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Scholarly Works (21 results)

  • Article
  • Peer Reviewed
UCLA Previously Published Works (2021)

Purpose of review

This study reviews the mechanisms of HDL cholesterol immunomodulation in the context of the mechanisms of chronic inflammation and immunosuppression causing persistent inflammation, immunosuppression and catabolism syndrome (PICS) and describes potential therapies and gaps in current research.

Recent findings

Low HDL cholesterol is predictive of acute sepsis severity and outcome. Recent research has indicated apolipoprotein is a prognostic indicator of long-term outcomes. The pathobiologic mechanisms of PICS have been elucidated in the past several years. Recent research of the interaction of HDL pathways in related chronic inflammatory diseases may provide insights into further mechanisms and therapeutic targets.

Summary

HDL significantly influences innate and adaptive immune pathways relating to chronic disease and inflammation. Further research is needed to better characterize these interactions in the setting of PICS.
    Cover page: HDL and persistent inflammation immunosuppression and catabolism syndrome
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2014)

    Introduction

    South Asian immigrants (SAIs) in the US exhibit higher prevalence of coronary artery disease (CAD) and its risk factors compared with other ethnic populations. Conventional CAD risk factors do not explain the excess CAD risk; therefore there is a need to identify other markers that can predict future risk of CAD in high-risk SAIs. The objective of the current study is to assess the presence of sub-clinical CAD using common carotid artery intima-media thickness (CCA-IMT), and its association with metabolic syndrome (MS) and pro-inflammatory/dysfunctional HDL (Dys-HDL).

    Material and methods

    A community-based study was conducted on 130 first generation SAIs aged 35-65 years. Dys-HDL was determined using the HDL inflammatory index. Analysis was completed using logistic regression and Fisher's exact test.

    Results

    Sub-clinical CAD using CCA-IMT ≥ 0.8 mm (as a surrogate marker) was seen in 31.46%. Age and gender adjusted CCA-IMT was significantly associated with type 2 diabetes (p = 0.008), hypertension (p = 0.012), high-sensitivity C-reactive protein (p < 0.001) and homocysteine (p = 0.051). Both the presence of MS and Dys-HDL was significantly correlated with CCA-IMT, even after age and gender adjustment. The odds of having Dys-HDL with CCA-IMT were 5 times (95% CI: 1.68, 10.78).

    Conclusions

    There is a need to explore and understand non-traditional CAD risk factors with a special focus on Dys-HDL, knowing that SAIs have low HDL levels. This information will not only help to stratify high-risk asymptomatic SAI groups, but will also be useful from a disease management point of view.
      Cover page: Carotid intima media thickness and low high-density lipoprotein (HDL) in South Asian immigrants: could dysfunctional HDL be the missing link?
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2021)
      In addition to their well-characterized roles in metabolism, lipids and lipoproteins have pleiotropic effects on the innate immune system. These undergo clinically relevant alterations during sepsis and acute inflammatory responses. High-density lipoprotein (HDL) plays an important role in regulating the immune response by clearing bacterial toxins, supporting corticosteroid release, decreasing platelet aggregation, inhibiting endothelial cell apoptosis, reducing the monocyte inflammatory response, and inhibiting expression of endothelial cell adhesion molecules. It undergoes quantitative as well as qualitative changes which can be measured using the HDL inflammatory index (HII). Pro-inflammatory, or dysfunctional HDL (dysHDL) lacks the ability to perform these functions, and we have also found it to independently predict adverse outcomes and organ failure in sepsis. Another important class of lipids known as specialized pro-resolving mediators (SPMs) positively affect the escalation and resolution of inflammation in a temporal fashion. These undergo phenotypic changes in sepsis and differ significantly between survivors and non-survivors. Certain subsets of sepsis survivors go on to have perilous post-hospitalization courses where this inflammation continues in a low grade fashion. This is associated with immunosuppression in a syndrome of persistent inflammation, immunosuppression, and catabolism syndrome (PICS). The continuous release of tissue damage-related patterns and viral reactivation secondary to immunosuppression feed this chronic cycle of inflammation. Animal data indicate that dysregulation of endogenous lipids and SPMs play important roles in this process. Lipids and their associated pathways have been the target of many clinical trials in recent years which have not shown mortality benefit. These results are limited by patient heterogeneity and poor animal models. Considerations of sepsis phenotypes and novel biomarkers in future trials are important factors to be considered in future research. Further characterization of lipid dysregulation and chronic inflammation during sepsis will aid mortality risk stratification, detection of sepsis, and inform individualized pharmacologic therapies.
        Cover page: Lipid and Lipoprotein Dysregulation in Sepsis: Clinical and Mechanistic Insights into Chronic Critical Illness
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2024)
        The purpose of this study was to investigate changes in the lipidome of patients with sepsis to identify signaling lipids associated with poor outcomes that could be linked to future therapies. Adult patients with sepsis were enrolled within 24h of sepsis recognition. Patients meeting Sepsis-3 criteria were enrolled from the emergency department or intensive care unit and blood samples were obtained. Clinical data were collected and outcomes of rapid recovery, chronic critical illness (CCI), or early death were adjudicated by clinicians. Lipidomic analysis was performed on two platforms, the Sciex™ 5500 device to perform a lipidomic screen of 1450 lipid species and a targeted signaling lipid panel using liquid-chromatography tandem mass spectrometry. For the lipidomic screen, there were 274 patients with sepsis: 192 with rapid recovery, 47 with CCI, and 35 with early deaths. CCI and early death patients were grouped together for analysis. Fatty acid (FA) 12:0 was decreased in CCI/early death, whereas FA 17:0 and 20:1 were elevated in CCI/early death, compared to rapid recovery patients. For the signaling lipid panel analysis, there were 262 patients with sepsis: 189 with rapid recovery, 45 with CCI, and 28 with early death. Pro-inflammatory signaling lipids from ω-6 poly-unsaturated fatty acids (PUFAs), including 15-hydroxyeicosatetraenoic (HETE), 12-HETE, and 11-HETE (oxidation products of arachidonic acid [AA]) were elevated in CCI/early death patients compared to rapid recovery. The pro-resolving lipid mediator from ω-3 PUFAs, 14(S)-hydroxy docosahexaenoic acid (14S-HDHA), was also elevated in CCI/early death compared to rapid recovery. Signaling lipids of the AA pathway were elevated in poor-outcome patients with sepsis and may serve as targets for future therapies.
          Cover page: Lipidomic changes in a novel sepsis outcome-based analysis reveals potent pro-inflammatory and pro-resolving signaling lipids.
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2021)

