Abstract
Introduction
Known to have pleiotropic functions, high-density lipoprotein (HDL) helps to regulate systemic inflammation during sepsis. As preserving HDL-C level is a promising therapeutic strategy for sepsis, the interaction between HDL and sepsis worth further investigation. This study aimed to determine the impact of sepsis on HDL’s anti-inflammatory capacity and explore its correlations with disease severity and laboratory parameters.
Methods and materials
We enrolled 80 septic subjects admitted to the intensive care unit and 50 controls admitted for scheduled coronary angiography in this cross-sectional study. We used apolipoprotein-B depleted (apoB-depleted) plasma to measure the anti-inflammatory capacity of HDL-C. ApoB-depleted plasma’s anti-inflammatory capacity is defined as its ability to suppress tumor necrosis factor-α–induced vascular cell adhesion molecule-1 (VCAM-1) expression in human umbilical-vein endothelial cells. A subgroup analysis was conducted to investigate in septic subjects according to disease severity.
Results
ApoB-depleted plasma’s anti-inflammatory capacity was reduced in septic subjects relative to controls (VCAM-1 mRNA fold change: 50.1% vs. 35.5%; p < 0.0001). The impairment was more pronounced in septic subjects with than in those without septic shock (55.8% vs. 45.3%, p = 0.0022). Both associations were rendered non-significant with the adjustment for the HDL-C level. In sepsis patients, VCAM-1 mRNA fold change correlated with the SOFA score (Spearman’s r = 0.231, p = 0.039), lactate level (r = 0.297, p = 0.0074), HDL-C level (r = –0.370, p = 0.0007), and inflammatory markers (C-reactive protein level: r = 0.441, p <0.0001; white blood cell: r = 0.353, p = 0.0013).
Conclusion
ApoB-depleted plasma’s anti-inflammatory capacity is reduced in sepsis patients and this association depends of HDL-C concentration. In sepsis patients, this capacity correlates with disease severity and inflammatory markers. These findings explain the prognostic role of the HDL-C level in sepsis and indirectly support the rationale for targeting HDL-C as sepsis treatment.
Introduction
Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, is the greatest challenge in critical care, contributing to one-fifth of deaths in this setting worldwide [1, 2]. With the failure of hundreds of clinical trials, the number of medications with the ability to counteract sepsis remains limited [3, 4]. A more comprehensive understanding of the pathogenesis of sepsis is needed for the identification of new therapeutic targets.
High-density lipoprotein (HDL), the scavenger of cholesterol, is known to play a role in the reverse cholesterol transport pathway [5]. It has pleiotropic functions that help to maintain circulatory hemostasis such as the regulation of the inflammatory response and liposaccharide binding, and an antioxidant effect [6–8]. Clinically, a drastic decline in the high-density lipoprotein cholesterol (HDL-C) level occurs during sepsis and can serve as a prognostic factor [9, 10]. Recent studies have revealed that an inhibitory variant of the human cholesteryl ester transfer protein (CETP) gene is associated with an increase in the plasma HDL-C concentration and better sepsis outcome, whereas a gain-of-function variant of this gene is associated with the opposite effect [11–13]. Given the success of a CETP inhibitor in improving the survival of septic mice [12, 14], further investigation of the interaction between HDL and sepsis is warranted.
The anti-inflammatory capacity of HDL, defined as its ability to suppress tumor necrosis factor-α (TNF-α)–induced vascular cell adhesion molecule-1 (VCAM-1) expression at the endothelial level [15], is important for the attenuation of endothelial dysfunction and systemic inflammation primarily through the blunting of transcriptional factors such as nuclear factor kappa-B [16–18]. Data on this capacity in patients with sepsis are lacking, however, as most studies have focused on its association with cardiovascular disease [15, 19–21]. Thus, the observation of this HDL functionality in a septic population and the determination of its clinical relevance are of interest. In this cross-sectional study, we used apolipoprotein-B depleted (apoB-depleted) plasma to measure HDL’s anti-inflammatory capacity. The aim of the study was to determine whether apoB-depleted plasma’s anti-inflammatory capacity is associated with the presence and/or severity of sepsis, and to explore its correlations with various laboratory and clinical parameters.
Methods
Study population and data collection
We randomly enrolled 80 patients aged ≥ 18 years with sepsis who were admitted to the medical intensive care unit (ICU) of Taipei Veterans General Hospital, a tertiary medical center in Taiwan, between May 2018 and June 2019. Sepsis was diagnosed according to the Society of Critical Care Medicine’s sepsis-3 criteria [2] as a sequential organ failure assessment (SOFA) score increase ≥ 2 within 24 hours in the presence of infection. In addition, we randomly enrolled 50 subjects admitted for scheduled coronary angiography (CAG) between May 2019 and Apr 2021, and without acute coronary syndrome, as controls. By detailed chart review, the remaining information on the enrolled patients was collected: age, sex, body mass index (BMI; kg/m2), history of smoking, and comorbidities [type 2 diabetes mellitus (T2DM), hypertension, atrial fibrillation (AF), gout, end-stage renal disease, coronary artery disease (≥50% stenosis of at least one coronary artery on CAG), and dyslipidemia]. White blood cell counts (WBCs) and blood chemistry tests [determination of the platelet, hemoglobin, uric acid, glucose, alanine transaminase (ALT), and creatinine levels] were performed at admission using routine laboratory methods for patients in both groups. For patients with sepsis, the C-reactive protein (CRP), procalcitonin, lactate, and albumin levels were also determined at the time of ICU admission. Information on infection sites was obtained from the descriptions of diagnoses in these patients’ medical records. Septic shock was defined as hypotension requiring vasopressor use to maintain a mean arterial pressure ≥ 65 mmHg and with a serum lactate level > 18 mg/dL [2]. Disease severity at the time of ICU admission was determined using the SOFA and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. This study was approved by the Research Ethics Committee of Taipei Veterans General Hospital (no. 2018-02-009AC) and conducted according to the principles of the Declaration of Helsinki. All participants provided written informed consent. All relevant data within this study were provided in the Supporting Information files (S1 Dataset).
Determination of lipid profiles
Blood samples were collected from the participants within 24 hours of admission and stored at –80°C until analysis. Lipid profiles, including the total cholesterol, HDL-C, and triglyceride levels, were determined using routine laboratory methods. The Friedewald formula was applied to estimate the low-density lipoprotein cholesterol (LDL-C) level. The serum amyloid A (SAA) protein level was measured using the commercial Human SAA1 DuoSet ELISA Kit DY3019-05 (R&D Systems, Inc., Minneapolis, MN, USA).
Determination of anti-inflammatory capacity in apoB-depleted plasma
The anti-inflammatory capacity of apoB-depleted plasma in each sample was determined using an in-vitro cell system following an established procedure [20]. For apoB-depleted plasma preparation, we mixed each sample with 36% polyethylene glycol 6000 (Merck, Darmstadt, Germany) in HEPES buffer (pH 8.0; Merck) at a 2:1 ratio and kept the mixture on ice for 30 minutes. The mixture was then centrifuged at 2200 × g for 30 minutes, and the supernatant (apoB-depleted plasma] was used directly for the determination of its anti-inflammatory capacity.
