Genetic Architecture and Clinical Outcomes of Combined Lipid Disturbances.

BACKGROUND: Dyslipoproteinemia often involves simultaneous derangements of multiple lipid traits. We aimed to evaluate the phenotypic and genetic characteristics of combined lipid disturbances in a general population-based cohort. METHODS: Among UK Biobank participants without prevalent coronary artery disease, we used blood lipid and apolipoprotein B concentrations to ascribe individuals into 1 of 6 reproducible and mutually exclusive dyslipoproteinemia subtypes. Incident coronary artery disease risk was estimated for each subtype using Cox proportional hazards models. Phenome-wide analyses and genome-wide association studies were performed for each subtype, followed by in silico causal gene prioritization and heritability analyses. Additionally, the prevalence of disruptive variants in causal genes for Mendelian lipid disorders was assessed using whole-exome sequence data. RESULTS: Among 450 636 UK Biobank participants: 63 (0.01%) had chylomicronemia; 40 005 (8.9%) had hypercholesterolemia; 94 785 (21.0%) had combined hyperlipidemia; 13 998 (3.1%) had remnant hypercholesterolemia; 110 389 (24.5%) had hypertriglyceridemia; and 49 (0.01%) had mixed hypertriglyceridemia and hypercholesterolemia. Over a median (interquartile range) follow-up of 11.1 (10.4-11.8) years, incident coronary artery disease risk varied across subtypes, with combined hyperlipidemia exhibiting the largest hazard (hazard ratio, 1.92 [95% CI, 1.84-2.01]; P=2×10-16), even when accounting for non-HDL-C (hazard ratio, 1.45 [95% CI, 1.30-1.60]; P=2.6×10-12). Genome-wide association studies revealed 250 loci significantly associated with dyslipoproteinemia subtypes, of which 72 (28.8%) were not detected in prior single lipid trait genome-wide association studies. Mendelian lipid variant carriers were rare (2.0%) among individuals with dyslipoproteinemia, but polygenic heritability was high, ranging from 23% for remnant hypercholesterolemia to 54% for combined hyperlipidemia. CONCLUSIONS: Simultaneous assessment of multiple lipid derangements revealed nuanced differences in coronary artery disease risk and genetic architectures across dyslipoproteinemia subtypes. These findings highlight the importance of looking beyond single lipid traits to better understand combined lipid and lipoprotein phenotypes and implications for disease risk.

AAV-mediated hepatic LPL expression ameliorates severe hypertriglyceridemia and acute pancreatitis in Gpihbp1 deficient mice and rats.

GPIHBP1 plays an important role in the hydrolysis of triglyceride (TG) lipoproteins by lipoprotein lipases (LPLs). However, Gpihbp1 knockout mice did not develop hypertriglyceridemia (HTG) during the suckling period but developed severe HTG after weaning on a chow diet. It has been postulated that LPL expression in the liver of suckling mice may be involved. To determine whether hepatic LPL expression could correct severe HTG in Gpihbp1 deficiency, liver-targeted LPL expression was achieved via intravenous administration of the adeno-associated virus (AAV)-human LPL gene, and the effects of AAV-LPL on HTG and HTG-related acute pancreatitis (HTG-AP) were observed. Suckling Gpihbp1-/- mice with high hepatic LPL expression did not develop HTG, whereas Gpihbp1-/- rat pups without hepatic LPL expression developed severe HTG. AAV-mediated liver-targeted LPL expression dose-dependently decreased plasma TG levels in Gpihbp1-/- mice and rats, increased post-heparin plasma LPL mass and activity, decreased mortality in Gpihbp1-/- rat pups, and reduced the susceptibility and severity of both Gpihbp1-/- animals to HTG-AP. However, the muscle expression of AAV-LPL had no significant effect on HTG. Targeted expression of LPL in the liver showed no obvious adverse reactions. Thus, liver-targeted LPL expression may be a new therapeutic approach for HTG-AP caused by GPIHBP1 deficiency.

Dyslipidemia-induced renal fibrosis related to ferroptosis and endoplasmic reticulum stress.

