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Pathophysiology of Sepsis-Related Cardiac Dysfunction: Driven by Inflammation, Energy Mismanagement, or Both?

  • Pathophysiology: Neuroendocrine, Vascular, and Metabolic Factors (SD Katz, Section Editor)
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Abstract

Sepsis is a systemic inflammatory response that follows bacterial infection. Cardiac dysfunction is an important consequence of sepsis that affects mortality and has been attributed to either elevated inflammation or suppression of both fatty acid and glucose oxidation and eventual ATP depletion. Moreover, cardiac adrenergic signaling is compromised in septic patients and this aggravates further heart function. While anti-inflammatory therapies are important for the treatment of the disease, administration of anti-inflammatory drugs did not improve survival in septic patients. This review article summarizes findings on inflammatory and other mechanisms that are triggered in sepsis and affect cardiac function and mortality. Particularly, it focuses on the effects of the disease in metabolic pathways, as well as in adrenergic signaling and the potential interplay of the latter with inflammation. It is suggested that therapeutic approaches should include combination of anti-inflammatory treatments, stimulation of energy production, and restoration of adrenergic signaling in the heart.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Lagu T, Rothberg MB, Shieh MS, et al. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med. 2012;40:754–61.

    PubMed  Google Scholar 

  2. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–10.

    CAS  PubMed  Google Scholar 

  3. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005;365:63–78.

    CAS  PubMed  Google Scholar 

  4. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med. 2003;31:1250–6.

    PubMed  Google Scholar 

  5. Zaky A, Deem S, Bendjelid K, Treggiari MM. Characterization of cardiac dysfunction in sepsis: an ongoing challenge. Shock. 2014;41:12–24.

    PubMed  Google Scholar 

  6. Ren J, Wu S. A burning issue: do sepsis and systemic inflammatory response syndrome (SIRS) directly contribute to cardiac dysfunction? Front Biosci. 2006;11:15–22.

    CAS  PubMed  Google Scholar 

  7. Hunter JD, Doddi M. Sepsis and the heart. Br J Anaesth. 2010;104:3–11.

    CAS  PubMed  Google Scholar 

  8. Court O, Kumar A, Parrillo JE. Clinical review: myocardial depression in sepsis and septic shock. Crit Care. 2002;6:500–8.

    PubMed Central  PubMed  Google Scholar 

  9. Zanotti-Cavazzoni SL, Hollenberg SM. Cardiac dysfunction in severe sepsis and septic shock. Curr Opin Crit Care. 2009;15:392–7.

    PubMed  Google Scholar 

  10. Landesberg G, Gilon D, Meroz Y, et al. Diastolic dysfunction and mortality in severe sepsis and septic shock. Eur Heart J. 2012;33:895–903.

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Kumar A, Thota V, Dee L, et al. Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum. J Exp Med. 1996;183:949–58.

    CAS  PubMed  Google Scholar 

  12. Hoffmann JN, Werdan K, Hartl WH, et al. Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds. Shock. 1999;12:174–80.

    CAS  PubMed  Google Scholar 

  13. Natanson C, Eichenholz PW, Danner RL, et al. Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J Exp Med. 1989;169:823–32.

    CAS  PubMed  Google Scholar 

  14. Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science. 1992;257:387–9.

    CAS  PubMed  Google Scholar 

  15. Stein B, Frank P, Schmitz W, et al. Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase. J Mol Cell Cardiol. 1996;28:1631–9.

    CAS  PubMed  Google Scholar 

  16. Schulz R, Panas DL, Catena R, et al. The role of nitric oxide in cardiac depression induced by interleukin-1 beta and tumour necrosis factor-alpha. Br J Pharmacol. 1995;114:27–34.

    PubMed Central  CAS  PubMed  Google Scholar 

  17. Zhong J, Hwang TC, Adams HR, Rubin LJ. Reduced L-type calcium current in ventricular myocytes from endotoxemic guinea pigs. Am J Physiol. 1997;273:H2312–24.

    CAS  PubMed  Google Scholar 

  18. Goldhaber JI, Kim KH, Natterson PD, et al. Effects of TNF-alpha on [Ca2+]i and contractility in isolated adult rabbit ventricular myocytes. Am J Physiol. 1996;271:H1449–55.

