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Critical Care
Published in: Critical Care 4/2007

Open Access 01-08-2007 | Research

Longitudinal increases in mitochondrial DNA levels in blood cells are associated with survival in critically ill patients

Authors: Hélène CF Côté, Andrew G Day, Daren K Heyland

Published in: Critical Care | Issue 4/2007

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Abstract

Background

Mitochondrial dysfunction may be causally related to the pathogenesis of organ failure in critically ill patients. Decreased mitochondrial DNA (mtDNA) levels have been associated with mitochondrial dysfunction and were investigated here in relation to short-term (31-day) survival.

Methods

This was a prospective longitudinal cohort study of 28 mechanically ventilated critically ill adults admitted to a single center tertiary care intensive care unit (ICU) with hypotension secondary to cardiogenic (N = 13), septic (N = 14) or hypovolemic (N = 1) disease processes. Clinical data and blood were collected at baseline and patients were followed until they expired or left the ICU. Blood was collected every Monday, Wednesday and Friday, and the buffycoat relative mtDNA/nuclear DNA (nDNA) ratio was determined. An archived pool of healthy controls was also studied.

Results

At baseline, the patients' mtDNA/nDNA ratio was 30% lower than a pool of 24 healthy controls (0.76 versus 1.09) and was not different between short-term survivors and non-survivors (0.74 ± 0.05 (N = 16) versus 0.79 ± 0.06 (N = 12), p = 0.49). By day 4, the percent mtDNA/nDNA change from baseline in survivors was significantly different from that in non-survivors (+29.5% versus -5.7%, p = 0.03). It also tended to be higher in survivors at last measurement (+38.4% versus +7.1%, p = 0.06). There was a weak correlation between within patient mtDNA/nDNA and platelet count (r = 0.20, p = 0.03) but not with Sequential Organ Failure Assessment (SOFA) scores (r = 0.12, p = 0.23). The mtDNA associations remained after adjustment for platelet.

