, ""', ~, ATP ATP ATP

t TCA ,., ~,"" . . . . . . . . . . . J~ ...... .9 ycle 1 ~'"xx'~x",_ ," 2,,., 2 . "" FADH2"~x "'",,., / ~ N A D + // st ,.,,- ResolratOrYchain

FAo- ',% "-o' "NAOH + H+,/""

~ ~ " " :"" ....... 7?"" NADH+H + NAD+

1/2 02

~k",,, Hz O

Mito<:hondrial metabolism of pyruvate. Decarboxylation of pyruvate yields acetyl CoA that can be used for anabolic reactions (gluconeogenesis, lipogenesis) or can condense with oxaloacetate to form citrate. Dehydrogenase reactions of pyruvate metabolism and tricarboxylic acid (TCA) cycle generaie reducing equivalents (NADH, FADH2J that donate electrons to respiratory chain for reduction of molecular oxygen to water and production of ATP. Reproduced with permission from Stacpoole PW. Endocr Metab Clin N Am 1993; 22:227.

To meet the demands of a high work load, as may occur during exercise, myocytes increasingly draw on carbohydrate as a substrate fuel. Glucose is metabolized by the Embden-bleyerhof pathway to pyruvate, and this intermediate has two principal fates: under anaerobic conditions it can be reduced to lactate or it can enter the mitochondria where, under aerobic conditions, it can be oxidized to acetyl CoA or carboxylated to oxaloacetate (Fig. 1).

The irreversible oxidation of pyruvate to acetyl CoA is catalyzed by the pyruvate dehydrogenase (PDH) complex (PDC), a series of covalently linked enzymes situat- ed in the mitochondrial inner membrane. 3,9 Moment-to- moment control of PDC activity is affected by various posttranslational mechanisms, including substrate activa- tion, product inhibition, and reversible phosphorylation. PDC kinase phosphorylates the E1-0~ subunit of PDC and inactivates PDC, whereas a calcium-dependent PDC phosphatase reconstitutes the active enzyme (Fig. 2).

The PDC reaction is the rate-determining step in the aerobic oxidation of glucose, pyruvate, and lactate and is thus a key enzyme in controlling the selection of respiratory fuels. Conditions, such as starvation or diabetes, in which both the availability and oxidation of LCFA are increased elevate intramitochondrial levels of acetyl CoA and NADH and inhibit PDC activity. 3

In contrast, intramitochondrial accumulation of pyruvate, as might occur during high rates of glycolysis, may stimulate PDC activity by inhibiting the PDC kinase. Consequently, acetyl CoA is produced from the oxidation of glucose rather than from the oxidation of LCFA. Accumulation of acetyl CoA exerts a positive allosteric effect on pyruvate carboxylase, leading to indreased formation of oxaloacetate. 1~ Thus glucose oxidation supplies the carbon source for two anapleurotic reactions of the TCA cycle, those catalyzed by PDC and pyruvate carboxylase.

When PDC activity is high, lipogenesis is stimulated. 1~ Under these circumstances, malonyl CoA, the initial intermediate in fatty acid synthesis, is elevated. An increase in the intracellular malonyl CoA concentration in cardiac cells in turn suppresses the activity of the enzyme carnitine palmitoyhransferase I, which controls tile entry of LCFA into mitochondria before I~-oxidation (Fig. 3). LCFA oxidation is thus sup- pressed and, as a result, tissue citrate levels fall. This relieves tile allosteric inhibition exerted by citrate on phosphofructokinase and glycolytic flux increases. 3

It is therefore evident that the reciprocal relation between glucose and LCFA metabolism depends, in large part, on and is controlled by tile activity of PDC. This enzyme complex functions as a metabolic switch

American Heart Journal November 1997

Bersin and Stacpoole 8 4 3

Figure 2

NAD +

E F A D H 2 ] ~ NADH 2

o .

