Thorac Cardiovasc Surg 2018; 66(01): 011-019
DOI: 10.1055/s-0037-1615263
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Heart and Mitochondria: Pathophysiology and Implications for Cardiac Surgeons

Bernd Niemann
1   Klinik für Herz-, Kinderherz- und Gefäßchirurgie, Justus-Liebig-Universität Giessen, UKGM, Giessen, Hessen, Germany
,
Michael Schwarzer
2   Department of Cardiothoracic Surgery, Friedrich Schiller University of Jena, Jena, Germany
,
Susanne Rohrbach
3   Institute for Physiology, Justus Liebig University Giessen, Giessen, Germany
› Author Affiliations
Further Information

Publication History

26 May 2017

30 November 2017

Publication Date:
19 December 2017 (online)

Abstract

Excluding the heart from systemic circulation during cardiac surgery renders the myocardium ischemic, resulting in cardiac damage. In addition, another hit to the myocardium will occur upon restoration of blood flow, in the reperfusion phase. Experimental data from animal models have revealed that loss of cardiac metabolic flexibility and mitochondrial dysfunctions contributes to contractile impairment in hypertrophied, failing, obese, and diabetic hearts. Such diseased hearts are prone to myocardial ischemia–reperfusion (I/R) injury. Although analyses in human cardiac samples are not as comprehensive as animal data, similar disease-associated metabolic and mitochondrial changes exist. Considering increasing age and comorbidities in patients nowadays, it is not surprising that I/R injuries remain a major cause of morbidity and mortality after cardiac surgery. Mitochondria have emerged as critical targets but also key regulators of myocardial I/R injury, and the extent of mitochondrial damage is a major determinant of myocardial I/R injury. Although cardioprotective mechanisms are diverse, many come together and involve steps at the point of mitochondria. We will, therefore, provide a description of mitochondrial alterations observed in various cardiac disease states and discuss the current experimental knowledge of the role of mitochondria in I/R and of potential protective mechanisms against myocardial I/R injury involving mitochondria. Within this review, we will focus on the protection against I/R injury conferred by caloric restriction (CR) and by ischemic conditioning. Further research is needed to establish whether strategies targeting mitochondria, which have been proposed from preclinical studies, could be translated into cardioprotective therapies against I/R injury in patients.