Conclusion

Blood mtDNA levels appeared initially low, increased over time in patients who ultimately survived, and remained low in those who did not. This is consistent with mitochondrial recovery being associated with survival and warrants further investigation as a marker of mitochondrial alterations and outcome in critical illness.
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Literature
1.
Broder G, Weil MH: Excess lactate: an index or reversibility of shock in human patients. Science. 1964, 143: 1457-1459. 10.1126/science.143.3613.1457.CrossRefPubMed
2.
Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D: Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med. 1994, 330: 1717-1722. 10.1056/NEJM199406163302404.CrossRefPubMed
3.
Crouser ED, Julian MW, Dorinsky PM: Ileal VO(2)-O(2) alterations induced by endotoxin correlate with severity of mitochondrial injury. Am J Respir Crit Care Med. 1999, 160: 1347-1353.CrossRefPubMed
4.
Crouser ED, Julian MW, Blaho DV, Pfeiffer DR: Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med. 2002, 30: 276-284. 10.1097/00003246-200202000-00002.CrossRefPubMed
5.
Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M: Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002, 360: 219-223. 10.1016/S0140-6736(02)09459-X.CrossRefPubMed
6.
Brealey D, Singer M: Mitochondrial dysfunction in sepsis. Curr Infect Dis Rep. 2003, 5: 365-371. 10.1007/s11908-003-0015-9.CrossRefPubMed
7.
Davies NA, Cooper CE, Stidwill R, Singer M: Inhibition of mitochondrial respiration during early stage sepsis. Adv Exp Med Biol. 2003, 530: 725-736.CrossRefPubMed
8.
Watts JA, Kline JA, Thornton LR, Grattan RM, Brar SS: Metabolic dysfunction and depletion of mitochondria in hearts of septic rats. J Mol Cell Cardiol. 2004, 36: 141-150. 10.1016/j.yjmcc.2003.10.015.CrossRefPubMed
9.
Crouser ED, Julian MW, Huff JE, Struck J, Cook CH: Carbamoyl phosphate synthase-1: a marker of mitochondrial damage and depletion in the liver during sepsis. Crit Care Med. 2006, 34: 2439-2446. 10.1097/01.CCM.0000230240.02216.21.CrossRefPubMed
10.
Suliman HB, Carraway MS, Piantadosi CA: Postlipopolysaccharide oxidative damage of mitochondrial DNA. Am J Respir Crit Care Med. 2003, 167: 570-579. 10.1164/rccm.200206-518OC.CrossRefPubMed
11.
Calvano SE, Xiao W, Richards DR, Felciano RM, Baker HV, Cho RJ, Chen RO, Brownstein BH, Cobb JP, Tschoeke SK, et al: A network-based analysis of systemic inflammation in humans. Nature. 2005, 437: 1032-1037. 10.1038/nature03985.CrossRefPubMed
12.
van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001, 345: 1359-1367. 10.1056/NEJMoa011300.CrossRefPubMed
13.
Vanhorebeek I, De Vos R, Mesotten D, Wouters PJ, De Wolf-Peeters C, Van den Berghe G: Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet. 2005, 365: 53-59. 10.1016/S0140-6736(04)17665-4.CrossRefPubMed
14.
Fredriksson K, Hammarqvist F, Strigård K, Hultenby K, Ljungqvist O, Wernerman J, Rooyackers O: Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure. Am J Physiol Endocrinol Metab. 2006, 291: E1044-1050. 10.1152/ajpendo.00218.2006.CrossRefPubMed
15.
Côté HC, Brumme ZL, Craib KJ, Alexander CS, Wynhoven B, Ting L, Wong H, Harris M, Harrigan PR, O'Shaughnessy MV, Montaner JS: Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med. 2002, 346: 811-820. 10.1056/NEJMoa012035.CrossRefPubMed
16.
Crouser ED: Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion. 2004, 4: 729-741. 10.1016/j.mito.2004.07.023.CrossRefPubMed
17.
Skulachev VP: Programmed death phenomena: from organelle to organism. Ann NY Acad Sci. 2002, 959: 214-237.CrossRefPubMed
18.
Lyamzaev KG, Pletjushkina OY, Saprunova VB, Bakeeva LE, Chernyak BV, Skulachev VP: Selective elimination of mitochondria from living cells induced by inhibitors of bioenergetic functions. Biochem Soc Trans. 2004, 32: 1070-1071. 10.1042/BST0321070.CrossRefPubMed
19.
Heyland DK, Dhaliwal R, Day A, Drover G, Côté H, Wischmeyer P: Optimizing the dose of glutamine dipeptides and antioxidants in critically ill patients: A phase I dose finding study. J Parenter Enteral Nutr. 2007, 31: 109-118.CrossRef
20.
Knaus WA, Draper EA, Wagner DP, Zimmerman JE: Apache II: a severity of diseases classification system. Crit Care Med. 1985, 13: 818-829. 10.1097/00003246-198510000-00009.CrossRefPubMed
