Metabolic Flexibility and Mitochondrial Bioenergetics in the Failing Heart. Therapeutic Approaches

1 Ziaeian B and Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol. 2016;13:368–78. ZiaeianB FonarowGC Epidemiology and aetiology of heart failure Nat Rev Cardiol 2016 13 368 78 10.1038/nrcardio.2016.25486877926935038 Search in Google Scholar

2 Brown DA, Perry JB, Allen ME, Sabbah HN, Stauffer BL, Shaikh SR, Cleland JG, Colucci WS, Butler J, Voors AA, Anker SD, Pitt B, Pieske B, Filippatos G, Greene SJ and Gheorghiade M. Expert consensus document: Mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol. 2017;14:238–250. BrownDA PerryJB AllenME SabbahHN StaufferBL ShaikhSR ClelandJG ColucciWS ButlerJ VoorsAA AnkerSD PittB PieskeB FilippatosG GreeneSJ GheorghiadeM Expert consensus document: Mitochondrial function as a therapeutic target in heart failure Nat Rev Cardiol 2017 14 238 250 10.1038/nrcardio.2016.203535003528004807 Search in Google Scholar

3 Writing Group M, Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C and Stroke Statistics S. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016;133:e38–360. Writing Group M MozaffarianD BenjaminEJ GoAS ArnettDK BlahaMJ CushmanM DasSR de FerrantiS DespresJP FullertonHJ HowardVJ HuffmanMD IsasiCR JimenezMC JuddSE KisselaBM LichtmanJH LisabethLD LiuS MackeyRH MagidDJ McGuireDK MohlerER3rd MoyCS MuntnerP MussolinoME NasirK NeumarRW NicholG PalaniappanL PandeyDK ReevesMJ RodriguezCJ RosamondW SorliePD SteinJ TowfighiA TuranTN ViraniSS WooD YehRW TurnerMB American Heart Association Statistics C and Stroke Statistics S Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association Circulation 2016 133 e38 360 10.1161/CIR.000000000000035026673558 Search in Google Scholar

4 Nagueh SF, Smiseth OA, Appleton CP, Byrd BF, 3rd, Dokainish H, Edvardsen T, Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, Alexandru Popescu B, Waggoner AD, Houston T, Oslo N, Phoenix A, Nashville T, Hamilton OC, Uppsala S, Ghent, Liege B, Cleveland O, Novara I, Rochester M, Bucharest R and St. Louis M. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2016;17:1321–1360. NaguehSF SmisethOA AppletonCP ByrdBF3rd DokainishH EdvardsenT FlachskampfFA GillebertTC KleinAL LancellottiP MarinoP OhJK Alexandru PopescuB WaggonerAD HoustonT OsloN PhoenixA NashvilleT HamiltonOC UppsalaS Ghent LiegeB ClevelandO NovaraI RochesterM BucharestR St. LouisM Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging Eur Heart J Cardiovasc Imaging 2016 17 1321 1360 10.1093/ehjci/jew08227422899 Search in Google Scholar

5 De Jong KA and Lopaschuk GD. Complex Energy Metabolic Changes in Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction. Can J Cardiol. 2017;33:860–871. De JongKA LopaschukGD Complex Energy Metabolic Changes in Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction Can J Cardiol 2017 33 860 871 10.1016/j.cjca.2017.03.00928579160 Search in Google Scholar

6 Stanley WC, Recchia FA and Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005;85:1093–129. StanleyWC RecchiaFA LopaschukGD Myocardial substrate metabolism in the normal and failing heart Physiol Rev 2005 85 1093 129 10.1152/physrev.00006.200415987803 Search in Google Scholar

7 Barth AS, Kumordzie A, Frangakis C, Margulies KB, Cappola TP and Tomaselli GF. Reciprocal transcriptional regulation of metabolic and signaling pathways correlates with disease severity in heart failure. Circ Cardiovasc Genet. 2011;4:475–83. BarthAS KumordzieA FrangakisC MarguliesKB CappolaTP TomaselliGF Reciprocal transcriptional regulation of metabolic and signaling pathways correlates with disease severity in heart failure Circ Cardiovasc Genet 2011 4 475 83 10.1161/CIRCGENETICS.110.957571339880521828333 Search in Google Scholar

8 Senni M, Gavazzi A, Gheorghiade M and Butler J. Heart failure at the crossroads: moving beyond blaming stakeholders to targeting the heart. Eur J Heart Fail. 2015;17:760–3. SenniM GavazziA GheorghiadeM ButlerJ Heart failure at the crossroads: moving beyond blaming stakeholders to targeting the heart Eur J Heart Fail 2015 17 760 3 10.1002/ejhf.31526179815 Search in Google Scholar

9 Bayeva M, Sawicki KT and Ardehali H. Taking diabetes to heart—deregulation of myocardial lipid metabolism in diabetic cardiomyopathy. Journal of the American Heart Association. 2013;2:e000433. BayevaM SawickiKT ArdehaliH Taking diabetes to heart—deregulation of myocardial lipid metabolism in diabetic cardiomyopathy Journal of the American Heart Association 2013 2 e000433 10.1161/JAHA.113.000433388673824275630 Search in Google Scholar

10 Puchalska P and Crawford PA. Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics. Cell metabolism. 2017;25:262–284. PuchalskaP CrawfordPA Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics Cell metabolism 2017 25 262 284 10.1016/j.cmet.2016.12.022531303828178565 Search in Google Scholar

11 Abel ED. Glucose transport in the heart. Front Biosci. 2004;9:201–15. AbelED Glucose transport in the heart Front Biosci 2004 9 201 15 10.2741/1216 Search in Google Scholar

12 Kerner J and Hoppel C. Fatty acid import into mitochondria. Biochim Biophys Acta. 2000;1486:1–17. KernerJ HoppelC Fatty acid import into mitochondria Biochim Biophys Acta 2000 1486 1 17 10.1016/S1388-1981(00)00044-5 Search in Google Scholar

13 Cook GA, Lavrentyev EN, Pham K and Park EA. Streptozotocin diabetes increases mRNA expression of ketogenic enzymes in the rat heart. Biochimica et biophysica acta. 2017;1861:307–312. CookGA LavrentyevEN PhamK ParkEA Streptozotocin diabetes increases mRNA expression of ketogenic enzymes in the rat heart Biochimica et biophysica acta 2017 1861 307 312 10.1016/j.bbagen.2016.11.012536282427845231 Search in Google Scholar

14 Sun W, Quan N, Wang L, Yang H, Chu D, Liu Q, Zhao X, Leng J and Li J. Cardiac-Specific Deletion of the Pdha1 Gene Sensitizes Heart to Toxicological Actions of Ischemic Stress. Toxicol Sci. 2016;153:411. SunW QuanN WangL YangH ChuD LiuQ ZhaoX LengJ LiJ Cardiac-Specific Deletion of the Pdha1 Gene Sensitizes Heart to Toxicological Actions of Ischemic Stress Toxicol Sci 2016 153 411 10.1093/toxsci/kfw154628088927605416 Search in Google Scholar

15 Abel ED, Kaulbach HC, Tian R, Hopkins JC, Duffy J, Doetschman T, Minnemann T, Boers ME, Hadro E, Oberste-Berghaus C, Quist W, Lowell BB, Ingwall JS and Kahn BB. Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart. The Journal of clinical investigation. 1999;104:1703–14. AbelED KaulbachHC TianR HopkinsJC DuffyJ DoetschmanT MinnemannT BoersME HadroE Oberste-BerghausC QuistW LowellBB IngwallJS KahnBB Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart The Journal of clinical investigation 1999 104 1703 14 10.1172/JCI760540988110606624 Search in Google Scholar

16 Anderson EJ, Kypson AP, Rodriguez E, Anderson CA, Lehr EJ and Neufer PD. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J Am Coll Cardiol. 2009;54:1891–8. AndersonEJ KypsonAP RodriguezE AndersonCA LehrEJ NeuferPD Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart J Am Coll Cardiol 2009 54 1891 8 10.1016/j.jacc.2009.07.031280013019892241 Search in Google Scholar

17 Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin CT, Price JW, 3rd, Kang L, Rabinovitch PS, Szeto HH, Houmard JA, Cortright RN, Wasserman DH and Neufer PD. Mitochondrial H₂O₂ emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest. 2009;119:573–81. AndersonEJ LustigME BoyleKE WoodliefTL KaneDA LinCT PriceJW3rd KangL RabinovitchPS SzetoHH HoumardJA CortrightRN WassermanDH NeuferPD Mitochondrial H₂O₂ emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans J Clin Invest 2009 119 573 81 10.1172/JCI37048264870019188683 Search in Google Scholar

18 Aon MA, Tocchetti CG, Bhatt N, Paolocci N and Cortassa S. Protective mechanisms of mitochondria and heart function in diabetes. Antioxid Redox Signal. 2015;22:1563–86. AonMA TocchettiCG BhattN PaolocciN CortassaS Protective mechanisms of mitochondria and heart function in diabetes Antioxid Redox Signal 2015 22 1563 86 10.1089/ars.2014.6123444963025674814 Search in Google Scholar

19 Bayeva M, Sawicki KT and Ardehali H. Taking diabetes to heart–deregulation of myocardial lipid metabolism in diabetic cardiomyopathy. J Am Heart Assoc. 2013;2:e000433. BayevaM SawickiKT ArdehaliH Taking diabetes to heart–deregulation of myocardial lipid metabolism in diabetic cardiomyopathy J Am Heart Assoc 2013 2 e000433 10.1161/JAHA.113.000433388673824275630 Search in Google Scholar

