A hypolipoprotein sepsis phenotype indicates reduced lipoprotein antioxidant capacity, increased endothelial dysfunction and organ failure, and worse clinical outcomes.

OBJECTIVE: Approximately one-third of sepsis patients experience poor outcomes including chronic critical illness (CCI, intensive care unit (ICU) stay > 14 days) or early death (in-hospital death within 14 days). We sought to characterize lipoprotein predictive ability for poor outcomes and contribution to sepsis heterogeneity. DESIGN: Prospective cohort study with independent replication cohort. SETTING: Emergency department and surgical ICU at two hospitals. PATIENTS: Sepsis patients presenting within 24 h. METHODS: Measures included cholesterol levels (total cholesterol, high density lipoprotein cholesterol [HDL-C], low density lipoprotein cholesterol [LDL-C]), triglycerides, paraoxonase-1 (PON-1), and apolipoprotein A-I (Apo A-I) in the first 24 h. Inflammatory and endothelial markers, and sequential organ failure assessment (SOFA) scores were also measured. LASSO selection assessed predictive ability for outcomes. Unsupervised clustering was used to investigate the contribution of lipid variation to sepsis heterogeneity. MEASUREMENTS AND MAIN RESULTS: 172 patients were enrolled. Most (~ 67%, 114/172) rapidly recovered, while ~ 23% (41/172) developed CCI, and ~ 10% (17/172) had early death. ApoA-I, LDL-C, mechanical ventilation, vasopressor use, and Charlson Comorbidity Score were significant predictors of CCI/early death in LASSO models. Unsupervised clustering yielded two discernible phenotypes. The Hypolipoprotein phenotype was characterized by lower lipoprotein levels, increased endothelial dysfunction (ICAM-1), higher SOFA scores, and worse clinical outcomes (45% rapid recovery, 40% CCI, 16% early death; 28-day mortality, 21%). The Normolipoprotein cluster patients had higher cholesterol levels, less endothelial dysfunction, lower SOFA scores and better outcomes (79% rapid recovery, 15% CCI, 6% early death; 28-day mortality, 15%). Phenotypes were validated in an independent replication cohort (N = 86) with greater sepsis severity, which similarly demonstrated lower HDL-C, ApoA-I, and higher ICAM-1 in the Hypolipoprotein cluster and worse outcomes (46% rapid recovery, 23% CCI, 31% early death; 28-day mortality, 42%). Normolipoprotein patients in the replication cohort had better outcomes (55% rapid recovery, 32% CCI, 13% early death; 28-day mortality, 28%) Top features for cluster discrimination were HDL-C, ApoA-I, total SOFA score, total cholesterol level, and ICAM-1. CONCLUSIONS: Lipoproteins predicted poor sepsis outcomes. A Hypolipoprotein sepsis phenotype was identified and characterized by lower lipoprotein levels, increased endothelial dysfunction (ICAM-1) and organ failure, and worse clinical outcomes.

Hypo-High-Density Lipoproteinemia Is Associated With Preoperative Tear Size and With Postoperative Retear in Large to Massive Rotator Cuff Tears.