          Background

          Reduced cholesterol levels are associated with increased organ failure and mortality in sepsis. Cholesterol levels may vary by infection type (gram negative vs positive), possibly reflecting differences in cholesterol-mediated bacterial clearance.

          Methods

          This was a secondary analysis of a combined data set of 2 prospective cohort studies of adult patients meeting Sepsis-3 criteria. Infection types were classified as gram negative, gram positive, or culture negative. We investigated quantitative (levels) and qualitative (dysfunctional high-density lipoprotein [HDL]) cholesterol differences. We used multivariable logistic regression to control for disease severity.

          Results

          Among 171 patients with sepsis, infections were gram negative in 67, gram positive in 46, and culture negative in 47. Both gram-negative and gram-positive infections occurred in 11 patients. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and HDL cholesterol (HDL-C) levels were lower for culture-positive sepsis at enrollment (TC, P < .001; LDL-C, P < .001; HDL-C, P = .011) and persisted after controlling for disease severity. Similarly, cholesterol levels were lower among culture-positive patients at 48 hours (TC, P = .012; LDL-C, P = .029; HDL-C, P = .002). Triglyceride (TG) levels were lower at enrollment (P =.033) but not at 48 hours (P = .212). There were no differences in dysfunctional HDL. Among bacteremic patients, cholesterol levels were lower at enrollment (TC, P = .010; LDL-C, P = .010; HDL-C, P ≤ .001; TG, P = .005) and at 48 hours (LDL-C, P = .027; HDL-C, P < .001; TG, P = .020), except for 48 hour TC (P = .051). In the bacteremia subgroup, enrollment TC and LDL-C were lower for gram-negative versus gram-positive infections (TC, P = .039; LDL-C, P = .023).

          Conclusion

          Cholesterol levels are significantly lower among patients with culture-positive sepsis and bacteremia.
            Cover page: Quantitative and Qualitative Assessments of Cholesterol Association With Bacterial Infection Type in Sepsis and Septic Shock
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2018)

            Background

            Proper functioning of high-density lipoprotein (HDL) is necessary for protection against sepsis. However, previous work has demonstrated that HDL becomes oxidized and dysfunctional (Dys-HDL) during sepsis. Older (aged >65 years) patients are at particularly high risk of sepsis and poor outcomes from sepsis.

            Study objective

            The aim of the study was to compare functional properties of HDL (cholesterol efflux capacity and paraoxonase enzyme 1 [PON-1] activity) and Dys-HDL between older (aged >65 years) sepsis patients and older healthy volunteers.