20 Rosca MG, Tandler B and Hoppel CL. Mitochondria in cardiac hypertrophy and heart failure. J Mol Cell Cardiol. 2013;55:31–41. RoscaMG TandlerB HoppelCL Mitochondria in cardiac hypertrophy and heart failure J Mol Cell Cardiol 2013 55 31 41 10.1016/j.yjmcc.2012.09.002380505022982369 Search in Google Scholar

21 Rosca MG and Hoppel CL. Mitochondrial dysfunction in heart failure. Heart Fail Rev. 2013;18:607–22. RoscaMG HoppelCL Mitochondrial dysfunction in heart failure Heart Fail Rev 2013 18 607 22 10.1007/s10741-012-9340-0385529122948484 Search in Google Scholar

22 Lai L, Leone TC, Zechner C, Schaeffer PJ, Kelly SM, Flanagan DP, Medeiros DM, Kovacs A and Kelly DP. Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart. Genes Dev. 2008;22:1948–61. LaiL LeoneTC ZechnerC SchaefferPJ KellySM FlanaganDP MedeirosDM KovacsA KellyDP Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart Genes Dev 2008 22 1948 61 10.1101/gad.1661708249274018628400 Search in Google Scholar

23 Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM and Kelly DP. Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest. 2000;106:847–56. LehmanJJ BargerPM KovacsA SaffitzJE MedeirosDM KellyDP Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis J Clin Invest 2000 106 847 56 10.1172/JCI1026851781511018072 Search in Google Scholar

24 Sack MN, Rader TA, Park S, Bastin J, McCune SA and Kelly DP. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation. 1996;94:2837–42. SackMN RaderTA ParkS BastinJ McCuneSA KellyDP Fatty acid oxidation enzyme gene expression is downregulated in the failing heart Circulation 1996 94 2837 42 10.1161/01.CIR.94.11.28378941110 Search in Google Scholar

25 Sihag S, Cresci S, Li AY, Sucharov CC and Lehman JJ. PGC-1alpha and ERRalpha target gene downregulation is a signature of the failing human heart. J Mol Cell Cardiol. 2009;46:201–12. SihagS CresciS LiAY SucharovCC LehmanJJ PGC-1alpha and ERRalpha target gene downregulation is a signature of the failing human heart J Mol Cell Cardiol 2009 46 201 12 10.1016/j.yjmcc.2008.10.025268126519061896 Search in Google Scholar

26 Goikoetxea MJ, Beaumont J, Gonzalez A, Lopez B, Querejeta R, Larman M and Diez J. Altered cardiac expression of peroxisome proliferator-activated receptor-isoforms in patients with hypertensive heart disease. Cardiovasc Res. 2006;69:899–907. GoikoetxeaMJ BeaumontJ GonzalezA LopezB QuerejetaR LarmanM DiezJ Altered cardiac expression of peroxisome proliferator-activated receptor-isoforms in patients with hypertensive heart disease Cardiovasc Res 2006 69 899 907 10.1016/j.cardiores.2005.11.01616371224 Search in Google Scholar

27 Lapuente-Brun E, Moreno-Loshuertos R, Acin-Perez R, Latorre-Pellicer A, Colas C, Balsa E, Perales-Clemente E, Quiros PM, Calvo E, Rodriguez-Hernandez MA, Navas P, Cruz R, Carracedo A, Lopez-Otin C, Perez-Martos A, Fernandez-Silva P, Fernandez-Vizarra E and Enriquez JA. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Science. 2013;340:1567–70. Lapuente-BrunE Moreno-LoshuertosR Acin-PerezR Latorre-PellicerA ColasC BalsaE Perales-ClementeE QuirosPM CalvoE Rodriguez-HernandezMA NavasP CruzR CarracedoA Lopez-OtinC Perez-MartosA Fernandez-SilvaP Fernandez-VizarraE EnriquezJA Supercomplex assembly determines electron flux in the mitochondrial electron transport chain Science 2013 340 1567 70 10.1126/science.123038123812712 Search in Google Scholar

28 Rosca MG, Vazquez EJ, Kerner J, Parland W, Chandler MP, Stanley W, Sabbah HN and Hoppel CL. Cardiac mitochondria in heart failure: decrease in respirasomes and oxidative phosphorylation. Cardiovasc Res. 2008;80:30–9. RoscaMG VazquezEJ KernerJ ParlandW ChandlerMP StanleyW SabbahHN HoppelCL Cardiac mitochondria in heart failure: decrease in respirasomes and oxidative phosphorylation Cardiovasc Res 2008 80 30 9 10.1093/cvr/cvn184253342318710878 Search in Google Scholar

29 Rosca M, Minkler P and Hoppel CL. Cardiac mitochondria in heart failure: normal cardiolipin profile and increased threonine phosphorylation of complex IV. Biochim Biophys Acta. 2011;1807:1373–82. RoscaM MinklerP HoppelCL Cardiac mitochondria in heart failure: normal cardiolipin profile and increased threonine phosphorylation of complex IV Biochim Biophys Acta 2011 1807 1373 82 10.1016/j.bbabio.2011.02.00321320465 Search in Google Scholar

30 Pfeiffer K, Gohil V, Stuart RA, Hunte C, Brandt U, Greenberg ML and Schagger H. Cardiolipin stabilizes respiratory chain supercomplexes. J Biol Chem. 2003;278:52873–80. PfeifferK GohilV StuartRA HunteC BrandtU GreenbergML SchaggerH Cardiolipin stabilizes respiratory chain supercomplexes J Biol Chem 2003 278 52873 80 10.1074/jbc.M30836620014561769 Search in Google Scholar

31 McKenzie M, Lazarou M, Thorburn DR and Ryan MT. Mitochondrial respiratory chain supercomplexes are destabilized in Barth Syndrome patients. J Mol Biol. 2006;361:462–9. McKenzieM LazarouM ThorburnDR RyanMT Mitochondrial respiratory chain supercomplexes are destabilized in Barth Syndrome patients J Mol Biol 2006 361 462 9 10.1016/j.jmb.2006.06.057 Search in Google Scholar

32 Lesnefsky EJ, Chen Q, Slabe TJ, Stoll MS, Minkler PE, Hassan MO, Tandler B and Hoppel CL. Ischemia, rather than reperfusion, inhibits respiration through cytochrome oxidase in the isolated, perfused rabbit heart: role of cardiolipin. Am J Physiol Heart Circ Physiol. 2004;287:H258–67. LesnefskyEJ ChenQ SlabeTJ StollMS MinklerPE HassanMO TandlerB HoppelCL Ischemia, rather than reperfusion, inhibits respiration through cytochrome oxidase in the isolated, perfused rabbit heart: role of cardiolipin Am J Physiol Heart Circ Physiol 2004 287 H258 67 10.1152/ajpheart.00348.2003 Search in Google Scholar

33 Sparagna GC, Chicco AJ, Murphy RC, Bristow MR, Johnson CA, Rees ML, Maxey ML, McCune SA and Moore RL. Loss of cardiac tetralinoleoyl cardiolipin in human and experimental heart failure. J Lipid Res. 2007;48:1559–70. SparagnaGC ChiccoAJ MurphyRC BristowMR JohnsonCA ReesML MaxeyML McCuneSA MooreRL Loss of cardiac tetralinoleoyl cardiolipin in human and experimental heart failure J Lipid Res 2007 48 1559 70 10.1194/jlr.M600551-JLR200 Search in Google Scholar

34 Chatfield KC, Sparagna GC, Sucharov CC, Miyamoto SD, Grudis JE, Sobus RD, Hijmans J and Stauffer BL. Dysregulation of cardiolipin biosynthesis in pediatric heart failure. J Mol Cell Cardiol. 2014;74:251–9. ChatfieldKC SparagnaGC SucharovCC MiyamotoSD GrudisJE SobusRD HijmansJ StaufferBL Dysregulation of cardiolipin biosynthesis in pediatric heart failure J Mol Cell Cardiol 2014 74 251 9 10.1016/j.yjmcc.2014.06.002 Search in Google Scholar

35 Saini-Chohan HK, Holmes MG, Chicco AJ, Taylor WA, Moore RL, McCune SA, Hickson-Bick DL, Hatch GM and Sparagna GC. Cardiolipin biosynthesis and remodeling enzymes are altered during development of heart failure. J Lipid Res. 2009;50:1600–8. Saini-ChohanHK HolmesMG ChiccoAJ TaylorWA MooreRL McCuneSA Hickson-BickDL HatchGM SparagnaGC Cardiolipin biosynthesis and remodeling enzymes are altered during development of heart failure J Lipid Res 2009 50 1600 8 10.1194/jlr.M800561-JLR200 Search in Google Scholar

36 Korshunov SS, Skulachev VP and Starkov AA. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett. 1997;416:15–8. KorshunovSS SkulachevVP StarkovAA High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria FEBS Lett 1997 416 15 8 10.1016/S0014-5793(97)01159-9 Search in Google Scholar

37 Frasier CR, Moore RL and Brown DA. Exercise-induced cardiac preconditioning: how exercise protects your achy-breaky heart. J Appl Physiol (1985). 2011;111:905–15. FrasierCR MooreRL BrownDA Exercise-induced cardiac preconditioning: how exercise protects your achy-breaky heart J Appl Physiol (1985) 2011 111 905 15 10.1152/japplphysiol.00004.201121393468 Search in Google Scholar

