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Thorac Cardiovasc Surg 2013; 61(01): 052-065
DOI: 10.1055/s-0032-1331501
Original Basic Science
Georg Thieme Verlag KG Stuttgart · New York

Functional Outcome in Female Rats after 45 Minutes of Deep Hypothermic Circulatory Arrest: Gender Matters

Kristine Kellermann
1   Klinik für Anaesthesiologie, Klinikum rechts der Isar der TU München, München, Germany
,
Lucia M. Gordan
1   Klinik für Anaesthesiologie, Klinikum rechts der Isar der TU München, München, Germany
,
Manfred Blobner
1   Klinik für Anaesthesiologie, Klinikum rechts der Isar der TU München, München, Germany
,
Peter Luppa
2   Institut für klinische Chemie und Pathobiochemie, Klinkum rechts der Isar der TU München, München, Germany
,
Eberhard F. Kochs
1   Klinik für Anaesthesiologie, Klinikum rechts der Isar der TU München, München, Germany
,
Bettina Jungwirth
1   Klinik für Anaesthesiologie, Klinikum rechts der Isar der TU München, München, Germany
› Author Affiliations
Further Information

Publication History

18 May 2012

21 August 2012

Publication Date:
10 January 2013 (online)

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Abstract

Background After adjusting for cofactors, female gender remains an independent risk factor. The aim of our study was to investigate the role of gender on functional outcome 14 days after 45 minutes of deep hypothermic circulatory arrest (DHCA) in rats.

Methods After institutional animal care committee Institutional Review Board approval, 40 male and 40 female rats were randomly divided into two groups (40 DHCA, 40 controls). The rats were neutered or sham-neutered and 40 of them were subjected to DHCA with 40 controls remaining naïve. Postoperative functional performance was assessed with modified hole-board test. Brain morphology was assessed using hematoxylin and eosin (HE) staining and cerebral inflammation/apoptosis determined immunohistochemically. Data were analyzed using general linear models (post hoc analysis of variance [ANOVA] and Bonferroni t tests) and Kruskal–Wallis (post hoc Mann–Whitney U test) (p < 0.05).

Results Cognition and behavior after 45 minutes of DHCA were comparable to that of four naïve rats in all four DHCA groups. Motor function and morphologic outcome were better in females. Nuclear factor kappa B (NFκB) was upregulated in the female normal group. Activated caspase-3 was higher in females whereas poly(ADP-ribose) polymerase was in males. Of note is the secondary finding of a high drop-out rate during the early postoperative phase in the female groups (16 out of 37).

Conclusions Postoperative motor skills were better in females, with less neuronal damage, more neuronal NFκB, and activated caspase-3. However, the chance finding of a high mortality rate in females warrants investigation with mortality as the principal aim, focusing on heart, liver, lung, kidney, and intestine with regard to its rate.

Keywords

experimental - ischemia/reperfusion - cardiopulmonary bypass - CPB outcomes (includes mortality morbidity)
 

