Cardiac Energetics in Congestive Heart Failure
2002; Lippincott Williams & Wilkins; Volume: 105; Issue: 6 Linguagem: Inglês
10.1161/circ.105.6.e44
ISSN1524-4539
Autores Tópico(s)Cardiac electrophysiology and arrhythmias
ResumoHomeCirculationVol. 105, No. 6Cardiac Energetics in Congestive Heart Failure Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBCardiac Energetics in Congestive Heart Failure Houman Ashrafian, MA, BM BCh Houman AshrafianHouman Ashrafian National Heart and Lung Institute, Imperial College School of Medicine, Royal Brompton and Harefield Hospital, London, UK, E-mail Originally published12 Feb 2002https://doi.org/10.1161/circ.105.6.e44Circulation. 2002;105:e44–e45To the Editor:Jóhannsson et al1 have recently observed upregulation of the Monocarboxylate transporter 1 (MCT1) in congestive heart failure (CHF). The implied increased uptake of exogenous (systemic) lactate confirms the potential significance of increased carbohydrate metabolism as a compensatory adaptation in CHF and also identifies a potential therapeutic focus. However, 3 points deserve emphasis:(1) Although increased MCT-1 appears to be a feature of at least a subgroup of ventricular dysfunction, certainly indicating an increased reliance on systemic lactate, Jóhannsson et al interpret a lack of comparable glucose transporter (Glut-1 and -4) upregulation to suggest endogenous glycolytically derived lactate is relatively insignificant. Their assertion derives from the widely held traditional notion that fatty acid metabolism (FAM), coincidentally the major energy source in normal hearts, antagonizes glycolysis and vice versa.Contemporary studies, while accepting a relative fuel polarization with mutual FAM/glycolysis antagonism, also emphasize the benefits of synergy between FAM/glycolysis in muscle.2 An example of this synergism is AMP-dependent protein kinase (AMPK), a fundamental orchestrator of myocyte energy regulation. Activation of AMPK, stimulates energy production from both glycolysis (by activating 6-phosphofructo-2-kinase) and activates β-oxidation of fatty acids by increasing the transport of fatty acids to mitochondria (by reducing malonyl-CoA).3Thus, although the significantly increased MCT-1 indicates a significant increase in systemic lactate use relative to controls, the lack of a commensurate GLUT upregulation (conventionally stimulated by acute ischemia and insulin, neither of which occurred) only suggests that this transporter may not be kinetically limiting. Conclusions about the importance of glycolysis or lack of it are therefore unsupported.(2) Furthermore, though a critical feature of the Wistar infarction model of CHF, MCT-1 may not be a typical feature of all CHF. Recent studies have indicated that the improvement in CHF prognosis associated with β-blockers may result from the increased metabolic efficiency derived from a reduction in FAM and a relative increase in glycolysis as well as exogenous lactate utilization.4 Thus, this CHF model with increased MCT-1 and carbohydrate utilization may represent a well-compensated form of ventricular dysfunction. Alternatively the upregulated carbohydrate metabolism in CHF may represent a marker of beneficial transcriptional switching responding to stress (eg, PPAR-a downregulation).5 Either way, the noted increase in MCT-1 may not be representative of all CHF.(3) Finally, the assertion that systemic lactate itself may be the stimulus to MCT-1 upregulation, though possible in the context of increased lactate in advanced CHF, need not be invoked. Both the increase in end-diastolic pressures and the increased ventricular radius result in significantly increased wall tensions. Thus, the increased myocardial work and the reduced pressure-dependent perfusion render the whole myocardium, particularly the subendocardium (both infarcted and noninfarcted segments), hypoxically/energetically compromised. The increased work and decreased ATP/Oxygen are sufficient/effective stimuli for an MCT-1 response. Furthermore, an increase in carbohydrate metabolism would directly mitigate these insults by reducing oxygen demand and increasing myocyte efficiency.4 References 1 Johannsson E, Lunde PK, Heddle C, et al. Upregulation of the cardiac monocarboxylate transporter MCT1 in a rat model of congestive heart failure. Circulation. 2001; 104: 729–734.CrossrefMedlineGoogle Scholar2 Hochachka PW, Somero GN. Biochemical Adaptation. Princeton, NJ: Princeton University Press; 1983.Google Scholar3 Ponticos M, Morgan JE, et al. Dual regulation of the AMP-activated protein kinase provides a novel mechanism for the control of creatine kinase in skeletal muscle. EMBO J. 1998; 17: 1688–1699.CrossrefMedlineGoogle Scholar4 Wallhaus TR, Taylor M, DeGrado TR, et al. Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation. 2001; 103: 2441–2446.CrossrefMedlineGoogle Scholar5 Barger PM, Brandt JM, Leone TC, et al. Deactivation of peroxisome proliferator-activated receptor-α during cardiac hypertrophic growth. J Clin Invest. 