Coenzyme Q10 levels are low and may be associated with the inflammatory cascade in septic shock

Michael W Donnino, Michael N Cocchi, Justin D Salciccioli, Daniel Kim, Ali B Naini, Catherine Buettner, Praveen Akuthota, Michael W Donnino, Michael N Cocchi, Justin D Salciccioli, Daniel Kim, Ali B Naini, Catherine Buettner, Praveen Akuthota

Abstract

Introduction: Mitochondrial dysfunction is associated with increased mortality in septic shock. Coenzyme Q10 (CoQ10) is a key cofactor in the mitochondrial respiratory chain, but whether CoQ10 is depleted in septic shock remains unknown. Moreover, statin therapy may decrease CoQ10 levels, but whether this occurs acutely remains unknown. We measured CoQ10 levels in septic shock patients enrolled in a randomized trial of simvastatin versus placebo.

Methods: We conducted a post hoc analysis of a prospective, randomized trial of simvastatin versus placebo in patients with septic shock (ClinicalTrials.gov ID: NCT00676897). Adult patients with suspected or confirmed infection and the need for vasopressor support were included in the initial trial. For the current analysis, blood specimens were analyzed for plasma CoQ10 and low-density lipoprotein (LDL) levels. The relationship between CoQ10 levels and inflammatory and vascular endothelial biomarkers was assessed using either the Pearson or Spearman correlation coefficient.

Results: We analyzed 28 samples from 14 patients. CoQ10 levels were low, with a median of 0.49 (interquartile range 0.26 to 0.62) compared to levels in healthy control patients (CoQ10 = 0.95 μmol/L ± 0.29; P < 0.0001). Statin therapy had no effect on plasma CoQ10 levels over time (P = 0.13). There was a statistically significant relationship between plasma CoQ10 levels and levels of vascular cell adhesion molecule (VCAM) (r2 = 0.2; P = 0.008), TNF-α (r2 = 0.28; P = 0.004), IL-8 (r2 = 0.21; P = 0.015), IL-10 (r2 = 0.18; P = 0.025), E-selectin (r2 = 0.17; P = -0.03), IL-1ra (r2 = 0.21; P = 0.014), IL-6 (r2 = 0.17; P = 0.029) and IL-2 (r2 = 0.23; P = 0.009). After adjusting for LDL levels, there was a statistically significant inverse relationship between plasma CoQ10 levels and levels of VCAM (r2 = 0.24; P = 0.01) (Figure 3) and IL-10 (r2 = 0.24; P = 0.02).

Conclusions: CoQ10 levels are significantly lower in septic shock patients than in healthy controls. CoQ10 is negatively associated with vascular endothelial markers and inflammatory molecules, though this association diminishes after adjusting for LDL levels.

Figures

Figure 1
Figure 1
Schematic of our study design. A total of 28 samples were analyzed (14 patients with baseline and follow-up blood specimens were included for analysis).
Figure 2
Figure 2
Comparison of ratios of coenzyme Q10 to low-density lipoprotein (CoQ10:LDL) between randomization groups in the parent trial. There was no significant difference in the change in plasma CoQ10 between the statin and placebo groups (P = 0.13). Bars are Standard Error of the Mean.
Figure 3
Figure 3
Association between CoQ10 and sVCAM1, soluble vascular cell adhesion molecule levels (P = 0.04).