  • References

  • 1 Vaccarino V, Abramson JL, Veledar E, Weintraub WS. Sex differences in hospital mortality after coronary artery bypass surgery: evidence for a higher mortality in younger women. Circulation 2002; 105 (10) 1176-1181
    CrossrefPubMedGoogle Scholar
  • 2 Edwards FH, Carey JS, Grover FL, Bero JW, Hartz RS. Impact of gender on coronary bypass operative mortality. Ann Thorac Surg 1998; 66 (1) 125-131
    CrossrefPubMedGoogle Scholar
  • 3 Ranucci M, Pazzaglia A, Bianchini C, Bozzetti G, Isgrò G. Body size, gender, and transfusions as determinants of outcome after coronary operations. Ann Thorac Surg 2008; 85 (2) 481-486
    CrossrefPubMedGoogle Scholar
  • 4 Guru V, Fremes SE, Austin PC, Blackstone EH, Tu JV. Gender differences in outcomes after hospital discharge from coronary artery bypass grafting. Circulation 2006; 113 (4) 507-516
    CrossrefPubMedGoogle Scholar
  • 5 Alam M, Lee VV, Elayda MA , et al. Association of gender with morbidity and mortality after isolated coronary artery bypass grafting. A propensity score matched analysis. Int J Cardiol 2012; (e-pub ahead of print). DOI: 10.1016/j.ijcard.2011.12.047.
    PubMedGoogle Scholar
  • 6 Melcangi RC, Mensah-Nyagan AG. Neurosteroids: measurement and pathophysiologic relevance. Neurochem Int 2008; 52 (4-5) 503-505
    CrossrefPubMedGoogle Scholar
  • 7 Zheng P. Neuroactive steroid regulation of neurotransmitter release in the CNS: action, mechanism and possible significance. Prog Neurobiol 2009; 89 (2) 134-152
    CrossrefPubMedGoogle Scholar
  • 8 Woolley CS, Gould E, Frankfurt M, McEwen BS. Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J Neurosci 1990; 10 (12) 4035-4039
    PubMedGoogle Scholar
  • 9 Pozzi S, Benedusi V, Maggi A, Vegeto E. Estrogen action in neuroprotection and brain inflammation. Ann N Y Acad Sci 2006; 1089: 302-323
    CrossrefPubMedGoogle Scholar
  • 10 Jungwirth B, Gordan ML, Blobner M, Schmehl W, Kochs EF, Mackensen GB. Xenon impairs neurocognitive and histologic outcome after cardiopulmonary bypass combined with cerebral air embolism in rats. Anesthesiology 2006; 104 (4) 770-776
    CrossrefPubMedGoogle Scholar
  • 11 Ohl F, Holsboer F, Landgraf R. The modified hole board as a differential screen for behavior in rodents. Behav Res Methods Instrum Comput 2001; 33 (3) 392-397
    CrossrefPubMedGoogle Scholar
  • 12 Jungwirth B, Mackensen GB, Blobner M , et al. Neurologic outcome after cardiopulmonary bypass with deep hypothermic circulatory arrest in rats: description of a new model. J Thorac Cardiovasc Surg 2006; 131 (4) 805-812
    CrossrefPubMedGoogle Scholar
  • 13 Gibbs RB, Gabor R. Estrogen and cognition: applying preclinical findings to clinical perspectives. J Neurosci Res 2003; 74 (5) 637-643
    CrossrefPubMedGoogle Scholar
  • 14 Hogue CW, Fucetola R, Hershey T , et al. Risk factors for neurocognitive dysfunction after cardiac surgery in postmenopausal women. Ann Thorac Surg 2008; 86 (2) 511-516
    CrossrefPubMedGoogle Scholar
  • 15 Elkin BS, Ilankovan A, Morrison III B. Age-dependent regional mechanical properties of the rat hippocampus and cortex. J Biomech Eng 2010; 132 (1) 011010
    CrossrefPubMedGoogle Scholar
  • 16 Ferraris VA, Ferraris SP, Saha SP , et al; Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg 2007; 83 (Suppl. 05) S27-S86
    CrossrefPubMedGoogle Scholar
  • 17 Shann KG, Likosky DS, Murkin JM , et al. An evidence-based review of the practice of cardiopulmonary bypass in adults: a focus on neurologic injury, glycemic control, hemodilution, and the inflammatory response. J Thorac Cardiovasc Surg 2006; 132 (2) 283-290
    CrossrefPubMedGoogle Scholar
  • 18 Horstman AM, Dillon EL, Urban RJ, Sheffield-Moore M. The role of androgens and estrogens on healthy aging and longevity. J Gerontol A Biol Sci Med Sci 2012; 67 (11) 1140-1152
    CrossrefPubMedGoogle Scholar