 
  • References

  • 1 Abdurrachim D, Luiken JJ, Nicolay K, Glatz JF, Prompers JJ, Nabben M. Good and bad consequences of altered fatty acid metabolism in heart failure: evidence from mouse models. Cardiovasc Res 2015; 106 (02) 194-205
  • 2 Doenst T, Pytel G, Schrepper A. , et al. Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload. Cardiovasc Res 2010; 86 (03) 461-470
  • 3 Zhang L, Jaswal JS, Ussher JR. , et al. Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy. Circ Heart Fail 2013; 6 (05) 1039-1048
  • 4 Buchanan J, Mazumder PK, Hu P. , et al. Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 2005; 146 (12) 5341-5349
  • 5 Peterson LR, Herrero P, Schechtman KB. , et al. Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation 2004; 109 (18) 2191-2196
  • 6 Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev 2010; 90 (01) 207-258
  • 7 Cole MA, Murray AJ, Cochlin LE. , et al. A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart. Basic Res Cardiol 2011; 106 (03) 447-457
  • 8 Duicu O, Juşcă C, Falniţă L. , et al. Substrate-specific impairment of mitochondrial respiration in permeabilized fibers from patients with coronary heart disease versus valvular disease. Mol Cell Biochem 2013; 379 (1-2): 229-234
  • 9 Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res 2013; 113 (06) 709-724
  • 10 Kato T, Niizuma S, Inuzuka Y. , et al. Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. Circ Heart Fail 2010; 3 (03) 420-430
  • 11 Scheubel RJ, Tostlebe M, Simm A. , et al. Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression. J Am Coll Cardiol 2002; 40 (12) 2174-2181
  • 12 Lemieux H, Semsroth S, Antretter H, Höfer D, Gnaiger E. Mitochondrial respiratory control and early defects of oxidative phosphorylation in the failing human heart. Int J Biochem Cell Biol 2011; 43 (12) 1729-1738
  • 13 Lehman JJ, Kelly DP. Gene regulatory mechanisms governing energy metabolism during cardiac hypertrophic growth. Heart Fail Rev 2002; 7 (02) 175-185
  • 14 Niemann B, Chen Y, Teschner M, Li L, Silber RE, Rohrbach S. Obesity induces signs of premature cardiac aging in younger patients: the role of mitochondria. J Am Coll Cardiol 2011; 57 (05) 577-585
  • 15 Montaigne D, Marechal X, Coisne A. , et al. Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation 2014; 130 (07) 554-564
  • 16 van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P. Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovasc Res 2011; 92 (01) 10-18
  • 17 Sharma S, Adrogue JV, Golfman L. , et al. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J 2004; 18 (14) 1692-1700
  • 18 Chokshi A, Drosatos K, Cheema FH. , et al. Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. Circulation 2012; 125 (23) 2844-2853
  • 19 Krishnan KJ, Greaves LC, Reeve AK, Turnbull DM. Mitochondrial DNA mutations and aging. Ann N Y Acad Sci 2007; 1100: 227-240
  • 20 Aurich AC, Niemann B, Pan R. , et al. Age-dependent effects of high fat-diet on murine left ventricles: role of palmitate. Basic Res Cardiol 2013; 108 (05) 369
  • 21 Preston CC, Oberlin AS, Holmuhamedov EL. , et al. Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart. Mech Ageing Dev 2008; 129 (06) 304-312
  • 22 Niemann B, Chen Y, Issa H, Silber RE, Rohrbach S. Caloric restriction delays cardiac ageing in rats: role of mitochondria. Cardiovasc Res 2010; 88 (02) 267-276
  • 23 Rohrbach S, Niemann B, Abushouk AM, Holtz J. Caloric restriction and mitochondrial function in the ageing myocardium. Exp Gerontol 2006; 41 (05) 525-531
  • 24 Boengler K, Kosiol M, Mayr M, Schulz R, Rohrbach S. Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue. J Cachexia Sarcopenia Muscle 2017; 8 (03) 349-369
  • 25 Tang Y, Mi C, Liu J, Gao F, Long J. Compromised mitochondrial remodeling in compensatory hypertrophied myocardium of spontaneously hypertensive rat. Cardiovasc Pathol 2014; 23 (02) 101-106
  • 26 Chen L, Gong Q, Stice JP, Knowlton AA. Mitochondrial OPA1, apoptosis, and heart failure. Cardiovasc Res 2009; 84 (01) 91-99
  • 27 Shirakabe A, Zhai P, Ikeda Y. , et al. Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure. Circulation 2016; 133 (13) 1249-1263
  • 28 Chen L, Liu T, Tran A. , et al. OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability. J Am Heart Assoc 2012; 1 (05) e003012
  • 29 Wai T, García-Prieto J, Baker MJ. , et al. Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 2015; 350 (6265): aad0116
  • 30 Zhao L, Zou X, Feng Z. , et al. Evidence for association of mitochondrial metabolism alteration with lipid accumulation in aging rats. Exp Gerontol 2014; 56: 3-12