References

    1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–1310. doi: 10.1097/00003246-200107000-00002.
    1. Dare AJ, Phillips AR, Hickey AJ, Mittal A, Loveday B, Thompson N, Windsor JA. A systematic review of experimental treatments for mitochondrial dysfunction in sepsis and multiple organ dysfunction syndrome. Free Radic Biol Med. 2009;47:1517–1525. doi: 10.1016/j.freeradbiomed.2009.08.019.
    1. 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. doi: 10.1016/S0140-6736(02)09459-X.
    1. Harrois A, Huet O, Duranteau J. Alterations of mitochondrial function in sepsis and critical illness. Curr Opin Anaesthesiol. 2009;22:143–149. doi: 10.1097/ACO.0b013e328328d1cc.
    1. Fink MP. Cytopathic hypoxia: mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis. Crit Care Clin. 2001;17:219–237. doi: 10.1016/S0749-0704(05)70161-5.
    1. Tomasetti M, Alleva R, Solenghi MD, Littarru GP. Distribution of antioxidants among blood components and lipoproteins: significance of lipids/CoQ10 ratio as a possible marker of increased risk for atherosclerosis. Biofactors. 1999;9:231–240. doi: 10.1002/biof.5520090218.
    1. Rundek T, Naini A, Sacco R, Coates K, DiMauro S. Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol. 2004;61:889–892. doi: 10.1001/archneur.61.6.889.
    1. Hedenmalm K, Alvan G, Ohagen P, Dahl ML. Muscle toxicity with statins. Pharmacoepidemiol Drug Saf. 2010;19:223–231. doi: 10.1002/pds.1895.
    1. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med. 2000;6:1399–1402. doi: 10.1038/82219.
    1. Park SY, Lee JS, Ko YJ, Kim AR, Choi MK, Kwak MK, Choi HG, Yong CS, Kim JA. Inhibitory effect of simvastatin on the TNF-α- and angiotensin II-induced monocyte adhesion to endothelial cells is mediated through the suppression of geranylgeranyl isoprenoid-dependent ROS generation. Arch Pharm Res. 2008;31:195–204. doi: 10.1007/s12272-001-1141-2.
    1. Terblanche M, Almog Y, Rosenson RS, Smith TS, Hackam DG. Statins and sepsis: multiple modifications at multiple levels. Lancet Infect Dis. 2007;7:358–368. doi: 10.1016/S1473-3099(07)70111-1.
    1. Donnino MW, Cocchi MN, Howell M, Clardy P, Talmor D, Cataldo L, Chase M, Al-Marshad A, Ngo L, Shapiro NI. Statin therapy is associated with decreased mortality in patients with infection. Acad Emerg Med. 2009;16:230–234. doi: 10.1111/j.1553-2712.2009.00350.x.
    1. Littarru GP, Tiano L. Clinical aspects of coenzyme Q10: an update. Nutrition. 2010;26:250–254. doi: 10.1016/j.nut.2009.08.008.
    1. Brealey DA, Singer M, Terblanche M. Potential metabolic consequences of statins in sepsis. Crit Care Med. 2011;39:1514–1520. doi: 10.1097/CCM.0b013e31820eb74f.
    1. Casey LC, Balk RA, Bone RC. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med. 1993;119:771–778.
    1. Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P, Lamy M. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg. 1992;215:356–362. doi: 10.1097/00000658-199204000-00009.
    1. Hack CE, De Groot ER, Felt-Bersma RJ, Nuijens JH, Strack Van Schijndel RJ, Eerenberg-Belmer AJ, Thijs LG, Aarden LA. Increased plasma levels of interleukin-6 in sepsis. Blood. 1989;74:1704–1710.
    1. Pinsky MR, Vincent JL, Deviere J, Alegre M, Kahn RJ, Dupont E. Serum cytokine levels in human septic shock: relation to multiple-system organ failure and mortality. Chest. 1993;103:565–575. doi: 10.1378/chest.103.2.565.
    1. Reinhart K, Bayer O, Brunkhorst F, Meisner M. Markers of endothelial damage in organ dysfunction and sepsis. Crit Care Med. 2002;30(5 Suppl):S302–S312.
    1. Miles MV, Horn PS, Tang PH, Morrison JA, Miles L, DeGrauw T, Pesce AJ. Age-related changes in plasma coenzyme Q10 concentrations and redox state in apparently healthy children and adults. Clin Chim Acta. 2004;347:139–144. doi: 10.1016/j.cccn.2004.04.003.
    1. Premkumar VG, Yuvaraj S, Vijayasarathy K, Gangadaran SG, Sachdanandam P. Serum cytokine levels of interleukin-1β, -6, -8, tumour necrosis factor-α and vascular endothelial growth factor in breast cancer patients treated with tamoxifen and supplemented with co-enzyme Q10, riboflavin and niacin. Basic Clin Pharmacol Toxicol. 2007;100:387–391. doi: 10.1111/j.1742-7843.2007.00065.x.
    1. van Leeuwen HJ, Heezius ECJM, Dallinga GM, van Strijp JAG, Verhoef J, van Kessel KPM. Lipoprotein metabolism in patients with severe sepsis. Crit Care Med. 2003;31:1359–1366. doi: 10.1097/01.CCM.0000059724.08290.51.
    1. Donnino MW, Carney E, Cocchi MN, Barbash I, Chase M, Joyce N, Chou PP, Ngo L. Thiamine deficiency in critically ill patients with sepsis. J Crit Care. 2010;25:576–581. doi: 10.1016/j.jcrc.2010.03.003.
    1. Lelli JL, Drongowski RA, Gastman B, Remick DG, Coran AG. Effects of coenzyme Q10 on the mediator cascade of sepsis. Circ Shock. 1993;39:178–187.
    1. Watts GF, Castelluccio C, Rice-Evans C, Taub NA, Baum H, Quinn PJ. Plasma coenzyme Q (ubiquinone) concentrations in patients treated with simvastatin. J Clin Pathol. 1993;46:1055–1057. doi: 10.1136/jcp.46.11.1055.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel