Pyruvate, a natural metabolic fuel and antioxidant in myocardium and other tissues, exerts a variety of cardioprotective actions when provided at supraphysiological concentrations. Pyruvate increases cardiac contractile performance and myocardial energy state, bolsters endogenous antioxidant systems, and protects myocardium from ischemia-reperfusion injury and oxidant stress. This article reviews and discusses basic and clinically oriented research conducted over the last several years that has yielded fundamental information on pyruvate's inotropic and cardioprotective mechanisms. Particular attention is placed on pyruvate's enhancement of sarcoplasmic reticular Ca2+ transport, its antioxidant properties, and its ability to mitigate reversible and irreversible myocardial injury. These research efforts are establishing the essential foundation for clinical application of pyruvate therapy in numerous settings including cardiopulmonary bypass surgery, cardiopulmonary resuscitation, myocardial stunning, and cardiac failure.
PanchalAR, ComteB, HuangH, KerwinT, DarvishA, Des RosiersC, BrunengraberH, StanleyWC. Partitioning of pyruvate between oxidation and anaplerosis in swine hearts. Am J Physiol Heart Circ Physiol279: H2390–H2398, 2000.
3.
PanchalAR, ComteB, HuangH, DudarB, RothB, ChandlerM, Des RosiersC, BrunengraberH, StanleyWC. Acute hibernation decreases myocardial pyruvate carboxylation and citrate release. Am J Physiol Heart Circ Physiol281: H1613–H1620, 2001.
4.
LloydS, BrocksC, ChathamJC. Differential modulation of glucose, lactate, and pyruvate oxidation by insulin and dichloroacetate in the rat heart. Am J Physiol Heart Circ Physiol285: H163–H172, 2003.
5.
KhairallahM, LabartheF, BouchardB, DanialouG, PetrofBJ, Des RosiersC. Profiling substrate fluxes in the isolated working mouse heart using 13C-labeled substrates: focusing on the origin and fate of pyruvate and citrate carbons. Am J Physiol Heart Circ Physiol286: H1461–H1470, 2004.
6.
LloydSG, WangP, ZengH, ChathamJC. Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat heart. Am J Physiol Heart Circ Physiol287: H351–H362, 2004.
7.
SharmaAB, KnottEM, BiJ, MartinezRR, SunJ, MalletRT. Pyruvate improves cardiac electromechanical and metabolic recovery from cardiopulmonary arrest and resuscitation. Resuscitation (in press), 2005.
8.
MonganPD, FontanaJL, ChenR, BüngerR. Intravenous pyruvate prolongs survival during hemorrhagic shock in swine. Am J Physiol Heart Circ Physiol277: H2253–H2263, 1999.
9.
MonganPD, CappachioneJ, FontanaJL, WestS, BüngerR. Pyruvate improves cerebral metabolism during hemorrhagic shock. Am J Physiol Heart Circ Physiol281: H854–H864, 2001.
10.
OwenOE, MozzoliMA, BodenG, PatelMS, ReichardGAJr, TrappV, ShumanCR, FeligP. Substrate, hormone, and temperature responses in males and females to a common breakfast. Metabolism29: 511–523, 1980.
11.
MeierhenrichR, JedickeH, VoigtA, LangeH. The effect of erythropoietin on lactate, pyruvate, and excess lactate under physical exercise in dialysis patients. Clin Nephrol45: 90–96, 1996.
12.
ZweierJL, JacobusWE. Substrate-induced alterations of high energy phosphate metabolism and contractile function in the perfused heart. J Biol Chem262: 8015–8021, 1987.
13.
MalletRT, BüngerR. Energetic modulation of cardiac inotropism and sarcoplasmic reticular Ca2+ uptake. Biochim Biophys Acta1224: 22–32, 1994.
14.
MalletRT, SunJ. Mitochondrial metabolism of pyruvate is required for its enhancement of cardiac function and energetics. Cardiovasc Res42: 149–161, 1999.
15.
BüngerR, MalletRT, HartmanDA. Pyruvate-enhanced phosphorylation potential and inotropism in normoxic and postischemic isolated working heart: near-complete prevention of reperfusion contractile failure. Eur J Biochem180: 221–233, 1989.
16.
OchiaiK, ZhangJ, GongG, ZhangY, LiuJ, YeY, WuX, LiuH, MurakamiY, BacheRJ, UgurbilK, FromAHL. Effects of augmented delivery of pyruvate on myocardial high-energy phosphate metabolism at high workstate. Am J Physiol Heart Circ Physiol286: H2237–H2242, 2004.
17.