  • 19 Pöllänen E, Sipilä S, Alen M , et al. Differential influence of peripheral and systemic sex steroids on skeletal muscle quality in pre- and postmenopausal women. Aging Cell 2011; 10 (4) 650-660
    CrossrefPubMedGoogle Scholar
  • 20 Dubal DB, Wise PM. Neuroprotective effects of estradiol in middle-aged female rats. Endocrinology 2001; 142 (1) 43-48
    CrossrefPubMedGoogle Scholar
  • 21 Nussmeier NA, Marino MR, Vaughn WK. Hormone replacement therapy is associated with improved survival in women undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2002; 124 (6) 1225-1229
    CrossrefPubMedGoogle Scholar
  • 22 Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR , et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA 2008; 299 (1) 39-52
    CrossrefPubMedGoogle Scholar
  • 23 Bingham D, Macrae IM, Carswell HV. Detrimental effects of 17beta-oestradiol after permanent middle cerebral artery occlusion. J Cereb Blood Flow Metab 2005; 25 (3) 414-420
    CrossrefPubMedGoogle Scholar
  • 24 Nakano T, Hurn PD, Herson PS, Traystman RJ. Testosterone exacerbates neuronal damage following cardiac arrest and cardiopulmonary resuscitation in mouse. Brain Res 2010; 1357: 124-130
    CrossrefPubMedGoogle Scholar
  • 25 Rossouw JE, Anderson GL, Prentice RL , et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288 (3) 321-333
    CrossrefPubMedGoogle Scholar
  • 26 Hogue Jr CW, Freedland K, Hershey T , et al. Neurocognitive outcomes are not improved by 17beta-estradiol in postmenopausal women undergoing cardiac surgery. Stroke 2007; 38 (7) 2048-2054
    CrossrefPubMedGoogle Scholar
  • 27 Durham JL, Jordan KA, Devos MJ, Williams EK, Sandstrom NJ. Estradiol protects against hippocampal damage and impairments in fear conditioning resulting from transient global ischemia in mice. Brain Res 2012; 1443: 64-74
    CrossrefPubMedGoogle Scholar
  • 28 Frye CA, Walf AA. Progesterone to ovariectomized mice enhances cognitive performance in the spontaneous alternation, object recognition, but not placement, water maze, and contextual and cued conditioned fear tasks. Neurobiol Learn Mem 2008; 90 (1) 171-177
    CrossrefPubMedGoogle Scholar
  • 29 Lebesgue D, Chevaleyre V, Zukin RS, Etgen AM. Estradiol rescues neurons from global ischemia-induced cell death: multiple cellular pathways of neuroprotection. Steroids 2009; 74 (7) 555-561
    CrossrefPubMedGoogle Scholar
  • 30 Merchenthaler I, Dellovade TL, Shughrue PJ. Neuroprotection by estrogen in animal models of global and focal ischemia. Ann N Y Acad Sci 2003; 1007: 89-100
    CrossrefPubMedGoogle Scholar
  • 31 Pan DS, Liu WG, Yang XF, Cao F. Inhibitory effect of progesterone on inflammatory factors after experimental traumatic brain injury. Biomed Environ Sci 2007; 20 (5) 432-438
    PubMedGoogle Scholar
  • 32 Jungwirth B, Kellermann K, Blobner M, Schmehl W, Kochs EF, Mackensen GB. Cerebral air emboli differentially alter outcome after cardiopulmonary bypass in rats compared with normal circulation. Anesthesiology 2007; 107 (5) 768-775
    CrossrefPubMedGoogle Scholar
  • 33 Kellermann K, Dertinger N, Blobner M, Kees F, Kochs EF, Jungwirth B. Perioperative moxifloxacin treatment in rats subjected to deep hypothermic circulatory arrest: reduction in cerebral inflammation but without improvement in cognitive performance. J Thorac Cardiovasc Surg 2011; 141 (3) 796-802
    CrossrefPubMedGoogle Scholar
  • 34 Pulsinelli WA, Brierley JB, Plum F. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 1982; 11 (5) 491-498
    CrossrefPubMedGoogle Scholar
  • 35 Behl C, Skutella T, Lezoualc'h F , et al. Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mol Pharmacol 1997; 51 (4) 535-541
    PubMedGoogle Scholar
  • 36 Bruce-Keller AJ, Keeling JL, Keller JN, Huang FF, Camondola S, Mattson MP. Antiinflammatory effects of estrogen on microglial activation. Endocrinology 2000; 141 (10) 3646-3656