Human umbilical-vein endothelial cells (HUVECs; ATCC, Manassas, VA, USA) were cultured in medium with 10% fetal bovine serum (FBS). After reaching 70% confluency, the cells were incubated with FBS-free medium for 2 hours; 3% apo-B–depleted plasma or phosphate-buffered saline (control) was then added. After 30 minutes of incubation, the HUVECs were treated with 10 ng/mL TNF-α (R&D Systems) and incubated for 7 hours to stimulate VCAM-1 mRNA expression. Subsequently, RNA isolation and cDNA synthesis were performed using NucleoZol (MACHEREY-NAGEL GmbH & Co. KG, Düren, Germany) and PrimeScript RT reagent (Perfect Real Time, RR037A; Takara Bio Inc., Shiga, Japan) kits, respectively, following the manufacturers’ instructions. VCAM-1 mRNA expression was determined by quantitative real-time polymerase chain reaction (StepOnePlus; Thermo Fisher scientific, Waltham, MA, USA) using cyclophilin A as the housekeeping gene and the following primers: VCAM-1 forward, 5’-GGGAAGATGGTCGTATCCTT-3’; VCAM-1 reverse, 5’-TCTGGGGTGGTCTCGATTTTA-3’; cyclophilin A forward, 5’-TGCTGGACCCAACACAAATGGT-3’; and cyclophilin A reverse, 5’-GCCAAACACCACATGCTTGC-3’ (Thermo Fisher, Waltham, MA, USA). The fold change in gene expression was calculated using the ΔΔCt method, normalized to the corresponding control for each 12-well plate. ApoB-depleted plasma’s anti-inflammatory capacity was measured at least in duplicate and represented by the averaged fold change for each plasma sample. Larger fold changes were taken to indicate lower anti-inflammatory capacity.
Statistical analysis
Continuous variables are presented as medians (interquartile ranges) and categorical variables are presented as numbers (percentages). The Mann–Whitney U test or Fisher’s exact test was used to detect between-group differences in the study variables. Multivariable logistic regression analysis was performed to control for variable imbalance and to assess whether associations of reduced anti-inflammatory capacity of apoB-depleted plasma with sepsis and septic shock were dependent on HDL-C or inflammatory markers. A subgroup analysis was conducted to investigate anti-inflammatory capacity of apoB-depleted plasma in the septic group stratified by disease severity (septic shock, lactate concentration > 18 mg/dL, or SOFA score > 8, established prognostic indicators for sepsis with clinically significant cut-off values) [2]. The Spearman coefficient was used to assess correlations of anti-inflammatory capacity of apoB-depleted plasma and HDL-C with continuous variables in the septic population. Two-tailed p values ≤ 0.05 were considered significant. All statistical analyses were performed with SPSS software ver. 24.0 (IBM, Armonk, NY, USA) and graph creation were performed with GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA).
Results
Baseline participant characteristics
Totally 80 septic patients and 50 non-septic subjects admitted for CAG were included in the cross-sectional study. The clinical and laboratory variables were described in Table 1. Relative to the control group, patients were older, the proportion of males was larger, and the BMI was lower in the sepsis group [Age: 67.0 (60.3–79.0) vs. 63.5 (53.8–70.0), p = 0.0098; male gender: 60 (75.0%) vs. 26 (52.0%), p = 0.0082; BMI: 22.4 (19.5–26.0) vs. 24.9 (22.9–28.0), p = 0.0049]. In addition, the WBC, ALT and creatinine levels were higher and the hemoglobin, platelet, total cholesterol, LDL-C, and HDL-C concentrations were lower in the sepsis group [WBC: 11.3 (6.4–16.9) vs. 6.0 (4.8–7.9), p < 0.0001; ALT: 29.0 (15.8–49.5) vs. 16.5 (12.0–22.0), p < 0.0001; creatinine: 2.0 (0.9–3.5) vs. 0.9 (0.7–1.1), p < 0.0001; hemoglobin: 8.7 (7.8–10.9) vs. 13.3 (12.6–14.1), p < 0.0001; platelet: 120.5 (71.5–227.5) vs. 206.0 (181.8–250.0), p < 0.0001; total cholesterol: 95.0 (70.3–118.0) vs. 151.0 (113.5–182.0), p < 0.0001; LDL-C: 50.3 (31.0–64.2) vs. 75.2 (64.4–96.9), p < 0.0001; HDL-C: 18.0 (10.2–31.8) vs. 47.6 (37.1–59.6), p < 0.0001; Table 1].
Table 1. Baseline characteristics among septic patients and controls.
| Control (N = 50) |
Sepsis (N = 80) |
P value | |
|---|---|---|---|
| Age (years) | 63.5 (53.8–70.0) | 67.0 (60.3–79.0) | 0.0098 |
| Male gender (%) | 26 (52.0) | 60 (75.0) | 0.0082 |
| Body mass index (kg/m2) | 24.9 (22.9–28.0) | 22.4 (19.5–26.0) | 0.0049 |
| Smoking history (%) | 11 (22.0) | 28 (35.0) | 0.17 |
| Co-morbidities (%) | |||
| Hypertension | 30 (60.0) | 41 (51.3) | 0.37 |
| Type 2 diabetic mellitus | 9 (18.0) | 22 (27.5) | 0.29 |
| Coronary artery disease | 10 (20.0) | 17 (21.3) | >0.99 |
| Atrial fibrillation | 3 (6.0) | 10 (12.5) | 0.37 |
| End-stage renal disease | 3 (6.0) | 5 (6.3) | >0.99 |
| Gout | 2 (4.0) | 9 (11.3) | 0.20 |
| Dyslipidemia | 23 (46.0) | 8 (10.0) | <0.0001 |
| Laboratory data | |||
| White blood cells (K) | 6.0 (4.8–7.9) | 11.3 (6.4–16.9) | <0.0001 |
| Hemoglobin (mg/dL) | 13.3 (12.6–14.1) | 8.7 (7.8–10.9) | <0.0001 |
| Platelets (K) | 206.0 (181.8–250.0) | 120.5 (71.5–227.5) | <0.0001 |
| ALT (U/L) | 16.5 (12.0–22.0) | 29.0 (15.8–49.5) | <0.0001 |
| Creatinine (mg/dL) | 0.9 (0.7–1.1) | 2.0 (0.9–3.5) | <0.0001 |
| Uric acid (mg/dL) | 5.2 (4.0–5.9) | 5.3 (3.2–7.8) | 0.40 |
| Total cholesterol (mg/dL) | 151.0 (113.5–182.0) | 95.0 (70.3–118.0) | <0.0001 |
| HDL-C (mg/dL) | 47.6 (37.1–59.6) | 18.0 (10.2–31.8) | <0.0001 |
| LDL-C (mg/dL) | 75.2 (64.4–96.9) | 50.3 (31.0–64.2) | <0.0001 |
| Triglyceride (mg/dL) | 122.0 (71.8–149.3) | 105 (73.5–146.3) | 0.29 |
Continuous variables were expressed as median (interquartile range) and categorical variables were expressed as number (percentage). Mann-Whitney U test or Fisher’s exact test was used to compare the variables between two groups. ALT, alanine transaminase; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol
Association between impaired anti-inflammatory capacity of apoB-depleted plasma and the presence of sepsis
The anti-inflammatory capacity of apoB-depleted plasma from patients with sepsis was lower than that of the control [VCAM-1 mRNA fold change: 50.1% (39.8–58.1%) vs. 35.5% (28.3–42.7%); p < 0.0001; Fig 1A]. The VCAM-1 mRNA fold change correlated well with the HDL-C level in the whole population (r = –0.563, p < 0.0001; Fig 1B) and the sepsis group (r = –0.370, p = 0.0007; Fig 1B).