~ ~

/ E. I I E, F'.i(..)=1 o I I i I t "" ~ II

o / \ / / A=e,,,ooA [TP ] " j

CoA8H

Net Reaction:

Pyruvate + NAD + + CoASH ~ AcetyF-SCoA + NADH + + H + + CO 2 pr~ (active)

" 4 , ~ ~..ATP pho,phatage ~ [ kineee

PDH (inactive)

The pyruvate dehydrogenase (PDH) complex. This mitochondrial inner membrane enzyme complex includes three major subunits (E 1 through Es) that irreversibly catalyze oxidation of pyruvate to acetyl CoA and carbon dioxide. Thiamine pyrophosphate (TPP) and lipoic acid (Lip) are requisite cofactors. PDH is reversibly phosphorylated, whereby PDH kinase phosphorylates and inactivates PDH and PDH phosphatase dephosphorylates and activates PDH. Moment-to-moment control of PDH activity is regulated by many factors that influence phosphorylation state of enzyme complex.

box to alternately promote carbohydrate oxidation when PDC activity is high and lipid oxidation when PDC activity is low.

When glucose oMdation is maximally stimulated, the PDC and pyruvate carboxylase reactions feed the TCA cycle. In turn, the reducing equivalents generated from the cycle, the PDC-catalyzed step and glycolysis, stimulate oxidative phosphorylation. Accordingly, when glucose is completely combusted, oxygen molecules are consumed and file maximum ATP yield is 3.18 tool ATP/atom of oxygen, or about 14% more ATP per atom of oxygen consumed, relative to LCFA. From a teleologic perspective, therefore, the demands of increasing w'ork load, as in strenuous exercise, are met by increasing the efficiency of energy yield as m a ~ a l myocardial oxygen consumption is approached, that is, by increasing the relative contribution of glucose as a metabolizable fuel.

Myocardial Metabolism During Ischemia and Reperfusion

Hearts fail and may die when energy demand exceeds supply. Although tile functional integrity of tile sarcolemma may be principally sustained by the ATP produced by glycolysis, oxidative phosphorylation provides the bulk of tile energy needed to maintain the contractile function of myocardial cells. 11-14

As recently reviewed, 15 mitochondrial energy failure is an early consequence of myocardial ischemia and a principal cause of ischemia-induced arrhythmias 14,15 and cardiac failure. 17,18 ATP synthesis declines, ion gradients are lost, lactate and protons accumulate, and "leakage" of electrons from a disrupted respiratory chain increases. These and other ischemia-related metabolic events enhance the vulnerability of cells to the further deleterious effects of reperfusion, many of

American Heart Journal Volume "134, Number 5, Part 1


Figure 3

CYI 'OSOL

FATTY ACIDS

MALONYL COA

TRIACYLGLYCEROL

I �9 ~ ,"ATrY ACYL CO.=

FATTY ACYLCARNITINE

ql.

GLUCOSE .---e,. PYRUVATE

ACETYL COA

~ ' ~ CARNmNE

ACETYLCARNITINE .41 X

MITOCHONDRIAL MATRIX

.~ FAI"rY ACYLCARNITINE

CARNITINI= ~ FATTY ACYL COA CO 2

.~ ACETYL COA

~ACETYLCARNmNE

Propor, ed relation among pyruvate dehydrogenase, acetyl CoA-carboxylase, and oxidative metabolism of fatty acids and glucose in heart. 1, Carnitine palmitoyltransferase 1; 2, carnitlne-acylcarnitine translocase; 3, pyruvate dehydrogenase; 4, [B-oxidation; 5, carnitine acetyltransferase; 6, carnitine-acetyl carnitine translocase; 7, acetyI-CoA carboxylase. Increasing PDH activity augments supply of acetyl CoA for carnitine acetyl transferase and short-chain carnitine carrier system. Consequently, cytosolic acetyl CoA levels rise in stimulating acetyl CoA carboxylase activity. Increased malonyl CoA production subsequently inhibits carnitlne polmitoyl transferase 1 activity, resulting in suppression of LCFA oxidation. Reproduced with permission from The American Society for Biochemistry & Molecular Biology.

which are mediated by free radicals. A vicious cycle ensues in which free radical damage to membrane- bound enzymes provokes further loss of TCA and oxidative phospho/'ylating capacity, increases electron leakage, and generates more reactive oxygen species) 5

LCFA are also thought to contribute to myocardial cell damage during ischemia and reperfusion. 18-23 Circulating levels of LCFA are elevated in subjects after an acute myocardial infarction or coronary artery bypass surgery and correlate with the extent of ischemic cell damage in human beings 24'25 and experimental animals. 21,2628 Intracellular hydrolysis of triglyceride stores in myocytes may be stimulated by the surge in cate- cholamine secretion associated with acute coronary artery occlusion and may further increase the intracar- diac pool of fatty acids. 29 Reperfusion of isolated, ischemic hearts with media containing LCFA leads to diminished mechanical efficiency and left ventricular recovery, compared with hearts perfused with glucose

or pyruvate. 7'22'28'3~ Some of this discrepancy can be

attributed to the increased oxygen consumption required for fatty acid oxidation. In addition, it is postu- lated that myocardial efficiency may be compromised by LCFA because of a relative decrease in coupling oxidation to phosphorylation and mechanical work in translocating mitochondrial ATP and in preserving ionic gradients. 15,19,22 Regardless of the precise mechanisms, LCFA, compared with glucose, appear capable of reducing tile threshold to which coronary blood flow can be reduced and still maintain sufficient energy supply to meet work-related demands during ischemia and reperfusion. Indeed, studies in healtily volunteers indicate that increased provision of LCFA augments myocardial oxygen consumption (iXWO 2) without improving mechanical function. 26,34

In a more general sense, therefore, the oxidative capacity of myocytes can easily become rate limiting for mechanical function during ischemia, irrespective of the

American Heorl Journol November 1997

Bersin and Stacpoole 845

Figure 4

O m O O ~ e & m A

Control 1 mM DCA at-Reperfuslon 1 mM DCA Pre-ischemia

o

O

a ~ x X

r~

o

T

40-

30 �84

20.

10-

l ,t

Ischemia

0 2'0 4'0 do

~ T

A - - . '

1/

60

Time (minutes)

Effect Of 1 mmol/L DCA on reperfusion recovery of function in isolated working rot hearts subjected to 30 min global ischemia. DCA, when present, was added 5 min before ischemia or immediately on reperfusion. Reproduced with permission from McVeigh JJ and Lopaschuk JD. Reproduced with permission of the American Physiological Society.

presence of pharmacologic perturbations that directly act on the contractile apparatus. Thus interventions that act to improve myocardial oxidative capacity could be useful in limiting cell injury--first in the low-flow state of hypoperfused cells comprising the penumbra of an ischemic zone, and second in cells undergoing subsequent reperfusion after a no-flow ischemic insult.

Dichloroacetate The general pharmacologic and therapeutic effects of

DCA have been recently reviewed. 35,36 Those effects relevant to its potential as a protective agent in myocardial ischemia or failure probably derive from the ability of the drug to rapidly enter mitochondria in vivo or in vitro and to inhibit pyruvate dehydrogenase kinase, 36

thereby maintaining PDC in its active, unphosphorylat- ed form (Fig. 2). Consequently, DCA stimulates the rate- controlling step in the aerobic oxidation of glucose, lactate, and pyruvate in most tissues, including the heart (Table I). 37-45 In cardiac and perhaps other cells, DCA also stimulates glucose uptake and glycolysis. 10,23,46,47 The mechanism for this effect is thought to be caused by the inhibition of myocardial LCFA uptake and oxidation, 10,23,41,4649 resulting in a lowering of intracellular

citrate concentration 41,46,50 and a reactivation of phosphofructokinase.

DCA improves cardiac output and left ventricular mechanical efficiency under conditions of myocardial ischemia or failure (Table I). In isolated, perfused rat hearts, DCA exerts little effect on baseline cardiac dynamics. When added to the reperfusate after up to 30 minutes of no-flow, global ischemia, however, the drug significantly improves the rate and magnitude .of left ventricular recovery (Fig. 4). 23,45,51-53 In contrast, addi-

tion of DCA to the perfusate before or during the period of ischemia does not increase cardiac work during recovery. 51 This may be caused by the ability of the drug to stimulate glycolysis, leading to the accumulation of glycolytic intermediates or products such as lactate and hydrogen ions that may exert a depressant effect on myocardial function. 54-57 In hearts isolated from rats

with endotoxemia, addition of DCA to the perfusate increases stroke work, cardiac output, and peak systolic pressure development over a wide range of left atrial filling pressures coincident vdth a stimulation of PDC activity and myocardial ATP levels (Fig. 5, A and B). 42'44 Moreover, in perfused hearts from endotoxin-treated rats, DCA enhances the inotropic effects of amrinone and ouabain. 44 DCA also stimulates contractile force in