38 Marshall KD, Muller BN, Krenz M, Hanft LM, McDonald KS, Dellsperger KC and Emter CA. Heart failure with preserved ejection fraction: chronic low-intensity interval exercise training preserves myocardial O₂ balance and diastolic function. J Appl Physiol (1985). 2013;114:131–47. MarshallKD MullerBN KrenzM HanftLM McDonaldKS DellspergerKC EmterCA Heart failure with preserved ejection fraction: chronic low-intensity interval exercise training preserves myocardial O₂ balance and diastolic function J Appl Physiol (1985) 2013 114 131 47 10.1152/japplphysiol.01059.2012354452023104696 Search in Google Scholar

39 Flynn KE, Pina IL, Whellan DJ, Lin L, Blumenthal JA, Ellis SJ, Fine LJ, Howlett JG, Keteyian SJ, Kitzman DW, Kraus WE, Miller NH, Schulman KA, Spertus JA, O’Connor CM, Weinfurt KP and Investigators H-A. Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA. 2009;301:1451–9. FlynnKE PinaIL WhellanDJ LinL BlumenthalJA EllisSJ FineLJ HowlettJG KeteyianSJ KitzmanDW KrausWE MillerNH SchulmanKA SpertusJA O’ConnorCM WeinfurtKP Investigators H-A Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial JAMA 2009 301 1451 9 10.1001/jama.2009.457269069919351942 Search in Google Scholar

40 O’Connor CM, Whellan DJ, Lee KL, Keteyian SJ, Cooper LS, Ellis SJ, Leifer ES, Kraus WE, Kitzman DW, Blumenthal JA, Rendall DS, Miller NH, Fleg JL, Schulman KA, McKelvie RS, Zannad F, Pina IL and Investigators H-A. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA. 2009;301:1439–50. O’ConnorCM WhellanDJ LeeKL KeteyianSJ CooperLS EllisSJ LeiferES KrausWE KitzmanDW BlumenthalJA RendallDS MillerNH FlegJL SchulmanKA McKelvieRS ZannadF PinaIL Investigators H-A Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial JAMA 2009 301 1439 50 10.1001/jama.2009.454291666119351941 Search in Google Scholar

41 Edelmann F, Gelbrich G, Dungen HD, Frohling S, Wachter R, Stahrenberg R, Binder L, Topper A, Lashki DJ, Schwarz S, Herrmann-Lingen C, Loffler M, Hasenfuss G, Halle M and Pieske B. Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study. J Am Coll Cardiol. 2011;58:1780–91. EdelmannF GelbrichG DungenHD FrohlingS WachterR StahrenbergR BinderL TopperA LashkiDJ SchwarzS Herrmann-LingenC LofflerM HasenfussG HalleM PieskeB Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study J Am Coll Cardiol 2011 58 1780 91 10.1016/j.jacc.2011.06.054 Search in Google Scholar

42 Akhmedov AT, Rybin V and Marin-Garcia J. Mitochondrial oxidative metabolism and uncoupling proteins in the failing heart. Heart Fail Rev. 2015;20:227–49. AkhmedovAT RybinV Marin-GarciaJ Mitochondrial oxidative metabolism and uncoupling proteins in the failing heart Heart Fail Rev 2015 20 227 49 10.1007/s10741-014-9457-4 Search in Google Scholar

43 Brand MD. Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp Gerontol. 2000;35:811–20. BrandMD Uncoupling to survive? The role of mitochondrial inefficiency in ageing Exp Gerontol 2000 35 811 20 10.1016/S0531-5565(00)00135-2 Search in Google Scholar

44 Jones DP and Sies H. The Redox Code. Antioxidants & redox signaling. 2015;23:734–46. JonesDP SiesH The Redox Code Antioxidants & redox signaling 2015 23 734 46 10.1089/ars.2015.6247458030825891126 Search in Google Scholar

45 Karamanlidis G, Lee CF, Garcia-Menendez L, Kolwicz SC, Jr., Suthammarak W, Gong G, Sedensky MM, Morgan PG, Wang W and Tian R. Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab. 2013;18:239–50. KaramanlidisG LeeCF Garcia-MenendezL KolwiczSCJr. SuthammarakW GongG SedenskyMM MorganPG WangW TianR Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure Cell Metab 2013 18 239 50 10.1016/j.cmet.2013.07.002377964723931755 Search in Google Scholar

46 Ronchi JA, Francisco A, Passos LA, Figueira TR and Castilho RF. The Contribution of Nicotinamide Nucleotide Transhydrogenase to Peroxide Detoxification Is Dependent on the Respiratory State and Counterbalanced by Other Sources of NADPH in Liver Mitochondria. The Journal of biological chemistry. 2016;291:20173–87. RonchiJA FranciscoA PassosLA FigueiraTR CastilhoRF The Contribution of Nicotinamide Nucleotide Transhydrogenase to Peroxide Detoxification Is Dependent on the Respiratory State and Counterbalanced by Other Sources of NADPH in Liver Mitochondria The Journal of biological chemistry 2016 291 20173 87 10.1074/jbc.M116.730473502570027474736 Search in Google Scholar

47 Rydstrom J. Mitochondrial NADPH, transhydrogenase and disease. Biochimica et biophysica acta. 2006;1757:721–6. RydstromJ Mitochondrial NADPH, transhydrogenase and disease Biochimica et biophysica acta 2006 1757 721 6 10.1016/j.bbabio.2006.03.01016730324 Search in Google Scholar

48 Alano CC, Tran A, Tao R, Ying W, Karliner JS and Swanson RA. Differences among cell types in NAD(+) compartmentalization: a comparison of neurons, astrocytes, and cardiac myocytes. Journal of neuroscience research. 2007;85:3378–85. AlanoCC TranA TaoR YingW KarlinerJS SwansonRA Differences among cell types in NAD(+) compartmentalization: a comparison of neurons, astrocytes, and cardiac myocytes Journal of neuroscience research 2007 85 3378 85 10.1002/jnr.2147917853438 Search in Google Scholar

49 Pillai VB, Sundaresan NR, Kim G, Gupta M, Rajamohan SB, Pillai JB, Samant S, Ravindra PV, Isbatan A and Gupta MP. Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. The Journal of biological chemistry. 2010;285:3133–44. PillaiVB SundaresanNR KimG GuptaM RajamohanSB PillaiJB SamantS RavindraPV IsbatanA GuptaMP Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway The Journal of biological chemistry 2010 285 3133 44 10.1074/jbc.M109.077271282345419940131 Search in Google Scholar

50 Khanra R, Dewanjee S, T KD, Sahu R, Gangopadhyay M, De Feo V and Zia-Ul-Haq M. Abroma augusta L. (Malvaceae) leaf extract attenuates diabetes induced nephropathy and cardiomyopathy via inhibition of oxidative stress and inflammatory response. Journal of translational medicine. 2015;13:6. KhanraR DewanjeeS TKD SahuR GangopadhyayM De FeoV Zia-Ul-HaqM Abroma augusta L. (Malvaceae) leaf extract attenuates diabetes induced nephropathy and cardiomyopathy via inhibition of oxidative stress and inflammatory response Journal of translational medicine 2015 13 6 10.1186/s12967-014-0364-1430189525591455 Search in Google Scholar

51 Akie TE, Liu L, Nam M, Lei S and Cooper MP. OXPHOS-Mediated Induction of NAD⁺ Promotes Complete Oxidation of Fatty Acids and Interdicts Non-Alcoholic Fatty Liver Disease. PloS one. 2015;10:e0125617. AkieTE LiuL NamM LeiS CooperMP OXPHOS-Mediated Induction of NAD⁺ Promotes Complete Oxidation of Fatty Acids and Interdicts Non-Alcoholic Fatty Liver Disease PloS one 2015 10 e0125617 10.1371/journal.pone.0125617441693125933096 Search in Google Scholar

52 Wagner GR, Pride PM, Babbey CM and Payne RM. Friedreich’s ataxia reveals a mechanism for coordinate regulation of oxidative metabolism via feedback inhibition of the SIRT3 deacetylase. Human molecular genetics. 2012;21:2688–97. WagnerGR PridePM BabbeyCM PayneRM Friedreich’s ataxia reveals a mechanism for coordinate regulation of oxidative metabolism via feedback inhibition of the SIRT3 deacetylase Human molecular genetics 2012 21 2688 97 10.1093/hmg/dds095336333622394676 Search in Google Scholar

53 Sung HJ, Ma W, Wang PY, Hynes J, O’Riordan TC, Combs CA, McCoy JP, Jr., Bunz F, Kang JG and Hwang PM. Mitochondrial respiration protects against oxygen-associated DNA damage. Nature communications. 2010;1:5. SungHJ MaW WangPY HynesJ O’RiordanTC CombsCA McCoyJPJr. BunzF KangJG HwangPM Mitochondrial respiration protects against oxygen-associated DNA damage Nature communications 2010 1 5 10.1038/ncomms1003339309320975668 Search in Google Scholar

54 Horton JL, Martin OJ, Lai L, Riley NM, Richards AL, Vega RB, Leone TC, Pagliarini DJ, Muoio DM, Bedi KC, Jr., Margulies KB, Coon JJ and Kelly DP. Mitochondrial protein hyperacetylation in the failing heart. JCI insight. 2016;2. HortonJL MartinOJ LaiL RileyNM RichardsAL VegaRB LeoneTC PagliariniDJ MuoioDM BediKCJr. MarguliesKB CoonJJ KellyDP Mitochondrial protein hyperacetylation in the failing heart JCI insight 2016 2 10.1172/jci.insight.84897479583626998524 Search in Google Scholar