    CAS  PubMed  Google Scholar 

  19. de Montmollin E, Aboab J, Mansart A, Annane D. Bench-to-bedside review: beta-adrenergic modulation in sepsis. Crit Care. 2009;13:230.

    PubMed Central  PubMed  Google Scholar 

  20. Drosatos K, Drosatos-Tampakaki Z, Khan R, et al. Inhibition of C-JUN-N-terminal kinase increases cardiac PPAR{alpha} expression and fatty acid oxidation and prevents LPS-induced heart dysfunction. J Biol Chem. 2011;286:36331–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Drosatos K, Khan RS, Trent CM, et al. Peroxisome proliferator-activated receptor-gamma activation prevents sepsis-related cardiac dysfunction and mortality in mice. Circ Heart Fail. 2013;6:550–62.

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Schilling J, Lai L, Sambandam N, et al. Toll-like receptor-mediated inflammatory signaling reprograms cardiac energy metabolism by repressing peroxisome proliferator-activated receptor {gamma} coactivator-1 signaling. Circ Heart Fail. 2011;4:474–82. This study showed that activation of PGC-1, a transcriptional co-activator of PPARs, which promotes cardiac fatty acid oxidation and mitochondrial biogenesis, prevents septic cardiac dysfunction.

  23. Doi K, Leelahavanichkul A, Yuen PS, Star RA. Animal models of sepsis and sepsis-induced kidney injury. J Clin Invest. 2009;119:2868–78.

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Cruz DN, Antonelli M, Fumagalli R, et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. 2009;301:2445–52.

    CAS  PubMed  Google Scholar 

  25. Docke WD, Randow F, Syrbe U, et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med. 1997;3:678–81.

    CAS  PubMed  Google Scholar 

  26. Meisel C, Schefold JC, Pschowski R, et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med. 2009;180:640–8.

    CAS  PubMed  Google Scholar 

  27. Venet F, Foray AP, Villars-Mechin A, et al. IL-7 restores lymphocyte functions in septic patients. J Immunol. 2012;189:5073–81.

    CAS  PubMed  Google Scholar 

  28. Schulte W, Bernhagen J, Bucala R. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets—an updated view. Mediat Inflamm. 2013;2013:165974.

    Google Scholar 

  29. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13:862–74.

    PubMed Central  CAS  PubMed  Google Scholar 

  30. Reddy RC, Chen GH, Tekchandani PK, Standiford TJ. Sepsis-induced immunosuppression: from bad to worse. Immunol Res. 2001;24:273–87.

    CAS  PubMed  Google Scholar 

  31. Volk HD, Reinke P, Docke WD. Clinical aspects: from systemic inflammation to ‘immunoparalysis’. Chem Immunol. 2000;74:162–77.

    CAS  PubMed  Google Scholar 

  32. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2:675–80.

    CAS  PubMed  Google Scholar 

  33. Zuckerman SH, Evans GF, Guthrie L. Transcriptional and post-transcriptional mechanisms involved in the differential expression of LPS-induced IL-1 and TNF mRNA. Immunology. 1991;73:460–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  34. Hambleton J, Weinstein SL, Lem L, DeFranco AL. Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. Proc Natl Acad Sci U S A. 1996;93:2774–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Sanghera JS, Weinstein SL, Aluwalia M, et al. Activation of multiple proline-directed kinases by bacterial lipopolysaccharide in murine macrophages. J Immunol. 1996;156:4457–65.

    CAS  PubMed  Google Scholar 

  36. Ebach DR, Riehl TE, Stenson WF. Opposing effects of tumor necrosis factor receptor 1 and 2 in sepsis due to cecal ligation and puncture. Shock. 2005;23:311–8.

    CAS  PubMed  Google Scholar 

  37. Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985;229:869–71.

    CAS  PubMed  Google Scholar 

  38. Redl H, Schlag G, Paul E, et al. Endogenous modulators of TNF and IL-1 response are under partial control of TNF in baboon bacteremia. Am J Physiol. 1996;271:R1193–8.