2000; 105: 1723–1730.CrossrefMedlineGoogle ScholarcirculationahaCirculationCirculationCirculation0009-73221524-4539Lippincott Williams & WilkinsResponseJóhannsson Erlingur, , PhD, Sejersted Ole M., , MD, PhD, Lunde Per Kristian, , MSc, Sjaastad Ivar, , MD, Thomas Marion J., , PhD, Bergersen Linda, , MSc, Blackstad Theodor W., , MD, PhD, Ottersen Ole Petter, , MD, PhD, Heddle Catherine, , PhD, and Halestrap Andrew P., , DSc12022002We are glad Ashrafian recognizes our identification of an upregulation of the monocarboxylate transporter (MCT1) in congestive heart failure (CHF) and the potential therapeutic implications.1 Also, our conclusion that this indicates an increased reliance of cardiac metabolism on circulating lactate seems undisputed. The main determinants of myocardial energy demand are heart rate, contractility, and wall tension. Available data indicate that energy demand is not necessarily increased in CHF,2 possibly because the effect of increased wall tension is counteracted by the reduced responsiveness to β-adrenergic stimulation. Thus, the myocardium is not "hypoxically/energetically compromised" in CHF unless there is a concomitant ischemic heart disease, as is most often the case in humans. There is also compelling evidence that the reliance on fatty acid oxidation is less in CHF hearts.3 These observations fit nicely together: the energy turnover is almost unchanged, oxidation of fatty acids is reduced, and oxidation of carbohydrates—possibly lactate when it is available—is increased. Tian et al4 recently reported that AMP-dependent protein kinase (AMPK) was activated in hypertrophied hearts, but concluded that because rate limiting enzymes for fatty acid oxidation are downregulated, long-term activation of AMPK is unable to increase flux through this pathway. Also, there would be no demand for higher rates of oxidation of substrates. In contrast to Ashrafian, we therefore believe that the Randle cycle is at work (see review, Randle5). We agree with Ashrafian that the lack of upregulation of GLUT4 and GLUT1 in CHF does not mean that circulating glucose cannot be metabolized at high rates, although these transporters are thought to limit the rate of glucose utilization by the heart.6 However, the upregulation of MCT1 would mean that circulating lactate—when available—gains access to the cell more easily, bypassing any rate limitation imposed by glycolysis and glucose transport. Because the failing heart is not ischemic, we do not agree with Ashrafian that the "decreased ATP/Oxygen are sufficient/effective stimuli for an MCT1 response." However, there are other candidate stimuli than the increased lactate concentration in blood that we suggested. Finally, our heart failure rats were undoubtedly in decompensated failure because, as a consequence of reduced velocity of shortening of the left ventricle and high end diastolic pressure, they had severe lung congestion. However, it remains to be seen whether MCT1 upregulation is a general feature of end stage heart failure irrespective of cause. Previous Back to top Next FiguresReferencesRelatedDetailsCited By Xue Y, Zhang L, Zhang L, Sun W, Fang Z, Leng Y, Li M, Ren X, Zhang R, Zhang Y, Chen L and Wang H (2022) Danshensu prevents thrombosis by inhibiting platelet activation via SIRT1/ROS/mtDNA pathways without increasing bleeding risk, Phytomedicine, 10.1016/j.phymed.2022.154271, 104, (154271), Online publication date: 1-Sep-2022. Yang Z, Zhang Q, Yu H, Li L, He Y, Zhu S, Li C, Zhang S, Luo B and Gao Y (2021) A Novel COX10 Deletion Polymorphism as a Susceptibility Factor for Sudden Cardiac Death Risk in Chinese Populations , DNA and Cell Biology, 10.1089/dna.2020.6086, 40:1, (10-17), Online publication date: 1-Jan-2021. Chistiakov D, Shkurat T, Melnichenko A, Grechko A and Orekhov A (2017) The role of mitochondrial dysfunction in cardiovascular disease: a brief review, Annals of Medicine, 10.1080/07853890.2017.1417631, 50:2, (121-127), Online publication date: 17-Feb-2018. Rosano G, Vitale C and Spoletini I (2015) Metabolic approach to heart failure: The role of metabolic modulators, The Egyptian Heart Journal, 10.1016/j.ehj.2015.03.004, 67:3, (177-181), Online publication date: 1-Sep-2015. Dominic E, Ramezani A, Anker S, Verma M, Mehta N and Rao M (2014) Mitochondrial cytopathies and cardiovascular disease, Heart, 10.1136/heartjnl-2013-304657, 100:8, (611-618), Online publication date: 15-Apr-2014. 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Tønnessen T and Sejersted O (2009) Molecular Medicine for the Cardiac Surgeon, Scandinavian Cardiovascular Journal, 10.1080/14017430260180346, 36:4, (201-208), Online publication date: 1-Jan-2002. Sorriento D, Gambardella J, Fiordelisi A, Iaccarino G and Illario M (2019) GRKs and β-Arrestins: "Gatekeepers" of Mitochondrial Function in the Failing Heart, Frontiers in Pharmacology, 10.3389/fphar.2019.00064, 10 February 12, 2002Vol 105, Issue 6 Advertisement Article InformationMetrics https://doi.org/10.1161/circ.105.6.e44PMID: 11839640 Originally publishedFebruary 12, 2002 PDF download Advertisement
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