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Open Access 01-12-2018 | Research

Survival benefit of a low ratio of visceral to subcutaneous adipose tissue depends on LDL clearance versus production in sepsis

Authors: Joseph G. H. Lee, Kelly R. Genga, Chawika Pisitsak, John H. Boyd, Alex K. K. Leung, James A. Russell, Keith R. Walley

Published in: Critical Care | Issue 1/2018

Abstract

Background

Patients with sepsis with a high ratio of visceral adipose tissue (VAT) to subcutaneous adipose tissue (SAT) have increased mortality. Our goal was to investigate the mechanism of this effect, noting that low LDL levels are also associated with increased sepsis mortality. Accordingly we tested for association between VAT/SAT, low-density lipoprotein (LDL) levels, and mortality. Then we examined the effect of statin treatment, which decreases LDL production, and the effect of PCSK9 genotype, which increases LDL clearance.

Methods

We performed retrospective analysis of a cohort of patients with sepsis from a tertiary care adult intensive care unit in Vancouver, Canada, who underwent abdominal computed tomography (CT) (n = 75) for clinical reasons. We compared LDL levels in patients with sepsis according to high versus low VAT/SAT and 90-day survival. We next examined the effects of statin therapy and PCSK9 loss-of-function genotype on survival.

Results

Patients with a low VAT/SAT had increased 90-day survival and were relatively protected against low LDL levels in sepsis compared to high VAT/SAT. Statin treatment abrogated the beneficial effects of low VAT/SAT; eliminating the difference in LDL levels and survival between patients with low and high VAT/SAT. PSCK9 loss-of-function genotype similarly eliminated the increased LDL levels in low VAT/SAT patients but, in contrast, increased the survival advantage of low VAT/SAT compared to high VAT/SAT.

Conclusions

Low LDL levels per se are not simply associated with decreased sepsis survival because lowering LDL levels by inhibiting LDL production (statin treatment) is associated with adverse outcomes, while increased LDL clearance (PCSK9 loss-of-function genotype) is associated with improved outcomes in patients with low VAT/SAT.

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Pepper DJ, Sun J, Welsh J, Cui X, Suffredini AF, Eichacker PQ. Increased body mass index and adjusted mortality in ICU patients with sepsis or septic shock: a systematic review and meta-analysis. Crit Care. 2016;20(1):181. https://doi.org/10.1186/s13054-016-1360-z. PubMed PMID: 27306751; PubMed Central PMCID: PMCPMC4908772.

Trivedi V, Bavishi C, Jean R. Impact of obesity on sepsis mortality: a systematic review. J Crit Care. 2015;30(3):518–524. https://doi.org/10.1016/j.jcrc.2014.12.007. PubMed PMID: 25575851.

Kuperman EF, Showalter JW, Lehman EB, Leib AE, Kraschnewski JL. The impact of obesity on sepsis mortality: a retrospective review. BMC Infect Dis. 2013;13:377. https://doi.org/10.1186/1471-2334-13-377. PubMed PMID: 23957291; PubMed Central PMCID: PMCPMC3765286.

Pisitsak C, Lee JG, Boyd JH, Coxson HO, Russell JA, Walley KR. Increased ratio of visceral to subcutaneous adipose tissue in septic patients is associated with adverse outcome. Crit Care Med. 2016;11:1966–1973. Epub 2016/08/12. https://doi.org/10.1097/CCM.0000000000001870. PubMed PMID: 27513541.

Kaess BM, Pedley A, Massaro JM, Murabito J, Hoffmann U, Fox CS. The ratio of visceral to subcutaneous fat, a metric of body fat distribution, is a unique correlate of cardiometabolic risk. Diabetologia. 2012;55(10):2622–2630. Epub 2012/08/18. https://doi.org/10.1007/s00125-012-2639-5. PubMed PMID: 22898763; PubMed Central PMCID: PMCPMC3636065.

Lemieux S, Prud'homme D, Moorjani S, Tremblay A, Bouchard C, Lupien PJ, et al. Do elevated levels of abdominal visceral adipose tissue contribute to age-related differences in plasma lipoprotein concentrations in men? Atherosclerosis 1995;118(1):155–164. Epub 1995/11/01. PubMed PMID: 8579625.

Shor R, Wainstein J, Oz D, Boaz M, Matas Z, Fux A, et al. Low serum LDL cholesterol levels and the risk of fever, sepsis, and malignancy. Ann Clin Lab Sci 2007;37(4):343–348. Epub 2007/11/15. PubMed PMID: 18000291.

Levels JH, Abraham PR, van Barreveld EP, Meijers JC, van Deventer SJ. Distribution and kinetics of lipoprotein-bound lipoteichoic acid. Infect Immun 2003;71(6):3280–3284. Epub 2003/05/23. PubMed PMID: 12761109; PubMed Central PMCID: PMC155762.