KammermeierH. High energy phosphate of the myocardium: concentration versus free energy change. Basic Res Cardiol82: 31–36, 1987.
18.
ChenW, LondonR, MurphyE, SteenbergenC. Regulation of the Ca2+ gradient across the sarcoplasmic reticulum in perfused rabbit heart: a 19F nuclear magnetic resonance study. Circ Res83: 898–907, 1998.
19.
FabiatoA. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol Cell Physiol245: C1–C14, 1983.
20.
MartinBJ, ValdiviaHH, BüngerR, LasleyRD, MentzerRMJr.Pyruvate augments calcium transients and cell shortening in rat ventricular myocytes. Am J Physiol Heart Circ Physiol274: H8–H17, 1998.
21.
MellorsLJ, KotsanasG, WendtIR. Effects of pyruvate on intracellular Ca2+ regulation in cardiac myocytes from normal and diabetic rats. Clin Exp Pharmacol Physiol26: 889–897, 1999.
22.
ZimaA, KockskämperJ, Mejia-AlvarezR, BlatterLA. Pyruvate modulates cardiac sarcoplasmic reticulum Ca2+ release in rats via mitochondria-dependent and -independent mechanisms. J Physiol550: 765–783, 2003.
23.
HüserJ, WangYG, SheehanKA, CifuentesF, LipsiusSL, BlatterLA. Functional coupling between glycolysis and excitation-contraction coupling underlies alternans in cat heart cells. J Physiol524: 795–806, 2000.
24.
KockskämperJ, BlatterLA. Subcellular Ca2+ alternans represents a novel mechanism for the generation of arrhythmogenic Ca2+ waves in cat atrial myocytes. J Physiol545: 65–79, 2002.
25.
HermannH-P, ZeitzO, KewelohB, HasenfussG, JanssenPML. Pyruvate potentiates inotropic effects of isoproterenol and Ca2+ in rabbit cardiac muscle preparations. Am J Physiol Heart Circ Physiol279: H702–H708, 2000.
26.
HalestrapAP, PriceNT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J343: 281–299, 1999.
27.
MaierLS, BraunhälterJ, HornW, WeichertS, PieskeB. The role of SR Ca2+-content in blunted inotropic responsiveness of failing human myocardium. J Mol Cell Cardiol34: 455–467, 2002.
28.
KentishJC. The effects of inorganic phosphate and creatine phosphate on force production in skinned muscles from rat ventricle. J Physiol370: 585–604, 1986.
29.
KawaiM, GüthK, WinnikesK, HaistC, RüeggJC. The effect of inorganic phosphate on the ATP hydrolysis rate and the tension transients in chemically skinned rabbit psoas fibers. Pflügers Arch408: 1–9, 1987.
HasenfussG, MaierLS, HermannH-P, LüersC, HünlichM, ZeitzO, JanssenPML, PieskeB. Influence of pyruvate on contractile performance and Ca2+ cycling in isolated failing human myocardium. Circulation105: 194–199, 2002.
32.
GulatiJ, BabuA. Effect of acidosis on Ca2+ sensitivity of skinned cardiac muscle with troponin C exchange. Implications for myocardial ischemia. FEBS Lett245: 279–282, 1989.
33.
BallKL, JohnsonMD, SolaroRJ. Isoform specific interactions of troponin I and troponin C determine pH sensitivity of myofibrillar Ca2+ activation. Biochemistry33: 8464–8471, 1994.
34.
WatanabeA, TomoikeH, EndohM. Ca2+-sensitizer Org-30029 reverses acidosis- and BDM-induced contractile depression in canine myocardium. Am J Physiol Heart Circ Physiol271: H1829–H1839, 1996.
35.
BolliR, MarbánE. Molecular and cellular mechanisms of myocardial stunning. Physiol Rev79: 609–634, 1999.
36.
AmbrosioG, TrittoI. Reperfusion injury: experimental evidence and clinical implications. Am Heart J138: S69–S75, 1999.
37.
GrossGJ, KerstenJR, WarltierDC. Mechanisms of postischemic contractile dysfunction. Ann Thorac Surg68: 1898–1904, 1999.
38.
LeferDJ, GrangerDN. Oxidative stress and cardiac disease. Am J Med109: 315–323, 2000.
39.
KaminskiKA, BondaTA, KoreckiJ, MusialWJ. Oxidative stress and neutrophil activation—the two keystones of ischemia/reperfusion injury. Int J Cardiol86: 41–59, 2002.
40.
ChathamJC, GilbertHF, RaddaGK. The metabolic consequences of hydroperoxide perfusion on the isolated rat heart. Eur J Biochem184: 657–662.
