A number of studies report that obesity, as indicated by high body mass index (BMI), is paradoxically associated with improved survival during sepsis [
] although this association has not been uniformly observed [
]. Discrepancies between studies may be partly explained by the recent discovery that patients with a high ratio of abdominal visceral adipose tissue to subcutaneous adipose tissue (VAT/SAT) have increased mortality from sepsis compared to patients with low VAT/SAT [
] at any level of BMI [
]. Thus, the distribution of adipose tissue in obesity appears important in sepsis. The mechanism of this VAT/SAT effect is not understood.
We postulated that lipoproteins may be involved since relationships between adipose tissue quantity and lipoprotein levels have been reported in non-septic states [
]. Low LDL levels are a risk factor for sepsis survival and also a risk factor for incidence of sepsis [
]. Since pathogen lipids are sequestered within lipoproteins such as LDL during sepsis, decreased production of LDL leading to low LDL levels may decrease the buffering capacity of LDL for pathogen lipids [
] and allow unbound pathogen lipid to trigger a greater inflammatory response leading to adverse clinical outcomes. In contrast, increased clearance of LDL during sepsis (for example, by loss-of-function genotypes of PCSK9) may be beneficial [
] because pathogen lipids within LDL particles are cleared along with LDL more rapidly [
]. Thus, considering only static serum LDL levels may be too simplistic. Instead, we suggest that it may be necessary to consider the underlying balance of LDL production versus LDL clearance mechanisms when considering prognostic prediction of survival according to LDL levels in sepsis.
To understand potential mechanisms that explain why increased VAT/SAT ratio is harmful in sepsis, we compared two known pathways affecting LDL production and LDL clearance. Statin therapy lowers LDL in the circulation primarily by inhibition of LDL production in hepatocytes [
]. Statin treatment is common and therefore sufficiently prevalent in patients presenting with sepsis to hospital emergency departments to serve as a test of the effect of decreased LDL production on LDL levels and survival in sepsis. PCSK9 inhibitors, which increase LDL clearance, have just been approved to treat certain types of hyperlipidemia [
] but their use is not yet sufficiently prevalent to examine their effect on increased LDL clearance in sepsis. We therefore chose the alternative strategy of measuring PCSK9 loss-of-function genotype, which is known to increase LDL clearance. Thus, in patients with low versus high VAT/SAT ratios, we examined the effect of statins to understand the effect of decreased LDL production, and examined the effect of PCSK9 loss-of-function genotype to understand the effect of increased LDL clearance in patients with sepsis.
Both statin treatment and PCSK9 loss-of-function took away the LDL-preserving effect of low VAT/SAT resulting in uniformly low LDL across both low and high VAT/SAT groups. Despite this similarity in LDL levels, the survival rates were not alike. When LDL was lowered using statins the survival benefit conferred from having a low VAT/SAT was eliminated. In contrast, PCSK9 loss-of-function genotype-driven changes in LDL levels (by increasing LDL clearance) were associated with statistically significantly improved outcomes. In other words, while PCSK9 loss-of-function led to the low VAT/SAT group losing their ability to preserve LDL levels, it did not take away the protective effect, and in fact, enhanced the survival benefit. Thus, it is not the static low LDL levels in sepsis that drive increased mortality. Rather, it may be the dynamic interplay between LDL production and clearance that contributes to clinical outcomes in sepsis.
These VAT/SAT observations in an independent cohort replicate the finding by Pisitsak et al. that low VAT/SAT is associated with longer survival in sepsis compared to high VAT/SAT [
]. Patients with sepsis in the current study were identified earlier in sepsis in the Emergency Department rather than in the ICU and therefore had less severe illness and lower mortality compared to the patients with septic shock who were recruited from an ICU, as described in the previous report [
]. In addition to this, we also found that the low VAT/SAT group was able to preserve their LDL levels at baseline (considering no statin treatment and PCSK9 wildtype genotype patients). This preservation of LDL levels was associated with increased survival. This observation is also concordant with previous studies suggesting that low LDL is associated with worse outcomes [
]. However, these previous studies did not examine the effect of the underlying determinants of LDL levels – LDL production (as altered by statins) and LDL clearance (as altered according to PCSK9 genotype). Statin therapy lowers LDL in the circulation primarily via the inhibition of LDL production in hepatocytes and, to a lesser extent, via a resulting feedback increase in LDL uptake by upregulation of LDL receptor expression (12). That statins primarily inhibit LDL production is confirmed by the observation that LDL levels are decreased by statins in patients with homozygous familial hypercholesterolemia, where LDL receptors are not functioning [
LDL serves an important role in buffering the response to endotoxins by forming an endotoxin-lipoprotein complex [
]. In vitro studies have demonstrated that lipopolysaccharide (LPS) binds readily to serum lipoproteins, and that LPS-lipoprotein complexes are less toxic than unbound LPS [
]. This LPS-lipoprotein-complex formation offers protection in an acute setting, but may also be implicated in the pathogenesis of atherosclerosis [
]. In either scenario, there is value to increasing the clearance of toxin-bound lipoproteins because they may otherwise increase the inflammatory response, leading to unfavorable clinical outcomes in sepsis and/or contribute to atherogenesis. In major inflammatory states, there is a reduction in plasma levels of LDL in parallel with other lipoproteins [
]. The mechanism behind our observation of patients with low VAT/SAT having the ability to preserve their LDL levels (no statin treatment and PCSK9 wildtype genotype) compared to those with high VAT/SAT is yet to be fully understood.