    CAS  PubMed  Google Scholar 

  39. Bengtsson A, Redl H, Schlag G, et al. Effects on complement activation and cytokine (TNF-alpha and IL-8) release of infusion of anti-TNF-antibodies or a xanthine derivative (HWA 138) in septic baboons. Acta Anaesthesiol Scand. 1996;40:244–9.

    CAS  PubMed  Google Scholar 

  40. Hinshaw LB, Tekamp-Olson P, Chang AC, et al. Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF alpha). Circ Shock. 1990;30:279–92.

    CAS  PubMed  Google Scholar 

  41. Fisher Jr CJ, Opal SM, Dhainaut JF, et al. Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. The CB0006 sepsis syndrome study group. Crit Care Med. 1993;21:318–27.

    PubMed  Google Scholar 

  42. Dhainaut JF, Vincent JL, Richard C, et al. CDP571, a humanized antibody to human tumor necrosis factor-alpha: safety, pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in patients with septic shock. CPD571 sepsis study group. Crit Care Med. 1995;23:1461–9.

    CAS  PubMed  Google Scholar 

  43. Fisher Jr CJ, Agosti JM, Opal SM, et al. Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. The soluble TNF receptor sepsis study group. N Engl J Med. 1996;334:1697–702.

    CAS  PubMed  Google Scholar 

  44. Abraham E, Glauser MP, Butler T, et al. p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45–2081 study group. JAMA. 1997;277:1531–8.

    CAS  PubMed  Google Scholar 

  45. Tsujino M, Hirata Y, Imai T, et al. Induction of nitric oxide synthase gene by interleukin-1 beta in cultured rat cardiomyocytes. Circulation. 1994;90:375–83.

    CAS  PubMed  Google Scholar 

  46. Brady AJ, Poole-Wilson PA, Harding SE, Warren JB. Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. Am J Physiol. 1992;263:H1963–6.

    CAS  PubMed  Google Scholar 

  47. Arnalich F, Lopez-Maderuelo D, Codoceo R, et al. Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis. Clin Exp Immunol. 2002;127:331–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Aiura K, Gelfand JA, Burke JF, et al. Interleukin-1 (IL-1) receptor antagonist prevents Staphylococcus epidermidis-induced hypotension and reduces circulating levels of tumor necrosis factor and IL-1 beta in rabbits. Infect Immun. 1993;61:3342–50.

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Remick DG, Call DR, Ebong SJ, et al. Combination immunotherapy with soluble tumor necrosis factor receptors plus interleukin 1 receptor antagonist decreases sepsis mortality. Crit Care Med. 2001;29:473–81.

    CAS  PubMed  Google Scholar 

  50. Opal SM, Fisher Jr CJ, Dhainaut JF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The interleukin-1 receptor antagonist sepsis investigator group. Crit Care Med. 1997;25:1115–24.

    CAS  PubMed  Google Scholar 

  51. Bone RC, Fisher Jr CJ, Clemmer TP, et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317:653–8.

    CAS  PubMed  Google Scholar 

  52. Luce JM, Montgomery AB, Marks JD, et al. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Respir Dis. 1988;138:62–8.

    CAS  PubMed  Google Scholar 

  53. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009;301:2362–75.

    CAS  PubMed  Google Scholar 

  54. Fisher Jr CJ, Dhainaut JF, Opal SM, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra sepsis syndrome study group. JAMA. 1994;271:1836–43.

    PubMed  Google Scholar 

  55. Reinhart K, Karzai W. Anti-tumor necrosis factor therapy in sepsis: update on clinical trials and lessons learned. Crit Care Med. 2001;29:S121–5.

    CAS  PubMed  Google Scholar 

  56. Boomer JS, To K, Chang KC, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306:2594–605.

    PubMed Central  CAS  PubMed  Google Scholar 

  57. Andreu-Ballester JC, Tormo-Calandin C, Garcia-Ballesteros C, et al. Association of gammadelta T cells with disease severity and mortality in septic patients. Clin Vaccine Immunol. 2013;20:738–46.

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Carson WF, Cavassani KA, Dou Y, Kunkel SL. Epigenetic regulation of immune cell functions during post-septic immunosuppression. Epigenetics. 2011;6:273–83.