PURPOSE: To evaluate any association of specific subtypes of dyslipidemia with increments of preoperative tear size and with structural integrity after arthroscopic rotator cuff repair (ARCR). METHODS: One surgeon's consecutive patients who underwent ARCR from January 2011 to June 2018 were reviewed. The inclusion criteria were minimum 1-year follow-up ultrasonography, blood tests, physical examination, and provision of informed consent. The exclusion criteria were incomplete laboratory tests, history of acute trauma, previous shoulder surgery, isolated subscapularis tendon tear, inappropriate radiographs, no 1-year follow-up ultrasonography, and medication with lipid-lowering drugs. Associated preoperative factors for the increments of tear size and for retear after ARCR were determined using logistic regression analysis. Statistical significance was set at P < .05. RESULTS: Of the 502 ARCR patients from the study period, 195 patients (195 shoulders), with a mean age of 60.5 ± 7.5 years, met the inclusion and exclusion criteria. Age (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.1-1.3), diabetes (OR, 3.6; 95% CI, 1.7-7.5), and hypo-high-density lipoproteinemia (hypo-HDLemia) (OR, 2.9; 95% CI, 1.5-5.6) were significantly associated with increments of preoperative tear size (P ≤ .01). Diabetes (OR, 3.0; 95% CI, 1.3-6.6), critical shoulder angle (OR, 2.0; 95% CI, 1.4-3.0), and tear size (OR, 2.1; 95% CI, 1.3-3.4) were significantly associated with retear after ARCR in overall study subjects (P = .01). Diabetes (OR, 3.8; 95% CI, 1.3-11.4), hypo-HDLemia (OR, 3.0; 95% CI, 1.1-8.8), and critical shoulder angle (OR, 1.5; 95% CI, 1.1-2.3) had significant associations with retear after ARCR in patients with a large to massive preoperative tear size (P ≤ .04). CONCLUSIONS: Preoperative hypo-HDLemia (high-density lipoprotein level < 40 mg/dL in male patients and < 50 mg/dL in female patients) has a significant association with the increments of preoperative tear size and with retear after ARCR in large- to massive-sized rotator cuff tears. LEVEL OF EVIDENCE: Level IV, case series.

Low serum levels of High-Density Lipoprotein cholesterol (HDL-c) as an indicator for the development of severe postpartum depressive symptoms.

Postpartum depression (PPD) is a psychiatric complication of childbirth affecting 10-20% of new mothers and has negative impact on both mother and infant. Serum lipid levels have been related to depressive disorders, but very limited literatures are available regarding the lipid levels in women with postpartum depression. The present study is aimed to examine the association of serum lipids with the development of postpartum depressive symptoms. This is a cross sectional study conducted at a tertiary care hospital in South India. Women who came for postpartum check-up at 6th week post-delivery were screened for PPD (September 2014-October 2015). Women with depressive symptoms were assessed using EPDS (Edinburgh Postnatal Depression Scale). The study involved 186 cases and 250 controls matched for age and BMI. Serum levels of lipid parameters were estimated through spectrophotometry and the atherogenic indices were calculated in all the subjects. Low serum levels of Total Cholesterol (TC) and High Density Lipoprotein cholesterol (HDL-c) were significantly low in PPD women with severe depressive symptoms. The study recorded a significant negative correlation between HDL-c and the EPDS score in PPD women (r = -0.140, p = 0.05). Interestingly, the study also observed a significant negative correlation between Body Mass Index (BMI) and EPDS scores in case group (r = -0.146, p = 0.047), whereas a positive correlation between the same in controls (r = 0.187, p = 0.004). Our study demonstrated that low levels of serum HDL-c is correlated with the development of severe depressive symptoms in postpartum women. Study highlights the role of lipids in the development of postpartum depressive symptoms.

Progression of carotid-artery disease in type 2 diabetic patients: a cohort prospective study.

In order to assess the progression of carotid-artery disease in type 2 diabetic cohort (n=207 patients), the dynamic change in carotid intima-media thickness (CIMT) and the occurrence of plaques were followed for a period of 31.35±10.59 months. The mean CIMT at the beginning of the study was 0.9178±0.1447 mm, with a maximal value of 1.1210±0.2366 mm. The maximal value of CIMT changed by 0.07 mm/year. Progression of CIMT was noted in 86.8% and its regression in 7.8% of patients. The occurrence of carotid plaques was detected in 41.8% of patients. Multiple regression analysis revealed the maximal value of CIMT to be associated with diastolic blood pressure, despite mean CIMT being predicted by body mass index. The presence of peripheral arterial disease and hypo-high-density lipoproteinemia were found to be predictors for the occurrence of carotid plaques. Our data have clinical implications in predicting risk factors for the progression of carotid-artery disease in type 2 diabetic patients for their appropriate management.

Significant association between hypolipoproteinemia(a) and lifetime risk of cancer: an autopsy study from a community-based Geriatric Hospital.

