Katherine RobinsonPeter KrugerLiza K. PhillipsJohn PrinsBala Venkatesh

Effect of statin therapyon plasma adiponectinconcentrations in patientswith the sepsis syndrome:a preliminary investigation

Accepted: 8 March 2011Published online: 27 May 2011� Copyright jointly held by Springer andESICM 2011

Dear Editor,Plasma concentrations of adiponectin,a vascular protective and an antiin-flammatory hormone, are reduced inpatients with sepsis [1]. Statins mayhave a protective effect in the septicstate; however, the mechanism ofbenefit is unclear. With adiponectin

known to play a pivotal role in tissueinflammation [2], we speculated thatmodulation of plasma adiponectinmay be responsible for the possiblebenefits of statins in sepsis. Statinshave been shown to have a variableeffect on adiponectin in other condi-tions [3, 4], and whether a similarmodulatory effect exists in sepsis onboth the total adiponectin and itsmultimers has not been investigated.

We therefore utilised availableplasma samples from a recently pub-lished randomised controlled trial ofatorvastatin (20 mg) versus placeboin 150 patients with sepsis [3]. Thisapriory substudy was independentlyapproved by the Princess AlexandraHospital Research Ethics Committee.Residual serum samples at baseline(D1) and D5 for adiponectin analysiswere available in 27 patients; ator-vastatin (n = 14), placebo (n = 13).A detailed description of inclusionand exclusion criteria was provided inthe original paper [3]. Briefly,patients on pre-existing statin therapywith proven or suspected infection(defined using the CDC Atlanta

criteria) for which antibiotic therapyhad been commenced were enrolledin the study. Total and high molecularweight (HMW) serum adiponectinwere measured using ELISA (AL-PCO Diagnostics, Salem, NH, USA),CRP by immunoturbidimetric assay(Roche/Hitachi Modular systems) andIL-6 by ELISA immunoassay (JomarBioscience).

The demographic details, plasmaadiponectin and the inflammatoryparameters are outlined in Table 1.Total adiponectin was highly corre-lated with HMW adiponectin for theentire cohort at baseline (r2 = 0.87,p \ 0.0001) and D5 (r2 = 0.88,p \ 0.0001). Although total andHMW adiponectin levels were lowerin the statins as compared to placebo,these differences were not statisticallysignificant. There was poor correla-tion between inflammatory markersand both D1 total adiponectin (IL-6,R = -0.09; CRP, R = 0.1) and day 5total adiponectin levels (IL-6, R =-0.06; CRP, R = -0.01).

To our knowledge, this is the firstpaper to examine the relationship

Table 1 Demographic, adiponectin and inflammatory parameters

Statins (n = 14) Placebo (n = 13) p value

Mean age (SD) (years) 66.3 (17.2) 65.2 (12.5) 0.56Sex 6F, 8M 7F, 6MSource of sepsisUrosepsis 4 0Skin sepsis 7 1Respiratory 2 7Line sepsis 0 2Gastrointestinal 1 3

ICU Admission 2 1Hospital survivors 13/14 13/13 0.89

Results

Day 1 Day 5

Statin Placebo p value Statin Placebo p value

Mean total serum adiponectin (SD) in mcg/ml 7.8 (3.3) 10 (7.5) 0.34 8.9 (3.9) 11.7 (6.8) 0.20Mean HMW serum adiponectin (SD) in mcg/ml 5.4 (3.4) 7.4 (6.1) 0.32 5.7 (4.4) 8.0 (5.0) 0.26Mean serum IL -6 (SD) in pg/ml 114.5 (158.5) 66.3 (68.5) 0.33 49.8 (80.5) 17.9 (18.2) 0.17Mean serum CRP (SD) in mg/ml 175 (141.6) 258.8 (157.9) 0.16 107.5 (95) 112.8 (111.2) 0.90

No significant differences were noted between the two groups between D1 and D5 with respect to total and HMW adiponectin, IL-6 andCRP

Intensive Care Med (2011) 37:1388–1389DOI 10.1007/s00134-011-2247-8 CORRESPONDENCE

between adiponectin and statin ther-apy in sepsis, particularly the use ofthe HMW component. The effect ofstatins on plasma adiponectin is var-iable. Some report an increase inadiponectin following atorvastatintherapy [4], while others show nosignificant change [5]. In this study,there was no significant associationbetween statin use and adiponectin.Recent research suggests that statinsmay result in an alteration in complexdistribution [6]. Simvastatin reducesthe circulating HMW form with nochange in the total adiponectin level,but an increase in intracellular HMWlevels suggesting that statin therapyresults in a secretion defect for HMWadiponectin in adipocytes. Thus, cir-culating plasma adiponectin levelsmay not be a reliable method ofassessing statin effects on adiponectinbiology [6].