55 Kouzu H, Miki T, Tanno M, Kuno A, Yano T, Itoh T, Sato T, Sunaga D, Murase H, Tobisawa T, Ogasawara M, Ishikawa S and Miura T. Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart. Journal of molecular and cellular cardiology. 2015;80:136–45. KouzuH MikiT TannoM KunoA YanoT ItohT SatoT SunagaD MuraseH TobisawaT OgasawaraM IshikawaS MiuraT Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart Journal of molecular and cellular cardiology 2015 80 136 45 10.1016/j.yjmcc.2015.01.00425599963 Search in Google Scholar

56 Bhatt NM, Aon MA, Tocchetti CG, Shen X, Dey S, Ramirez-Correa G, O’Rourke B, Gao WD and Cortassa S. Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose. American journal of physiology Heart and circulatory physiology. 2015;308:H291–302. BhattNM AonMA TocchettiCG ShenX DeyS Ramirez-CorreaG O’RourkeB GaoWD CortassaS Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose American journal of physiology Heart and circulatory physiology 2015 308 H291 302 10.1152/ajpheart.00378.2014432948125485897 Search in Google Scholar

57 Imai S, Armstrong CM, Kaeberlein M and Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403:795–800. ImaiS ArmstrongCM KaeberleinM GuarenteL Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase Nature 2000 403 795 800 10.1038/3500162210693811 Search in Google Scholar

58 Satoh A, Brace CS, Rensing N, Cliften P, Wozniak DF, Herzog ED, Yamada KA and Imai S. SIRT 1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell metabolism. 2013;18:416–30. SatohA BraceCS RensingN CliftenP WozniakDF HerzogED YamadaKA ImaiS SIRT 1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH Cell metabolism 2013 18 416 30 10.1016/j.cmet.2013.07.013379471224011076 Search in Google Scholar

59 Cheng HL, Mostoslavsky R, Saito S, Manis JP, Gu Y, Patel P, Bronson R, Appella E, Alt FW and Chua KF. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT 1)-deficient mice. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:10794–9. ChengHL MostoslavskyR SaitoS ManisJP GuY PatelP BronsonR AppellaE AltFW ChuaKF Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT 1)-deficient mice Proceedings of the National Academy of Sciences of the United States of America 2003 100 10794 9 10.1073/pnas.193471310019688212960381 Search in Google Scholar

60 Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, Tian B, Wagner T, Vatner SF and Sadoshima J. SIRT 1 regulates aging and resistance to oxidative stress in the heart. Circulation research. 2007;100:1512–21. AlcendorRR GaoS ZhaiP ZablockiD HolleE YuX TianB WagnerT VatnerSF SadoshimaJ SIRT 1 regulates aging and resistance to oxidative stress in the heart Circulation research 2007 100 1512 21 10.1161/01.RES.0000267723.65696.4a17446436 Search in Google Scholar

61 Nemoto S, Fergusson MM and Finkel T. SIRT 1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. The Journal of biological chemistry. 2005;280:16456–60. NemotoS FergussonMM FinkelT SIRT 1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha} The Journal of biological chemistry 2005 280 16456 60 10.1074/jbc.M50148520015716268 Search in Google Scholar

62 Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z and Puigserver P. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT 1/PGC-1alpha. The EMBO journal. 2007;26:1913–23. Gerhart-HinesZ RodgersJT BareO LerinC KimSH MostoslavskyR AltFW WuZ PuigserverP Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT 1/PGC-1alpha The EMBO journal 2007 26 1913 23 10.1038/sj.emboj.7601633184766117347648 Search in Google Scholar

63 Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, Kim J, Yancopoulos G, Valenzuela D, Murphy A, Yang Y, Chen Y, Hirschey MD, Bronson RT, Haigis M, Guarente LP, Farese RV, Jr., Weissman S, Verdin E and Schwer B. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Molecular and cellular biology. 2007;27:8807–14. LombardDB AltFW ChengHL BunkenborgJ StreeperRS MostoslavskyR KimJ YancopoulosG ValenzuelaD MurphyA YangY ChenY HirscheyMD BronsonRT HaigisM GuarenteLP FareseRVJr. WeissmanS VerdinE SchwerB Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation Molecular and cellular biology 2007 27 8807 14 10.1128/MCB.01636-07216941817923681 Search in Google Scholar

64 Koentges C, Pfeil K, Schnick T, Wiese S, Dahlbock R, Cimolai MC, Meyer-Steenbuck M, Cenkerova K, Hoffmann MM, Jaeger C, Odening KE, Kammerer B, Hein L, Bode C and Bugger H. SIRT3 deficiency impairs mitochondrial and contractile function in the heart. Basic research in cardiology. 2015;110:36. KoentgesC PfeilK SchnickT WieseS DahlbockR CimolaiMC Meyer-SteenbuckM CenkerovaK HoffmannMM JaegerC OdeningKE KammererB HeinL BodeC BuggerH SIRT3 deficiency impairs mitochondrial and contractile function in the heart Basic research in cardiology 2015 110 36 10.1007/s00395-015-0493-625962702 Search in Google Scholar

65 Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A and Gupta MP. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. The Journal of clinical investigation. 2009;119:2758–71. SundaresanNR GuptaM KimG RajamohanSB IsbatanA GuptaMP Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice The Journal of clinical investigation 2009 119 2758 71 10.1172/JCI39162273593319652361 Search in Google Scholar

66 Jing E, O’Neill BT, Rardin MJ, Kleinridders A, Ilkeyeva OR, Ussar S, Bain JR, Lee KY, Verdin EM, Newgard CB, Gibson BW and Kahn CR. Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation. Diabetes. 2013;62:3404–17. JingE O’NeillBT RardinMJ KleinriddersA IlkeyevaOR UssarS BainJR LeeKY VerdinEM NewgardCB GibsonBW KahnCR Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation Diabetes 2013 62 3404 17 10.2337/db12-1650378146523835326 Search in Google Scholar

67 Ozden O, Park SH, Wagner BA, Yong Song H, Zhu Y, Vassilopoulos A, Jung B, Buettner GR and Gius D. SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells. Free radical biology & medicine. 2014;76:163–72. OzdenO ParkSH WagnerBA Yong SongH ZhuY VassilopoulosA JungB BuettnerGR GiusD SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells Free radical biology & medicine 2014 76 163 72 10.1016/j.freeradbiomed.2014.08.001436430425152236 Search in Google Scholar

68 Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, Grueter CA, Harris C, Biddinger S, Ilkayeva OR, Stevens RD, Li Y, Saha AK, Ruderman NB, Bain JR, Newgard CB, Farese RV, Jr., Alt FW, Kahn CR and Verdin E. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature. 2010;464:121–5. HirscheyMD ShimazuT GoetzmanE JingE SchwerB LombardDB GrueterCA HarrisC BiddingerS IlkayevaOR StevensRD LiY SahaAK RudermanNB BainJR NewgardCB FareseRVJr. AltFW KahnCR VerdinE SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation Nature 2010 464 121 5 10.1038/nature08778284147720203611 Search in Google Scholar

69 Hirschey MD, Shimazu T, Jing E, Grueter CA, Collins AM, Aouizerat B, Stancakova A, Goetzman E, Lam MM, Schwer B, Stevens RD, Muehlbauer MJ, Kakar S, Bass NM, Kuusisto J, Laakso M, Alt FW, Newgard CB, Farese RV, Jr., Kahn CR and Verdin E. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Molecular cell. 2011;44:177–90. HirscheyMD ShimazuT JingE GrueterCA CollinsAM AouizeratB StancakovaA GoetzmanE LamMM SchwerB StevensRD MuehlbauerMJ KakarS BassNM KuusistoJ LaaksoM AltFW NewgardCB FareseRVJr. KahnCR VerdinE SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome Molecular cell 2011 44 177 90 10.1016/j.molcel.2011.07.019356343421856199 Search in Google Scholar

70 Bharathi SS, Zhang Y, Mohsen AW, Uppala R, Balasubramani M, Schreiber E, Uechi G, Beck ME, Rardin MJ, Vockley J, Verdin E, Gibson BW, Hirschey MD and Goetzman ES. Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site. The Journal of biological chemistry. 2013;288:33837–47. BharathiSS ZhangY MohsenAW UppalaR BalasubramaniM SchreiberE UechiG BeckME RardinMJ VockleyJ VerdinE GibsonBW HirscheyMD GoetzmanES Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site The Journal of biological chemistry 2013 288 33837 47 10.1074/jbc.M113.510354383712624121500 Search in Google Scholar

71 Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, Tanokura M, Denu JM and Prolla TA. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell. 2010;143:802–12. SomeyaS YuW HallowsWC XuJ VannJM LeeuwenburghC TanokuraM DenuJM ProllaTA Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction Cell 2010 143 802 12 10.1016/j.cell.2010.10.002301884921094524 Search in Google Scholar

72 Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, Deng CX and Finkel T. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:14447–52. AhnBH KimHS SongS LeeIH LiuJ VassilopoulosA DengCX FinkelT A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis Proceedings of the National Academy of Sciences of the United States of America 2008 105 14447 52 10.1073/pnas.0803790105256718318794531 Search in Google Scholar

73 Smith CS, Bottomley PA, Schulman SP, Gerstenblith G and Weiss RG. Altered creatine kinase adenosine triphosphate kinetics in failing hypertrophied human myocardium. Circulation. 2006;114:1151–8. SmithCS BottomleyPA SchulmanSP GerstenblithG WeissRG Altered creatine kinase adenosine triphosphate kinetics in failing hypertrophied human myocardium Circulation 2006 114 1151 8 10.1161/CIRCULATIONAHA.106.613646180843816952984 Search in Google Scholar