    PubMed Central  CAS  PubMed  Google Scholar 

  59. Monneret G, Lepape A, Voirin N, et al. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med. 2006;32:1175–83.

    PubMed  Google Scholar 

  60. Xiang Y, Kobilka BK. Myocyte adrenoceptor signaling pathways. Science. 2003;300:1530–2.

    CAS  PubMed  Google Scholar 

  61. Xiao RP, Zhu W, Zheng M, et al. Subtype-specific beta-adrenoceptor signaling pathways in the heart and their potential clinical implications. Trends Pharmacol Sci. 2004;25:358–65.

    CAS  PubMed  Google Scholar 

  62. Devic E, Xiang Y, Gould D, Kobilka B. Beta-adrenergic receptor subtype-specific signaling in cardiac myocytes from beta(1) and beta(2) adrenoceptor knockout mice. Mol Pharmacol. 2001;60:577–83.

    CAS  PubMed  Google Scholar 

  63. Bernstein D, Fajardo G, Zhao M, et al. Differential cardioprotective/cardiotoxic effects mediated by beta-adrenergic receptor subtypes. Am J Physiol Heart Circ Physiol. 2005;289:H2441–9.

    CAS  PubMed  Google Scholar 

  64. Chesley A, Lundberg MS, Asai T, et al. The beta(2)-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through G(i)-dependent coupling to phosphatidylinositol 3′-kinase. Circ Res. 2000;87:1172–9.

    CAS  PubMed  Google Scholar 

  65. Patterson AJ, Zhu W, Chow A, et al. Protecting the myocardium: a role for the beta2 adrenergic receptor in the heart. Crit Care Med. 2004;32:1041–8.

    PubMed  Google Scholar 

  66. Xiao RP, Avdonin P, Zhou YY, et al. Coupling of beta2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes. Circ Res. 1999;84:43–52.

    CAS  PubMed  Google Scholar 

  67. Communal C, Singh K, Sawyer DB, Colucci WS. Opposing effects of beta(1)- and beta(2)-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein. Circulation. 1999;100:2210–2.

    CAS  PubMed  Google Scholar 

  68. Zhu WZ, Zheng M, Koch WJ, et al. Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes. Proc Natl Acad Sci U S A. 2001;98:1607–12.

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Richter W, Day P, Agrawal R, et al. Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4. EMBO J. 2008;27:384–93.

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Rengo G, Lymperopoulos A, Koch WJ. Future g protein-coupled receptor targets for treatment of heart failure. Curr Treat Options Cardiovasc Med. 2009;11:328–38.

    PubMed  Google Scholar 

  71. Lymperopoulos A, Bathgate A. Arrestins in the cardiovascular system. Prog Mol Biol Transl Sci. 2013;118:297–334.

    CAS  PubMed  Google Scholar 

  72. DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK. Beta-arrestins and cell signaling. Annu Rev Physiol. 2007;69:483–510.

    CAS  PubMed  Google Scholar 

  73. Witherow DS, Garrison TR, Miller WE, Lefkowitz RJ. Beta-arrestin inhibits NF-kappaB activity by means of its interaction with the NF-kappaB inhibitor IkappaBalpha. Proc Natl Acad Sci U S A. 2004;101:8603–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  74. Gao H, Sun Y, Wu Y, et al. Identification of beta-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-kappaB pathways. Mol Cell. 2004;14:303–17.

    CAS  PubMed  Google Scholar 

  75. Annane D, Trabold F, Sharshar T, et al. Inappropriate sympathetic activation at onset of septic shock: a spectral analysis approach. Am J Respir Crit Care Med. 1999;160:458–65.

    CAS  PubMed  Google Scholar 

  76. Kovarik MF, Jones SB, Romano FD. Plasma catecholamines following cecal ligation and puncture in the rat. Circ Shock. 1987;22:281–90.

    CAS  PubMed  Google Scholar 

  77. Boldt J, Menges T, Kuhn D, et al. Alterations in circulating vasoactive substances in the critically ill—a comparison between survivors and non-survivors. Intensive Care Med. 1995;21:218–25.

    CAS  PubMed  Google Scholar 

  78. Jones AE, Craddock PA, Tayal VS, Kline JA. Diagnostic accuracy of left ventricular function for identifying sepsis among emergency department patients with nontraumatic symptomatic undifferentiated hypotension. Shock. 2005;24:513–7.