This is a preliminary study limitedby small sample size. Moreover,whether the effect of statin cessationon plasma adiponectin may benoticeable in the short term is unclear[7].

In conclusion, in this preliminarysub-study, a strong correlationbetween total and HMW componentwas evident and suggests that totaladiponectin may be used as a surro-gate for the HMW fraction in patientswith sepsis. Moreover, acute cessa-tion of statin therapy was not found toinfluence total and HMW adiponectinin patients with the sepsis syndrome.

Larger studies examining the effect ofstatins on both plasma adiponectinand tissue adiponectin concentrationsare warranted to delineate anymechanistic basis for the protectiveeffects of statins in sepsis.

References

1. Venkatesh B, Hickman I, Nisbet J,Cohen J, Prins J (2009) Changes inserum adiponectin concentrations incritical illness: a preliminaryinvestigation. Crit Care 13:R105

2. Whitehead JP, Richards AA, Hickman IJ,Macdonald GA, Prins JB (2006)Adiponectin—a key adipokine in themetabolic syndrome. Diabetes ObesMetab 8:264–280

3. Kruger PS, Harward ML, Jones MA,Joyce CJ, Kostner KM, Roberts MS,Venkatesh B (2011) Continuation ofstatin therapy in patients with presumedinfection: a randomised controlled trial.Am J Respir Crit Care Med 183:774–781

4. Hyogo H, Tazuma S, Arihiro K, IwamotoK, Nabeshima Y, Inoue M, Ishitobi T,Nonaka M, Chayama K (2008) Efficacyof atorvastatin for the treatment ofnonalcoholic steatohepatitis withdyslipidemia. Metabolism 57:1711–1718

5. van Hoek M, van Tol A, der Zee LC,Jansen H, Kastelein JJ, Sijbrands EJ,Dallinga-Thie GM (2009) Role ofplasma adiponectin on the HDL-cholesterol raising effect of atorvastatinin patients with type 2 diabetes. CurrMed Res Opin 25:93–101

6. Khan T, Hamilton MP, Mundy DI, ChuaSC, Scherer PE (2009) Impact ofsimvastatin on adipose tissue: pleiotropiceffects in vivo. Endocrinology150:5262–5272

7. Ohashi T, Shibata R, Morimoto T,Kanashiro M, Ishii H, Ichimiya S, HiroT, Miyauchi K, Nakagawa Y, YamagishiM, Ozaki Y, Kimura T, Daida H,Murohara T, Matsuzaki M (2010)Correlation between circulatingadiponectin levels and coronary plaqueregression during aggressive lipid-lowering therapy in patients with acutecoronary syndrome: subgroup analysis ofJAPAN-ACS study. Atherosclerosis212:237–242

K. Robinson ())Intensive Care Unit, The Wesley Hospital,451 Coronation Drive, Auchenflower,Brisbane, QLD, Australiae-mail: katherine.robinson2@

uqconnect.edu.au

P. KrugerIntensive Care Unit, Princess AlexandraHospital, Brisbane, QLD, Australiae-mail: peter_kruger@health.qld.gov.au

L. K. PhillipsDiamantina Institute for Cancer,Immunology and Metabolic Medicine,Princess Alexandra Hospital,University of Queensland,Brisbane, QLD, Australiae-mail: liza.phillips@uqconnect.edu.au

J. PrinsEndocrinology, Mater Medical ResearchInstitute, University of Queensland,Level 3 Aubigny Place, South Brisbane,Brisbane, QLD, Australiae-mail: j.prins@uq.edu.au

B. VenkateshIntensive Care, Princess Alexandraand Wesley Hospitals, Universityof Queensland, Brisbane, QLD, Australiae-mail: bala_venkatesh@health.qld.gov.au

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