SlaterAFG, NobelSI, OrreniusS. The role of intracellular oxidants in apoptosis. Biochim Biophys Acta1271: 59–62, 1995.
43.
VaageJ, AntonelliM, BufiM, IrtunO, DeBlasiRA, CorbucciGG, GasparettoA, SembAG. Exogenous reactive oxygen species deplete the isolated rat heart of antioxidants. Free Radic Biol Med22: 85–92, 1997.
44.
TretterL, Adam-ViziV. Inhibition of Krebs cycle enzymes by hydrogen peroxide: a key role of α-ketoglutarate dehydrogenase in limiting NADH production under oxidative stress. J Neurosci20: 8972–8979, 2000.
45.
EatonP, HearseDJ, ShattockMJ. Lipid hydroperoxide modification of proteins during myocardial ischemia. Cardiovasc Res51: 294–303.
ConstantopoulosG, BarrangerJA. Nonenzymatic decarboxylation of pyruvate. Anal Biochem139: 353–358, 1984.
48.
DeBoerLWV, BekxPA, HanL, SteinkeL. Pyruvate enhances recovery of rat hearts after ischemia and reperfusion by preventing free radical generation. Am J Physiol Heart Circ Physiol265: H1571–H1576, 1993.
49.
CrestanelloJA, KamelgardJ, WhitmanGJR. The cumulative nature of pyruvate's dual mechanism for myocardial protection. J Surg Res59: 198–204, 1995.
50.
LeonH, AtkinsonLL, SawickaJ, StrynadkaK, LopaschukGD, SchulzR. Pyruvate prevents cardiac dysfunction and AMP-activated protein kinase activation by hydrogen peroxide in isolated rat hearts. Can J Physiol Pharmacol82: 409–416, 2004.
51.
Vásquez-VivarJ, DenicolaA, RadiR, AugustoO. Peroxynitrite-mediated decarboxylation of pyruvate to both carbon dioxide and carbon dioxide radical anion. Chem Res Toxicol10: 786–794, 1997.
52.
ComteB, VincentG, BouchardB, JettéM, CordeauS, Des RosiersC. A 13C mass isotopomer study of anaplerotic pyruvate carboxylation in perfused rat hearts. J Biol Chem272: 26125–26131, 1997.
53.
SchaferFQ, BuettnerGR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med30: 1191–1212, 2001.
54.
Tejero-TaldoMI, CaffreyJL, SunJ, MalletRT. Antioxidant properties of pyruvate mediate its potentiation of β-adrenergic inotropism in stunned myocardium. J Mol Cell Cardiol31: 1863–1872, 1999.
55.
MalletRT, SquiresJE, BhatiaS, SunJ. Pyruvate restores contractile function and antioxidant defenses of hydrogen peroxide-challenged myocardium. J Mol Cell Cardiol34: 1173–1184, 2002.
56.
BassengeE, SommerO, SchwemmerM, BüngerR. Antioxidant pyruvate inhibits cardiac formation of reactive oxygen species through changes in redox state. Am J Physiol Heart Circ Physiol279: H2431–H2438, 2000.
57.
Mohazzab-HKM, KaminskiPM, WolinMS. Lactate and Po2 modulate superoxide anion production in bovine cardiac myocytes: potential role of NADH oxidase. Circulation96: 614–620, 1997.
SquiresJE, SunJ, CaffreyJL, YoshishigeD, MalletRT. Acetoacetate augments β-adrenergic inotropism of stunned myocardium by an antioxidant mechanism. Am J Physiol Heart Circ Physiol284: H1340–H1347, 2003.
61.
HermannH-P, ZeitzO, LehnartSE, KewelohB, DatzN, HasenfussG, JanssenPML. Potentiation of beta-adrenergic inotropic response by pyruvate in failing human myocardium. Cardiovasc Res53: 116–123, 2002.
62.
HermannH-P, PieskeB, SchwarzmüllerE, KeulJ, JustH, HasenfussG. Haemodynamic effects of intracoronary pyruvate in patients with congestive heart failure: an open study. Lancet353: 1321–1323, 1999.
63.
HermannH-P, ArpJ, PieskeB, KöglerH, BaronS, JanssenPML, HasenfussG. Improved systolic and diastolic myocardial function with intracoronary pyruvate in patients with congestive heart failure. Eur J Heart Fail6: 213–218, 2004.
64.
RegitzV, AzumiT, StephanH, NaujocksS, SchaperW. Biochemical mechanism of infarct size reduction by pyruvate. Cardiovasc Res15: 652–658, 1981.