American Head Journal Volume 134, Number 5, Parl I

8 4 6 Bersin and StacpooJe

Table I. Summary of cardiovascular metabolic and hemodynamic effects of dichloroacetate

Experimental conditions Clinical

In vitro Invivo conditions UPG M L MpH CBF MVO 2 SVR CF/CO PDC Meff ATP BP ST-T HR Ref

Rat heart no-flow ischemia/ reperfusion

Rat heart no-flow ischemia/ reperfusion

Rat heart

Dog LAD occl. + is oproterenol

Dog

Dog hear t_ diabetes

Rat heart

Rat heart normoxic ___ LCFA

Guinea pig heart

Rat heart ischemia/reperfusion

Pig hypoxic LA

T

T

T

Rat heart __. diabetes hydralazine

Rat heart endotoxin, amrione, ouabain

Rat heart low- flow ischemia/ reperfusion

Rat heart _+ endotoxin

T

"1"

T

bog tAD $ $ occlusion

T

T

Tat reperL -.--> before

reperf.

J, T T

,1,

.->

T T

- +

--,,. 51

T 45

--~ J, --~ 47

-~ ,I,

101

46

41

10

12

51

"59

62

52

T 1" 1" 44

--~ preisch. 1" or basal

--> basal "J'endotox. J, glucose-

free media

43

"1" ~ 42 T

UPG, Utilization pyruvate glucose, M t, myocardial extraclion laclate; CBF, coronary blood flow; SVR, systemic vascular resistance; CF/CO, contractile force/cardiac output;/'Aeff, mechanical efficiency; ATP, adenosine triphosphate; BP, blood pressure; ST-T, ST-T segmenl on electrocardiogram; HR, heart ra~e; Ref, reference; LA, left atrium.

perfused hearts from streptozotocin-diabetic rats and rdverses tile depression of mechanical recovery induced by hydralazine in these hearts subjected to global ischemia and reperfusion. 52

The beneficial effects of DCA on ischemic or failing hearts in vitro have also been demonstrated in intact animals. The drug stimulates cardiac index and decreases systemic vascular resistance in endotoxin-treated

America~ Heart Journal November 1997


Table h Continued

Experimental conditions Clinical

In vitro In viva conditions UPG ML MpH CBF MVO.~ SVR a / c o PDC Meff ATlP BP ST-T HR Ref

Rat heart mitochondria

Rat heart

Rat heart

Rat heart

Hamster heart cordiomyopalhy

Dog coroN. ocd .

Dog endotox.

Dog incomp. LAD occlusion norma! heart

Dog shock

Rat heart ischemia/repedusion

Pig tAD low flow

Normal

CAD

Normal

CHF

I.A

T

,I,

T

.T

,1,

$

T

,(--

,L

,1,

<--

T

T

,L ,I. T T

T

1"/--> 1"

1"

.-).

1"

40

38

37

102

103

,1. 104

58

"1"/--~ 60

J.

105

22

~-- 61

--~ 73

--~ 76

--~ 106

77

t z4

dogs, whereas it increases bW02 .Ss DCA also increases cardiac output, blood pressure, and short-term survival rates in various experimental animal models of lactic acidosis and hypotension. 35,59 In a canine model of incomplete occlusion of the left anterior descending (LAD) coronary artery, administration of DCA 30 minutes before tim onset of a 90-minute occlusion reversed the ischemia-induced falls in myocardial pit, ATP, creatine phosphate, and energy charge levels and blunted the attendant rise in myocardial lactate, a) Transient increases in heart rate and in both systolic and diastolic blood pressure occurred in treated animals, but DCA did not improve the elevation in epicardial ST segments

induced by ischemia. Likewise, in a porcine model of mild (30%) LAD flow reduction, 61 DCA improved myocardial lactate extraction and oxidation but failed to alter systolic function. In contrast, administration of DCA to open-chest dogs before 47,62 or during 47 com-

plete LAD occlusion significantly reduced the rise in ST segments without altering systemic hemodynamics, coronary blood flow to the ischemic area, or myocardial levels of ATP or creatine phosphate (Fig. 6).