    PubMed  Google Scholar 

  79. Azimi G, Vincent JL. Ultimate survival from septic shock. Resuscitation. 1986;14:245–53.

    CAS  PubMed  Google Scholar 

  80. Dunser MW, Hasibeder WR. Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress. J Intensive Care Med. 2009;24:293–316.

    PubMed  Google Scholar 

  81. Hahn PY, Wang P, Tait SM, et al. Sustained elevation in circulating catecholamine levels during polymicrobial sepsis. Shock. 1995;4:269–73.

    CAS  PubMed  Google Scholar 

  82. Gulick T, Chung MK, Pieper SJ, et al. Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness. Proc Natl Acad Sci U S A. 1989;86:6753–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  83. Bohm M, Kirchmayr R, Gierschik P, Erdmann E. Increase of myocardial inhibitory G-proteins in catecholamine-refractory septic shock or in septic multiorgan failure. Am J Med. 1995;98:183–6.

    CAS  PubMed  Google Scholar 

  84. Macarthur H, Westfall TC, Riley DP, et al. Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock. Proc Natl Acad Sci U S A. 2000;97:9753–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Hare JM, Loh E, Creager MA, Colucci WS. Nitric oxide inhibits the positive inotropic response to beta-adrenergic stimulation in humans with left ventricular dysfunction. Circulation. 1995;92:2198–203.

    CAS  PubMed  Google Scholar 

  86. Barth E, Radermacher P, Thiemermann C, et al. Role of inducible nitric oxide synthase in the reduced responsiveness of the myocardium to catecholamines in a hyperdynamic, murine model of septic shock. Crit Care Med. 2006;34:307–13.

    CAS  PubMed  Google Scholar 

  87. Lymperopoulos A, Rengo G, Koch WJ. GRK2 inhibition in heart failure: something old, something new. Curr Pharm Des. 2012;18:186–91.

    CAS  PubMed  Google Scholar 

  88. Salazar NC, Vallejos X, Siryk A, et al. GRK2 blockade with betaARKct is essential for cardiac beta2-adrenergic receptor signaling towards increased contractility. Cell Commun Signal. 2013;11:64.

    PubMed Central  CAS  PubMed  Google Scholar 

  89. Fan H, Bitto A, Zingarelli B, et al. Beta-arrestin 2 negatively regulates sepsis-induced inflammation. Immunology. 2010;130:344–51.

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Valen G, Yan ZQ, Hansson GK. Nuclear factor kappa-B and the heart. J Am Coll Cardiol. 2001;38:307–14.

    CAS  PubMed  Google Scholar 

  91. Ibrahim-Zada I, Rhee P, Gomez CT, et al. Inhibition of sepsis-induced inflammatory response by beta1-adrenergic antagonists. J Trauma Acute Care Surg. 2014;76:320–7. discussion 327–8.

    CAS  PubMed  Google Scholar 

  92. Pinsky MR. Is there a role for beta-blockade in septic shock? JAMA. 2013;310:1677–8.

    CAS  PubMed  Google Scholar 

  93. Godlewski G, Schlicker E, Baranowska U, Malinowska B. Recruitment of functionally active heart beta2-adrenoceptors in the initial phase of endotoxic shock in pithed rats. Shock. 2006;26:510–5.

    CAS  PubMed  Google Scholar 

  94. Valen G. Innate immunity and remodelling. Heart Fail Rev. 2011;16:71–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  95. Leone M, Boyadjiev I, Boulos E, et al. A reappraisal of isoproterenol in goal-directed therapy of septic shock. Shock. 2006;26:353–7.

    CAS  PubMed  Google Scholar 

  96. Fink T, Heymann P, Taha-Melitz S, et al. Dobutamine pretreatment improves survival, liver function, and hepatic microcirculation after polymicrobial sepsis in rat. Shock. 2013;40:129–35.

    CAS  PubMed  Google Scholar 

  97. Cudmore LA, Muurlink T, Whittem T, Bailey SR. Effects of oral clenbuterol on the clinical and inflammatory response to endotoxaemia in the horse. Res Vet Sci. 2013;94:682–6.