BACKGROUND: Our recent study showed that a low lipoproteinemia(a) [Lp(a)] level was a risk factor for cancer and all-cause deaths. The purpose of this study was to verify the role of the Lp(a) level on cancer among consecutive autopsy cases. METHODS: The subjects consisted of 1354 cases (775 men and 579 women). The average age at death was 79.9 years. Hypolipoproteinemia(a) was defined as an Lp(a) level of below 80 mg/L. Overall, 62.3% of the subjects had suffered from at least one to a maximum of five malignancies throughout their lives. The most frequent type of malignancy was gastric cancer, followed by leukemia, lung cancer, and colon cancer. RESULTS: The cancer-bearing status decreased linearly according to the Lp(a) level in both men and women (P=0.01 and P<0.001, respectively). The median Lp(a) level was significantly lower among the cases with hepato-biliary-pancreatic cancers or hematopoietic malignancy, but was higher among cases with lung cancer, especially lung adenocarcinoma. Hypolipoproteinemia(a) was a significant risk factor for any origins of cancer, with an odds ratio of 1.94 (95% CI, 1.45-2.60; P<0.001). It was also a risk factor for hepato-biliary cancers and leukemia, but it was a protective factor for lung cancer. CONCLUSIONS: Our findings suggested hypolipoproteinemia(a) would be a significant risk factor for cancer except lung cancer. This study complements our previous study showing that hypolipoproteinemia(a) would increase the lifetime risk of cancer other than lung cancer.

Hypertriglyceridemia and low high-density lipoprotein cholesterolemia are associated with increased hazard for urolithiasis.

PURPOSE: To assess the association between dyslipidemia and urolithiasis, a propensity score-matching study was performed. PATIENTS AND METHODS: Fasting blood samples were taken, and serum lipid profiles were measured in 655 stone formers (SF) and 1965 propensity score-matched controls between 2005 and 2011. The controls, from a health-screening program, did not have a history of dyslipidemia or statin use and have any evidence of stone disease, as determined by abdominal radiography, ultrasonography examination. Propensity score-matching with respect to age, sex, and body mass index was used to minimize selection bias, and the logistic regression analysis was adjusted for other components of metabolic syndrome. RESULTS: Compared with controls, the SF group had significantly higher mean triglyceride and lower total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels (each P<0.001). The SF group was also more likely to have hypertriglyceridemia and low HDL-cholesterolemia, and less likely to have hypercholesterolemia and high LDL cholesterolemia compared with controls (each P<0.05). When adjusted for other components of metabolic syndrome including obesity, presence of diabetes mellitus or hypertension, the odds ratio (OR) for urinary stones appeared with hypercholesterolemia (OR=0.747, P=0.003), hypertriglyceridemia (OR=1.901, P<0.001), low HDL cholesterolemia (OR=1.886, P<0.001) and high LDL cholesterolemia (OR=0.610, P<0.001). CONCLUSIONS: Our study implies that dyslipidemia may play a crucial part in urinary stone risk.

Serum low density lipoprotein subclasses in asthma.

BACKGROUND: The levels of serum low-density lipoproteins (LDL) have been implicated in the inflammatory cascade in a murine model of asthma. Recent findings suggest that LDL may modulate the inflammatory state of the asthmatic airways in humans. OBJECTIVE: We explored whether LDL subclasses are associated with the occurrence and severity of asthma. METHODS: 24 asthmatics (M/F: 11/13) and 24 healthy individuals, with normal BMI and absence of metabolic syndrome, matched for age and gender. Serum concentrations of LDL subclasses were distributed as seven bands (LDL-1 and -2 defined as large, least pro-inflammatory LDL, and LDL-3 to -7 defined as small, most pro-inflammatory LDL), using the LipoPrint(©) System (Quantimetrix Corporation, Redondo Beach, CA, USA). RESULTS: LDL-1 was similar in the two groups (56 ± 16% vs. 53 ± 11, p = NS), while LDL-2 was significantly lower in asthmatics as compared to controls (35 ± 8% vs. 43 ± 10%, p = 0.0074). LDL-3 levels were two-fold higher in the asthmatics, but the difference did not reach the statistical significance (8 ± 7.3% vs. 4 ± 3%, p = NS). Smaller subclasses LDL-4 to LDL-7 were undetectable in controls. In asthmatics, LDL-1 was positively associated with VC% predicted (r = +0.572, p = 0.0035) and FEV1% predicted (r = +0.492, p = 0.0146). LDL-3 was inversely correlated with both VC% predicted (r = -0.535, p = 0.0071) and FEV1% predicted (r = -0.465, p = 0.0222). CONCLUSIONS: The findings of this pilot study suggest a role of LDL in asthma, and advocate for larger studies to confirm the association between asthma and dyslipidemia.