There is little doubt that DCA exerts a positive inotropic effect in failing or ischemic hearts or in healthy hearts perfused with LCFA. The mechanism responsible for this effect, however, is uncertain. Neither

American Head Journal Volume 134, Number 5, Porl 1

848 Bersin and Stacpoote

Figure 5

25.

c o

~20. e l

,%

E 15.

0T

A20-- E

O.

Z E

O. c:

f~ iO_ E c:

ot A

\ ' \ M

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\ \ \ \ \ \ \ \ N \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \

-{ - - \"\"" I \ \ \ \ \ \ \ \ \ \

N % . \ % % I -DCA -I'DCA -DCA +DCA

C ONTROL E N D O T O X I N

160

14.0

�9 12.0_

I0.0.

lg e,r

O

I~l l,r E ~i 60.

4 0

2 . 0

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ENDO 0

ENOO t. OCA �9

7.~, ,b ,f~ 6 sb LEFT ATRIAL FILLING PRESSURE

(cm HzO)

2~

Effect of in vivo endotoxin and in vitro DCA on mechanical performance (A) and on tissue levels of pyruvate dehydrogenase activity and ATP (B) of isolated working rat hearts. Reproduced with permission from Burns AH, et al. J Crit Care 1986;1:11-7.

high-energy phosphate levels nor the overall energy charge of myocardial cells is consistently altered by DCA, even though contractile force uniformly increases (Table I). Nevertheless, it is reasonable to assume that propor- tionately more ATP is generated by glycolysis and glucose oxidation than by fatty acid oxidation in DCA-treated hearts, and this also would account for tile increase in mechanical efficiency induced by DCA in vitro and in vivo. Indeed, isolated, working rat hea~.s aerobically perfused with media containing DCA demonstrate a shift away from LCFA to glucose use and a proportionate change in the steady-state level of ATP generated from the metabolism of these substrates. 23

In theory, DCA should increase the efficiency of ATP production by myocardial cells. In this regard, recent studies 1~ with the isolated, peffused rat heart have con- firmed and extended tile results of earlier.investigations 35 of tile drug's metabolic effects on tile heart. Stimulation of myocardial glucose oxidation by DCA increases tissue concentrations of acetyl CoA; the prod-

uct of the PDC-mtalyzed reaction and a positive regula- tor of acetyl CoA carboxylase (ACC). In turn, increased ACC activity increases the formation of malonyl CoA, which is both a substrate for lipogenesis and a potent inhibitor of fatty acid oxidation. 62 Thus intracellular citrate levels fall in DCA-treated hearts because of suppression of LCFA oxidation by malonyl CoA. This removes the allosteric inhibition by citrate on phosphofructokinase and stimulates glycolysis.

Acetyl CoA is also an activator of pyruvate carboxylase, which carboxylates acetyl CoA to oxaloacetate. Thus DCA may stimulate two anapleurotic reactions that provide substrates, in the forms of acetyl CoA and oxaloacetate, for the TCA cycle. Consequently, an increase in the provision of reducing equivalents from glycolysis, the PDC reaction, and the TCA cycle may "prime" the respiratory chain by augmenting the ther- modynamic driving force for electron transport, thereby stimulating oxidative phosphorylation and the efficiency of ATP production; that is, DCA should lead to



Figure 6

Time ( n l n s ) 5 1 5

C o r o n a r y O c c l u s i o n

D l c h l o r o a c e t a t e

20 35 40

, I i ! I ~ ! I I ! ~ ~ I I ! i ' '

, rV'v '>V'v /

/ / ~~,' " I I I " ' , , ,

eve,

. _ _ I I ! ! 1 ! , a ,

: ' % %

: %

" I I I I I I , i ! " I ! I : " " I I I ~ " %

Effect of DCA (120 mg/kg) on in sltu canine epicardial ECG recordings after occlusion [occln.) of LAD. LV~ Left ventri- cle. Reprinted from Cardiovascular Research, Volume 10, Mjos OD et al. Effects of dichloroacetate on myocardial sub strate extraction, ST-segment elevation, and ventricular blood flow following coronary occlusion in dogs. pp. 427-36, 1976, with kind permission of Elsevier Science-NL, Sara Burgerhartstraat 25, 1055 KV Amsterdam, The Netherlands.

an increase in the phosphorylation/oxidation ratio of myocardial cells.