    CAS  PubMed  Google Scholar 

  98. Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA. 2013;310:1683–91.

    PubMed  Google Scholar 

  99. Gouni I, Oka K, Etienne J, Chan L. Endotoxin-induced hypertriglyceridemia is mediated by suppression of lipoprotein lipase at a post-transcriptional level. J Lipid Res. 1993;34:139–46.

    CAS  PubMed  Google Scholar 

  100. Kaufmann RL, Matson CF, Beisel WR. Hypertriglyceridemia produced by endotoxin: role of impaired triglyceride disposal mechanisms. J Infect Dis. 1976;133:548–55.

    CAS  PubMed  Google Scholar 

  101. Nogueira AC, Kawabata V, Biselli P, et al. Changes in plasma free fatty acid levels in septic patients are associated with cardiac damage and reduction in heart rate variability. Shock. 2008;29:342–8.

    CAS  PubMed  Google Scholar 

  102. Bagby GJ, Spitzer JA. Lipoprotein lipase activity in rat heart and adipose tissue during endotoxic shock. Am J Physiol. 1980;238:H325–30.

    CAS  PubMed  Google Scholar 

  103. Scholl RA, Lang CH, Bagby GJ. Hypertriglyceridemia and its relation to tissue lipoprotein lipase activity in endotoxemic, Escherichia coli bacteremic, and polymicrobial septic rats. J Surg Res. 1984;37:394–401.

    CAS  PubMed  Google Scholar 

  104. Bagby GJ, Corll CB, Martinez RR. Triacylglycerol kinetics in endotoxic rats with suppressed lipoprotein lipase activity. Am J Physiol. 1987;253:E59–64.

    CAS  PubMed  Google Scholar 

  105. Neubauer S. The failing heart—an engine out of fuel. N Engl J Med. 2007;356:1140–51.

    PubMed  Google Scholar 

  106. Osorio JC, Stanley WC, Linke A, et al. Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure. Circulation. 2002;106:606–12.

    CAS  PubMed  Google Scholar 

  107. Raymond RM, McLane MP, Law WR, et al. Myocardial insulin resistance during acute endotoxin shock in dogs. Diabetes. 1988;37:1684–8.

    CAS  PubMed  Google Scholar 

  108. Tessier JP, Thurner B, Jungling E, et al. Impairment of glucose metabolism in hearts from rats treated with endotoxin. Cardiovasc Res. 2003;60:119–30.

    CAS  PubMed  Google Scholar 

  109. Dhainaut JF, Huyghebaert MF, Monsallier JF, et al. Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock. Circulation. 1987;75:533–41.

    CAS  PubMed  Google Scholar 

  110. Hotchkiss RS, Rust RS, Dence CS, et al. Evaluation of the role of cellular hypoxia in sepsis by the hypoxic marker [18F]fluoromisonidazole. Am J Physiol. 1991;261:R965–72.

    CAS  PubMed  Google Scholar 

  111. Lu B, Moser A, Shigenaga JK, et al. The acute phase response stimulates the expression of angiopoietin like protein 4. Biochem Biophys Res Commun. 2010;391:1737–41.

    CAS  PubMed  Google Scholar 

  112. Feingold K, Kim MS, Shigenaga J, et al. Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. Am J Physiol Endocrinol Metab. 2004;286:E201–7.

    CAS  PubMed  Google Scholar 

  113. Jia L, Takahashi M, Morimoto H, et al. Changes in cardiac lipid metabolism during sepsis: the essential role of very low-density lipoprotein receptors. Cardiovasc Res. 2006;69:545–55.

    CAS  PubMed  Google Scholar 

  114. Read TE, Harris HW, Grunfeld C, et al. The protective effect of serum lipoproteins against bacterial lipopolysaccharide. Eur Heart J. 1993;14(Suppl K):125–9.

    CAS  PubMed  Google Scholar 

  115. Ghoshal S, Witta J, Zhong J, et al. Chylomicrons promote intestinal absorption of lipopolysaccharides. J Lipid Res. 2009;50:90–7.