74 Weiss RG, Gerstenblith G and Bottomley PA. ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc Natl Acad Sci U S A. 2005;102:808–13. WeissRG GerstenblithG BottomleyPA ATP flux through creatine kinase in the normal, stressed, and failing human heart Proc Natl Acad Sci U S A 2005 102 808 13 10.1073/pnas.040896210254554615647364 Search in Google Scholar

75 Phan TT, Abozguia K, Nallur Shivu G, Mahadevan G, Ahmed I, Williams L, Dwivedi G, Patel K, Steendijk P, Ashrafian H, Henning A and Frenneaux M. Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J Am Coll Cardiol. 2009;54:402–9. PhanTT AbozguiaK Nallur ShivuG MahadevanG AhmedI WilliamsL DwivediG PatelK SteendijkP AshrafianH HenningA FrenneauxM Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency J Am Coll Cardiol 2009 54 402 9 10.1016/j.jacc.2009.05.01219628114 Search in Google Scholar

76 Esposito A, De Cobelli F, Perseghin G, Pieroni M, Belloni E, Mellone R, Canu T, Gentinetta F, Scifo P, Chimenti C, Frustaci A, Luzi L, Maseri A and Maschio AD. Impaired left ventricular energy metabolism in patients with hypertrophic cardiomyopathy is related to the extension of fibrosis at delayed gadolinium-enhanced magnetic resonance imaging. Heart. 2009;95:228–33. EspositoA De CobelliF PerseghinG PieroniM BelloniE MelloneR CanuT GentinettaF ScifoP ChimentiC FrustaciA LuziL MaseriA MaschioAD Impaired left ventricular energy metabolism in patients with hypertrophic cardiomyopathy is related to the extension of fibrosis at delayed gadolinium-enhanced magnetic resonance imaging Heart 2009 95 228 33 10.1136/hrt.2008.14256218708417 Search in Google Scholar

77 Berthiaume JM, Kurdys JG, Muntean DM and Rosca MG. Mitochondrial NAD(+)/NADH Redox State and Diabetic Cardiomyopathy. Antioxid Redox Signal. 2019;30:375–398. BerthiaumeJM KurdysJG MunteanDM RoscaMG Mitochondrial NAD(+)/NADH Redox State and Diabetic Cardiomyopathy Antioxid Redox Signal 2019 30 375 398 10.1089/ars.2017.7415630667929073779 Search in Google Scholar

78 Igarashi N, Nozawa T, Fujii N, Suzuki T, Matsuki A, Nakadate T, Igawa A and Inoue H. Influence of beta-adrenoceptor blockade on the myocardial accumulation of fatty acid tracer and its intracellular metabolism in the heart after ischemia-reperfusion injury. Circ J. 2006;70:1509–14. IgarashiN NozawaT FujiiN SuzukiT MatsukiA NakadateT IgawaA InoueH Influence of beta-adrenoceptor blockade on the myocardial accumulation of fatty acid tracer and its intracellular metabolism in the heart after ischemia-reperfusion injury Circ J 2006 70 1509 14 10.1253/circj.70.150917062979 Search in Google Scholar

79 Stanley WC, Morgan EE, Huang H, McElfresh TA, Sterk JP, Okere IC, Chandler MP, Cheng J, Dyck JR and Lopaschuk GD. Malonyl-CoA decarboxylase inhibition suppresses fatty acid oxidation and reduces lactate production during demand-induced ischemia. Am J Physiol Heart Circ Physiol. 2005;289:H2304–9. StanleyWC MorganEE HuangH McElfreshTA SterkJP OkereIC ChandlerMP ChengJ DyckJR LopaschukGD Malonyl-CoA decarboxylase inhibition suppresses fatty acid oxidation and reduces lactate production during demand-induced ischemia Am J Physiol Heart Circ Physiol 2005 289 H2304 9 10.1152/ajpheart.00599.200516100246 Search in Google Scholar

80 Fukushima A, Milner K, Gupta A and Lopaschuk GD. Myocardial Energy Substrate Metabolism in Heart Failure : from Pathways to Therapeutic Targets. Curr Pharm Des. 2015;21:3654–64. FukushimaA MilnerK GuptaA LopaschukGD Myocardial Energy Substrate Metabolism in Heart Failure : from Pathways to Therapeutic Targets Curr Pharm Des 2015 21 3654 64 10.2174/138161282166615071015044526166604 Search in Google Scholar

81 Kolwicz SC, Jr., Airhart S and Tian R. Ketones Step to the Plate: A Game Changer for Metabolic Remodeling in Heart Failure? Circulation. 2016;133:689–91. KolwiczSCJr. AirhartS TianR Ketones Step to the Plate: A Game Changer for Metabolic Remodeling in Heart Failure? Circulation 2016 133 689 91 10.1161/CIRCULATIONAHA.116.021230482655926819375 Search in Google Scholar

82 Bedi KC, Jr., Snyder NW, Brandimarto J, Aziz M, Mesaros C, Worth AJ, Wang LL, Javaheri A, Blair IA, Margulies KB and Rame JE. Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure. Circulation. 2016;133:706–16. BediKCJr. SnyderNW BrandimartoJ AzizM MesarosC WorthAJ WangLL JavaheriA BlairIA MarguliesKB RameJE Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure Circulation 2016 133 706 16 10.1161/CIRCULATIONAHA.115.017545477933926819374 Search in Google Scholar

83 Heart Outcomes Prevention Evaluation Study I, Yusuf S, Dagenais G, Pogue J, Bosch J and Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med. 2000;342:154–60. Heart Outcomes Prevention Evaluation Study I YusufS DagenaisG PogueJ BoschJ SleightP Vitamin E supplementation and cardiovascular events in high-risk patients N Engl J Med 2000 342 154 60 10.1056/NEJM20000120342030210639540 Search in Google Scholar

84 Downey JM and Cohen MV. Why do we still not have cardioprotective drugs? Circ J. 2009;73:1171–7. DowneyJM CohenMV Why do we still not have cardioprotective drugs? Circ J 2009 73 1171 7 10.1253/circj.CJ-09-033819506318 Search in Google Scholar

85 Escobales N, Nunez RE, Jang S, Parodi-Rullan R, Ayala-Pena S, Sacher JR, Skoda EM, Wipf P, Frontera W and Javadov S. Mitochondria-targeted ROS scavenger improves post-ischemic recovery of cardiac function and attenuates mitochondrial abnormalities in aged rats. J Mol Cell Cardiol. 2014;77:136–46. EscobalesN NunezRE JangS Parodi-RullanR Ayala-PenaS SacherJR SkodaEM WipfP FronteraW JavadovS Mitochondria-targeted ROS scavenger improves post-ischemic recovery of cardiac function and attenuates mitochondrial abnormalities in aged rats J Mol Cell Cardiol 2014 77 136 46 10.1016/j.yjmcc.2014.10.009431219425451170 Search in Google Scholar

86 Liang HL, Sedlic F, Bosnjak Z and Nilakantan V. SOD1 and Mito-TEMPO partially prevent mitochondrial permeability transition pore opening, necrosis, and mitochondrial apoptosis after ATP depletion recovery. Free Radic Biol Med. 2010;49:1550–60. LiangHL SedlicF BosnjakZ NilakantanV SOD1 and Mito-TEMPO partially prevent mitochondrial permeability transition pore opening, necrosis, and mitochondrial apoptosis after ATP depletion recovery Free Radic Biol Med 2010 49 1550 60 10.1016/j.freeradbiomed.2010.08.018386311620736062 Search in Google Scholar

87 Kawakami S, Matsuda A, Sunagawa T, Noda Y, Kaneko T, Tahara S, Hiraumi Y, Adachi S, Matsui H, Ando K, Fujita T, Maruyama N, Shirasawa T and Shimizu T. Antioxidant, EUK-8, prevents murine dilated cardiomyopathy. Circ J. 2009;73:2125–34. KawakamiS MatsudaA SunagawaT NodaY KanekoT TaharaS HiraumiY AdachiS MatsuiH AndoK FujitaT MaruyamaN ShirasawaT ShimizuT Antioxidant, EUK-8, prevents murine dilated cardiomyopathy Circ J 2009 73 2125 34 10.1253/circj.CJ-09-020419749480 Search in Google Scholar

88 Breton M, Costemale-Lacoste JF, Li Z, Lafuente-Lafuente C, Belmin J and Mericskay M. Blood NAD levels are reduced in very old patients hospitalized for heart failure. Exp Gerontol. 2020;139:111051. BretonM Costemale-LacosteJF LiZ Lafuente-LafuenteC BelminJ MericskayM Blood NAD levels are reduced in very old patients hospitalized for heart failure Exp Gerontol 2020 139 111051 10.1016/j.exger.2020.11105132783906 Search in Google Scholar

89 Diguet N, Trammell SAJ, Tannous C, Deloux R, Piquereau J, Mougenot N, Gouge A, Gressette M, Manoury B, Blanc J, Breton M, Decaux JF, Lavery GG, Baczko I, Zoll J, Garnier A, Li Z, Brenner C and Mericskay M. Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy. Circulation. 2018;137:2256–2273. DiguetN TrammellSAJ TannousC DelouxR PiquereauJ MougenotN GougeA GressetteM ManouryB BlancJ BretonM DecauxJF LaveryGG BaczkoI ZollJ GarnierA LiZ BrennerC MericskayM Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy Circulation 2018 137 2256 2273 10.1161/CIRCULATIONAHA.116.026099695468829217642 Search in Google Scholar