            Methods

            This was a subanalysis of a prospective study in which patients with sepsis were prospectively enrolled from the emergency department within the first 24 h. Serum and plasma samples were drawn from septic patients and age- and sex-matched control subjects. Percent cholesterol efflux, HDL inflammatory index, and PON1 activity were measured. Data were analyzed using Student t test or Wilcoxon rank-sum test.

            Results

            Ten sepsis and 10 healthy controls were analyzed. Mean age of sepsis patients (80 ± 2 years [SD]) and control subjects (77 ± 2 years) was similar (P = 0.31). Mean systolic blood pressures were significantly different in sepsis patients (113 ± 8 mmHg) compared with controls (133 ± 6 mmHg) (P = 0.049). Median SOFA scores for sepsis patients were 5.5 (interquartile range [IQR] 4-9). Mean percent cholesterol efflux was significantly reduced in sepsis (24.1 ± 1.2%) compared with controls (31.5 ± 1.0%) (P < 0.001). HDL inflammatory index was also significantly elevated in septic patients (1.63, IQR 1.3-2.34) compared with controls (0.62, IQR 0.56-0.67) (P < 0.001). However, PON1 activity was not significantly different between septic patients (70.3 ± 16.3 nmol/min/mL) and control subjects (88.8 ± 18.3 nmol/min/mL).

            Conclusions

            Cholesterol efflux capacity seems to be significantly impaired in sepsis patients who also exhibited a higher index of Dys-HDL. The findings suggest that HDL function may be impaired in older individuals with sepsis.
              Cover page: HDL Cholesterol Efflux is Impaired in Older Patients with Early Sepsis
              • Article
              • Peer Reviewed
              Western Journal of Emergency Medicine: Integrating Emergency Care with Population Health, Volume 15, Issue 2 (2014)

              Introduction: In 2007 there were 64,000 visits to the emergency department (ED) for possible myocardial infarction (MI) related to cocaine use. Prior studies have demonstrated that low- to intermediate-risk patients with cocaine-associated chest pain can be safely discharged after 9-12 hours of observation. The goal of this study was to determine the safety of an 8-hour protocol for ruling out MI in patients who presented with cocaine-associated chest pain.

              Methods: We conducted a retrospective review of patients treated with an 8-hour cocaine chest pain protocol between May 1, 2011 and November 30, 2012 who were sent to the clinical decision unit (CDU) for observation. The protocol included serial cardiac biomarker testing with Troponin-T, CK-MB (including delta CK-MB), and total CK at 0, 2, 4, and 8 hours after presentation with cardiac monitoring for the observation period. Patients were followed up for adverse cardiac events or death within 30 days of discharge.

              Results: There were 111 admissions to the CDU for cocaine chest pain during the study period. One patient had a delta CK-MB of 1.6 ng/ml, but had negative Troponin-T at all time points. No patient had a positive Troponin-T or CK-MB at 0, 2, 4 or 8 hours, and there were no MIs or deaths within 30 days of discharge. Most patients were discharged home (103) and there were 8 inpatient admissions from the CDU. Of the admitted patients, 2 had additional stress tests that were negative, 1 had additional cardiac biomarkers that were negative, and all 8 patients were discharged home. The estimated risk of missing MI using our protocol is, with 99% confidence, less than 5.1% and with 95% confidence, less than 3.6% (99% CI, 0-5.1%; 95% CI, 0-3.6%).

              Conclusion: Application of an abbreviated cardiac enzyme protocol resulted in the safe and rapid discharge of patients presenting to the ED with cocaine-associated chest pain. [West J Emerg Med. 2014;15(2):180–183.]

                Cover page: Impact of an Abbreviated Cardiac Enzyme Protocol to Aid Rapid Discharge of Patients with Cocaine-associated Chest Pain in the Clinical Decision UnitCreative Commons 'BY-NC' version 4.0 license
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2017)

                Background

                High density lipoprotein (HDL) can be readily oxidized in inflammatory conditions and exhibit pro-inflammatory and dysfunctional (Dys-HDL) characteristics. We hypothesize that Dys-HDL may predict adverse outcomes and correlate with inflammatory cytokines in sepsis.

                Methods

                Emergency department (ED) patients with sepsis were enrolled. Blood was drawn at enrollment and after 48 h. Dys-HDL, expressed as HDL inflammatory index (HII), and cytokines were measured. Multivariable logistic regression was used to determine the predictive ability of Dys-HDL for adverse outcomes (death, discharge to hospice, or nursing home).