21.
Moreno R, Vincent JL, Matos R, Mendonca A, Cantraine F, Thijs L, Takala J, Sprung C, Antonelli M, Bruining H, Willatts S: The use of maximum SOFA score to quantify organ dysfunction/failure in intensive care. Results of a prospective, multicenter study. Intensive Care Med. 1999, 25: 686-696. 10.1007/s001340050931.CrossRefPubMed
22.
Côté HC, Yip B, Asselin JJ, Chan JW, Hogg RS, Harrigan PR, O'Shaughnessy MV, Montaner JS: Mitochondrial:nuclear DNA ratios in peripheral blood cells from human immunodeficiency virus (HIV)-infected patients who received selected HIV antiretroviral drug regimens. J Infect Dis. 2003, 187: 1972-1976. 10.1086/375353.CrossRefPubMed
23.
Shuster RC, Rubenstein AJ, Wallace DC: Mitochondrial DNA in anucleate human blood cells. Biochem Biophys Res Commun. 1988, 155: 1360-1365. 10.1016/S0006-291X(88)81291-9.CrossRefPubMed
24.
Banas B, Kost BP, Goebel FD: Platelets, a typical source of error in real-time PCR quantification of mitochondrial DNA content in human peripheral blood cells. Eur J Med Res. 2004, 9: 371-377.PubMed
25.
Miller FJ, Rosenfeldt FL, Zhang C, Linnane AW, Nagley P: Precise determination of mitochondrial DNA copy number in human skeletal and cardiac muscle by a PCR-based assay: lack of change of copy number with age. Nucleic Acids Res. 2003, 31: e61-10.1093/nar/gng060.PubMedCentralCrossRefPubMed
26.
Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, Nair KS: Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci USA. 2005, 102: 5618-5623. 10.1073/pnas.0501559102.PubMedCentralCrossRefPubMed
27.
SAS Institute Inc: The MIXED Procedure. SAS/STAT User's Guide, Version 8. 1999, Cary, NC: SAS Institute Inc, 2083-2226.
28.
Mollen KP, Anand RJ, Tsung A, Prince JM, Levy RM, Billiar TR: Emerging paradigm: toll-like receptor 4-sentinel for the detection of tissue damage. Shock. 2006, 26: 430-437. 10.1097/01.shk.0000228797.41044.08.CrossRefPubMed
29.
Suliman HB, Welty-Wolf KE, Carraway MS, Schwartz DA, Hollingsworth JW, Piantadosi CA: Toll-like receptor 4 mediates mitochondrial DNA damage and biogenic responses after heat-inactivated E. coli. FASEB J. 2005, 19: 1531-1533.PubMed
30.
Hang T, Jiang SS, Gong JB, Lü TF, Song Y, Zhuge HH: Expression of Toll-like receptor 2/4 mRNA in myocardium in mice with hemorrhagic shock. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2006, 18: 554-557.PubMed
31.
Prince JM, Levy RM, Yang R, Mollen KP, Fink MP, Vodovotz Y, Billiar TR: Toll-like receptor-4 signaling mediates hepatic injury and systemic inflammation in hemorrhagic shock. J Am Coll Surg. 2006, 202: 407-417. 10.1016/j.jamcollsurg.2005.11.021.CrossRefPubMed
32.
Hsieh YC, Frink M, Kawasaki T, Thobe BM, Choudhry MA, Schwacha MG, Bland KI, Chaudry IH: Downregulation of TLR4-dependent ATP production is critical for estrogen-mediated immunoprotection in Kupffer cells following trauma-hemorrhage. J Cell Physiol. 2007, 211: 364-370. 10.1002/jcp.20943.CrossRefPubMed
33.
Gonzalez PK, Zhuang J, Doctrow SR, Malfroy B, Benson PF, Menconi MJ, Fink MP: Role of oxidant stress in the adult respiratory distress syndrome: evaluation of a novel antioxidant strategy in a porcine model of endotoxin-induced acute lung injury. Shock. 1996, 6: S23-S26.CrossRefPubMed
34.
Heyland DK, Dhaliwal R, Suchner U, Berger MM: Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient. Intensive Care Med. 2005, 31: 327-337. 10.1007/s00134-004-2522-z.CrossRefPubMed
35.
Xue L, Fletcher GC, Tolkovsky AM: Mitochondria are selectively eliminated from eukaryotic cells after blockade of caspases during apoptosis. Curr Biol. 2001, 11: 361-365. 10.1016/S0960-9822(01)00100-2.CrossRefPubMed
36.
Fink MP: Cytopathic hypoxia: Is oxygen use impaired in sepsis as a result of an acquired intrinsic derangement in cellular respiration?. Crit Care Clin. 2002, 18: 165-175. 10.1016/S0749-0704(03)00071-X.CrossRefPubMed
Metadata
Title
Longitudinal increases in mitochondrial DNA levels in blood cells are associated with survival in critically ill patients
Authors
Hélène CF Côté
Andrew G Day
Daren K Heyland
Publication date
01-08-2007
Publisher
BioMed Central
Published in
Critical Care / Issue 4/2007
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc6096

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