90 Zhou B, Wang DD, Qiu Y, Airhart S, Liu Y, Stempien-Otero A, O’Brien KD and Tian R. Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure. J Clin Invest. 2020;130:6054–6063. ZhouB WangDD QiuY AirhartS LiuY Stempien-OteroA O’BrienKD TianR Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure J Clin Invest 2020 130 6054 6063 10.1172/JCI138538759808132790648 Search in Google Scholar

91 Lee CF, Chavez JD, Garcia-Menendez L, Choi Y, Roe ND, Chiao YA, Edgar JS, Goo YA, Goodlett DR, Bruce JE and Tian R. Normalization of NAD⁺ Redox Balance as a Therapy for Heart Failure. Circulation. 2016;134:883–94. LeeCF ChavezJD Garcia-MenendezL ChoiY RoeND ChiaoYA EdgarJS GooYA GoodlettDR BruceJE TianR Normalization of NAD⁺ Redox Balance as a Therapy for Heart Failure Circulation 2016 134 883 94 10.1161/CIRCULATIONAHA.116.022495 Search in Google Scholar

92 Bagul PK, Dinda AK and Banerjee SK. Effect of resveratrol on sirtuins expression and cardiac complications in diabetes. Biochemical and biophysical research communications. 2015;468:221–7. BagulPK DindaAK BanerjeeSK Effect of resveratrol on sirtuins expression and cardiac complications in diabetes Biochemical and biophysical research communications 2015 468 221 7 10.1016/j.bbrc.2015.10.126 Search in Google Scholar

93 Bagul PK, Deepthi N, Sultana R and Banerjee SK. Resveratrol ameliorates cardiac oxidative stress in diabetes through deacetylation of NFkB-p65 and histone 3. The Journal of nutritional biochemistry. 2015;26:1298–307. BagulPK DeepthiN SultanaR BanerjeeSK Resveratrol ameliorates cardiac oxidative stress in diabetes through deacetylation of NFkB-p65 and histone 3 The Journal of nutritional biochemistry 2015 26 1298 307 10.1016/j.jnutbio.2015.06.006 Search in Google Scholar

94 Bhatt JK, Thomas S and Nanjan MJ. Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutrition research. 2012;32:537–41. BhattJK ThomasS NanjanMJ Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus Nutrition research 2012 32 537 41 10.1016/j.nutres.2012.06.003 Search in Google Scholar

95 Liu K, Zhou R, Wang B and Mi MT. Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials. The American journal of clinical nutrition. 2014;99:1510–9. LiuK ZhouR WangB MiMT Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials The American journal of clinical nutrition 2014 99 1510 9 10.3945/ajcn.113.082024 Search in Google Scholar

96 Tanno M, Kuno A, Yano T, Miura T, Hisahara S, Ishikawa S, Shimamoto K and Horio Y. Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT 1 promotes cell survival in chronic heart failure. The Journal of biological chemistry. 2010;285:8375–82. TannoM KunoA YanoT MiuraT HisaharaS IshikawaS ShimamotoK HorioY Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT 1 promotes cell survival in chronic heart failure The Journal of biological chemistry 2010 285 8375 82 10.1074/jbc.M109.090266 Search in Google Scholar

97 Beaudoin MS, Perry CG, Arkell AM, Chabowski A, Simpson JA, Wright DC and Holloway GP. Impairments in mitochondrial palmitoyl-CoA respiratory kinetics that precede development of diabetic cardiomyopathy are prevented by resveratrol in ZDF rats. The Journal of physiology. 2014;592:2519–33. BeaudoinMS PerryCG ArkellAM ChabowskiA SimpsonJA WrightDC HollowayGP Impairments in mitochondrial palmitoyl-CoA respiratory kinetics that precede development of diabetic cardiomyopathy are prevented by resveratrol in ZDF rats The Journal of physiology 2014 592 2519 33 10.1113/jphysiol.2013.270538 Search in Google Scholar

98 Visarius TM, Stucki JW and Lauterburg BH. Inhibition and stimulation of long-chain fatty acid oxidation by chloroacetaldehyde and methylene blue in rats. The Journal of pharmacology and experimental therapeutics. 1999;289:820–4. VisariusTM StuckiJW LauterburgBH Inhibition and stimulation of long-chain fatty acid oxidation by chloroacetaldehyde and methylene blue in rats The Journal of pharmacology and experimental therapeutics 1999 289 820 4 Search in Google Scholar

99 Callaway NL, Riha PD, Bruchey AK, Munshi Z and Gonzalez-Lima F. Methylene blue improves brain oxidative metabolism and memory retention in rats. Pharmacology, biochemistry, and behavior. 2004;77:175–81. CallawayNL RihaPD BrucheyAK MunshiZ Gonzalez-LimaF Methylene blue improves brain oxidative metabolism and memory retention in rats Pharmacology, biochemistry, and behavior 2004 77 175 81 10.1016/j.pbb.2003.10.007 Search in Google Scholar

100 Callaway NL, Riha PD, Wrubel KM, McCollum D and Gonzalez-Lima F. Methylene blue restores spatial memory retention impaired by an inhibitor of cytochrome oxidase in rats. Neuroscience letters. 2002;332:83–6. CallawayNL RihaPD WrubelKM McCollumD Gonzalez-LimaF Methylene blue restores spatial memory retention impaired by an inhibitor of cytochrome oxidase in rats Neuroscience letters 2002 332 83 6 10.1016/S0304-3940(02)00827-3 Search in Google Scholar

101 Furian AF, Fighera MR, Oliveira MS, Ferreira AP, Fiorenza NG, de Carvalho Myskiw J, Petry JC, Coelho RC, Mello CF and Royes LF. Methylene blue prevents methylmalonate-induced seizures and oxidative damage in rat striatum. Neurochemistry international. 2007;50:164–71. FurianAF FigheraMR OliveiraMS FerreiraAP FiorenzaNG de Carvalho MyskiwJ PetryJC CoelhoRC MelloCF RoyesLF Methylene blue prevents methylmalonate-induced seizures and oxidative damage in rat striatum Neurochemistry international 2007 50 164 71 10.1016/j.neuint.2006.07.01216963161 Search in Google Scholar

102 Kwok ES and Howes D. Use of methylene blue in sepsis: a systematic review. Journal of intensive care medicine. 2006;21:359–63. KwokES HowesD Use of methylene blue in sepsis: a systematic review Journal of intensive care medicine 2006 21 359 63 10.1177/0885066606290671 Search in Google Scholar

103 Clifton J, 2nd and Leikin JB. Methylene blue. American journal of therapeutics. 2003;10:289–91. CliftonJ2nd LeikinJB Methylene blue American journal of therapeutics 2003 10 289 91 10.1097/00045391-200307000-00009 Search in Google Scholar

104 Demirbilek S, Sizanli E, Karadag N, Karaman A, Bayraktar N, Turkmen E and Ersoy MO. The effects of methylene blue on lung injury in septic rats. European surgical research Europaische chirurgische Forschung. 2006;38:35–41. DemirbilekS SizanliE KaradagN KaramanA BayraktarN TurkmenE ErsoyMO The effects of methylene blue on lung injury in septic rats European surgical research Europaische chirurgische Forschung 2006 38 35 41 10.1159/000091525 Search in Google Scholar

105 Riedel W, Lang U, Oetjen U, Schlapp U and Shibata M. Inhibition of oxygen radical formation by methylene blue, aspirin, or alpha-lipoic acid, prevents bacterial-lipopolysaccharide-induced fever. Molecular and cellular biochemistry. 2003;247:83–94. RiedelW LangU OetjenU SchlappU ShibataM Inhibition of oxygen radical formation by methylene blue, aspirin, or alpha-lipoic acid, prevents bacterial-lipopolysaccharide-induced fever Molecular and cellular biochemistry 2003 247 83 94 10.1023/A:1024142400835 Search in Google Scholar

106 Rezzani R, Rodella L, Corsetti G and Bianchi R. Does methylene blue protect the kidney tissues from damage induced by ciclosporin A treatment? Nephron. 2001;89:329–36. RezzaniR RodellaL CorsettiG BianchiR Does methylene blue protect the kidney tissues from damage induced by ciclosporin A treatment? Nephron 2001 89 329 36 10.1159/000046094 Search in Google Scholar

107 Hrushesky WJ, Olshefski R, Wood P, Meshnick S and Eaton JW. Modifying intracellular redox balance: an approach to improving therapeutic index. Lancet. 1985;1:565–7. HrusheskyWJ OlshefskiR WoodP MeshnickS EatonJW Modifying intracellular redox balance: an approach to improving therapeutic index Lancet 1985 1 565 7 10.1016/S0140-6736(85)91218-8 Search in Google Scholar

108 Haluzik M, Nedvidkova J and Skrha J. Treatment with the NO-synthase inhibitor, methylene blue, moderates the decrease in serum leptin concentration in streptozotocin-induced diabetes. Endocrine research. 1999;25:163–71. HaluzikM NedvidkovaJ SkrhaJ Treatment with the NO-synthase inhibitor, methylene blue, moderates the decrease in serum leptin concentration in streptozotocin-induced diabetes Endocrine research 1999 25 163 71 10.1080/07435809909066138 Search in Google Scholar

109 Salaris SC, Babbs CF and Voorhees WD, 3rd. Methylene blue as an inhibitor of superoxide generation by xanthine oxidase. A potential new drug for the attenuation of ischemia/reperfusion injury. Biochemical pharmacology. 1991;42:499–506. SalarisSC BabbsCF VoorheesWD3rd Methylene blue as an inhibitor of superoxide generation by xanthine oxidase. A potential new drug for the attenuation of ischemia/reperfusion injury Biochemical pharmacology 1991 42 499 506 10.1016/0006-2952(91)90311-R Search in Google Scholar