  • 31 Ljubicic V, Menzies KJ, Hood DA. Mitochondrial dysfunction is associated with a pro-apoptotic cellular environment in senescent cardiac muscle. Mech Ageing Dev 2010; 131 (02) 79-88
  • 32 Hudson KF. A phenomenon of paradox: myocardial reperfusion injury. Heart Lung 1994; 23 (05) 384-393 , quiz 394–396
  • 33 Palmer JW, Tandler B, Hoppel CL. Biochemical properties of subsarcolemmal and interfibrillar mitochondria isolated from rat cardiac muscle. J Biol Chem 1977; 252 (23) 8731-8739
  • 34 Piquereau J, Caffin F, Novotova M. , et al. Mitochondrial dynamics in the adult cardiomyocytes: which roles for a highly specialized cell?. Front Physiol 2013; 4: 102
  • 35 Hollander JM, Thapa D, Shepherd DL. Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: influence of cardiac pathologies. Am J Physiol Heart Circ Physiol 2014; 307 (01) H1-H14
  • 36 García-Niño WR, Correa F, Rodríguez-Barrena JI. , et al. Cardioprotective kinase signaling to subsarcolemmal and interfibrillar mitochondria is mediated by caveolar structures. Basic Res Cardiol 2017; 112 (02) 15
  • 37 Lesnefsky EJ, Tandler B, Ye J, Slabe TJ, Turkaly J, Hoppel CL. Myocardial ischemia decreases oxidative phosphorylation through cytochrome oxidase in subsarcolemmal mitochondria. Am J Physiol 1997; 273 (3 Pt 2): H1544-H1554
  • 38 Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Federici A, Ruggiero FM. Decrease in mitochondrial complex I activity in ischemic/reperfused rat heart: involvement of reactive oxygen species and cardiolipin. Circ Res 2004; 94 (01) 53-59
  • 39 Grover GJ, Atwal KS, Sleph PG. , et al. Excessive ATP hydrolysis in ischemic myocardium by mitochondrial F1F0-ATPase: effect of selective pharmacological inhibition of mitochondrial ATPase hydrolase activity. Am J Physiol Heart Circ Physiol 2004; 287 (04) H1747-H1755
  • 40 Rohrbach S, Aslam M, Niemann B, Schulz R. Impact of caloric restriction on myocardial ischaemia/reperfusion injury and new therapeutic options to mimic its effects. Br J Pharmacol 2014; 171 (12) 2964-2992
  • 41 Kaludercic N, Carpi A, Menabò R, Di Lisa F, Paolocci N. Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury. Biochim Biophys Acta 2011; 1813 (07) 1323-1332
  • 42 Di Lisa F, Giorgio M, Ferdinandy P, Schulz R. New aspects of p66Shc in ischaemia reperfusion injury and other cardiovascular diseases. Br J Pharmacol 2017; 174 (12) 1690-1703
  • 43 Di Lisa F, Carpi A, Giorgio V, Bernardi P. The mitochondrial permeability transition pore and cyclophilin D in cardioprotection. Biochim Biophys Acta 2011; 1813 (07) 1316-1322
  • 44 Williams GS, Boyman L, Lederer WJ. Mitochondrial calcium and the regulation of metabolism in the heart. J Mol Cell Cardiol 2015; 78: 35-45
  • 45 Finkel T, Menazza S, Holmström KM. , et al. The ins and outs of mitochondrial calcium. Circ Res 2015; 116 (11) 1810-1819
  • 46 Garcia-Dorado D, Ruiz-Meana M, Inserte J, Rodriguez-Sinovas A, Piper HM. Calcium-mediated cell death during myocardial reperfusion. Cardiovasc Res 2012; 94 (02) 168-180
  • 47 Ong SB, Kalkhoran SB, Hernández-Reséndiz S, Samangouei P, Ong SG, Hausenloy DJ. Mitochondrial-shaping proteins in cardiac health and disease - the long and the short of it!. Cardiovasc Drugs Ther 2017; 31 (01) 87-107
  • 48 Papanicolaou KN, Ngoh GA, Dabkowski ER. , et al. Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death. Am J Physiol Heart Circ Physiol 2012; 302 (01) H167-H179
  • 49 Hall AR, Burke N, Dongworth RK. , et al. Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction. Cell Death Dis 2016; 7: e2238
  • 50 Disatnik MH, Ferreira JC, Campos JC. , et al. Acute inhibition of excessive mitochondrial fission after myocardial infarction prevents long-term cardiac dysfunction. J Am Heart Assoc 2013; 2 (05) e000461
  • 51 Ishikita A, Matoba T, Ikeda G. , et al. Nanoparticle-mediated delivery of mitochondrial division inhibitor 1 to the myocardium protects the heart from ischemia-reperfusion injury through inhibition of mitochondria outer membrane permeabilization: a new therapeutic modality for acute myocardial infarction. J Am Heart Assoc 2016; 5 (07) 5
  • 52 Ikeda Y, Shirakabe A, Maejima Y. , et al. Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ Res 2015; 116 (02) 264-278
  • 53 Gottlieb RA, Finley KD, Mentzer Jr RM. Cardioprotection requires taking out the trash. Basic Res Cardiol 2009; 104 (02) 169-180
  • 54 Huang C, Andres AM, Ratliff EP, Hernandez G, Lee P, Gottlieb RA. Preconditioning involves selective mitophagy mediated by Parkin and p62/SQSTM1. PLoS One 2011; 6 (06) e20975