Levels JH, Abraham PR, van den Ende A, van Deventer SJ. Distribution and kinetics of lipoprotein-bound endotoxin. Infect Immun 2001;69(5):2821–2828. Epub 2001/04/09. https://doi.org/10.1128/IAI.69.5.2821-2828.2001. PubMed PMID: 11292694; PubMed Central PMCID: PMC98230.

10.

Walley KR, Thain KR, Russell JA, Reilly MP, Meyer NJ, Ferguson JF, et al. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med. 2014;6(258):258ra143. Epub 2014/10/17. https://doi.org/10.1126/scitranslmed.3008782. PubMed PMID: 25320235.

11.

Dwivedi DJ, Grin PM, Khan M, Prat A, Zhou J, Fox-Robichaud AE, et al. Differential expression of PCSK9 modulates infection, inflammation and coagulation in a murine model of sepsis. Shock. 2016;46:672–80. Epub 2016/07/13. https://doi.org/10.1097/SHK.0000000000000682. PubMed PMID: 27405064.

12.

Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med 2001;5(4):378–387. Epub 2002/06/18. PubMed PMID: 12067471.

13.

Marais AD, Naoumova RP, Firth JC, Penny C, Neuwirth CK, Thompson GR. Decreased production of low density lipoprotein by atorvastatin after apheresis in homozygous familial hypercholesterolemia. J Lipid Res 1997;38(10):2071–2078. Epub 1997/11/28. PubMed PMID: 9374129.

14.

Raal FJ, Pilcher GJ, Illingworth DR, Pappu AS, Stein EA, Laskarzewski P, et al. Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia. Atherosclerosis 1997;135(2):249–256. Epub 1998/01/16. PubMed PMID: 9430375.

15.

Lepor NE, Kereiakes DJ. The PCSK9 inhibitors: a novel therapeutic target enters clinical practice. Am Health Drug Benefits 2015;8(9):483–489. PubMed PMID: 26834934; PubMed Central PMCID: PMC4719137.

16.

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–810. https://doi.org/10.1001/jama.2016.0287. PubMed PMID: 26903338; PubMed Central PMCID: PMC4968574.

17.

Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 2003;29(4):530–538. Epub 2003/03/29. https://doi.org/10.1007/s00134-003-1662-x. PubMed PMID: 12664219.

18.

Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889-2934. Epub 2013/11/19. doi: https://doi.org/10.1016/j.jacc.2013.11.002. PubMed PMID: 24239923.

19.

Yoshizumi T, Nakamura T, Yamane M, Islam AH, Menju M, Yamasaki K, et al. Abdominal fat: standardized technique for measurement at CT. Radiology 1999;211(1):283–286. Epub 1999/04/06. https://doi.org/10.1148/radiology.211.1.r99ap15283. PubMed PMID: 10189485.

20.

Kvist H, Chowdhury B, Sjostrom L, Tylen U, Cederblad A. Adipose tissue volume determination in males by computed tomography and 40K. Int J Obes 1988;12(3):249–266. Epub 1988/01/01. PubMed PMID: 3391740.

21.

Rossner S, Bo WJ, Hiltbrandt E, Hinson W, Karstaedt N, Santago P, et al. Adipose tissue determinations in cadavers–a comparison between cross-sectional planimetry and computed tomography. Int J Obes 1990;14(10):893–902. Epub 1990/10/01. PubMed PMID: 2269582.

22.

Flegel WA, Baumstark MW, Weinstock C, Berg A, Northoff H. Prevention of endotoxin-induced monokine release by human low- and high-density lipoproteins and by apolipoprotein A-I. Infection & Immunity. 1993;61(12):5140–6.

23.

Netea MG, Demacker PN, Kullberg BJ, Boerman OC, Verschueren I, Stalenhoef AF, et al. Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections. J Clin Invest 1996;97(6):1366–1372. Epub 1996/03/15. https://doi.org/10.1172/JCI118556. PubMed PMID: 8617867; PubMed Central PMCID: PMC507194.

24.

Emancipator K, Csako G, Elin RJ. In vitro inactivation of bacterial endotoxin by human lipoproteins and apolipoproteins. Infect Immun 1992;60(2):596–601. PubMed PMID: 1730494; PubMed Central PMCID: PMC257670.

25.

Flegel WA, Wölpl A, Männel DN, Northoff H. Inhibition of endotoxin-induced activation of human monocytes by human lipoproteins. Infect Immun 1989;57(7):2237–2245. PubMed PMID: 2731990; PubMed Central PMCID: PMC313866.

26.

Schwartz YSh, Dushkin MI. Endotoxin-lipoprotein complex formation as a factor in atherogenesis: associations with hyperlipidemia and with lecithin:cholesterol acyltransferase activity. Biochemistry (Mosc) 2002;67(7):747–752. PubMed PMID: 12139471.

27.