                Results

                Thirty-five patients were included in the study. HII was not significantly different at baseline or 48 h between patients with adverse outcomes versus those without. However, there was a significant difference in change in HII over the first 48 h between those with adverse outcomes (+0.21, 95% CI -0.13 to 0.31) versus those without (-0.11, 95% CI -1 to 0.11) (P = 0.025). Logistic regression revealed increasing HII to be an independent predictor of adverse outcomes (OR 5.2, 95% CI 1.1-25.1 P = 0.040). Of the 24 patents with cytokine measurements at both time points, significant inverse correlations between change in HII and change in GRO (rs = -0.52, P = 0.0088) and monocyte chemotactic protein-1 (rs = -0.61, P = 0.0014) concentrations over 48 h were observed.

                Conclusion

                Increasing Dys-HDL concentrations in the first 48 h of sepsis are associated with an ongoing inflammatory response and adverse clinical outcomes. Early changes in HII may be a potential biomarker in ED patients admitted with sepsis.
                  Cover page: Exploring the Predictive Ability of Dysfunctional High-Density Lipoprotein for Adverse Outcomes in Emergency Department Patients with Sepsis
                  • Article
                  • Peer Reviewed
                  Western Journal of Emergency Medicine: Integrating Emergency Care with Population Health, Volume 24, Issue 3 (2023)

                  Background: Metabolic derangements in sepsis influence phosphate levels, which may predict mortality outcomes. We investigated the association between initial phosphate levels and 28-day mortality in patients with sepsis.

                  Methods: We conducted a retrospective analysis of patients with sepsis. Initial (first 24 hours) phosphate levels were divided into phosphate quartile groups for comparisons. We used repeated-measures mixed-models to assess differences in 28-day mortality across the phosphate groups, adjusting for other predictors identified by the Least Absolute Shrinkage and Selection Operator variable selection technique.

                  Results: A total of 1,855 patients were included with 13% overall 28-day mortality (n=237). The highest phosphate quartile (>4.0 milligrams per deciliter [mg/dL]) had a higher mortality rate (28%) than the three lower quartiles (P<0.001). After adjustment (age, organ failure, vasopressor administration, liver disease), the highest initial phosphate was associated with increased odds of 28-day mortality. Patients in the highest phosphate quartile had 2.4 times higher odds of death than the lowest (≤2.6 mg/dL) quartile (P<0.01), 2.6 times higher than the second (2.6-3.2 mg/dL) quartile (P<0.01), and 2.0 times higher than the third (3.2-4.0 mg/dL) quartile (P=0.04).

                  Conclusion: Septic patients with the highest phosphate levels had increased odds of mortality. Hyperphosphatemia may be an early indicator of disease severity and risk of adverse outcomes from sepsis.

                  • 4 supplemental ZIPs
                  Cover page: Association of Early Serum Phosphate Levels and Mortality in Patients with SepsisCreative Commons 'BY' version 4.0 license
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2021)

                  Rationale

                  Sepsis is a life-threatening, dysregulated response to infection. Lipid biomarkers including cholesterol are dynamically regulated during sepsis and predict short-term outcomes. In this study, we investigated the predictive ability of lipid biomarkers for physical function and long-term mortality after sepsis.

                  Methods

                  Prospective cohort study of sepsis patients admitted to a surgical intensive-care unit (ICU) within 24 h of sepsis bundle initiation. Samples were obtained at enrollment for lipid biomarkers. Multivariate regression models determined independent risk factors predictive of poor performance status (Zubrod score of 3/4/5) or survival at 1-year follow-up.

                  Measurements and main results

                  The study included 104 patients with surgical sepsis. Enrollment total cholesterol and high-density lipoprotein (HDL-C) levels were lower, and myeloperoxidase (MPO) levels were higher for patients with poor performance status at 1 year. A similar trend was seen in comparisons based on 1-year mortality, with HDL-C and ApoA-I levels being lower and MPO levels being higher in non-survivors. However, multivariable logistic regression only identified baseline Zubrod and initial SOFA score as significant independent predictors of poor performance status at 1 year. Multivariable Cox regression modeling for 1-year survival identified high Charlson comorbidity score, low ApoA-I levels, and longer vasopressor duration as predictors of mortality over 1-year post-sepsis.

                  Conclusions

                  In this surgical sepsis study, lipoproteins were not found to predict poor performance status at 1 year. ApoA-I levels, Charlson comorbidity scores, and duration of vasopressor use predicted 1 year survival. These data implicate cholesterol and lipoproteins as contributors to the underlying pathobiology of sepsis.
                    Cover page: Lipid and lipoprotein predictors of functional outcomes and long-term mortality after surgical sepsis
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