    CAS  PubMed  Google Scholar 

  116. Memon RA, Bass NM, Moser AH, et al. Down-regulation of liver and heart specific fatty acid binding proteins by endotoxin and cytokines in vivo. Biochim Biophys Acta. 1999;1440:118–26.

    CAS  PubMed  Google Scholar 

  117. Memon RA, Fuller J, Moser AH, et al. In vivo regulation of acyl-CoA synthetase mRNA and activity by endotoxin and cytokines. Am J Physiol. 1998;275:E64–72.

    CAS  PubMed  Google Scholar 

  118. Uji Y, Yamamoto H, Tsuchihashi H, et al. Adiponectin deficiency is associated with severe polymicrobial sepsis, high inflammatory cytokine levels, and high mortality. Surgery. 2009;145:550–7.

    PubMed  Google Scholar 

  119. Haraguchi G, Kosuge H, Maejima Y, et al. Pioglitazone reduces systematic inflammation and improves mortality in apolipoprotein E knockout mice with sepsis. Intensive Care Med. 2008;34:1304–12.

    CAS  PubMed  Google Scholar 

  120. Chima RS, Hake PW, Piraino G, et al. Ciglitazone ameliorates lung inflammation by modulating the inhibitor kappaB protein kinase/nuclear factor-kappaB pathway after hemorrhagic shock. Crit Care Med. 2008;36:2849–57.

    PubMed Central  CAS  PubMed  Google Scholar 

  121. Siddiqui AM, Cui X, Wu R, et al. The anti-inflammatory effect of curcumin in an experimental model of sepsis is mediated by up-regulation of peroxisome proliferator-activated receptor-gamma. Crit Care Med. 2006;34:1874–82.

    CAS  PubMed  Google Scholar 

  122. Liu D, Zeng BX, Zhang SH, Yao SL. Rosiglitazone, an agonist of peroxisome proliferator-activated receptor gamma, reduces pulmonary inflammatory response in a rat model of endotoxemia. Inflamm Res. 2005;54:464–70.

    CAS  PubMed  Google Scholar 

  123. Zingarelli B, Cook JA. Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation. Shock. 2005;23:393–9.

    CAS  PubMed  Google Scholar 

  124. Yamauchi T, Kamon J, Waki H, et al. The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem. 2001;276:41245–54.

    CAS  PubMed  Google Scholar 

  125. Yang WS, Jeng CY, Wu TJ, et al. Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care. 2002;25:376–80.

    CAS  PubMed  Google Scholar 

  126. Gustafson B, Jack MM, Cushman SW, Smith U. Adiponectin gene activation by thiazolidinediones requires PPAR gamma 2, but not C/EBP alpha-evidence for differential regulation of the aP2 and adiponectin genes. Biochem Biophys Res Commun. 2003;308:933–9.

    CAS  PubMed  Google Scholar 

  127. Fang X, Palanivel R, Cresser J, et al. An APPL1-AMPK signaling axis mediates beneficial metabolic effects of adiponectin in the heart. Am J Physiol Endocrinol Metab. 2010;299:E721–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  128. Yoon MJ, Lee GY, Chung JJ, et al. Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes. 2006;55:2562–70.

    CAS  PubMed  Google Scholar 

  129. Reynolds K, Novosad B, Hoffhines A, et al. Pretreatment with troglitazone decreases lethality during endotoxemia in mice. J Endotoxin Res. 2002;8:307–14.

    CAS  PubMed  Google Scholar 

  130. Kapoor A, Shintani Y, Collino M, et al. Protective role of peroxisome proliferator-activated receptor-beta/delta in septic shock. Am J Respir Crit Care Med. 2010;182:1506–15.

    CAS  PubMed  Google Scholar 

  131. Langley RJ, Tsalik EL, Velkinburgh JC, et al. An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci Transl Med. 2013;5:195ra95. This study showed that markers of increased tissue fatty acid oxidation detected in plasma of septic patients predict improved survival in sepsis.

  132. Watts JA, Kline JA, Thornton LR, et al. Metabolic dysfunction and depletion of mitochondria in hearts of septic rats. J Mol Cell Cardiol. 2004;36:141–50.

    CAS  PubMed  Google Scholar 

  133. Levy RJ. Mitochondrial dysfunction, bioenergetic impairment, and metabolic down-regulation in sepsis. Shock. 2007;28:24–8.