Mooser V, Berger MM, Tappy L, Cayeux C, Marcovina SM, Darioli R, et al. Major reduction in plasma Lp(a) levels during sepsis and burns. Arterioscler Thromb Vasc Biol 2000;20(4):1137–1142. PubMed PMID: 10764684.

28.

Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000;21(6):697–738. Epub 2001/01/02. https://doi.org/10.1210/edrv.21.6.0415. PubMed PMID: 11133069.

29.

Asayama K, Dobashi K, Hayashibe H, Kodera K, Uchida N, Nakane T, et al. Threshold values of visceral fat measures and their anthropometric alternatives for metabolic derangement in Japanese obese boys. Int J Obes Relat Metab Disord 2002;26(2):208–213. Epub 2002/02/19. https://doi.org/10.1038/sj.ijo.0801865. PubMed PMID: 11850752.

30.

Bays HE, Gonzalez-Campoy JM, Bray GA, Kitabchi AE, Bergman DA, Schorr AB, et al. Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity. Expert Rev Cardiovasc Ther 2008;6(3):343–368. Epub 2008/03/11. https://doi.org/10.1586/14779072.6.3.343. PubMed PMID: 18327995.

31.

Bray GA, Jablonski KA, Fujimoto WY, Barrett-Connor E, Haffner S, Hanson RL, et al. Relation of central adiposity and body mass index to the development of diabetes in the Diabetes Prevention Program. 2008.

32.

Wee CC, Girotra S, Weinstein AR, Mittleman MA, Mukamal KJ. The relationship between obesity and atherosclerotic progression and prognosis among patients with coronary artery bypass grafts the effect of aggressive statin therapy. J Am Coll Cardiol. 2008;52(8):620–5.

33.

Arsenault BJ, Pelletier-Beaumont E, Almeras N, Tremblay A, Poirier P, Bergeron J, et al. PCSK9 levels in abdominally obese men: association with cardiometabolic risk profile and effects of a one-year lifestyle modification program. Atherosclerosis 2014;236(2):321–326. Epub 2014/08/17. https://doi.org/10.1016/j.atherosclerosis.2014.07.010. PubMed PMID: 25128757.

34.

Deschenes D, Couture P, Dupont P, Tchernof A. Subdivision of the subcutaneous adipose tissue compartment and lipid-lipoprotein levels in women. Obes Res 2003;11(3):469–476. Epub 2003/03/14. https://doi.org/10.1038/oby.2003.64. PubMed PMID: 12634447.

35.

Kopterides P, Falagas ME. Statins for sepsis: a critical and updated review. Clin Microbiol Infect 2009;15(4):325–334. Epub 2009/05/07. https://doi.org/10.1111/j.1469-0691.2009.02750.x. PubMed PMID: 19416304.

36.

Wan YD, Sun TW, Kan QC, Guan FX, Zhang SG. Effect of statin therapy on mortality from infection and sepsis: a meta-analysis of randomized and observational studies. Crit Care. 2014;182014:R71.

37.

Patel JM, Snaith C, Thickett DR, Linhartova L, Melody T, Hawkey P, et al. Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial). Crit Care. 2012;16(6):R231. Epub 2012/12/13. https://doi.org/10.1186/cc11895. PubMed PMID: 23232151; PubMed Central PMCID: PMCPMC3672620.

38.

Beed M, Brindley PG, Mahajan R, Juttner I, Campion-Smith J, Wilson VG. The association between prior statin use and long-term outcomes after critical care admission. J Crit Care 2016;35:63–68. Epub 2016/08/03. https://doi.org/10.1016/j.jcrc.2016.04.031. PubMed PMID: 27481737.

39.

Almog Y, Shefer A, Novack V, Maimon N, Barski L. Eizinger M, et al. Prior statin therapy is associated with a decreased rate of severe sepsis. 2004; https://doi.org/10.1161/01.CIR.0000138932.17956.F1.

40.

Fuller BM, Gajera M, Schorr C, Gerber D, Dellinger RP, Zanotti S. The association of prior statin use in septic shock treated with early goal directed therapy. Eur J Emerg Med. 2012;19(4):226–230. Epub 2011/09/15. https://doi.org/10.1097/MEJ.0b013e32834b3467. PubMed PMID: 21915053; PubMed Central PMCID: PMCPMC3556478.

Title: Survival benefit of a low ratio of visceral to subcutaneous adipose tissue depends on LDL clearance versus production in sepsis
Authors: Joseph G. H. Lee
Kelly R. Genga
Chawika Pisitsak
John H. Boyd
Alex K. K. Leung
James A. Russell
Keith R. Walley
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Critical Care / Issue 1/2018
Electronic ISSN: 1364-8535
DOI: https://doi.org/10.1186/s13054-018-1985-1

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Survival benefit of a low ratio of visceral to subcutaneous adipose tissue depends on LDL clearance versus production in sepsis

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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