Fig 1. Relative expression of VCAM-1 mRNA, indicating anti-inflammatory capacity of apoB-depleted plasma.
(A) Comparison of apoB-depleted plasma’s anti-inflammatory capacity between sepsis (n = 80) and control (n = 50). (B) Scatter plot showing univariate relationship between apoB-depleted plasma’s anti-inflammatory capacity and HDL-C levels in the whole population (n = 130, spearman correlation coefficient r = -0.563, p < 0.0001). Separating the two populations, the correlation between VCAM mRNA fold change and HDL-C is significant only in sepsis population (control: n = 50, r = -0.229, p = 0.11; sepsis: n = 80, r = -0.370; p = 0.0007).
ApoB-depleted plasma’s anti-inflammatory capacity was associated significantly with the presence of sepsis in a univariable logistic regression analysis {odds ratio [95% confidence interval (CI)] = 2.60 [1.82–3.93]; p < 0.0001}. This association remained significant with adjustment for age, sex, BMI, and dyslipidemia [odds ratio (95% CI) = 2.78 (1.78–4.36); p < 0.0001], but not with additional adjustment for the HDL-C level (Table 2, S1 Fig). The association between anti-inflammatory capacity and sepsis remained the same, even after excluding ten CAD subjects from control group (S1 Table, the left 40 control samples are with normal angiography findings, representing a relatively healthier population).
Table 2. Univariable and multivariable logistic regression for the association between apoB-depleted plasma’s anti-inflammatory capacity (represented by VCAM-1 mRNA fold change value) and the presence of sepsis (n = 130).
| Dependent variable: sepsis | Odds ratio* | 95% confidence interval | P value |
|---|---|---|---|
| Univariable | 2.60 | 1.82–3.93 | <0.0001 |
| Model 1 | 2.88 | 1.88–4.41 | <0.0001 |
| Model 2 | 2.78 | 1.78–4.36 | <0.0001 |
| Model 3 | 1.71 | 0.98–2.98 | 0.059 |
| Model 4 | 1.51 | 0.94–2.43 | 0.088 |
*VCAM-1 mRNA fold change values were rescaled by a factor of 10
Model 1: adjusted for age, gender, BMI
Model 2: adjusted for age, gender, BMI, Dyslipidemia
Model 3: adjusted for age, gender, BMI, Dyslipidemia, HDL-C
Model 4: adjusted for HDL-C
BMI, body mass index; HDL-C, high-density lipoprotein cholesterol
Association between impaired apoB-depleted plasma’s anti-inflammatory capacity and the severity of sepsis
Subgroup analysis was conducted to explore the association between sepsis severity and apoB-depleted plasma’s anti-inflammatory capacity. Of the patients with sepsis, 37 had septic shock and 43 did not. Their clinical characteristics and laboratory data were described in Table 3. Relative to patients without septic shock, those with this condition had higher SOFA and APACHE II scores and lactate and procalcitonin levels, and lower total cholesterol and HDL-C concentrations [SOFA score: 11.0 (9.0–13.0) vs. 9.0 (7.0–11.0), p = 0.0007; APACHE II score: 32.0 (26.5–39.5) vs. 24.0 (20.0–30.0), p = 0.0001; lactate level: 40.5 (25.6, 65.3) vs. 11.0 (9.1–15.4), p < 0.0001; procalcitonin level: 3.4 (1.1–18.9) vs. 1.0 (0.4–3.8), p = 0.0060; total cholesterol: 85.0 (61.5–107.0) vs. 101.0 (81.0, 128.0), p = 0.0056; HDL-C: 18.0 (10.2–31.8) vs. 23.5 (14.0–35.2), p = 0.0022; Table 3). ApoB-depleted plasma’s anti-inflammatory capacity (represented by the VCAM-1 mRNA fold change) was impaired more significantly in patients with greater disease severity, defined by septic shock [55.8% (48.0–62.6%) vs. 45.3% (37.6–53.5%), p = 0.0022; Fig 2A], lactate level > 18 mg/dL [53.5% (43.0–61.5%) vs. 45.3% (38.7–53.5%), p = 0.0076; Fig 2B], and SOFA score > 8 [53.5% (41.2–61.5%) vs. 45.6% (38.3%–52.3%), p = 0.015; Fig 2C]. Notably, the distributions of apoB-depleted plasma’s anti-inflammatory capacity were sparser for these three subgroups than for their counterparts with less-severe disease.
Table 3. Clinical and laboratory characteristics among septic subjects without and with septic shock.