Dyslipidemia may induce chronic kidney disease and trigger both ferroptosis and endoplasmic reticulum (ER) stress, but the instigating factors are incompletely understood. We tested the hypothesis that different models of dyslipidemia engage distinct kidney injury mechanisms. Wild-type (WT) or proprotein-convertase subtilisin/kexin type-9 (PCSK9)-gain-of-function (GOF) Ossabaw pigs were fed with a 6-months normal (ND) or high-fat (HFD) diet (n=5-6 each). Renal function and fat deposition were studied in-vivo using CT, and blood and kidney tissue studied ex-vivo for lipid profile, systemic and renal vein free fatty acids (FFA) levels, and renal injury mechanisms including lipid peroxidation (LPO), ferroptosis, and ER stress. Compared with WT-ND pigs, both HFD and PCSK9-GOF elevated triglyceride levels, which were highest in WT-HFD, whereas total and low-density lipoprotein (LDL) cholesterol levels rose only in PCSK9-GOF pigs, particularly in PCSK9-GOF/HFD. The HFD groups had worse kidney function than ND. The WT-HFD kidneys retained more FFA than other groups, but all kidneys developed fibrosis. Furthermore, HFD-induced ferroptosis in WT-HFD indicated by increased free iron, and LPO, and decreased glutathione peroxidase-4 mRNA expression, while PCSK9-GOF induced ER stress with upregulated GRP94 and CHOP protein expression. In vitro, PK1 cells treated with palmitic acid (PA) and oxidized-LDL to mimic HFD and PCSK9-GOF showed similar trends to those observed in vivo. Taken together, HFD-induced hypertriglyceridemia promotes renal FFA retention and ferroptosis, whereas PCSK9-GOF-induced hypercholesterolemia elicits ER stress, both resulting in renal fibrosis. These observations suggest different targets for preventing and treating renal fibrosis in subjects with specific types of dyslipidemia.

Clinical characterization and mutation spectrum of patients with hypertriglyceridemia in a German outpatient clinic.

BACKGROUND: Severe hypertriglyceridemia (HTG) has predominantly multifactorial causes (MCS). Yet a small subset of patients have the monogenetic form (FCS). It remains a challenge to distinguish patients clinically, since decompensated MCS might mimic FCS´s severity. Aim of the current study was to determine clinical criteria that could sufficiently distinguish both forms as well as to apply the FCS score proposed by Moulin and colleagues. METHODS: We retrospectively studied 72 patients who presented with severe HTG in our clinic during a time span of seven years and received genetic testing. We classified genetic variants (ACMG-criteria), followed by genetic categorization into MCS or FCS. Clinical data were gathered from the medical records and the FCS score was calculated for each patient. RESULTS: Molecular genetic screening revealed eight FCS patients and 64 MCS patients. Altogether, we found 13 pathogenic variants of which four have not been described before. The FCS patients showed a significantly higher median triglyceride level compared to the MCS. The FCS score yielded a sensitivity of 75% and a specificity of 93.7% in our cohort, and significantly differentiated between the FCS and MCS group (p<0.001). CONCLUSIONS: In our cohort we identified several variables that significantly differentiated FCS from MCS. The FCS score performed similar to the original study by Moulin, thereby further validating the discriminatory power of the FCS score in an independent cohort.

APOA5 deficiency causes hypertriglyceridemia by reducing amounts of lipoprotein lipase in capillaries.

Apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia in mice and humans. For years, the cause remained a mystery, but the mechanisms have now come into focus. Here, we review progress in defining APOA5's function in plasma triglyceride metabolism. Biochemical studies revealed that APOA5 binds to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppresses its ability to inhibit the activity of lipoprotein lipase (LPL). Thus, APOA5 deficiency is accompanied by increased ANGPTL3/8 activity and lower levels of LPL activity. APOA5 deficiency also reduces amounts of LPL in capillaries of oxidative tissues (e.g., heart, brown adipose tissue). Cell culture experiments revealed the likely explanation: ANGPTL3/8 detaches LPL from its binding sites on the surface of cells, and that effect is blocked by APOA5. Both the low intracapillary LPL levels and the high plasma triglyceride levels in Apoa5-/- mice are normalized by recombinant APOA5. Carboxyl-terminal sequences in APOA5 are crucial for its function; a mutant APOA5 lacking 40-carboxyl-terminal residues cannot bind to ANGPTL3/8 and lacks the ability to change intracapillary LPL levels or plasma triglyceride levels in Apoa5-/- mice. Also, an antibody against the last 26 amino acids of APOA5 reduces intracapillary LPL levels and increases plasma triglyceride levels in wild-type mice. An inhibitory ANGPTL3/8-specific antibody functions as an APOA5-mimetic reagent, increasing intracapillary LPL levels and lowering plasma triglyceride levels in both Apoa5-/- and wild-type mice. That antibody is a potentially attractive strategy for treating elevated plasma lipid levels in human patients.