Pancreatitis in hyperlipemic mink (Mustela vison).

In both man and animals, inflammatory changes in the pancreas often occur with disturbances in lipid metabolism, including hypertriglyceridemia and an excess of free fatty acids. Hyperlipoproteinemia type I is a human condition caused by a deficiency of lipoprotein lipase. A similar metabolic disturbance that occurs in mink is of considerable comparative interest, as it is also followed by pancreatitis. Pancreatic lesions in hyperlipoproteinemic mink included overt variably sized nodules with hemorrhage and necrosis. These lesions began as intralobular necrosis of exocrine cells and progressed to total lobular destruction, with eventual involvement of interlobular tissue. Remnants of epithelial cells and lipid-filled macrophages were seen in necrotic areas, along with other types of inflammatory cells scattered in a lipid-rich exudate. Granulation tissue developed rapidly in necrotic areas. Additional observations included ductal proliferation, replacement of epithelial cells with fat, and mural arterial thickening, most conspicuously with vacuolated cells and endothelial proliferation. Extravasation of lipid-rich plasma is thought to be a major intensifier of the inflammatory response.

Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice.

OBJECTIVE: To demonstrate that hypolipidemia is a typical feature of the mouse model of amyotrophic lateral sclerosis (ALS) and to assess the association between hypolipidemia and disease stage, dietary intake, and sex. METHODS: We compared daily dietary intake, body weight, and serumlipid and glucose levels in ALS mice and wild-type controls at different stages of the disease. FINDINGS: Total cholesterol low-density lipoprotein (LDL) and LDL/high-density lipoprotein (HDL) ratio were significantly lower in ALS mice compared with controls. Subgroup analysis revealed that the incidence of hypolipidemia was significantly greater in male, but not female, ALS mice compared with control mice and that hypolipidemia was present at the presymptomatic stage of the disease. This hypolipidemia can be found without a decrease in the serum levels of other energy sources, such as glucose, in the presymptomatic stage. CONCLUSIONS: Hypolipidemia is present at the presymptomatic stage of the ALS mouse model in the absence of malnutrition, significant neuromuscular degeneration or regeneration, and respiratory difficulty. Our findings suggest that hypolipidemia might be associated with the pathomechanism of ALS and/or lipid-specific metabolism rather than simply an epiphenomenon of neuromuscular degeneration or energy imbalance.

Controversy on high density lipoprotein raising therapy.

Decreased high density lipoproteins (HDL) plasma levels are a recognized independent risk factor for atherosclerotic cardiovascular disease. Attempts were therefore initiated to pharmacologically raise plasma HDL cholesterol, and the most impressive increase was obtained by inhibiting cholesteryl ester transfer protein (CETP) by means of the synthetic compound torcetrapib. Clinical trials were however disappointing, as torcetrapib increased mortality and did not reduce the progression of atherosclerosis. According to some view, it was claimed that CETP inhibition is unfavourable and that development of this class of compounds should be abandoned. Controversy nevertheless stimulated research on HDL structure, heterogeneity and functions which are not limited to reverse cholesterol transport and exert antioxidant and antiinflammatory actions. It could also be demonstrated that the deleterious effects of torcetrapib are compound specific, including its tight binding to CETP on HDL particles, thereby blocking both neutral lipids and phospholipid transfer from HDL to other lipoproteins, and would also exert an off-target effect by increasing plasma sodium and decreasing potasium concentrations (an aldosterone-like effect). As the structure of CETP was elucidated, it became possible to design CETP inhibitors that lack such off-target toxicity and may successfully slow the progression of atherosclerosis. Noteworthy, mice and rats naturally lacking CETP are resistant to diet induced atherosclerosis, while rabbits with high CETP levels are very susceptible. Families with deficient activity and exceptional longevity had also been reported.