An alternative explanation for the beneficial effects of DCA during myocardial ischemia is that the drag stimulates tile removal of positive hydrogen ions, increases intracellular pH, and reverses the depressant effects of acidosis on mechanical contraction. Mthough ATP derived from glycolysis is probably important in preserving certain critical myocardial functions during a relatively brief hypoxic or ischemic episode, 57,6t,65 accumulation of lactate 54,66,67 and hydrogen s6,57,67,68 ions during prolonged ischemia may independently inhibit glycolysis and various steps along tile excitation- contraction coupling pathway. Acidosis, by altering H+/Na + and Na+/Ca §247 exchange mechanisms, may lead to intracellular calcium accumulation and myocyte damage during repeffusion. 17,55,69 Indeed, depletion of myocardial glycogen stores before experimental induc-

tion of ischemia limits tissue damage, 57,'~~ presumably because less glucose is available for lactate formation and fewer protons accumulate as a result of the decreased production of glycolytically derived ATP. Thus the ability of DCA to improve mechanical recovery during reperfusion of previously ischemic hearts may be due in part to its ability to rapidly oxidize lactate, thereby increasing bicarbonate production by the TCA cycle and reversing the reduced redox state of the cytoplasm. 9 Such changes in systemic acid-base metabolism have been observed in animals and human beings treated with DCA. 35,72

The results of limited clinical investigations are con- sistent with this hypothesis. Healthy male subjects infused with DCA demonstrated a significant increase in cardiac index, reductions in both peripheral vascular resistance and blood lactate, and no change in heart rate. 73 Because arterial oxygen saturation was not

American Hearl Journal Volumo 134, Number 5, Part 1


Figure 7

+Z7

+16 I +12

+4.7

+0.3

"" _k a_ -2.8 -3.0

CBF MOT MV02 LVME P-NS P<.05 P-.06 P<.O5

Differential effects of DCA (50 mg/kg) (hatched bars) or dobuta-

mine (12.5 ~g/kg rain) (solid bars) on Coronary blood flow (CBF), myocprdial oxygen transport (MOT), MVO 2, and left ventricular mechanical efficiency (LVME) in patients with American Heart Association class IIHV heart failure. Reprinted with permission from the American College of Cardiology (Journal of the American College of Cardiology), 1994;23:1617-24.

altered and cardiac output rose, tissue oxygen delivery was assumed to have increased. Moreover, the fall i n peripheral vascular resistance was not associated with an increase in heart rate, and so was likely the result of the positive inotropic effect of DCA.

In adults with lactic acidosis and hypotension, DCA may increase arterial systolic blood pressure and cardiac output, 74 although these effects have not always been found. 72,75 In normotensive patients with stable coronary artery disease 76 or severe congestive heart failure, 77 intravenous DCA rapidly decreased systemic lactate and peripheral vascular resistance and increased myocardial lactate extraction, cardiac output, and stroke volume, whereas heart rate, coronary blood flow, and MVO 2 did not change or decrease. Because DCA did not change MVO 2 in the patients with coronary artery disease despite increasing left ventricular work, myocardial efficiency improved. The hemodynamic effects of DCA in the patients with heart failure were similar to those achieved by the administration of maximally tolerated doses of dobutamine, but the myocardial metabolic effects of the two drags differed (Fig. 7). MVO 2 was increased by DCA and decreased by dobutamine. Consequently, although both drags increased cardiac index, only DCA significantly improved myocardial efficiency.

Together, the preliminary clinical data obtained in healthy subjects and in patients with myocardial

ischemia or failure indicate that DCA increases left ventricular work, not by enhancing coronary blood flow or oxygen consumption, but by stimulating the efficiency by which myocardial substrates are converted into use- able energy at no additional demand for oxygen.

These claims are supported by several lines of evi- dence. First, the normal relation between carbohydrate and lipid metabolism in the human heart is reciprocal 4 and relatively less ATP level is generated per unit of

oxygen consumed during the oxidation of fat compared with carbohydrate. Second, high levels of LCFA are reported to exert deleterious effects on the integrity and function of cell membranes and enzymes. 29,78 Third, the

circulating levels of LCFA are elevated in patients with acute myocardial infarction and positively correlate with infarct size and mortality rate. 24,25 Fourth, both clinical

and experimental data indicate that a shift occurs in the myocardial oxidation of fatty acids to glucose during a postischemic reperfusion phase. 26,79,8~

blyocardial ischemic injury can be exacerbated by LCFA, and a physiologic response to ischemic injury is a relative increase in the reliance by threatened myocardial cells on glucose as a substrate fuel.