110 Rojas JC, John JM, Lee J and Gonzalez-Lima F. Methylene blue provides behavioral and metabolic neuroprotection against optic neuropathy. Neurotoxicity research. 2009;15:260–73. RojasJC JohnJM LeeJ Gonzalez-LimaF Methylene blue provides behavioral and metabolic neuroprotection against optic neuropathy Neurotoxicity research 2009 15 260 73 10.1007/s12640-009-9027-z19384599 Search in Google Scholar

111 Miclescu A, Basu S and Wiklund L. Methylene blue added to a hypertonic-hyperoncotic solution increases short-term survival in experimental cardiac arrest. Critical care medicine. 2006;34:2806–13. MiclescuA BasuS WiklundL Methylene blue added to a hypertonic-hyperoncotic solution increases short-term survival in experimental cardiac arrest Critical care medicine 2006 34 2806 13 10.1097/01.CCM.0000242517.23324.2716957637 Search in Google Scholar

112 Medina DX, Caccamo A and Oddo S. Methylene blue reduces abeta levels and rescues early cognitive deficit by increasing proteasome activity. Brain pathology (Zurich, Switzerland). 21:140–9. MedinaDX CaccamoA OddoS Methylene blue reduces abeta levels and rescues early cognitive deficit by increasing proteasome activity Brain pathology (Zurich, Switzerland) 21 140 9 10.1111/j.1750-3639.2010.00430.x Search in Google Scholar

113 O’Leary JC, 3rd, Li Q, Marinec P, Blair LJ, Congdon EE, Johnson AG, Jinwal UK, Koren J, 3rd, Jones JR, Kraft C, Peters M, Abisambra JF, Duff KE, Weeber EJ, Gestwicki JE and Dickey CA. Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuro-protection and reduced soluble tau burden. Molecular neurodegeneration. 5:45. O’LearyJC3rd LiQ MarinecP BlairLJ CongdonEE JohnsonAG JinwalUK KorenJ3rd JonesJR KraftC PetersM AbisambraJF DuffKE WeeberEJ GestwickiJE DickeyCA Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuro-protection and reduced soluble tau burden Molecular neurodegeneration 5 45 10.1186/1750-1326-5-45 Search in Google Scholar

114 Wen Y, Li W, Poteet EC, Xie L, Tan C, Yan LJ, Ju X, Liu R, Qian H, Marvin MA, Goldberg MS, She H, Mao Z, Simpkins JW and Yang SH. Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. The Journal of biological chemistry. 286:16504–15. WenY LiW PoteetEC XieL TanC YanLJ JuX LiuR QianH MarvinMA GoldbergMS SheH MaoZ SimpkinsJW YangSH Alternative mitochondrial electron transfer as a novel strategy for neuroprotection The Journal of biological chemistry 286 16504 15 10.1074/jbc.M110.208447 Search in Google Scholar

115 Gabrielli D, Belisle E, Severino D, Kowaltowski AJ and Baptista MS. Binding, aggregation and photochemical properties of methylene blue in mitochondrial suspensions. Photochemistry and photobiology. 2004;79:227–32. GabrielliD BelisleE SeverinoD KowaltowskiAJ BaptistaMS Binding, aggregation and photochemical properties of methylene blue in mitochondrial suspensions Photochemistry and photobiology 2004 79 227 32 10.1562/BE-03-27.1 Search in Google Scholar

116 Mellish KJ, Cox RD, Vernon DI, Griffiths J and Brown SB. In vitro photodynamic activity of a series of methylene blue analogues. Photochemistry and photobiology. 2002;75:392–7. MellishKJ CoxRD VernonDI GriffithsJ BrownSB In vitro photodynamic activity of a series of methylene blue analogues Photochemistry and photobiology 2002 75 392 7 10.1562/0031-8655(2002)075<0392:IVPAOA>2.0.CO;2 Search in Google Scholar

117 Tretter L, Horvath G, Holgyesi A, Essek F and Adam-Vizi V. Enhanced hydrogen peroxide generation accompanies the beneficial bioenergetic effects of methylene blue in isolated brain mitochondria. Free radical biology & medicine. 2014;77:317–30. TretterL HorvathG HolgyesiA EssekF Adam-ViziV Enhanced hydrogen peroxide generation accompanies the beneficial bioenergetic effects of methylene blue in isolated brain mitochondria Free radical biology & medicine 2014 77 317 30 10.1016/j.freeradbiomed.2014.09.024 Search in Google Scholar

118 Mekala NK, Kurdys J, Depuydt MM, Vazquez EJ and Rosca MG. Apoptosis inducing factor deficiency causes retinal photoreceptor degeneration. The protective role of the redox compound methylene blue. Redox Biol. 2019;20:107–117. MekalaNK KurdysJ DepuydtMM VazquezEJ RoscaMG Apoptosis inducing factor deficiency causes retinal photoreceptor degeneration. The protective role of the redox compound methylene blue Redox Biol 2019 20 107 117 10.1016/j.redox.2018.09.023 Search in Google Scholar

119 Berthiaume JM, Hsiung CH, Austin AB, McBrayer SP, Depuydt MM, Chandler MP, Miyagi M and Rosca MG. Methylene blue decreases mitochondrial lysine acetylation in the diabetic heart. Mol Cell Biochem. 2017;432:7–24. BerthiaumeJM HsiungCH AustinAB McBrayerSP DepuydtMM ChandlerMP MiyagiM RoscaMG Methylene blue decreases mitochondrial lysine acetylation in the diabetic heart Mol Cell Biochem 2017 432 7 24 10.1007/s11010-017-2993-1 Search in Google Scholar

120 Chouchani ET, Pell VR, Gaude E, Aksentijevic D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord ENJ, Smith AC, Eyassu F, Shirley R, Hu CH, Dare AJ, James AM, Rogatti S, Hartley RC, Eaton S, Costa ASH, Brookes PS, Davidson SM, Duchen MR, Saeb-Parsy K, Shattock MJ, Robinson AJ, Work LM, Frezza C, Krieg T and Murphy MP. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014;515:431–435. ChouchaniET PellVR GaudeE AksentijevicD SundierSY RobbEL LoganA NadtochiySM OrdENJ SmithAC EyassuF ShirleyR HuCH DareAJ JamesAM RogattiS HartleyRC EatonS CostaASH BrookesPS DavidsonSM DuchenMR Saeb-ParsyK ShattockMJ RobinsonAJ WorkLM FrezzaC KriegT MurphyMP Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS Nature 2014 515 431 435 10.1038/nature13909 Search in Google Scholar

121 Molyneux SL, Florkowski CM, George PM, Pilbrow AP, Frampton CM, Lever M and Richards AM. Coenzyme Q10: an independent predictor of mortality in chronic heart failure. J Am Coll Cardiol. 2008;52:1435–41. MolyneuxSL FlorkowskiCM GeorgePM PilbrowAP FramptonCM LeverM RichardsAM Coenzyme Q10: an independent predictor of mortality in chronic heart failure J Am Coll Cardiol 2008 52 1435 41 10.1016/j.jacc.2008.07.044 Search in Google Scholar

122 McMurray JJ, Dunselman P, Wedel H, Cleland JG, Lindberg M, Hjalmarson A, Kjekshus J, Waagstein F, Apetrei E, Barrios V, Bohm M, Kamensky G, Komajda M, Mareev V, Wikstrand J and Group CS. Coenzyme Q10, rosuvastatin, and clinical outcomes in heart failure: a pre-specified substudy of CORONA (controlled rosuvastatin multinational study in heart failure). J Am Coll Cardiol. 2010;56:1196–204. McMurrayJJ DunselmanP WedelH ClelandJG LindbergM HjalmarsonA KjekshusJ WaagsteinF ApetreiE BarriosV BohmM KamenskyG KomajdaM MareevV WikstrandJ Group CS Coenzyme Q10, rosuvastatin, and clinical outcomes in heart failure: a pre-specified substudy of CORONA (controlled rosuvastatin multinational study in heart failure) J Am Coll Cardiol 2010 56 1196 204 10.1016/j.jacc.2010.02.07520883926 Search in Google Scholar

123 Mortensen SA, Rosenfeldt F, Kumar A, Dolliner P, Filipiak KJ, Pella D, Alehagen U, Steurer G, Littarru GP and Investigators QSS. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail. 2014;2:641–9. MortensenSA RosenfeldtF KumarA DollinerP FilipiakKJ PellaD AlehagenU SteurerG LittarruGP Investigators QSS The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial JACC Heart Fail 2014 2 641 9 10.1016/j.jchf.2014.06.00825282031 Search in Google Scholar

124 Murphy MP. Targeting lipophilic cations to mitochondria. Biochim Biophys Acta. 2008;1777:1028–31. MurphyMP Targeting lipophilic cations to mitochondria Biochim Biophys Acta 2008 1777 1028 31 10.1016/j.bbabio.2008.03.02918439417 Search in Google Scholar

125 Graham D, Huynh NN, Hamilton CA, Beattie E, Smith RA, Cocheme HM, Murphy MP and Dominiczak AF. Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension. 2009;54:322–8. GrahamD HuynhNN HamiltonCA BeattieE SmithRA CochemeHM MurphyMP DominiczakAF Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy Hypertension 2009 54 322 8 10.1161/HYPERTENSIONAHA.109.13035119581509 Search in Google Scholar