| Non-shock sepsis (N = 43) |
Septic shock (N = 37) |
P value | |
|---|---|---|---|
| Age (years) | 69.0 (62.0–83.0) | 67.5 (55.5–77.5) | 0.15 |
| Male gender (%) | 33 (76.3) | 27 (70.3) | 0.80 |
| Body mass index (kg/m2) | 23.1 (19.5–26.1) | 22.2 (19.7–25.9) | >0.99 |
| Smoking history (%) | 19 (44.2) | 9 (24.3) | 0.099 |
| SOFA score | 9.0 (7.0–11.0) | 11.0 (9.0–13.0) | 0.0007 |
| APACHE II score | 24.0 (20.0–30.0) | 32.0 (26.5–39.5) | 0.0001 |
| Infection sites (%) | |||
| Pneumonia | 28 (65.1) | 22 (59.5) | 0.65 |
| Urinary tract infection | 4 (9.3) | 4 (10.8) | >0.99 |
| Blood-stream infection | 3 (7.0) | 3 (8.1) | >0.99 |
| Intraabdominal infection | 8 (18.6) | 6 (16.2) | >0.99 |
| Soft tissue infection | 5 (11.6) | 2 (5.4) | 0.44 |
| CNS infection | 0 (0) | 1 (2.7) | 0.46 |
| Co-morbidities (%) | |||
| Hypertension | 25 (58.1) | 16 (43.2) | 0.26 |
| Type 2 diabetic mellitus | 13 (30.2) | 9 (24.3) | 0.62 |
| Coronary artery disease | 10 (23.3) | 7 (19.0) | 0.76 |
| Atrial fibrillation | 5 (11.2) | 5 (13.5) | >0.99 |
| End-stage renal disease | 3 (7.0) | 2 (5.4) | >0.99 |
| Gout | 6 (14.0) | 3 (8.1) | 0.49 |
| Dyslipidemia | 6 (14.0) | 2 (5.4) | 0.28 |
| Laboratory data | |||
| White blood cells (K) | 9.2 (5.5–13.5) | 12.8 (6.5–19.0) | 0.077 |
| Hemoglobin (mg/dL) | 9.2 (7.7–11.1) | 8.5 (7.9–9.7) | 0.23 |
| Platelets (K) | 140.0 (77.0–242.2) | 98 (49–206) | 0.16 |
| ALT (U/L) | 29.0 (15.0–39.0) | 29.0 (16.0–91.0) | 0.42 |
| Creatinine (mg/dL) | 1.55 (0.8–4.0) | 2.5 (1.0–3.5) | 0.42 |
| Uric acid (mg/dL) | 4.4 (3.0–7.0) | 6.6 (4.3–9.9) | 0.023 |
| Total cholesterol (mg/dL) | 101.0 (81.0, 128.0) | 85.0 (61.5–107.0) | 0.0056 |
| HDL-C (mg/dL) | 23.5 (14.0–35.2) | 18.0 (10.2–31.8) | 0.0022 |
| LDL-C (mg/dL) | 55.3 (37.3–74.1) | 46.1 (23.0–63.2) | 0.052 |
| Triglyceride (mg/dL) | 102.0 (76.0–141.0) | 107.0 (57.0–150.0) | 0.67 |
| Albumin (mg/dL) | 3.0 (2.7–3.6) | 2.9 (2.5,3.2) | 0.095 |
| Lactate (mg/dL) | 11.0 (9.1–15.4) | 40.5 (25.6, 65.3) | <0.0001 |
| CRP (mg/dL) | 12.0 (5.9–16.7) | 15.9 (7.2–24.7) | 0.052 |
| Procalcitonin (ng/dL) | 1.0 (0.4–3.8) | 3.4 (1.1–18.9) | 0.0060 |
| Serum amyloid A (mg/dL) | 70.7 (36.1–140.7) | 73.3 (8.4, 164.3) | 0.25 |
Continuous variables were expressed as median (interquartile range) and categorical variables were expressed as number (frequency percentage). Mann-Whitney U test or Fisher’s exact test was used to compare the variables between two groups. CNS, central nervous system; ALT, alanine transaminase; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; CRP, c-reactive protein
Fig 2. Comparison of apoB-depleted plasma’s anti-inflammatory capacity (represented as VCAM-1 mRNA fold change) between septic patients with different disease severity.
(A) Subjects with septic shock (n = 37) vs. non-shock sepsis (n = 43). (B) Subjects with serum lactate > 18 mg/dL (n = 45) vs. lactate ≤ 18 mg/dL (n = 35). (C) Subjects with SOFA score > 8 (n = 50) vs. SOFA score ≤ 8 (n = 30).
The association between the impairment of apoB-depleted plasma’s anti-inflammatory capacity and the presence of septic shock was significant in multivariable logistic analyses adjusted for the WBC [odds ratio (95% CI) = 1.54 (1.03–2.29), p = 0.035], CRP level [odds ratio (95% CI) = 1.53 (1.04–2.26), p = 0.030], procalcitonin level [odds ratio (95% CI) = 1.68 (1.12–2.51), p = 0.012], and SAA level [odds ratio (95% CI) = 1.68 (1.15–2.46), p = 0.0078], but not in an analysis adjusted for the HDL-C level [odds ratio (95% CI) = 1.43 (0.95–2.14), p = 0.087; Table 4, S2 Fig]. These results suggest that the impairment of apoB-depleted plasma’s anti-inflammatory capacity during sepsis was dependent on the HDL-C concentration.
Table 4. Univariable and multivariable logistic regression for the association between apoB-depleted plasma’s anti-inflammatory capacity and the presence of septic shock (n = 80).
| Dependent variable: septic shock | Odds ratio* | 95% confidence interval | P value |
|---|---|---|---|
| Univariable | 1.68 | 1.15–2.47 | 0.0078 |
| Model 1 | 1.68 | 1.15–2.46 | 0.0078 |
| Model 2 | 1.68 | 1.12–2.51 | 0.012 |
| Model 3 | 1.53 | 1.04–2.26 | 0.030 |
| Model 4 | 1.54 | 1.03–2.29 | 0.035 |
| Model 5 | 1.43 | 0.95–2.14 | 0.087 |
*VCAM-1 mRNA fold change values were rescaled by a factor of 10
Model 1: adjusted for serum amyloid A
Model 2: adjusted for procalcitonin
Model 3: adjusted for C-reactive protein
Model 4: adjusted for white blood cell
Model 5: adjusted for HDL-C
HDL-C, high-density lipoprotein cholesterol
Correlations of apoB-depleted plasma’s anti-inflammatory capacity and HDL-C concentration with clinical variables
In septic population, the correlations between VCAM-1 mRNA fold change and other continuous variables were presented in Table 5. Consistent with the result obtained for the whole population, the HDL-C concentration correlated positively with the VCAM-1 mRNA fold change in the sepsis group (r = 0.370, p = 0.0007). This fold change also correlated moderately with the CRP level (r = 0.441, p < 0.0001) and WBC (r = 0.353, p = 0.0013), and with the SOFA score (r = 0.231, p = 0.039), lactate level (r = 0.297, p = 0.0074), and procalcitonin level (r = 0.258, p = 0.025; Table 5). The HDL-C concentration correlated with disease severity indicators (SOFA score: r = –0.435, p < 0.0001; lactate level: r = –0.378, p = 0.0005; APACHE II score: r = –0.243, p = 0.030) and inflammatory markers (procalcitonin level: r = 0.444, p < 0.0001; CRP level: r = –0.431, p < 0.0001). Neither the HDL-C concentration nor VCAM-1 mRNA fold change correlated significantly with the SAA level.