Other Metabolic Therapies Accordingly, several strategies other than DCA have

been investigated to promote glucose metabolism and limit fatty acid use during and immediately after acute myocardial ischemia. Experimental studies with the isolated rat heart have shown that perfusion with glucose, pyruvate, or both enhance contractile recovery beyond that achieved with fatty acids. 5,7,30,65,81 Pyruvate may

limit reperfusion injury by at least two potential mechanisms. First, millimolar concentrations of pyruvate stimulate PDC 82,83 and replenish, through anaplerotic reac-

tions, critical intermediates of the TCA cycle that are depleted by ischemia. As pyruvate oxidation is increased, LCFA oxidation is inhibited. 8t Second, pyruvate is reported to be a free radical scavenger and antioxidant. As an ~-ketoacid, pyruvate is capable of metabolizing hydrogen peroxide to carbon dioxide and water, thus preventing its conversion to the highly reactive hydroxyl radical. 85 High concentrations of pyruvate may also maintain intracellular levels of reduced glu- tathione and other antioxidants. 86 Such mechanisms have been invoked to explain the increased mechanical recovery of isolated, ischemic hearts after their reperfusion with pymvate-supplemented media, m,86,87 To our

knowledge, however, the myocardial metabolic and



hemodynamic effects of pyruvate salts have not been investigated in human beings.

In contrast, a putative metabolic therapy that has been clinically evaluated is the combined intravenous infusion of glucose, insulin, and potassium (GIK). 88 In theory, insulin should promote myocardial glucose use by inhibiting both adipose tissue lipolysis, thereby decreasing circulating free fatty acid levels and myocardial LCFA oxidation, thereby relieving the inhibition of glucose oxidation. A potential concern, however, is that insulin's principal effect on myocardial carbohydrate metabolism is to'stimulate glycolysis rather than glucose oxidation; this imbalance could lead to a worsening of the intracellular acidosis associated with very low flow or no-flow ischemia. 53,54,71 From a mechanistic stand-

point, therefore, GIK fundamentally differs from both DCA and pyruvate, both of which directly act to

�9 I ,

enhance mltochondnal oxidative metabolism�9 Some evi- dence also stipports a role of GIK in limiting free radical generation during experimental ischemia-reperfusion injury. 89 Regard!ess of its precise mechanism(s) of action, it has been difficult to experimentally 53 or clinically 9~ demonstrate a beneficial role of GIK in improving contractile force or decreasing tissue damage from myocardial infarction.

More recently, pharmacologic inhibitors of myocardial LCFA oxidation have been experimentally tested as a means of reducing reperfusion damage after ischemia. Among the best studied is carnitine palmitoyltransferase I inhibitor, which inhibits carnitine palmitoyltransferase I, the mitochondrial enzyme that converts long chain acyl CoA esters to their acyl camitine derivatives and thereby facilitates passage of LCFA from the cytoplasm into mitochondria for l-oxidation. Thus Etomoxir indi- rectly promotes myocardial glucose oxidation. This action is considered to underlie the ability of the drag to improve mechanical function in the isolated rat heart after ischemia. 21,23,28

Two other investigational agents that may increase postischemic left ventricular recovery are ranolazine and adenosine. Ranolazine is a piperazine derivative initially developed as an antianginal drag9! ,92 that was subsequently found to reduce myocardial cell damage in experimental models of ischemia. 93 In the isolated guinea pig heart subjected to low-flow ischemia, perfusion with mnolazine before and during ischemia result- ed in an increase in PDC activity and a preservation of tissue ATP content, whereas the release of lactate, lactate dehydrogenase, and creatine kinase from perfused hearts was decreased. 94 Despite encouraging data from

open-label clinical studies, however, a recent placebo- controlled trial of ranolazine in patients with stable angina failed to demonstrate significant improvement in decreasing the number or duration of ischemic episodes or the magnitude of exercise-induced ST segment depression. 33