65.
GuttermanDD, ChilianWM, EasthamCL, InouT, WhiteCW, MarcusML. Failure of pyruvate to salvage myocardium after prolonged ischemia. Am J Physiol Heart Circ Physiol250: H114–H120, 1986.
66.
KristoG, YoshimuraY, NiuJ, KeithBJ, MentzerRMJr, LasleyRD. The intermediary metabolite pyruvate attenuates stunning and reduces infarct size in in vivo porcine myocardium. Am J Physiol Heart Circ Physiol286: H517–H524, 2004.
67.
StanleyWC, KiviloKM, PanchalAR, HallowellPH, BomontC, KasumovT, BrunengraberH. Post-ischemic treatment with dipyruvylacetyl-glycerol decreases myocardial infarct size in the pig. Cardiovasc Drugs Ther17: 209–216, 2003.
68.
ThelMC, O'connorCM. Cardiopulmonary resuscitation: historical Perspective to recent investigations. Am Heart J137: 39–48, 1999.
69.
EisenbergMS, MengertTJ. Cardiac resuscitation. New Engl J Med344: 1304–1313, 2001.
70.
CerchiariEL, SafarP, KleinE, CantadoreR, PinskyM. Cardiovascular function and neurologic outcome after cardiac arrest in dogs: the cardiovascular post-resuscitation syndrome. Resuscitation25: 9–33, 1993.
SafarP, XiaoF, RadovskyA, TanigawaK, EbmeyerU, BircherN, AlexanderH, StezoskiSW. Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke27: 105–113, 2002.
73.
KernKB, HilwigRW, RheeKH, BergRA. Myocardial dysfunction after resuscitation from cardiac arrest: an example of global myocardial stunning. J Am Coll Cardiol28: 232–240, 1996.
74.
Olivencia-YurvatiAH, BlairJL, BaigM, MalletRT. Pyruvate-enhanced cardioprotection during surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth17: 715–720, 2003.
75.
ManganoDT. Biventricular function after myocardial revascularization in humans: deterioration and recovery patterns during the first 24 hours. Anesthesiology62: 571–577, 1985.
76.
BreisblattWM, SteinKL, WolfeCJ, FollansbeeWP, CapozziJ, ArmitageJM, HardestyRL. Acute myocardial dysfunction and recovery: a common occurrence after coronary bypass surgery. J Am Coll Cardiol15: 1261–1269, 1990.
77.
RoysterRL. Myocardial dysfunction following cardiopulmonary bypass: recovery patterns, predictors of inotropic need, theoretical concepts of inotropic administration. J Cardiothorac Vasc Anesth7: 19–25, 1993.
78.
SavarisN, PolanczykC, ClausellN. Cytokines and troponin-I in cardiac dysfunction after coronary artery grafting with cardiopulmonary bypass. Arq Bras Cardiol77: 114–119, 2001.
MontgomeryCM, FairhurstAS, WebbJL. Metabolic studies on heart mitochondria. III. The action of parapyruvate on α-ketoglutaric oxidase. J Biol Chem221: 369–376, 1956.
83.
Von KorffRW. Pyruvate-C14, purity and stability. Anal Biochem8: 171–178, 1964.
84.
MargolisSA, CoxonB. Identification and quantitation of the impurities in sodium pyruvate. Anal Biochem58: 2504–2510, 1986.
85.
MontgomeryCM, WebbJL. Metabolic studies on heart mitochondria. II. The inhibitory action of parapyruvate on the tricarboxylic acid cycle. J Biol Chem221: 359–368, 1956.
86.
VarmaSD, DevamanoharanPS, AliAH. Prevention of intracellular oxidative stress to lens by pyruvate and its ester. Free Radic Res28: 131–135, 1998.
UchiyamaT, DeludeRL, FinkMP. Dose-dependent effects of ethyl pyruvate in mice subjected to mesenteric ischemia and reperfusion. Intensive Care Med29: 2050–2058, 2003.
89.
WooYJ, TaylorMD, CohenJE, JayasankarV, BishLT, BurdickJ, PirolliTJ, BerryMF, HsuV, GrandT. Ethyl pyruvate preserves cardiac function and attenuates oxidative injury after prolonged myocardial ischemia. J Thorac Cardiovasc Surg127: 1262–1269, 2004.
90.
PutterJ, BeckerR. Peroxidases. In: BergmeyerHU, Ed. Methods of Enzymatic Analysis (3rd ed.). New York: Academic Press, Vol 3: pp286–293, 1983.