Table 5. Correlations of clinical variables with apoB-depleted plasma’s anti-inflammatory capacity (represented as VCAM-1 mRNA fold change value) or HDL-C among septic patients (n = 80).
| With VCAM-1 mRNA FC value With HDL-C | ||||
|---|---|---|---|---|
| Coefficient (r) | P | Coefficient (r) | P | |
| Age | 0.070 | 0.54 | -0.147 | 0.20 |
| Body mass index | 0.140 | 0.22 | -0.168 | 0.14 |
| APACHE II score | 0.137 | 0.23 | -0.243 | 0.030 |
| SOFA score | 0.231 | 0.039 | -0.435 | <0.0001 |
| Lactate | 0.297 | 0.0074 | -0.378 | 0.0005 |
| Total cholesterol | -0.341 | 0.0019 | 0.571 | <0.0001 |
| HDL-C | -0.370 | 0.0007 | - | - |
| LDL-C | -0.308 | 0.0055 | 0.454 | <0.0001 |
| Triglyceride | 0.134 | 0.24 | -0.504 | <0.0001 |
| Procalcitonin | 0.258 | 0.025 | -0.444 | <0.0001 |
| C-reactive protein | 0.441 | <0.0001 | -0.438 | <0.0001 |
| Serum amyloid A | 0.052 | 0.65 | -0.136 | 0.23 |
| White blood cells | 0.353 | 0.0013 | -0.149 | 0.19 |
| Hemoglobin | -0.137 | 0.22 | 0.060 | 0.60 |
| Platelets | 0.004 | 0.97 | 0.236 | 0.035 |
| Creatinine | -0.027 | 0.81 | -0.077 | 0.50 |
| Alanine transaminase | -0.079 | 0.49 | -0.078 | 0.49 |
| Albumin | -0.279 | 0.012 | 0.321 | 0.0037 |
| Uric acid | -0.051 | 0.66 | 0.003 | 0.98 |
FC, fold change; APACHE II, acute physiology and chronic health evaluation II; SOFA, sequential organ failure assessment; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol
Discussion
In this cross-sectional study, we demonstrated that the anti-inflammatory capacity of apoB-depleted plasma was significantly reduced in patients with sepsis, and that this reduction was more pronounced in patients with than in those without septic shock and depended on the HDL-C concentration. Moreover, the anti-inflammatory capacity of apoB-depleted plasma correlated with the SOFA score, lactate level, and inflammatory markers in the septic population. These findings improve our understanding of the role of HDL in sepsis. HDL and its anti-inflammatory capacity could be novel prognostic markers, or even treatment targets, for sepsis.
Sepsis-associated impairment of HDL’s anti-inflammatory capacity
The term “anti-inflammatory capacity” refers to HDL’s ability to inhibit TNF-α–induced VCAM-1 expression in endothelial cells. Several diseases featuring chronic or acute inflammation, including acute myocardial infarction (AMI), T2DM, AF and nonalcoholic fatty live disease, have been reported to associate with the impairment of HDL’s anti-inflammatory capacity [19–22]. This impairment causes the loss of HDL’s vasoprotective effect and contributes to endothelial dysfunction, facilitating systemic inflammation and tissue impairment in sepsis [8, 17, 23]. A previous study revealed an overall property transition of HDL isolated from patients with septic acute respiratory distress syndrome [24]; the present work had a narrower measurement target, enabling focused investigation of the clinical relevance of HDL’s functionality.
In the present study, the association between impaired apoB-depleted plasma’s anti-inflammatory capacity and the presence of sepsis depended on the HDL-C level. In addition, the anti-inflammatory capacity correlated moderately with the HDL-C level in the whole population and sepsis group, but not the control group. These observations are important given emerging evidence, such as that from the REVEAL clinical trial [25], suggesting that the HDL-C level is not necessarily indicative of the functional capacity of HDL particles [15, 25–28]. The revealed dependency may explain the prognostic role of the HDL-C index in sepsis [10] and indirectly supports the rationale for the targeting of the HDL-C level in the treatment of sepsis [12]. A CETP inhibitor that prevented HDL from exchanging its cholesterol component for triglycerides carried by non-HDL lipoprotein was found to improve the survival of septic mice [12]. The decreased CETP activity observed in sepsis is regarded as a compensatory mechanism preventing systemic endotoxemia [14, 29]. A CETP inhibitor was hypothesized to attenuate HDL-C loss and help to preserve functionality of HDL particles during sepsis. Although this agent was not found to contribute significantly to the reduction of the incidence of cardiovascular disease by elevated HDL-C level in recent trials [25], whether a CETP inhibitor can improve the prognosis of sepsis in humans is worth investigating, as the decline of the HDL-C level is more pathologically striking and appears to be combined with decreased functional metrics in sepsis [23, 30, 31].
Association of the impairment of HDL anti-inflammatory capacity with sepsis severity
We found that apoB-depleted plasma’s anti-inflammatory capacity was impaired more strongly in patients with more severe disease (defined as septic shock, SOFA score > 8, and lactate level > 18 mg/dL) [2]. Consistently, the association of the anti-inflammatory capacity with septic shock depended on the HDL-C level. Although the temporality of the association between the impairment of anti-inflammatory capacity and greater disease severity could not be examined in this cross-sectional study, our findings raise some intriguing points worth discussing. First, the association of the SOFA score (which reflects organ dysfunction) [32], but not the APACHE II score, with apoB-depleted plasma’s anti-inflammatory capacity seems to be reasonable because the regulation of endothelial VCAM-1 expression plays an important role in the avoidance of shock and tissue damage during sepsis [3, 17]. Second, the distribution of apoB-depleted plasma’s anti-inflammatory capacity was sparser (reflecting more intragroup variation) for patients with more severe disease (i.e. septic shock, SOFA > 8, lactate > 18mg/dL). The heterogeneity nature of sepsis was amplified in subgroups with higher severity. In an RNA sequencing–based classification [33], most patients with sepsis and poor prognoses were classified as having strong inflammation or neutrophilic suppression endotypes, which have very different genetic profiles. The dysregulation of the host response varies bipolarly among septic subjects and may influence HDL’s composition and functions in different ways [3, 33, 34]. More cautious, subtype-based, methods of sepsis classification should be applied in future work.
HDL’s anti-inflammatory capacity as a potential biomarker in sepsis
HDL dysfunctionality is known to result from compositional remodeling related to inflammation [35, 36]. Proteome alterations of HDL during sepsis have been described [37, 38]. In our study, the CRP level and WBC, generic inflammatory markers, correlated inversely with apoB-depleted plasma’s anti-inflammatory capacity in patients with sepsis, consistent with the concept of inflammation-induced HDL dysfunction. However, no such correlation was observed for the plasma level of SAA, regarded as the culprit for apolipoprotein-AI replacement in HDL particles [39, 40]. The plasma SAA level in septic subjects may be too high to have distinguishable effects on HDL’s anti-inflammatory capacity. As we did not examine the composition of HDL, we could not determine whether the plasma SAA level was proportionate to the accumulation of SAA in HDL species. Additionally, a recent study found no association between SAA and 28-day mortality in a sepsis population, while other markers such as activity of HDL-associated paraoxonase-1 and lecithin-cholesterol acyltransferase activity displayed promising prognostic potentials [41, 42]. Seemingly, although SAA becomes predominant in the proteome of acute phase HDL, it is not necessarily the key determinant of HDL functionality.