Finally, adenosine has been extensively investigated as a cardioprotective agent in experimental models of myocardial ischemia and reperfusion. It increases cardiac functional recovery 95-97 and decreases infarct size 98,99 when administered during the ischemic period. Perfusion with adenosine before or immediately after global, low-flow ischemia decreased glycolysis and lactate production but increased glucose oxidation, ATP levels, and mechanical recovery. 31 LCFA oxidation was unchanged by adenosine under these conditions. These data are particularly intriguing in view of the fact that production of adenosine by cardiac tissue increases in response to hypoxia. 1~176 Although adenosine has multiple other physiologic effects on cardiac function, 1~ it seems plausible that an important function of adenosine during states of diminished oxygen supply is to maxi- mize the efficiency of myocardial ATP production by switching hypoxic or ischemic cells from metabolizing fatty acids to metabolizing glucose.

Conclusions Positive inotropic stimulation of a failing heart is gen-

erally desirable, but it could increase the risk of myocardial damage under conditions of limited oxygen supply, unless mechanical efficiency were concordantly increased. Drugs, such as DCA or Etomoxir, or endoge- nous metabolites, such as pyruvate and adenosine, may fulfill that criterion by promoting aerobic glucose oxickl- tion at the expense of lipid metabolism.

Why do agents that stimulate glucose oxidation bene- fit the heart during mechanical failure or reperfusion? Myocardial ATP levels do not appear to be responsible because DCA produces variable effects on ATP concentrations under conditions in which it uniformly increases cardiac output. For instance, in the perfused rat heart subjected to no-flow ischemia and reperfusion, both DCA and adenosine improve functional recovery, but only adenosine elevates tissue ATP content. 31 Moreover, DCA stimulates glycolysis in the reperfused heart, whereas adenosine has no significant effect on this pathway. These data indicate that preservation of highenergy phosphate levels is not of primary importance in stimulating cardiac output after ischemia or during failure. They also imply that stimulation of glycolysis, with-

American Heart Journal Volume 134, Number& Part ]


out a concomitant and proportionate increase in pyru- rate oxidation, is unlikely to be successful in preserving cardiac function and may actually be detrimental because of the accumulation of lactate and hydrogen ions.

Regardless of the precise molecular mechanisms involved in translating an increase in myocardial glucose oxidation into an increase in left ventricular work, it seems clear that ischemia restricts the maximal oxidative capacity of mitochondria and this, in turn, limits the

maximal mechanical output of the heart. In this regard, DCA offers several advantages as metabolic therapy for the short-term treatment of myocardial ischemia or failure. First, its ease of administration, as opposed to more

complex regimens such as GIK, facilitate its use in emergent conditions, either in the hospital or in the field. Second, its safety, when intravenously administered to critically ill patients, has been demonstrated in

several opeln-label studies 36,74,75 and in a multicenter,

controlled clinical trial. 72 Third, its principal mechanism of action is to stimulate mitochondrial pyruvate oxidation by activating PDC. Thus DCA not only has the

capacity to limit tissue lactic acidosis but also to stimulate the activities of the TCA cycle and respiratory chain. Fourth, the onset of action of DCA is rapid and pretreat- ment with the drug is not required for it to exert its beneficial effects on myocardial metabolism and func-

tion; rather it can be administered during or after an ischemic event. Finally, both clinical and experimental

investigations have demonstrated that DCA improves cardiac hemodynamics without increasing myocardial oxygen demand.

DCA represents a novel potential metabolic therapy in both the prevention and acute intervention of ischemic heart disease. It may complement the more traditional

approaches that reduce afterload (e,g., vasodilators, ]I- -blockers, calcium antagonists), stimulate coronary blood flow (e.g., intraaortic and external counterpulsation), or lyse thrombi (e.g., streptokinase, tissue plasminogen

activator). Additional laboratory and clinical investigations are warranted to evaluate DCA solely or as combi-

nation therapy to improve myocardial function under conditions of limited oxygen availability and impaired substrate use.

We tha,zk Ms. Faith Clark for editol~al assistalzce.

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American Heart Journal Volume 134, Number 5, Part 1

dichloroacetate as metabolic therapy for myocardial ischemia and failure

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