Pitavastatin treatment remodels the HDL subclass lipidome and proteome in hypertriglyceridemia.

HDL particles vary in lipidome and proteome, which dictate their individual physicochemical properties, metabolism, and biological activities. HDL dysmetabolism in nondiabetic hypertriglyceridemia (HTG) involves subnormal HDL-cholesterol and apoAI levels. Metabolic anomalies may impact the qualitative features of both the HDL lipidome and proteome. Whether particle content of bioactive lipids and proteins may differentiate HDL subclasses (HDL2b, 2a, 3a, 3b, and 3c) in HTG is unknown. Moreover, little is known of the effect of statin treatment on the proteolipidome of hypertriglyceridemic HDL and its subclasses. Nondiabetic, obese, HTG males (n = 12) received pitavastatin calcium (4 mg/day) for 180 days in a single-phase, unblinded study. ApoB-containing lipoproteins were normalized poststatin. Individual proteolipidomes of density-defined HDL subclasses were characterized prestatin and poststatin. At baseline, dense HDL3c was distinguished by marked protein diversity and peak abundance of surface lysophospholipids, amphipathic diacylglycerol and dihydroceramide, and core cholesteryl ester and triacylglycerol, (normalized to mol phosphatidylcholine), whereas light HDL2b showed peak abundance of free cholesterol, sphingomyelin, glycosphingolipids (monohexosylceramide, dihexosylceramide, trihexosylceramide, and anionic GM3), thereby arguing for differential lipid transport and metabolism between subclasses. Poststatin, bioactive lysophospholipid (lysophosphatidylcholine, lysoalkylphosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylinositol) cargo was preferentially depleted in HDL3c. By contrast, baseline lipidomic profiles of ceramide, dihydroceramide and related glycosphingolipids, and GM3/phosphatidylcholine were maintained across particle subclasses. All subclasses were depleted in triacylglycerol and diacylglycerol/phosphatidylcholine. The abundance of apolipoproteins CI, CII, CIV, and M diminished in the HDL proteome. Statin treatment principally impacts metabolic remodeling of the abnormal lipidome of HDL particle subclasses in nondiabetic HTG, with lesser effects on the proteome.

Characterizing genetic profiles for high triglyceride levels in U.S. patients of African ancestry.

Hypertriglyceridemia (HTG) is a common cardiovascular risk factor characterized by elevated triglyceride (TG) levels. Researchers have assessed the genetic factors that influence HTG in studies focused predominantly on individuals of European ancestry. However, relatively little is known about the contribution of genetic variation of HTG in people of African ancestry (AA), potentially constraining research and treatment opportunities. Our objective was to characterize genetic profiles among individuals of AA with mild-to-moderate HTG and severe HTG versus those with normal TGs by leveraging whole-genome sequencing data and longitudinal electronic health records available in the All of Us program. We compared the enrichment of functional variants within five canonical TG metabolism genes, an AA-specific polygenic risk score for TGs, and frequencies of 145 known potentially causal TG variants between HTG patients and normal TG among a cohort of AA patients (N = 15,373). Those with mild-to-moderate HTG (N = 342) and severe HTG (N ≤ 20) were more likely to carry APOA5 p.S19W (odds ratio = 1.94, 95% confidence interval = [1.48-2.54], P = 1.63 × 10-6 and OR = 3.65, 95% confidence interval: [1.22-10.93], P = 0.02, respectively) than those with normal TG. They were also more likely to have an elevated (top 10%) polygenic risk score, elevated carriage of potentially causal variant alleles, and carry any genetic risk factor. Alternative definitions of HTG yielded comparable results. In conclusion, individuals of AA with HTG were enriched for genetic risk factors compared to individuals with normal TGs.

Deletion of Elovl5 leads to dyslipidemia and atherosclerosis in LDLR-deficient mice.