As apoB-depleted plasma’s anti-inflammatory capacity has been shown to have added value relative to the HDL-C level for the prediction of incident cardiovascular events in general and post-AMI populations [15, 43], we explored this metrics’ potential as a sepsis biomarker by evaluating its correlations with clinical variables. It did not correlate more strongly than the HDL-C level, an existing prognostic factor for sepsis [10], with the SOFA or APACHE II scores or laboratory parameters except the WBC, indicating that this functional index may have no added value. From the prospective of pathogenesis, the decline in the circulatory HDL-C level is related to endotoxin clearance, which is probably a more critical core event in sepsis [11, 12, 44, 45]. However, an examination of the usefulness of the HDL inflammatory index (i.e., HDL’s ability to protect LDL from oxidization) as a sepsis biomarker showed that a dynamic change in HDL functionality is more useful in the evaluation of prognosis because it reflects the recovery or deterioration of patients’ physiological status [46]. As we performed only static measurement at a single timepoint in this study, further investigation is needed to determine whether HDL’s anti-inflammatory capacity is more informative than the HDL-C level about the prognosis of sepsis.
Limitations
This study has several limitations. First, it was conducted with a small sample size at a single center. Given the heterogeneity of lipid profiles among people of different ethnicities [47, 48], our findings may not be applicable to other populations. Second, demographic differences existed between the patients with sepsis and those admitted for CAG. Although we adjusted for these variables in the multivariable logistic regression analysis, residual confounding may have existed. Third, due to the cross-sectional study design, we could not infer causal relationships. In addition, the prognostic value of HDL’s anti-inflammatory capacity was not explored completely, as sepsis outcomes and prospective parameters were not examined. Fourth, as HDL is versatile and has pleiotropic effects on endothelial cells, macrophages, smooth muscle cells, etc., there are many other assays of HDL anti-inflammatory functions [16]. Our work examined only one aspect of HDL anti-inflammatory functions and was thus limited to the assay we have done. Finally, it should be noted that we use apoB-depleted plasma, which does not equal purely isolated HDL, to measure HDL anti-inflammatory capacity. In contrast to ultracentrifugation, the method that we used for HDL preparation preserves not only HDL particles but also few other unbounded proteins in plasma [49]. Although, according to previous study, 83% of the biological effect of apoB–depleted plasma is attributed to HDL particles [15], this is not necessarily the case in acute phase samples. The cost-effectiveness of apo-B depletion allows for a relatively larger sample size in researching on HDL functionality. Due to the concern that the measurements were biased by the high amount of inflammatory cytokines presented in septic samples [50], we had checked interleukin-6 (IL-6) levels in 12 selected samples by ELISA kits (R&D Systems, Inc., Minneapolis, MN, USA). The highest IL-6 level among those samples (75 pg/mL in cell cultures) was a lot lower than 10 ng/mL TNF-α added following our experimental protocol (S2 Table). We found no correlation trend (spearman’s r = 0.021) between VCAM-1 mRNA fold change value and IL-6 level in these samples (S2 Table). Further studies are needed to compare the anti-inflammatory capacity of purely isolated HDL and apoB-depleted plasma in sepsis.
Conclusion
This study showed that apoB-depleted plasma’s anti-inflammatory capacity is significantly reduced in patients with sepsis, and that this association depends on the HDL-C concentration. In patients with sepsis, apoB-depleted plasma’s anti-inflammatory capacity correlates with disease severity and various inflammatory markers, such as the CRP level and WBC. These findings link HDL functionality to clinical variables, provide an explanation for the prognostic role of the HDL-C level in sepsis, and indirectly support the rationale for HDL-C targeting as a sepsis treatment.
Supporting information
Univariable and multivariable logistic regression for the association between apoB-depleted plasma’s anti-inflammatory capacity (represented by VCAM-1 mRNA fold change value) and the presence of sepsis (n = 130). *VCAM-1 mRNA fold change values were rescaled by a factor of 10. Model 1: adjusted for age, gender, BMI. Model 2: adjusted for age, gender, BMI, Dyslipidemia. Model 3: adjusted for age, gender, BMI, Dyslipidemia, HDL-C. Model 4: adjusted for HDL-C.
(TIF)
Univariable and multivariable logistic regression for the association between apoB-depleted plasma’s anti-inflammatory capacity and the presence of septic shock (n = 80). *VCAM-1 mRNA fold change values were rescaled by a factor of 10.
(TIF)
(XLSX)
(DOCX)
(DOCX)
List of abbreviations
- HDL
high-density lipoprotein
- HDL-C
high-density lipoprotein cholesterol
- VCAM-1
vascular cell adhesion molecule-1
- BMI
body mass index
- SOFA
sequential organ failure assessment
- CETP
cholesteryl ester transfer protein
- TNF-α
tumor necrosis factor-α
- APACHE II
acute physiology and chronic health evaluation II
- ICU
intensive care unit
- CAG
coronary angiography
- T2DM
type 2 diabetes mellitus
- AF
atrial fibrillation
- WBC
white blood cell
- CRP
c-reactive protein
- ALT
alanine transaminase
- LDL-C
low-density lipoprotein cholesterol
- SAA
serum amyloid A
- HUVEC
human umbilical-vein endothelial cells
- FBS
fetal bovine serum
- apoB-depleted
apolipoprotein-B depleted
- CI
confidence interval
- AMI
acute myocardial infarction
Data Availability
All relevant data are within the paper and its Supporting Information files.