126 Jaber S and Polster BM. Idebenone and neuroprotection: anti-oxidant, pro-oxidant, or electron carrier? J Bioenerg Biomembr. 2015;47:111–8. JaberS PolsterBM Idebenone and neuroprotection: anti-oxidant, pro-oxidant, or electron carrier? J Bioenerg Biomembr 2015 47 111 8 10.1007/s10863-014-9571-y448781525262284 Search in Google Scholar

127 El-Hattab AW, Zarante AM, Almannai M and Scaglia F. Therapies for mitochondrial diseases and current clinical trials. Mol Genet Metab. 2017;122:1–9. El-HattabAW ZaranteAM AlmannaiM ScagliaF Therapies for mitochondrial diseases and current clinical trials Mol Genet Metab 2017 122 1 9 10.1016/j.ymgme.2017.09.009577311328943110 Search in Google Scholar

128 Buyse GM, Van der Mieren G, Erb M, D’Hooge J, Herijgers P, Verbeken E, Jara A, Van Den Bergh A, Mertens L, Courdier-Fruh I, Barzaghi P and Meier T. Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance. Eur Heart J. 2009;30:116–24. BuyseGM Van der MierenG ErbM D’HoogeJ HerijgersP VerbekenE JaraA Van Den BerghA MertensL Courdier-FruhI BarzaghiP MeierT Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance Eur Heart J 2009 30 116 24 10.1093/eurheartj/ehn406263908618784063 Search in Google Scholar

129 Lerman-Sagie T, Rustin P, Lev D, Yanoov M, Leshinsky-Silver E, Sagie A, Ben-Gal T and Munnich A. Dramatic improvement in mitochondrial cardiomyopathy following treatment with idebenone. J Inherit Metab Dis. 2001;24:28–34. Lerman-SagieT RustinP LevD YanoovM Leshinsky-SilverE SagieA Ben-GalT MunnichA Dramatic improvement in mitochondrial cardiomyopathy following treatment with idebenone J Inherit Metab Dis 2001 24 28 34 10.1023/A:1005642302316 Search in Google Scholar

130 Szeto HH. Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury. Antioxid Redox Signal. 2008;10:601–19. SzetoHH Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury Antioxid Redox Signal 2008 10 601 19 10.1089/ars.2007.189217999629 Search in Google Scholar

131 Szeto HH, Liu S, Soong Y, Wu D, Darrah SF, Cheng FY, Zhao Z, Ganger M, Tow CY and Seshan SV. Mitochondria-targeted peptide accelerates ATP recovery and reduces ischemic kidney injury. J Am Soc Nephrol. 2011;22:1041–52. SzetoHH LiuS SoongY WuD DarrahSF ChengFY ZhaoZ GangerM TowCY SeshanSV Mitochondria-targeted peptide accelerates ATP recovery and reduces ischemic kidney injury J Am Soc Nephrol 2011 22 1041 52 10.1681/ASN.2010080808310372421546574 Search in Google Scholar

132 Birk AV, Liu S, Soong Y, Mills W, Singh P, Warren JD, Seshan SV, Pardee JD and Szeto HH. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 2013;24:1250–61. BirkAV LiuS SoongY MillsW SinghP WarrenJD SeshanSV PardeeJD SzetoHH The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin J Am Soc Nephrol 2013 24 1250 61 10.1681/ASN.2012121216373670023813215 Search in Google Scholar

133 Dai DF, Chen T, Szeto H, Nieves-Cintron M, Kutyavin V, Santana LF and Rabinovitch PS. Mitochondrial targeted antioxidant Peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol. 2011;58:73–82. DaiDF ChenT SzetoH Nieves-CintronM KutyavinV SantanaLF RabinovitchPS Mitochondrial targeted antioxidant Peptide ameliorates hypertensive cardiomyopathy J Am Coll Cardiol 2011 58 73 82 10.1016/j.jacc.2010.12.044374201021620606 Search in Google Scholar

134 Dai DF, Hsieh EJ, Chen T, Menendez LG, Basisty NB, Tsai L, Beyer RP, Crispin DA, Shulman NJ, Szeto HH, Tian R, MacCoss MJ and Rabinovitch PS. Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail. 2013;6:1067–76. DaiDF HsiehEJ ChenT MenendezLG BasistyNB TsaiL BeyerRP CrispinDA ShulmanNJ SzetoHH TianR MacCossMJ RabinovitchPS Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides Circ Heart Fail 2013 6 1067 76 10.1161/CIRCHEARTFAILURE.113.000406385623823935006 Search in Google Scholar

135 Shi J, Dai W, Hale SL, Brown DA, Wang M, Han X and Kloner RA. Bendavia restores mitochondrial energy metabolism gene expression and suppresses cardiac fibrosis in the border zone of the infarcted heart. Life Sci. 2015;141:170–8. ShiJ DaiW HaleSL BrownDA WangM HanX KlonerRA Bendavia restores mitochondrial energy metabolism gene expression and suppresses cardiac fibrosis in the border zone of the infarcted heart Life Sci 2015 141 170 8 10.1016/j.lfs.2015.09.022497330926431885 Search in Google Scholar

136 Eirin A, Williams BJ, Ebrahimi B, Zhang X, Crane JA, Lerman A, Textor SC and Lerman LO. Mitochondrial targeted peptides attenuate residual myocardial damage after reversal of experimental renovascular hypertension. J Hypertens. 2014;32:154–65. EirinA WilliamsBJ EbrahimiB ZhangX CraneJA LermanA TextorSC LermanLO Mitochondrial targeted peptides attenuate residual myocardial damage after reversal of experimental renovascular hypertension J Hypertens 2014 32 154 65 10.1097/HJH.0b013e3283658a53397656724048008 Search in Google Scholar

137 Sabbah HN, Gupta RC, Kohli S, Wang M, Hachem S and Zhang K. Chronic Therapy With Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs With Advanced Heart Failure. Circ Heart Fail. 2016;9:e002206. SabbahHN GuptaRC KohliS WangM HachemS ZhangK Chronic Therapy With Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs With Advanced Heart Failure Circ Heart Fail 2016 9 e002206 10.1161/CIRCHEARTFAILURE.115.002206474354326839394 Search in Google Scholar

138 Daubert MA, Yow E, Dunn G, Marchev S, Barnhart H, Douglas PS, O’Connor C, Goldstein S, Udelson JE and Sabbah HN. Novel Mitochondria-Targeting Peptide in Heart Failure Treatment: A Randomized, Placebo-Controlled Trial of Elamipretide. Circ Heart Fail. 2017;10. DaubertMA YowE DunnG MarchevS BarnhartH DouglasPS O’ConnorC GoldsteinS UdelsonJE SabbahHN Novel Mitochondria-Targeting Peptide in Heart Failure Treatment: A Randomized, Placebo-Controlled Trial of Elamipretide Circ Heart Fail 2017 10 10.1161/CIRCHEARTFAILURE.117.00438929217757 Search in Google Scholar

139 Brown DA and O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88:241–9. BrownDA O’RourkeB Cardiac mitochondria and arrhythmias Cardiovasc Res 2010 88 241 9 10.1093/cvr/cvq231298094320621924 Search in Google Scholar

140 Kosmala W, Holland DJ, Rojek A, Wright L, Przewlocka-Kosmala M and Marwick TH. Effect of If-channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: a randomized trial. J Am Coll Cardiol. 2013;62:1330–8. KosmalaW HollandDJ RojekA WrightL Przewlocka-KosmalaM MarwickTH Effect of If-channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: a randomized trial J Am Coll Cardiol 2013 62 1330 8 10.1016/j.jacc.2013.06.04323916925 Search in Google Scholar

141 Gorski PA, Ceholski DK and Hajjar RJ. Altered myocardial calcium cycling and energetics in heart failure–a rational approach for disease treatment. Cell Metab. 2015;21:183–194. GorskiPA CeholskiDK HajjarRJ Altered myocardial calcium cycling and energetics in heart failure–a rational approach for disease treatment Cell Metab 2015 21 183 194 10.1016/j.cmet.2015.01.005433899725651173 Search in Google Scholar

142 Gong HB, Wang L, Lv Q and Wang J. Improved systolic function of rat cardiocytes during heart failure by overexpression of SERCA2a. Eur Rev Med Pharmacol Sci. 2016;20:1590–6. GongHB WangL LvQ WangJ Improved systolic function of rat cardiocytes during heart failure by overexpression of SERCA2a Eur Rev Med Pharmacol Sci 2016 20 1590 6 Search in Google Scholar

143 Mattila M, Koskenvuo J, Soderstrom M, Eerola K and Savontaus M. Intramyocardial injection of SERCA2a-expressing lentivirus improves myocardial function in doxorubicin-induced heart failure. J Gene Med. 2016;18:124–33. MattilaM KoskenvuoJ SoderstromM EerolaK SavontausM Intramyocardial injection of SERCA2a-expressing lentivirus improves myocardial function in doxorubicin-induced heart failure J Gene Med 2016 18 124 33 10.1002/jgm.2885 Search in Google Scholar

144 Greenberg B, Butler J, Felker GM, Ponikowski P, Voors AA, Desai AS, Barnard D, Bouchard A, Jaski B, Lyon AR, Pogoda JM, Rudy JJ and Zsebo KM. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet. 2016;387:1178–86. GreenbergB ButlerJ FelkerGM PonikowskiP VoorsAA DesaiAS BarnardD BouchardA JaskiB LyonAR PogodaJM RudyJJ ZseboKM Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial Lancet 2016 387 1178 86 10.1016/S0140-6736(16)00082-9 Search in Google Scholar