    CrossrefPubMedGoogle Scholar
  • 37 Yang SH, Perez E, Cutright J , et al. Testosterone increases neurotoxicity of glutamate in vitro and ischemia-reperfusion injury in an animal model. J Appl Physiol 2002; 92 (1) 195-201
    PubMedGoogle Scholar
  • 38 Nijboer CH, Kavelaars A, van Bel F, Heijnen CJ, Groenendaal F. Gender-dependent pathways of hypoxia-ischemia-induced cell death and neuroprotection in the immature P3 rat. Dev Neurosci 2007; 29 (4-5) 385-392
    CrossrefPubMedGoogle Scholar
  • 39 Rosamond W, Flegal K, Friday G , et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007; 115 (5) e69-e171
    CrossrefPubMedGoogle Scholar
  • 40 Verthelyi D, Klinman DM. Sex hormone levels correlate with the activity of cytokine-secreting cells in vivo. Immunology 2000; 100 (3) 384-390
    CrossrefPubMedGoogle Scholar
  • 41 Liu T, Clark RK, McDonnell PC , et al. Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 1994; 25 (7) 1481-1488
    CrossrefPubMedGoogle Scholar
  • 42 Jin H, Qiu WB, Mei YF, Wang DM, Li YG, Tan XR. Testosterone alleviates tumor necrosis factor-alpha-mediated tissue factor pathway inhibitor downregulation via suppression of nuclear factor-kappa B in endothelial cells. Asian J Androl 2009; 11 (2) 266-271
    CrossrefPubMedGoogle Scholar
  • 43 Matthews JR, Hay RT. Regulation of the DNA binding activity of NF-kappa B. Int J Biochem Cell Biol 1995; 27 (9) 865-879
    CrossrefPubMedGoogle Scholar
  • 44 De Bosscher K, Vanden Berghe W, Haegeman G. Cross-talk between nuclear receptors and nuclear factor kappaB. Oncogene 2006; 25 (51) 6868-6886
    CrossrefPubMedGoogle Scholar
  • 45 Cerillo G, Rees A, Manchanda N , et al. The oestrogen receptor regulates NFkappaB and AP-1 activity in a cell-specific manner. J Steroid Biochem Mol Biol 1998; 67 (2) 79-88
    CrossrefPubMedGoogle Scholar
  • 46 Bhat-Nakshatri P, Campbell RA, Patel NM , et al. Tumor necrosis factor and PI3-kinase control oestrogen receptor alpha protein level and its transrepression function. Br J Cancer 2004; 90 (4) 853-859
    CrossrefPubMedGoogle Scholar
  • 47 Mattson MP. NF-kappaB in the survival and plasticity of neurons. Neurochem Res 2005; 30 (6-7) 883-893
    CrossrefPubMedGoogle Scholar
  • 48 Bethea CL, Reddy AP, Smith LJ. Nuclear factor kappa B in the dorsal raphe of macaques: an anatomical link for steroids, cytokines and serotonin. J Psychiatry Neurosci 2006; 31 (2) 105-114
    PubMedGoogle Scholar
  • 49 Park EM, Cho S, Frys KA , et al. Inducible nitric oxide synthase contributes to gender differences in ischemic brain injury. J Cereb Blood Flow Metab 2006; 26 (3) 392-401
    CrossrefPubMedGoogle Scholar
  • 50 Kellermann K, Gordan ML, Nollert G, Blobner M, Kochs EF, Jungwirth B. Long-term assessment of NFkappaB expression in the brain and neurologic outcome following deep hypothermic circulatory arrest in rats. Perfusion 2009; 24 (6) 429-436
    CrossrefPubMedGoogle Scholar
  • 51 Lang JT, McCullough LD. Pathways to ischemic neuronal cell death: are sex differences relevant?. J Transl Med 2008; 6: 33
    CrossrefPubMedGoogle Scholar
  • 52 Aggarwal BB. Apoptosis and nuclear factor-kappa B: a tale of association and dissociation. Biochem Pharmacol 2000; 60 (8) 1033-1039
    CrossrefPubMedGoogle Scholar
  • 53 Renolleau S, Fau S, Charriaut-Marlangue C. Gender-related differences in apoptotic pathways after neonatal cerebral ischemia. Neuroscientist 2008; 14 (1) 46-52
    PubMedGoogle Scholar
  • 54 McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab 2005; 25 (4) 502-512
    CrossrefPubMedGoogle Scholar
  • 55 Jungwirth B, Eckel B, Blobner M, Kellermann K, Kochs EF, Mackensen GB. The impact of cardiopulmonary bypass on systemic interleukin-6 release, cerebral nuclear factor-kappa B expression, and neurocognitive outcome in rats. Anesth Analg 2010; 110 (2) 312-320
    CrossrefPubMedGoogle Scholar