Changes in HDL-associated apolipoproteins relate to mortality in human sepsis and correlate to monocyte and platelet activation.

OBJECTIVE: Lipoproteins modulate vascular cell function in inflammation. In this study, we analyzed whether plasma concentrations of lipoproteins and apolipoproteins in human sepsis are related to patient survival and the activation of blood monocytes and platelets. DESIGN: Observational study. SETTING: Medical and surgical intensive care units (ICU) of a university hospital. PATIENTS: 151 consecutive patients after sepsis criteria had been met for the first time. INTERVENTIONS: None. MEASUREMENTS: Plasma lipoproteins, apolipoproteins, platelet CD62P-expression, monocyte HLA-DR-expression, SAPS II-scores (Simplified Acute Physiology Score) and 30-day-mortality were recorded. RESULTS: Total cholesterol, high-density-lipoprotein (HDL) and low-density-lipoprotein (LDL) cholesterol, apolipoprotein (apo)-AI and apo-B were all found to be significantly lower in non-survivors than in survivors. In contrast to other (apo)lipoproteins, apo-AI and HDL cholesterol further decreased in non-survivors during the ICU stay. Logistic regression analysis revealed apo-AI to be an independent predictor of 30-day-mortality. A significant inverse correlation was found for apo-AI/HDL-cholesterol and platelet activation. Later in the course of the disease, HLA-DR expression on monocytes correlated positively to apo-AI and apo-CI concentrations and inversely to the apo-E concentration. CONCLUSION: Low apo-AI is independently related to 30-day mortality in human sepsis and the decrease in apo-AI/HDL cholesterol correlates to increased platelet activation. Moreover, changes in apolipoproteins supposed to modulate lipopolysaccharide effects, such as apo-CI and apo-E, correlate to monocyte activation.

Marked high density lipoprotein deficiency due to apolipoprotein A-I Tomioka (codon 138 deletion).

We report a novel apolipoprotein A-I (apoA-I) mutation identified in a 64-year-old patient with marked plasma high density lipoprotein (HDL) cholesterol (4 mg/dl) and apoA-I (5mg/dl) deficiency, prior myocardial infarction, and moderate corneal opacities. Coronary angiography revealed extensive atherosclerosis in all three major vessels. Genomic DNA sequencing of the proband revealed a homozygous novel deletion of two successive adenine residues in codon 138 in the apoA-I gene, resulting in a frameshift mutation at amino acid residues 138-178, which we have designated as apoA-I Tomioka. His elder brother was also homozygous for apoA-I Tomioka with marked HDL cholesterol and apoA-I deficiency, but had no clinical evidence of coronary heart disease. Other family members including three siblings and two sons were heterozygous for the mutation, and had approximately 50% of normal plasma HDL cholesterol, and apoA-I. Analysis of apoA-I-containing HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I HDL particles in the homozygotes, while in heterozygotes, the mean concentrations of apoA-I in large alpha-1 and very small prebeta-1 HDL subpopulations were significantly decreased at about 35% of normal. Thus, apoA-I Tomioka, a novel deletion mutation in codon 138 of the apoA-I gene, is the causative defect in this case of HDL deficiency.

[Pan-European survey on the undertreatment of hypercholesterolemia in hypolipidemias(Luxembourg)]. / Une etude paneuropéenne centralisée sur le traitement insuffisant de l'hypercholestérolémie chez les patients sous hypolipidémiants (Cepheus-Luxembourg).

Cepheus (Centralized Pan-European survey on the undertreatment of hypercholesterolemia) is an observational centralized study realized in 8 European countries including Luxemburg. The aim was to evaluate the percentage of patients reaching the TJETF and 2004 NCEP ATP III recommendations for LDL-cholesterol. A secondary aim was to identify by questionnaires the determinants of patients and physicians explaining this undertreatment. Data from 706 patients in Luxemburg have shown that only 40.6% of patients and only 17.5% of high risk patients (CVD and diabetes) reach the newest european target values of LDL-cholesterol (post-hoc analysis). 90% of patients had statins prescribed and 9.7% fibrates. 60% of patients had still the same medication at the same dosage at the moment of the study, after at least 3 months treatment with a mean of 6.2 years. 40% of patients said that they forget sometimes their treatment and 13% were convinced that forgetting their tablets more than once a week did not affect their cholesterol level. These disappointing results could be due partly to insufficient dosages, too less adaptation of the treatment and a bad compliance of patients.