  • 55 McLeod CJ, Pagel I, Sack MN. The mitochondrial biogenesis regulatory program in cardiac adaptation to ischemia--a putative target for therapeutic intervention. Trends Cardiovasc Med 2005; 15 (03) 118-123
  • 56 Andres AM, Tucker KC, Thomas A. , et al. Mitophagy and mitochondrial biogenesis in atrial tissue of patients undergoing heart surgery with cardiopulmonary bypass. JCI Insight 2017; 2 (04) e89303
  • 57 Jahania SM, Sengstock D, Vaitkevicius P. , et al. Activation of the homeostatic intracellular repair response during cardiac surgery. J Am Coll Surg 2013; 216 (04) 719-726 , discussion 726–729
  • 58 Barja G. Rate of generation of oxidative stress-related damage and animal longevity. Free Radic Biol Med 2002; 33 (09) 1167-1172
  • 59 Speakman JR, Mitchell SE. Caloric restriction. Mol Aspects Med 2011; 32 (03) 159-221
  • 60 Rae M. It's never too late: calorie restriction is effective in older mammals. Rejuvenation Res 2004; 7 (01) 3-8
  • 61 Dirks AJ, Leeuwenburgh C. Caloric restriction in humans: potential pitfalls and health concerns. Mech Ageing Dev 2006; 127 (01) 1-7
  • 62 Shanley DP, Kirkwood TB. Caloric restriction does not enhance longevity in all species and is unlikely to do so in humans. Biogerontology 2006; 7 (03) 165-168
  • 63 Mattison JA, Roth GS, Beasley TM. , et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 2012; 489 (7415): 318-321
  • 64 Morley JE, Chahla E, Alkaade S. Antiaging, longevity and calorie restriction. Curr Opin Clin Nutr Metab Care 2010; 13 (01) 40-45
  • 65 Meyer TE, Kovács SJ, Ehsani AA, Klein S, Holloszy JO, Fontana L. Long-term caloric restriction ameliorates the decline in diastolic function in humans. J Am Coll Cardiol 2006; 47 (02) 398-402
  • 66 Rochon J, Bales CW, Ravussin E. , et al; CALERIE Study Group. Design and conduct of the CALERIE study: comprehensive assessment of the long-term effects of reducing intake of energy. J Gerontol A Biol Sci Med Sci 2011; 66 (01) 97-108
  • 67 Romashkan SV, Das SK, Villareal DT. , et al; CALERIE Study Group. Safety of two-year caloric restriction in non-obese healthy individuals. Oncotarget 2016; 7 (15) 19124-19133
  • 68 Sparks LM, Redman LM, Conley KE. , et al. Effects of 12 months of caloric restriction on muscle mitochondrial function in healthy individuals. J Clin Endocrinol Metab 2017; 102 (01) 111-121
  • 69 Edwards AG, Donato AJ, Lesniewski LA, Gioscia RA, Seals DR, Moore RL. Life-long caloric restriction elicits pronounced protection of the aged myocardium: a role for AMPK. Mech Ageing Dev 2010; 131 (11-12): 739-742
  • 70 Shinmura K, Tamaki K, Bolli R. Short-term caloric restriction improves ischemic tolerance independent of opening of ATP-sensitive K+ channels in both young and aged hearts. J Mol Cell Cardiol 2005; 39 (02) 285-296
  • 71 Xing Y, Musi N, Fujii N. , et al. Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase. J Biol Chem 2003; 278 (31) 28372-28377
  • 72 Russell III RR, Li J, Coven DL. , et al. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 2004; 114 (04) 495-503
  • 73 Carvajal K, Zarrinpashneh E, Szarszoi O. , et al. Dual cardiac contractile effects of the alpha2-AMPK deletion in low-flow ischemia and reperfusion. Am J Physiol Heart Circ Physiol 2007; 292 (06) H3136-H3147
  • 74 Nishino Y, Miura T, Miki T. , et al. Ischemic preconditioning activates AMPK in a PKC-dependent manner and induces GLUT4 up-regulation in the late phase of cardioprotection. Cardiovasc Res 2004; 61 (03) 610-619
  • 75 Niemann B, Pan R, Teschner M, Boening A, Silber RE, Rohrbach S. Age and obesity-associated changes in the expression and activation of components of the AMPK signaling pathway in human right atrial tissue. Exp Gerontol 2013; 48 (01) 55-63
  • 76 Tani M, Suganuma Y, Hasegawa H. , et al. Decrease in ischemic tolerance with aging in isolated perfused Fischer 344 rat hearts: relation to increases in intracellular Na+ after ischemia. J Mol Cell Cardiol 1997; 29 (11) 3081-3089
  • 77 Abete P, Ferrara N, Cioppa A. , et al. Preconditioning does not prevent postischemic dysfunction in aging heart. J Am Coll Cardiol 1996; 27 (07) 1777-1786
  • 78 Schulman D, Latchman DS, Yellon DM. Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2001; 281 (04) H1630-H1636
  • 79 Lee TM, Su SF, Chou TF, Lee YT, Tsai CH. Loss of preconditioning by attenuated activation of myocardial ATP-sensitive potassium channels in elderly patients undergoing coronary angioplasty. Circulation 2002; 105 (03) 334-340
  • 80 Boengler K, Buechert A, Heinen Y. , et al. Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res 2008; 102 (01) 131-135