Atherosclerosis is a chronic inflammatory disease for which hepatic steatosis and atherogenic dyslipidemia are significant risk factors. We investigated the effects of endogenously generated very-long-chain polyunsaturated fatty acids (VL-PUFAs) on dyslipidemia and atherosclerosis development using mice that lack ELOVL5, a PUFA elongase that is required for the synthesis of arachidonic acid, EPA, and DHA from the essential fatty acids linoleic and linolenic acids, and the LDL receptor (LDLR). Elovl5-/-;Ldlr-/- mice manifest increased liver triglyceride and cholesterol concentrations due to the activation of sterol regulatory element binding protein-1, a transcription factor that activates enzymes required for de novo lipogenesis. Plasma levels of triglycerides and cholesterol in VLDL, IDL, and LDL were markedly elevated in Elovl5-/-;Ldlr-/- mice fed a chow and the mice exhibited marked aortic atherosclerotic plaques. Bone marrow-derived monocytes from wild-type (WT) and Elovl5-/- mice were polarized to M1 and M2 macrophages, and the effects of ELOVL5 on inflammatory activity were determined. There were no differences in most of the markers tested for M1 and M2 polarized cells between WT and Elovl5-/- cells, except for a slight increase in PGE2 secretion in Elovl5-/- cells, likely due to elevated Cox-2 expression. These results suggest that the deletion of Elovl5 leads to hepatic steatosis and dyslipidemia, which are the major factors in severe atherosclerosis in Elovl5-/-;Ldlr-/- mice.

Breaking the chains of lipoprotein lipase deficiency: A pediatric perspective on the efficacy and safety of Volanesorsen.

RATIONALE: Lipoprotein lipase (LPL) deficiency, a rare inherited metabolic disorder, is characterized by high triglyceride (TG) levels and life-threatening acute pancreatitis. Current treatment for pediatric patients involves a lifelong severely fat-restricted diet, posing adherence challenges. Volanesorsen, an EMA-approved RNA therapy for adults, effectively reduces TG levels by decreasing the production of apolipoprotein C-III. This 96-week observational open-label study explores Volanesorsen's safety and efficacy in a 13-year-old female with LPL deficiency. METHODS: The patient, with a history of severe TG elevations, 53 hospital admissions, and life-threatening recurrent pancreatitis despite dietary restrictions, received weekly subcutaneous Volanesorsen injections. We designed a protocol for this investigator-initiated study, primarily focusing on changes in fasting TG levels and hospital admissions. RESULTS: While the injections caused occasional pain and swelling, no other adverse events were observed. TG levels decreased during treatment, with more measurements below the pancreatitis risk threshold compared to pre-treatment. No hospital admissions occurred in the initial 14 months of treatment, contrasting with 21 admissions in the 96 weeks before. In the past 10 months, two pancreatitis episodes may have been linked to dietary noncompliance. Dietary restrictions were relaxed, increasing fat intake by 65% compared to baseline. While not fully reflected in the PedsQL, both parents and the patient narratively reported an improved quality of life. CONCLUSION: This study demonstrates, for the first time, that Volanesorsen is tolerated in a pediatric patient with severe LPL deficiency and effectively lowers TG levels, preventing life-threatening complications. This warrants consideration for expanded access in this population.

Hypoxia-Induced Insulin Resistance Mediates the Elevated Cardiovascular Risk in Patients with Obstructive Sleep Apnea: A Comprehensive Review.

Patients with obstructive sleep apnea (OSA) experience insulin resistance and its clinical consequences, including hypertriglyceridemia, reduced high density lipoprotein-associated cholesterol (HDL-c), visceral adiposity, hepatic steatosis, increased epicardial fat thickness, essential hypertension, glucose intolerance, increased risk for type 2 diabetes, chronic kidney disease, subclinical vascular damage, and increased risk for cardiovascular events. Obesity is a major contributor to OSA. The prevalence of OSA is almost universal among patients with severe obesity undergoing bariatric surgery. However, insulin resistance and its clinical complications occur in OSA patients irrespective of general obesity (body mass index). In OSA patients, apnea episodes during sleep induce oxyhemoglobin desaturation and tissue hypoxia. Insulin resistance is an adaptive response to tissue hypoxia and develops in conditions with limited tissue oxygen supply, including healthy subjects exposed to hypobaric hypoxia (high altitude) and OSA patients. Indicators of oxyhemoglobin desaturation have been robustly and independently linked to insulin resistance and its clinical manifestations in patients with OSA. Insulin resistance mediates the elevated rate of type 2 diabetes, chronic kidney disease, and cardiovascular disease unexplained with traditional cardiovascular risk factors present in OSA patients. Pathophysiological processes underlying hypoxia-induced insulin resistance involve hypoxia inducible factor-1 upregulation and peroxisome proliferator-activated receptor-gamma (PPAR- γ ) downregulation. In human adipose tissue, PPAR- γ activity promotes glucose transport into adipocytes, lipid droplet biogenesis, and whole-body insulin sensitivity. Silencing of PPAR- γ in the adipose tissue reduces glucose uptake and fat accumulation into adipocytes and promotes insulin resistance. In conclusion, tissue hypoxia drives insulin resistance and its clinical consequences in patients with OSA, regardless of body mass index.