Funding Statement
This work was supported by: PHH: 1. Taiwan Ministry of Science and Technology of Taiwan (MOST 106-2314-B-350-001-MY3, MOST 108-2633-B-009-001), https://www.most.gov.tw/en/) 2. Taiwan Ministry of Health and Welfare (MOHW106-TDU-B-211-113001, https://www.mohw.gov.tw/mp-2.html) 3. Taipei Veterans General Hospital (V105C-207, V106C-045, V108C-195, V109B-010, and V109D50-003-MY3-1, https://www.vghtpe.gov.tw/Index.action) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
References
- 1.Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200–11. doi: 10.1016/S0140-6736(19)32989-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.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):801–10. doi: 10.1001/jama.2016.0287 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Jarczak D, Kluge S, Nierhaus A. Sepsis-Pathophysiology and Therapeutic Concepts. Front Med (Lausanne). 2021;8:628302. doi: 10.3389/fmed.2021.628302 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20(4):195–203. doi: 10.1016/j.molmed.2014.01.007 [DOI] [PubMed] [Google Scholar]
- 5.Ouimet M, Barrett TJ, Fisher EA. HDL and Reverse Cholesterol Transport. Circ Res. 2019;124(10):1505–18. doi: 10.1161/CIRCRESAHA.119.312617 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Rohatgi A, Westerterp M, von Eckardstein A, Remaley A, Rye KA. HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research. Circulation. 2021;143(23):2293–309. doi: 10.1161/CIRCULATIONAHA.120.044221 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Singh IM, Shishehbor MH, Ansell BJ. High-density lipoprotein as a therapeutic target: a systematic review. JAMA. 2007;298(7):786–98. doi: 10.1001/jama.298.7.786 [DOI] [PubMed] [Google Scholar]
- 8.Tanaka S, Couret D, Tran-Dinh A, Duranteau J, Montravers P, Schwendeman A, et al. High-density lipoproteins during sepsis: from bench to bedside. Crit Care. 2020;24(1):134. doi: 10.1186/s13054-020-02860-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Tanaka S, Diallo D, Delbosc S, Geneve C, Zappella N, Yong-Sang J, et al. High-density lipoprotein (HDL) particle size and concentration changes in septic shock patients. Ann Intensive Care. 2019;9(1):68. doi: 10.1186/s13613-019-0541-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Cirstea M, Walley KR, Russell JA, Brunham LR, Genga KR, Boyd JH. Decreased high-density lipoprotein cholesterol level is an early prognostic marker for organ dysfunction and death in patients with suspected sepsis. J Crit Care. 2017;38:289–94. doi: 10.1016/j.jcrc.2016.11.041 [DOI] [PubMed] [Google Scholar]
- 11.Trinder M, Walley KR, Boyd JH, Brunham LR. Causal Inference for Genetically Determined Levels of High-Density Lipoprotein Cholesterol and Risk of Infectious Disease. Arterioscler Thromb Vasc Biol. 2020;40(1):267–78. doi: 10.1161/ATVBAHA.119.313381 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Trinder M, Wang Y, Madsen CM, Ponomarev T, Bohunek L, Daisely BA, et al. Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis. Circulation. 2021;143(9):921–34. doi: 10.1161/CIRCULATIONAHA.120.048568 [DOI] [PubMed] [Google Scholar]
- 13.Genga KR, Trinder M, Kong HJ, Li X, Leung AKK, Shimada T, et al. CETP genetic variant rs1800777 (allele A) is associated with abnormally low HDL-C levels and increased risk of AKI during sepsis. Sci Rep. 2018;8(1):16764. doi: 10.1038/s41598-018-35261-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Blauw LL, Wang Y, Willems van Dijk K, Rensen PCN. A Novel Role for CETP as Immunological Gatekeeper: Raising HDL to Cure Sepsis? Trends Endocrinol Metab. 2020;31(5):334–43. doi: 10.1016/j.tem.2020.01.003 [DOI] [PubMed] [Google Scholar]
- 15.Jia C, Anderson JLC, Gruppen EG, Lei Y, Bakker SJL, Dullaart RPF, et al. High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events. Circulation. 2021;143(20):1935–45. doi: 10.1161/CIRCULATIONAHA.120.050808 [DOI] [PubMed] [Google Scholar]
- 16.Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ Res. 2004;95(8):764–72. doi: 10.1161/01.RES.0000146094.59640.13 [DOI] [PubMed] [Google Scholar]
- 17.Boisrame-Helms J, Kremer H, Schini-Kerth V, Meziani F. Endothelial dysfunction in sepsis. Curr Vasc Pharmacol. 2013;11(2):150–60. [PubMed] [Google Scholar]
- 18.Park SH, Park JH, Kang JS, Kang YH. Involvement of transcription factors in plasma HDL protection against TNF-alpha-induced vascular cell adhesion molecule-1 expression. Int J Biochem Cell Biol. 2003;35(2):168–82. doi: 10.1016/s1357-2725(02)00173-5 [DOI] [PubMed] [Google Scholar]
- 19.Ebtehaj S, Gruppen EG, Parvizi M, Tietge UJF, Dullaart RPF. The anti-inflammatory function of HDL is impaired in type 2 diabetes: role of hyperglycemia, paraoxonase-1 and low grade inflammation. Cardiovasc Diabetol. 2017;16(1):132. doi: 10.1186/s12933-017-0613-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Annema W, Willemsen HM, de Boer JF, Dikkers A, van der Giet M, Nieuwland W, et al. HDL function is impaired in acute myocardial infarction independent of plasma HDL cholesterol levels. J Clin Lipidol. 2016;10(6):1318–28. doi: 10.1016/j.jacl.2016.08.003 [DOI] [PubMed] [Google Scholar]
- 21.Sarmadi N, Poustchi H, Ali Yari F, Radmard AR, Karami S, Pakdel A, et al. Anti-inflammatory function of apolipoprotein B-depleted plasma is impaired in non-alcoholic fatty liver disease. PLoS One. 2022;17(4):e0266227. doi: 10.1371/journal.pone.0266227 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Holzwirth E, Fischer-Schaepmann T, Obradovic D, von Lucadou M, Schwedhelm E, Daum G, et al. Anti-inflammatory HDL effects are impaired in atrial fibrillation. Heart Vessels. 2022;37(1):161–71. doi: 10.1007/s00380-021-01908-w [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Morin EE, Guo L, Schwendeman A, Li XA. HDL in sepsis—risk factor and therapeutic approach. Front Pharmacol. 2015;6:244. doi: 10.3389/fphar.2015.00244 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Yang L, Liu S, Han S, Hu Y, Wu Z, Shi X, et al. The HDL from septic-ARDS patients with composition changes exacerbates pulmonary endothelial dysfunction and acute lung injury induced by cecal ligation and puncture (CLP) in mice. Respir Res. 2020;21(1):293. doi: 10.1186/s12931-020-01553-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Tall AR, Rader DJ. Trials and Tribulations of CETP Inhibitors. Circ Res. 2018;122(1):106–12. doi: 10.1161/CIRCRESAHA.117.311978 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.von Eckardstein A, Nordestgaard BG, Remaley AT, Catapano AL. High-density lipoprotein revisited: biological functions and clinical relevance. Eur Heart J. 2023;44(16):1394–407. doi: 10.1093/eurheartj/ehac605 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Bonizzi A, Piuri G, Corsi F, Cazzola R, Mazzucchelli S. HDL Dysfunctionality: Clinical Relevance of Quality Rather Than Quantity. Biomedicines. 2021;9(7). doi: 10.3390/biomedicines9070729 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Marz W, Kleber ME, Scharnagl H, Speer T, Zewinger S, Ritsch A, et al. HDL cholesterol: reappraisal of its clinical relevance. Clin Res Cardiol. 2017;106(9):663–75. doi: 10.1007/s00392-017-1106-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.van der Tuin SJL, Li Z, Berbee JFP, Verkouter I, Ringnalda LE, Neele AE, et al. Lipopolysaccharide Lowers Cholesteryl Ester Transfer Protein by Activating F4/80(+)Clec4f(+)Vsig4(+)Ly6C(-) Kupffer Cell Subsets. J Am Heart Assoc. 2018;7(6). doi: 10.1161/JAHA.117.008105 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Pirillo A, Catapano AL, Norata GD. HDL in infectious diseases and sepsis. Handb Exp Pharmacol. 2015;224:483–508. doi: 10.1007/978-3-319-09665-0_15 [DOI] [PubMed] [Google Scholar]