Although static LDL levels have some value for estimating the buffering capacity of the patient against endotoxins in sepsis, it does not fully explain the complex dynamic role of LDL production and clearance, which interact to determine plasma LDL levels. Our results show that there are marked differences between modulating LDL production and LDL clearance in understanding the association between LDL levels and survival in sepsis. Thus, it may be incomplete and in some cases incorrect to conclude that absolute LDL levels are of primary importance in sepsis. Rather, decreased production of LDL may contribute to adverse outcomes but increased clearance appears to be associated with beneficial outcomes. Perhaps this is because inhibiting the production of LDL hinders the buffering capacity of the body against LPS, whereas increased clearance helps eliminate the LDL-endotoxin complex.
Our results further highlight the differential contributions from VAT and SAT in sepsis, which cannot be explained by BMI alone. Several factors that contribute differently towards VAT and SAT have been established, including gender, age, and the onset of menopause in females [
]. When looking at VAT/SAT ratios, one study suggested that VAT/SAT ratios are closely associated with age [
], while another found the opposite when looking at young Japanese male subjects [
]. As such, our cohort showed great age variability on analysis according to low and high VAT/SAT ratios. In parallel with its inflammatory properties, adipose tissue is implicated in the development of metabolic conditions, so adipose tissue is both an active immune and endocrine organ [
]. VAT is a known predictor of diabetes mellitus, while SAT is not [
]. An analysis of the Framingham Heart Study found that high VAT/SAT ratio was associated with increased cardiometabolic risk [
]. Our results identify a novel difference between VAT and SAT by modulating lipoprotein levels differentially during sepsis. Furthermore, both statins [
] and PCSK9 [
] may also be differentially related to visceral versus subcutaneous obesity. In health, LDL and other lipoprotein particles are correlated more strongly with visceral adipose tissue (VAT) than with subcutaneous adipose tissue (SAT) [
Statin use may not improve or worsen survival outcomes on a uniform basis in sepsis and our findings may help elucidate the discrepancy found in currently available statin versus sepsis survival studies [
]. A meta-analysis by Wan et al. showed that prospective studies found no benefit of statin use in sepsis survival, while retrospective studies have demonstrated statin benefit [
]. One prospective double-blind, randomized, controlled trial in 2012 (ASEPSIS trial) found that acute administration of atorvastatin was associated with less progression to severe sepsis, but did not change survival [
]. In addition, Beed et al. showed that prior statin use had no benefit in patients who developed sepsis [
], while other studies report benefit of statins on sepsis survival [
]. Our results demonstrate that VAT/SAT status – and other factors – may influence the effect of statins on survival in sepsis.
Limitations of our study include but are not limited to the inherent biases of a retrospective study design and that the design is an association study so causal inference is not possible. Because our study started before publication of the new Sepsis-3 [
] definition we used the previous definition of sepsis in patients at first contact in the Emergency Department. This means that our patients had a wide range of severity of illness and included a significant contribution from patients without organ failure who had low mortality rates. A weakness of this is that our patient population is more heterogeneous than if the Sepsis-3 definition were used. A strength of this is that our findings may be more broadly applicable. Patients in our study only had abdominal CT scans when the treating physician ordered them for clinical purposes, and this may present an unknown bias. We used PCSK9 loss-of-function genotype as a surrogate to mark PCSK9 inhibition in vivo; however, it is unclear whether our PCSK9 genotype findings will translate to effects on sepsis outcomes by modulating PCSK9 with PCSK9-inhibiting drugs. We took into account the production and clearance of LDL in lowering LDL, but there may be other important mechanisms involved in LDL homeostasis (e.g. sequestration by macrophages). Further studies looking into this these VAT/SAT subgroups and their immunogenic response, or lack thereof, to statin therapy and the implications of PCSK9 loss-of-function genotype will be necessary to elucidate causal pathways.
In conclusion, low VAT/SAT is associated with relative preservation of LDL levels during sepsis and improved survival. However, low LDL levels per se do not appear to cause decreased sepsis survival because inhibiting LDL production with statins (which lowers LDL levels) is associated with adverse outcomes, while lowering plasma LDL by increasing LDL clearance (PCSK9 loss-of-function genotype) was associated with higher survival in patients with a low VAT/SAT.
Ethics approval and consent to participate
All patients provided written informed consent. This protocol was reviewed and approved by the St. Paul’s Hospital/University of British Columbia research ethics board.
Consent for publication
JHB, JAR, and KRW report patents owned by the University of British Columbia (UBC) that are related to PCSK9 inhibitor(s) and sepsis. JHB, JAR, and KRW are founders and shareholders of Cyon Therapeutics, a company that holds patents for use of PCSK9 inhibitors to treat sepsis.
JAR reports patents owned by the University of British Columbia (UBC) that are related to the use of vasopressin in septic shock. Dr. Russell is an inventor on these patents. JAR has share options in Leading Biosciences Inc. JAR is a shareholder in Molecular You Corp. JAR reports receiving consulting fees from:
1. Cubist Pharmaceuticals (now owned by Merck; formerly was Trius Pharmaceuticals; developing antibiotics),
2. Leading Biosciences (developing a sepsis therapeutic),
3. Ferring Pharmaceuticals (manufactures vasopressin and is developing selepressin),
4. Grifols (sells albumin),
5. La Jolla Pharmaceuticals (developing angiotensin II; Dr. Russell chairs the Data Safety Monitoring Board (DSMB) of a trial of angiotensin II),
6. CytoVale Inc. (developing a sepsis diagnostic),
7. Asahi Kesai Pharmaceuticals of America (AKPA) (developing recombinant thrombomodulin).
JAR reports having received an investigator-initiated grant from Grifols that is provided and administered by UBC.
No other authors have any conflict of interests.
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