  • 81 Shinmura K, Tamaki K, Bolli R. Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1. Am J Physiol Heart Circ Physiol 2008; 295 (06) H2348-H2355
  • 82 Abete P, Testa G, Galizia G. , et al. Tandem action of exercise training and food restriction completely preserves ischemic preconditioning in the aging heart. Exp Gerontol 2005; 40 (1-2): 43-50
  • 83 Broderick TL, Belke T, Driedzic WR. Effects of chronic caloric restriction on mitochondrial respiration in the ischemic reperfused rat heart. Mol Cell Biochem 2002; 233 (1-2): 119-125
  • 84 Mitchell JR, Verweij M, Brand K. , et al. Short-term dietary restriction and fasting precondition against ischemia reperfusion injury in mice. Aging Cell 2010; 9 (01) 40-53
  • 85 Yamagishi T, Bessho M, Yanagida S. , et al. Severe, short-term food restriction improves cardiac function following ischemia/reperfusion in perfused rat hearts. Heart Vessels 2010; 25 (05) 417-425
  • 86 Cerqueira FM, Laurindo FR, Kowaltowski AJ. Mild mitochondrial uncoupling and calorie restriction increase fasting eNOS, akt and mitochondrial biogenesis. PLoS One 2011; 6 (03) e18433
  • 87 Gomes LC, Di Benedetto G, Scorrano L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 2011; 13 (05) 589-598
  • 88 Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132 (01) 27-42
  • 89 Wohlgemuth SE, Seo AY, Marzetti E, Lees HA, Leeuwenburgh C. Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise. Exp Gerontol 2010; 45 (02) 138-148
  • 90 Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74 (05) 1124-1136
  • 91 Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet 1993; 342 (8866): 276-277
  • 92 Lesnefsky EJ, Chen Q, Tandler B, Hoppel CL. Mitochondrial dysfunction and myocardial ischemia-reperfusion: implications for novel therapies. Annu Rev Pharmacol Toxicol 2017; 57: 535-565
  • 93 Zhao ZQ, Corvera JS, Halkos ME. , et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 2003; 285 (02) H579-H588
  • 94 Heusch G. Remote conditioning: the future of cardioprotection?. J Cardiovasc Med (Hagerstown) 2013; 14 (03) 176-179
  • 95 Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD. Myocardial protection by brief ischemia in noncardiac tissue. Circulation 1996; 94 (09) 2193-2200
  • 96 Birnbaum Y, Hale SL, Kloner RA. Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation 1997; 96 (05) 1641-1646
  • 97 Slagsvold KH, Rognmo O, Høydal M, Wisløff U, Wahba A. Remote ischemic preconditioning preserves mitochondrial function and influences myocardial microRNA expression in atrial myocardium during coronary bypass surgery. Circ Res 2014; 114 (05) 851-859
  • 98 Skyschally A, Gent S, Amanakis G, Schulte C, Kleinbongard P, Heusch G. Across-species transfer of protection by remote ischemic preconditioning with species-specific myocardial signal transduction by reperfusion injury salvage kinase and survival activating factor enhancement pathways. Circ Res 2015; 117 (03) 279-288
  • 99 Thielmann M, Kottenberg E, Kleinbongard P. , et al. Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial. Lancet 2013; 382 (9892): 597-604
  • 100 Hausenloy DJ, Candilio L, Evans R. , et al; ERICCA Trial Investigators. Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med 2015; 373 (15) 1408-1417
  • 101 Meybohm P, Bein B, Brosteanu O. , et al; RIPHeart Study Collaborators. A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med 2015; 373 (15) 1397-1407
  • 102 Heusch G. Critical issues for the translation of cardioprotection. Circ Res 2017; 120 (09) 1477-1486
  • 103 Kristiansen SB, Løfgren B, Støttrup NB. , et al. Ischaemic preconditioning does not protect the heart in obese and lean animal models of type 2 diabetes. Diabetologia 2004; 47 (10) 1716-1721
  • 104 Katakam PV, Jordan JE, Snipes JA, Tulbert CD, Miller AW, Busija DW. Myocardial preconditioning against ischemia-reperfusion injury is abolished in Zucker obese rats with insulin resistance. Am J Physiol Regul Integr Comp Physiol 2007; 292 (02) R920-R926
  • 105 Balakumar P, Singh H, Singh M, Anand-Srivastava MB. The impairment of preconditioning-mediated cardioprotection in pathological conditions. Pharmacol Res 2009; 60 (01) 18-23
  • 106 Kottenberg E, Thielmann M, Bergmann L. , et al. Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol - a clinical trial. Acta Anaesthesiol Scand 2012; 56 (01) 30-38
  • 107 Lemoine S, Zhu L, Gress S, Gérard JL, Allouche S, Hanouz JL. Mitochondrial involvement in propofol-induced cardioprotection: an in vitro study in human myocardium. Exp Biol Med (Maywood) 2016; 241 (05) 527-538