- 31.Tanaka S, Labreuche J, Drumez E, Harrois A, Hamada S, Vigue B, et al. Low HDL levels in sepsis versus trauma patients in intensive care unit. Ann Intensive Care. 2017;7(1):60. doi: 10.1186/s13613-017-0284-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Naqvi IH, Mahmood K, Ziaullaha S, Kashif SM, Sharif A. Better prognostic marker in ICU—APACHE II, SOFA or SAP II! Pak J Med Sci. 2016;32(5):1146–51. doi: 10.12669/pjms.325.10080 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Baghela A, Pena OM, Lee AH, Baquir B, Falsafi R, An A, et al. Predicting sepsis severity at first clinical presentation: The role of endotypes and mechanistic signatures. EBioMedicine. 2022;75:103776. doi: 10.1016/j.ebiom.2021.103776 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Kellum JA, Formeck CL, Kernan KF, Gomez H, Carcillo JA. Subtypes and Mimics of Sepsis. Crit Care Clin. 2022;38(2):195–211. doi: 10.1016/j.ccc.2021.11.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Feingold KR, Grunfeld C. Effect of inflammation on HDL structure and function. Curr Opin Lipidol. 2016;27(5):521–30. doi: 10.1097/MOL.0000000000000333 [DOI] [PubMed] [Google Scholar]
- 36.de la Llera Moya M, McGillicuddy FC, Hinkle CC, Byrne M, Joshi MR, Nguyen V, et al. Inflammation modulates human HDL composition and function in vivo. Atherosclerosis. 2012;222(2):390–4. doi: 10.1016/j.atherosclerosis.2012.02.032 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Sharma NK, Tashima AK, Brunialti MKC, Ferreira ER, Torquato RJS, Mortara RA, et al. Proteomic study revealed cellular assembly and lipid metabolism dysregulation in sepsis secondary to community-acquired pneumonia. Sci Rep. 2017;7(1):15606. doi: 10.1038/s41598-017-15755-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Sharma NK, Ferreira BL, Tashima AK, Brunialti MKC, Torquato RJS, Bafi A, et al. Lipid metabolism impairment in patients with sepsis secondary to hospital acquired pneumonia, a proteomic analysis. Clin Proteomics. 2019;16:29. doi: 10.1186/s12014-019-9252-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Tolle M, Huang T, Schuchardt M, Jankowski V, Prufer N, Jankowski J, et al. High-density lipoprotein loses its anti-inflammatory capacity by accumulation of pro-inflammatory-serum amyloid A. Cardiovasc Res. 2012;94(1):154–62. doi: 10.1093/cvr/cvs089 [DOI] [PubMed] [Google Scholar]
- 40.Han CY, Tang C, Guevara ME, Wei H, Wietecha T, Shao B, et al. Serum amyloid A impairs the antiinflammatory properties of HDL. J Clin Invest. 2016;126(2):796. doi: 10.1172/JCI86401 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Reisinger AC, Schuller M, Sourij H, Stadler JT, Hackl G, Eller P, et al. Impact of Sepsis on High-Density Lipoprotein Metabolism. Front Cell Dev Biol. 2021;9:795460. doi: 10.3389/fcell.2021.795460 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Reisinger AC, Schuller M, Holzer M, Stadler JT, Hackl G, Posch F, et al. Arylesterase Activity of HDL Associated Paraoxonase as a Potential Prognostic Marker in Patients With Sepsis and Septic Shock-A Prospective Pilot Study. Front Med (Lausanne). 2020;7:579677. doi: 10.3389/fmed.2020.579677 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Dullaart RP, Annema W, Tio RA, Tietge UJ. The HDL anti-inflammatory function is impaired in myocardial infarction and may predict new cardiac events independent of HDL cholesterol. Clin Chim Acta. 2014;433:34–8. doi: 10.1016/j.cca.2014.02.026 [DOI] [PubMed] [Google Scholar]
- 44.Stasi A, Franzin R, Fiorentino M, Squiccimarro E, Castellano G, Gesualdo L. Multifaced Roles of HDL in Sepsis and SARS-CoV-2 Infection: Renal Implications. Int J Mol Sci. 2021;22(11). doi: 10.3390/ijms22115980 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Speer T, Zewinger S. High-density lipoprotein (HDL) and infections: a versatile culprit. Eur Heart J. 2018;39(14):1191–3. doi: 10.1093/eurheartj/ehx734 [DOI] [PubMed] [Google Scholar]
- 46.Guirgis FW, Dodani S, Leeuwenburgh C, Moldawer L, Bowman J, Kalynych C, et al. HDL inflammatory index correlates with and predicts severity of organ failure in patients with sepsis and septic shock. PLoS One. 2018;13(9):e0203813. doi: 10.1371/journal.pone.0203813 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Meshkini M, Alaei-Shahmiri F, Mamotte C, Earnest J. Ethnic Variation in Lipid Profile and Its Associations with Body Composition and Diet: Differences Between Iranians, Indians and Caucasians Living in Australia. J Immigr Minor Health. 2017;19(1):67–73. doi: 10.1007/s10903-015-0320-z [DOI] [PubMed] [Google Scholar]
- 48.Singh K, Chandra A, Sperry T, Joshi PH, Khera A, Virani SS, et al. Associations Between High-Density Lipoprotein Particles and Ischemic Events by Vascular Domain, Sex, and Ethnicity: A Pooled Cohort Analysis. Circulation. 2020;142(7):657–69. doi: 10.1161/CIRCULATIONAHA.120.045713 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Davidson WS, Heink A, Sexmith H, Melchior JT, Gordon SM, Kuklenyik Z, et al. The effects of apolipoprotein B depletion on HDL subspecies composition and function. J Lipid Res. 2016;57(4):674–86. doi: 10.1194/jlr.M066613 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Hamilton F, Pedersen KM, Ghazal P, Nordestgaard BG, Smith GD. Low levels of small HDL particles predict but do not influence risk of sepsis. Crit Care. 2023;27(1):389. doi: 10.1186/s13054-023-04589-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Univariable and multivariable logistic regression for the association between apoB-depleted plasma’s anti-inflammatory capacity (represented by VCAM-1 mRNA fold change value) and the presence of sepsis (n = 130). *VCAM-1 mRNA fold change values were rescaled by a factor of 10. Model 1: adjusted for age, gender, BMI. Model 2: adjusted for age, gender, BMI, Dyslipidemia. Model 3: adjusted for age, gender, BMI, Dyslipidemia, HDL-C. Model 4: adjusted for HDL-C.
(TIF)
Univariable and multivariable logistic regression for the association between apoB-depleted plasma’s anti-inflammatory capacity and the presence of septic shock (n = 80). *VCAM-1 mRNA fold change values were rescaled by a factor of 10.
(TIF)
(XLSX)
(DOCX)
(DOCX)
Data Availability Statement
All relevant data are within the paper and its Supporting Information files.