Cytokine storm associated with severe COVID-19 infections: The potential mitigating role of omega-3 fatty acid triglycerides in the ICU.

Cytokine storm during severe COVID-19 infection increases the risk of mortality in critically ill patients in the intensive care unit. Multiple therapeutic proposals include, for example, anti-inflammatory and immunosuppressive agents, selective inhibitors of key pro-inflammatory receptors, and key enzymes necessary for viral replication. Unfortunately, safe and effective therapy remains an elusive goal. An alternative anti-inflammatory approach vis á vis omega-3 fatty acids, which yields less pro-inflammatory mediators by altering eicosanoid metabolism, has been proposed. Although theoretically promising, enteral tube delivery or oral capsules containing specific doses of omega-3 fatty acids take precious time (7 days to 6 weeks) to be incorporated in plasma cell membranes to be most effective, making this route of administration in the acute care setting an unfeasible therapeutic approach. Parenteral administration of precise doses of omega-3 fatty acid triglycerides in an injectable emulsion can greatly accelerate the incorporation and potential therapeutic effects (within hours), but at present, there is no commercially available product designed for this purpose. We describe a potential formulation that may address this deficiency, while recognizing that the high incidence of hyperlipidemia that occurs during severe COVID-19 infection must be recognized as a complicating factor, and, therefore, caution is advised.

Machine learning improves early prediction of organ failure in hyperlipidemia acute pancreatitis using clinical and abdominal CT features.

BACKGROUND: This study aimed to investigate and validate machine-learning predictive models combining computed tomography and clinical data to early predict organ failure (OF) in Hyperlipidemic acute pancreatitis (HLAP). METHODS: Demographics, laboratory parameters and computed tomography imaging data of 314 patients with HLAP from the First Affiliated Hospital of Wenzhou Medical University between 2017 and 2021, were retrospectively analyzed. Sixty-five percent of patients (n = 204) were assigned to the training group and categorized as patients with and without OF. Parameters were compared by univariate analysis. Machine-learning methods including random forest (RF) were used to establish model to predict OF of HLAP. Areas under the curves (AUCs) of receiver operating characteristic were calculated. The remaining 35% patients (n = 110) were assigned to the validation group to evaluate the performance of models to predict OF. RESULTS: Ninety-three (45.59%) and fifty (45.45%) patients from the training and the validation cohort, respectively, developed OF. The RF model showed the best performance to predict OF, with the highest AUC value of 0.915. The sensitivity (0.828) and accuracy (0.814) of RF model were both the highest among the five models in the study cohort. In the validation cohort, RF model continued to show the highest AUC (0.820), accuracy (0.773) and sensitivity (0.800) to predict OF in HLAP, while the positive and negative likelihood ratios and post-test probability were 3.22, 0.267 and 72.85%, respectively. CONCLUSIONS: Machine-learning models can be used to predict OF occurrence in HLAP in our pilot study. RF model showed the best predictive performance, which may be a promising candidate for further clinical validation.

Incidence of Hypertriglyceridemia in Patients on Propofol, Clevidipine, or Both.

BACKGROUND: Propofol and clevidipine (PC) are commonly used in the treatment of critically ill patients. While both medications are lipid emulsions, there is limited evidence concerning the incidence of hypertriglyceridemia (HTG) when these agents are used individually or concurrently. OBJECTIVE: The objective of this study is to determine the effects of propofol, clevidipine, or concurrent PC on triglycerides (TGs) and related outcomes in critically ill adults. METHODS: This was a retrospective cohort study conducted at an academic medical center. Patients were included if they received ≥24 hours of continuous propofol and/or clevidipine. Excluded were those without TG levels after ≥24 hours of infusion, baseline HTG, acute pancreatitis at admission, or receiving total parenteral nutrition with lipids. The primary outcome was incidence of HTG (defined as a TG level >400 mg/dL). Secondary outcomes included median and peak TG levels, hospital length of stay, intensive care unit length of stay, total lipid infused, time to peak TG level, peak lipase level, and development of pancreatitis. RESULTS: In total, 190 patients were studied: 109 in the propofol group, 50 in the clevidipine group, and 31 in the PC group. Incidence of HTG was similar (19 [17.4%] vs 6 [12%] vs 4 [12.9%] patients, P = 0.6246). Peak and median TG levels were similar for propofol, clevidipine, and PC groups (216 mg/dL vs 189.5 mg/dL vs 205 mg/dL, P = 0.7069; 177 mg/dL vs 185.5 mg/dL vs 177 mg/dL, P = 0.6791). CONCLUSIONS AND RELEVANCE: There was a similar incidence of HTG in all groups. The results of this study suggest that the concurrent use of PC should not modify the frequency of TG level monitoring.