    CAS  PubMed  Google Scholar 

  134. Turdi S, Han X, Huff AF, et al. Cardiac-specific overexpression of catalase attenuates lipopolysaccharide-induced myocardial contractile dysfunction: role of autophagy. Free Radic Biol Med. 2012;53:1327–38.

    PubMed Central  CAS  PubMed  Google Scholar 

  135. Vanasco V, Magnani ND, Cimolai MC, et al. Endotoxemia impairs heart mitochondrial function by decreasing electron transfer, ATP synthesis and ATP content without affecting membrane potential. J Bioenerg Biomembr. 2012;44:243–52.

    CAS  PubMed  Google Scholar 

  136. Chen HW, Hsu C, Lu TS, et al. Heat shock pretreatment prevents cardiac mitochondrial dysfunction during sepsis. Shock. 2003;20:274–9.

    PubMed  Google Scholar 

  137. Piquereau J, Godin R, Deschenes S, et al. Protective role of PARK2/Parkin in sepsis-induced cardiac contractile and mitochondrial dysfunction. Autophagy. 2013;9:1837–51.

    CAS  PubMed  Google Scholar 

  138. Noto A, Giacomini M, Palandi A, et al. Levosimendan in septic cardiac failure. Intensive Care Med. 2005;31:164–5.

    CAS  PubMed  Google Scholar 

  139. Givertz MM, Andreou C, Conrad CH, Colucci WS. Direct myocardial effects of levosimendan in humans with left ventricular dysfunction: alteration of force-frequency and relaxation-frequency relationships. Circulation. 2007;115:1218–24.

    CAS  PubMed  Google Scholar 

  140. Torraco A, Carrozzo R, Piemonte F, et al. Effects of levosimendan on mitochondrial function in patients with septic shock: a randomized trial. Biochimie. 2014;102:166–73.

    CAS  PubMed  Google Scholar 

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Conflict of Interest

Konstantinos Drosatos, Anastasios Lymperopoulos, Peter Johannes Kennel, Nina Pollak, P. Christian Schulze, and Ira J. Goldberg declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Funding

Drs. Drosatos, Schulze, and Goldberg are supported by grants through the National Heart, Lung, and Blood Institute (NHLBI) (HL112853, KD; HL114813, PCS; HL45095 and HL73029, IJG). Dr. Lymperopoulos is supported by an AHA Scientist Development Grant (No. 09SDG2010138, National Center).

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Authors and Affiliations

  1. Metabolic Biology Laboratory, Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, 3500 N. Broad Street, MERB-951, Philadelphia, PA, 19140, USA

    Konstantinos Drosatos

  2. Neurohormonal Control of the Circulation Lab, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, 3200 S. University Dr., Health Professions Division (Terry) Bldg/Room 1338, Fort Lauderdale, FL, 33328, USA

    Anastasios Lymperopoulos

  3. Division of Cardiology, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA

    Peter Johannes Kennel & P. Christian Schulze

  4. Institute of Molecular Biosciences, University of Graz, 8010, Graz, Austria

    Nina Pollak

  5. Division of Endocrinology, Diabetes & Metabolism, NYU-Langone School of Medicine, 522 First Avenue, New York, NY, 10016, USA

    Ira J. Goldberg

Authors
  1. Konstantinos Drosatos
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  2. Anastasios Lymperopoulos
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  3. Peter Johannes Kennel
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  4. Nina Pollak
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  5. P. Christian Schulze
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  6. Ira J. Goldberg
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Corresponding author

Correspondence to Konstantinos Drosatos.

Additional information

Anastasios Lymperopoulos and Peter Johannes Kennel contributed equally to this review.

This article is part of the Topical Collection on Pathophysiology: Neuroendocrine, Vascular, and Metabolic Factors

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Drosatos, K., Lymperopoulos, A., Kennel, P.J. et al. Pathophysiology of Sepsis-Related Cardiac Dysfunction: Driven by Inflammation, Energy Mismanagement, or Both?. Curr Heart Fail Rep 12, 130–140 (2015). https://doi.org/10.1007/s11897-014-0247-z

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