Predominance of a proinflammatory phenotype in monocyte-derived macrophages from subjects with low plasma HDL-cholesterol.

OBJECTIVE: Reduced plasma concentrations of high-density lipoprotein-cholesterol (HDL-C) are a significant risk factor for cardiovascular disease. Mechanisms that regulate HDL-C concentrations represent an important area of investigation. METHODS AND RESULTS: Comparative transcriptome analyses of monocyte-derived macrophages (MDM) from a large population of low HDL-C subjects and age- and sex-matched controls revealed a cluster of inflammatory genes highly expressed in low HDL-C subjects. The expression levels of peroxisome proliferator activated receptor (PPAR) gamma and several antioxidant metallothionein genes were decreased in MDM from all low HDL-C groups compared with controls, as was the expression of other genes regulated by PPARgamma, including CD36, adipocyte fatty acid binding protein (FABP4), and adipophilin (ADFP). In contrast, PPARdelta expression was increased in MDM from low HDL-C groups. Quantitative RT-PCR corroborated all major findings from the microarray analysis in two separate patient cohorts. Expression of several inflammatory cytokine genes including interleukin 1beta, interleukin 8, and tumor necrosis factor alpha were highly increased in low HDL-C subjects. CONCLUSIONS: The activated proinflammatory state of monocytes and MDM in low HDL-C subjects constitutes a novel parameter of risk associated with HDL deficiency, related to altered expression of metallothionein genes and the reciprocal regulation of PPARgamma and PPARdelta.

[Hypolipoproteinemia and secondary role of atherosclerosis in the development of ischemic heart disease in patients with polycythemia vera].

Relationship between presence of coronary heart disease (CHD), coronary risk factors (parameters of lipid transport system and hypertension) and disturbances of microcirculation was studied in patients with myeloproliferative blood disease Polycythemia Vera (PV). Probability of tissue (including blood vessel wall) cholesterol accumulation was estimated by measurement of its content in skin surface layers. PV patients (n=55, including 27 patients with CHD) had predominant hypolipoproteinemia with normal proportion of various lipoprotein classes. Absence of substantial increase of skin surface cholesterol content both in patients with and without CHD was considered to be a sign of low probability of the presence of severe atherosclerotic processes. However patients with CHD had substantially more pronounced disturbances of microcirculation. Basing on these data the authors suggest that CHD in PV patients had non-lipoprotein genesis and present discussion of alternative mechanisms of vascular changes.

C-reactive protein levels and prevalence of chronic infections in subjects with hypoalphalipoproteinemia.

Low levels of high-density lipoprotein cholesterol (HDL-C) show a consistent relationship with the development of atherosclerosis. The underlying mechanisms are not well understood, but recent studies in subjects with primary hypoalphalipoproteinemia suggest that this could represent a proinflammatory condition. To better assess the link between HDL-C levels and C-reactive protein levels and the possible role of chronic infections as putative mediators of this relationship, we studied a population sample with nonselected causes of hypoalphalipoproteinemia. Eighty-six consecutive patients with HDL-C levels below 40 mg/dL who attend our lipid clinic and 86 control subjects with normal concentrations matched for gender, age, smoking habit, and weight were included in the study. Mean HDL-C levels were 34 +/- 3.9 and 55.4 +/- 8.8 mg/dL for subjects with hypoalphalipoproteinemia and control subjects, respectively. C-reactive protein concentrations were increased in case patients as compared with control subjects (2.13 +/- 2.0 vs 1.52 +/- 1.8 mg/L; P = .025). The prevalence of herpes simplex virus type 1, cytomegalovirus, Chlamydia pneumoniae , and Helicobacter pylori infections did not differ between the 2 groups. Although a possible confounding variable could be a degree of insulin resistance within the group of patients with low HDL-C levels, our results indicate that C-reactive protein levels are increased in subjects with nonselected hypoalphalipoproteinemia and that chronic infections do not appear to mediate this relationship.