Evinacumab Reduces Triglyceride-Rich Lipoproteins in Patients with Hyperlipidemia: A Post-Hoc Analysis of Three Randomized Clinical Trials.

PURPOSE: Natural selection (Mendelian randomization) studies support a causal relationship between elevated triglyceride-rich lipoproteins (TRLs) and atherosclerotic cardiovascular disease (ASCVD). This post-hoc analysis assessed the efficacy of evinacumab in reducing TRLs in patient cohorts from three separate clinical trials with evinacumab. METHODS: Patients with homozygous familial hypercholesterolemia (HoFH) and low-density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dL were enrolled in a phase III trial (R1500-CL-1629; NCT03399786). Patients diagnosed with refractory hypercholesterolemia, with LDL-C ≥ 70 mg/dL or ≥ 100 mg/dL for those with or without ASCVD, respectively, were enrolled in a phase II trial (R1500-CL-1643; NCT03175367). Patients with severe hypertriglyceridemia (fasting TGs ≥ 500 mg/dL) were enrolled in a phase II trial (R1500-HTG-1522; NCT03452228). Patients received evinacumab intravenously (5 or 15 mg/kg) every 4 weeks, or subcutaneously (300 or 450 mg) every week or every 2 weeks. Efficacy outcomes included change in TRLs (calculated as total cholesterol minus high-density lipoprotein cholesterol minus LDL-C) and other lipid parameters from baseline to 12, 16, or 24 weeks for trial 1522, 1643, and 1629, respectively. RESULTS: At baseline, TRL levels were higher for patients with severe hypertriglyceridemia entering the 1522 trial vs. other cohorts. Reductions in TRLs were observed across all studies with evinacumab, with > 50% reduction from baseline observed at the highest doses evaluated in patients with HoFH or refractory hypercholesterolemia. Within all three trials, evinacumab was generally well tolerated. CONCLUSIONS: Despite limitations in direct comparisons between study groups, these data indicate that TRL levels could be a future target for lipid-lowering therapies.

A Practical Approach to the Management of Residual Cardiovascular Risk: United Arab Emirates Expert Consensus Panel on the Evidence for Icosapent Ethyl and Omega-3 Fatty Acids.

PURPOSE: Patients with hyperlipidemia treated with statins remain at a residual cardiovascular (CV) risk. Omega-3 polyunsaturated fatty acids hold the potential to mitigate the residual CV risk in statin-treated patients, with persistently elevated triglyceride (TG) levels. METHOD: We reviewed the current evidence on the use of icosapent ethyl (IPE), an omega-3 fatty acid yielding a pure form of eicosapentaenoic acid. RESULTS: REDUCE-IT reported a significant 25% reduction in CV events, including the need for coronary revascularization, the risk of fatal/nonfatal myocardial infarction, stroke, hospitalization for unstable angina, and CV death in patients on IPE, unseen with other omega-3 fatty acids treatments. IPE was effective in all patients regardless of baseline CV risk enhancers (TG levels, type-2 diabetes status, weight status, prior revascularization, or renal function). Adverse events (atrial fibrillation/flutter) related to IPE have occurred mostly in patients with prior atrial fibrillation. Yet, the net clinical benefit largely exceeded potential risks. The combination with other omega-3 polyunsaturated fatty acids, in particular DHA, eliminated the effect of EPA alone, as reported in the STRENGTH and OMEMI trials. Adding IPE to statin treatment seems to be cost-effective, especially in the context of secondary prevention of CVD, decreasing CV event frequency and subsequently the use of healthcare resources. CONCLUSION: Importantly, IPE has been endorsed by 20 international medical societies as a statin add-on treatment in patients with dyslipidemia and high CV risk. Robust medical evidence supports IPE as a pillar in the management of dyslipidemia.

Familial chylomicronemia syndrome: case reports of siblings with deletions of the GPIHBP1 gene.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare monogenic form of severe hypertriglyceridemia, caused by mutations in genes involved in triglyceride metabolism. Herein, we report the case of a Korean family with familial chylomicronemia syndrome caused by compound heterozygous deletions of glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). CASE PRESENTATION: A 4-year-old boy was referred for the evaluation of severe hypertriglyceridemia (3734 mg/dL) that was incidentally detected 4 months prior. His elder brother also demonstrated an elevated triglyceride level of 2133 mg/dL at the age of 9. Lipoprotein electrophoresis revealed the presence of chylomicrons, an increase in the proportion of pre-beta lipoproteins, and low serum lipoprotein lipase levels. The patient's parents and first elder brother had stable lipid profiles. For suspected FCS, genetic testing was performed using the next-generation sequencing-based analysis of 31 lipid metabolism-associated genes, which revealed no pathogenic variants. However, copy number variant screening using sequencing depth information suggested large heterozygous deletion encompassing all the coding exons of GPIHBP1. A real-time quantitative polymerase chain reaction was performed to validate the deletion site. The results showed that the siblings had two heterozygous copy number variants consisting of the whole gene and an exon 4 deletion, each inherited from their parents. During the follow-up period of 17 months, the patient did not develop pancreatitis, following dietary intervention. CONCLUSION: These siblings' case of familial chylomicronemia syndrome caused by rare GPIHBP1 deletions highlight the implementation of copy number variants-beyond next-generation sequencing-as an important consideration in diagnosis. Accurate genetic diagnosis is necessary to establish the etiology of severe hypertriglyceridemia, which increases the risk of pancreatitis.

Parameters Predictive of Propofol-Associated Acute Pancreatitis in Critically Ill Patients with COVID-19 Pneumonia: A Retrospective Cohort Study.

BACKGROUND: Propofol, a commonly used agent for short- and long-term sedation, is associated with acute pancreatitis. The main indirect mechanism of propofol-associated acute pancreatitis is by inducing hypertriglyceridemia. Patients with severe coronavirus disease 2019 (COVID-19) pneumonia often require prolonged mechanical ventilation and sedation. We examined the incidence rate of acute pancreatitis among critically ill adults with COVID-19 pneumonia on mechanical ventilation receiving propofol. In addition, we attempted to determine cutoff levels of serum triglycerides and doses of propofol that are predictive of propofol-associated acute pancreatitis. METHODS: This was a multicenter retrospective cohort study using a large dataset of hospitalized patients with COVID-19. The collected data included the number of days on propofol, cumulative doses of propofol, peak levels of serum triglycerides, serum lipase levels, and abdominal imaging findings. We used receiver-operating characteristic analysis in conjunction with Youden's index to identify the optimal thresholds for propofol administration parameters and levels of triglycerides that would provide maximal sensitivity and specificity for predicting acute pancreatitis. RESULTS: Out of 499 critically ill patients with COVID-19 pneumonia, 154 met the inclusion criteria. Six (4%) patients had suspected acute pancreatitis based on elevated serum lipase levels. Cutoff values greater than 688 mg/dL for peak level of triglycerides, 4.5 days on propofol, 3007 mg/day for average daily propofol dose, and 24 113 mg for cumulative propofol dose were associated with high risk of suspected acute pancreatitis. The negative predictive values for suspected acute pancreatitis using these cutoffs ranged from 98% to 100%. CONCLUSIONS: Propofol use in critically ill COVID-19 patients is associated with a low incidence rate of acute pancreatitis. We identified cutoff values for serum triglycerides and cumulative propofol dose that are linked to higher risk of propofol-associated pancreatitis. More research is needed to examine the true incidence of propofol-associated pancreatitis and help develop optimal cutoff values for certain parameters to help guide safe propofol administration.

Development and Validation of a Clinical Predictive Nomogram for Assessing the Risk of Recurrence of Acute Pancreatitis in Combined Hypertriglyceridemia.

BACKGROUND: The objective of this study is to develop and validate a new nomogram-based scoring system for anticipating the recurrence of acute pancreatitis (AP) in combined hypertriglyceridemia (HTG). METHODS: A total of 292 patients diagnosed with AP combined with HTG participated in this research. Among them, 201 patients meeting the inclusion criteria were randomly divided into training and validation sets at a ratio of 7:3. Clinical data were collected for all patients. In the training set, predictive indicators were chosen through backward stepwise multivariable logistic regression analysis. Subsequently, a nomogram was developed based on the selected indicators. Finally, the model's performance was validated in both the training and validation sets. RESULTS: By employing backward stepwise multivariable logistic regression analysis, we identified diabetes, gallstones, alcohol consumption, and triglyceride levels as predictive indicators. Subsequently, a clinical nomogram that incorporates these four independent risk factors was constructed. Model validation demonstrated an AUC of 0.726 (95% CI 0.644-0.809) in the training set and an AUC of 0.712 (95% CI 0.583-0.842) in the validation set, indicating a good discriminative ability. The Hosmer-Lemeshow test yielded P-values of 0.882 and 0.536 in the training and validation sets, respectively, suggesting good calibration. Calibration curves further confirmed good agreement. Ultimately, decision curve analysis (DCA) emphasized the clinical utility of our model. CONCLUSION: We have developed a nomogram for predicting the recurrence of AP combined with HTG in patients, and this nomogram demonstrates good discriminative ability, calibration, and clinical utility. This tool holds the potential to assist clinicians in offering more personalized treatment strategies for AP combined with HTG.

Hypertriglyceridemia, Hypercholesterolemia, Body Mass Index, and the Risk of Acute Pancreatitis.

OBJECTIVE: The purpose of this work was to check the connection between parameters of lipid profile and body mass index (BMI) in relation to the occurrence of acute pancreatitis within a sample of adults from northern China. METHODOLOGY: A total of 123,214 participants from the Kailuan Group were incorporated into this prospective study. The subjects were categorized into quartiles on the basis of their initial levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). On the basis of BMI classification, the individuals in the study were divided into three distinct groups: normal weight, overweight, and obese. The data were analyzed to explore the correlation between lipid profile and BMI with acute pancreatitis. RESULTS: Over a period of 12.59 ± 0.98 years, during the median follow-up duration, a total of 410 new patients with acute pancreatitis were recorded. The occurrence rate and total occurrence of acute pancreatitis demonstrated an upward trend in correlation with elevated levels of TG, TC, and BMI. Following adjustment for multiple variables, it was observed that individuals in the fourth quartile of TG and TC levels demonstrated the highest likelihood of developing acute pancreatitis. Furthermore, our analysis revealed that a proportion of 19.29% of the correlation between BMI and the likelihood of experiencing acute pancreatitis can be attributed to the influence of elevated TG levels, whereas 12.69% of the association was mediated by higher TC. CONCLUSIONS: We found that hypertriglyceridemia, hypercholesterolemia, and obesity were risk factors for acute pancreatitis, especially in young and middle-aged men.TG and TC were the mediating factors between BMI and the risk of acute pancreatitis.

Triglycerides: A Sensitizer but Not a Trigger for Hypertriglyceridemic Acute Pancreatitis.

BACKGROUND: The incidence of hypertriglyceridemic acute pancreatitis (HTG-AP) is increasing. Although the guideline defines the diagnostic criteria as triglyceride (TG) greater than 11.3 mmol/L, there is actually no specific threshold. Many people with hypertriglyceridemia (HTG) or obvious chyloid blood do not develop acute pancreatitis (AP). AIMS: To explore the role of HTG in the pathogenesis of AP. METHODS: Thirty-six male SD rats were randomly assigned into normal control, AP, HTG, HTG-AP, low-dose fenofibrate and high-dose fenofibrate groups. Serum indices and cytokine levels in serum, and pathological changes in pancreatic tissues were observed. The expression levels of TLR4 and NF-κBp65 in pancreatic tissues were detected by immunohistochemistry and Western blot. RESULTS: In normal rats, HTG alone did not induce AP. However, after establishing the HTG-AP model with Poloxam 407 and L-arginine, serum-free fatty acid and TG levels were positively correlated with the levels of lipase, amylase, IL-1ß, IL-6, pancreatic inflammation scores, and the expressions of TLR4 and NF-κBp65 (all P < 0.001). Expressions of TLR4 and NF-κBp65 were significantly increased in the pancreatic tissues of HTG-AP rats. Fenofibrate effectively decreased TG levels in HTG-AP rats and reduced the expression of TLR4 and NF-κBp65 (all P < 0.001). CONCLUSIONS: HTG does not directly cause AP, but rather increases the susceptibility to AP or aggravates the inflammatory response. It is more like a sensitizer of inflammation rather than an activator.