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Background and Aim: Elevated triglyceride (TG) levels seem to identify subjects at increased cardiovascular risk, independent of LDL-C levels. We sought to evaluate the predictive role of hypertriglyceridemia, defined as TG levels ≥150 mg/dl, in very high risk (VHR) patients with chronic coronary syndromes (CCS) treated with statins., Methods and Results: Using the data from the STable Coronary Artery Diseases RegisTry (START) study, an Italian nationwide registry, we assessed the association between the TG levels and baseline clinical characteristics, pharmacological treatment and major adverse cardio-cerebrovascular events (MACCE) at 1 year in a large cohort of statin-treated patients at VHR. Of the 4751 consecutive patients with CCS enrolled in the registry and classified as VHR, 2652 (55.8%) had TG values available (mean 120.6 ± 54.9) and were treated with at least a statin at baseline: 2019 (76.1%) with TG < 150 and 633 (23.9%) with TG ≥ 150 mg/dl. At 1 year from enrolment, MACCE occurred in 168 (6.3%) patients, without differences between the two groups of TG (5.9 vs 7.6%; p = 0.14). At multivariable analysis, hypertriglyceridemia did not result as independent predictor of the MACCE (hazard ratio: 1.16; 95% confidence intervals: 0.82-1.64; p = 0.42)., Conclusions: In the present large, nationwide cohort of consecutive CCS patients at VHR with statin-controlled LDL-C levels, hypertriglyceridemia was present in around 24% of cases and did not result as predictor of MACCE at 1 year. Further studies with a longer follow-up and larger sample size are needed to better define the prognostic role of TG levels when intensive LDL lowering therapies are used., Competing Interests: Declaration of competing interest All authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Severe hypertriglyceridemia (HTG) may result from mutations in genes affecting the intravascular lipolysis of triglyceride (TG)-rich lipoproteins., Objective: The aim of this study was to develop a targeted next-generation sequencing panel for the molecular diagnosis of disorders characterized by severe HTG., Methods: We developed a targeted customized panel for next-generation sequencing Ion Torrent Personal Genome Machine to capture the coding exons and intron/exon boundaries of 18 genes affecting the main pathways of TG synthesis and metabolism. We sequenced 11 samples of patients with severe HTG (TG>885 mg/dL-10 mmol/L): 4 positive controls in whom pathogenic mutations had previously been identified by Sanger sequencing and 7 patients in whom the molecular defect was still unknown., Results: The customized panel was accurate, and it allowed to confirm genetic variants previously identified in all positive controls with primary severe HTG. Only 1 patient of 7 with HTG was found to be carrier of a homozygous pathogenic mutation of the third novel mutation of LMF1 gene (c.1380C>G-p.Y460X). The clinical and molecular familial cascade screening allowed the identification of 2 additional affected siblings and 7 heterozygous carriers of the mutation., Conclusions: We showed that our targeted resequencing approach for genetic diagnosis of severe HTG appears to be accurate, less time consuming, and more economical compared with traditional Sanger resequencing. The identification of pathogenic mutations in candidate genes remains challenging and clinical resequencing should mainly intended for patients with strong clinical criteria for monogenic severe HTG., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Chylomicronemia syndrome is a metabolic condition characterized by severe fasting hypertrigliceridemia (≥ 1000 mg/dL) and other clinical features including chronic abdominal pain and recurrent acute pancreatitis. In patients with acute or recurrent pancreatitis, plasma exchange (PEx) is indicated for the treatment of acute disease and prevention of recurrence. The use of plasma instead of albumin as replacement fluid has been suggested for its putative ability to replace the deficient enzyme possibly leading to better clinical improvement., Case Report: A 40-year-old man with chylomicronemia syndrome due to a newly identified loss-of-function mutation in the lipoprotein lipase (LPL) gene (IVS2, c.250-1G/C) has been treated at our hospital since the age of 13. From age 18 to age 34, the patient had five episodes of acute pancreatitis while his triglyceride (TG) levels were extremely high (2500-4000 mg/dL). As the TG levels remained stable over 4000 mg/dL despite the maximum medical treatment, the patient started long-term PEx treatment on a weekly basIs. Both albumin and plasma have been used as replacement solution. Thirty months from the beginning of this treatment, no episode of acute pancreatitis has been reported, and the chronic abdominal pain fully disappeared. No differences were observed between the use of albumin or plasma as replacement solution., Conclusion: Long-term PEx is effective in preventing the recurrence of acute pancreatitis and in treatment of chronic abdominal pain in this patient with chylomicronemia syndrome. Plasma is not more effective than albumin in lipid reduction, likely because of its extremely low enzyme content. Therefore, in patients with LPL deficiency serum albumin should be preferred to plasma as replacement fluid because of the low rate of side effects and reduced costs., (© 2015 AABB.)

Objective: Cyclic AMP responsive element-binding protein 3-like 3 (CREB3L3) is a novel candidate gene for dominant hypertriglyceridemia. To date, only 4 kindred with dominant hypertriglyceridemia have been found to be carriers of 2 nonsense mutations in CREB3L3 gene (245fs and W46X). We investigated a family in which hypertriglyceridemia displayed an autosomal dominant pattern of inheritance., Approach and Results: The proband was a 49-year-old woman with high plasma triglycerides (≤1300 mg/dL; 14.68 mmol/L). Her father had a history of moderate hypertriglyceridemia, and her 51-year-old brother had triglycerides levels as high as 1600 mg/dL (18.06 mmol/L). To identify the causal mutation in this family, we analyzed the candidate genes of recessive and dominant forms of primary hypertriglyceridemia by direct sequencing. The sequencing of CREB3L3 gene led to the discovery of a novel minute frame shift mutation in exon 3 of CREB3L3 gene, predicted to result in the formation of a truncated protein devoid of function (c.359delG-p.K120fsX20). Heterozygosity for the c.359delG mutation resulted in a severe phenotype occurring later in life in the proband and her brother and a good response to diet and a hypotriglyceridemic treatment. The same mutation was detected in a 13-year-old daughter who to date is normotriglyceridemic., Conclusions: We have identified a novel pathogenic mutation in CREB3L3 gene in a family with dominant hypertriglyceridemia with a variable pattern of penetrance., (© 2015 American Heart Association, Inc.)

Lipase maturation factor 1 (Lmf1) is an endoplasmic reticulum (ER) membrane protein involved in the posttranslational folding and/or assembly of lipoprotein lipase (LPL) and hepatic lipase (HL) into active enzymes. Mutations in Lmf1 are associated with diminished LPL and HL activities ("combined lipase deficiency") and result in severe hypertriglyceridemia in mice as well as in human subjects. Here, we investigate whether endothelial lipase (EL) also requires Lmf1 to attain enzymatic activity. We demonstrate that cells harboring a (cld) loss-of-function mutation in the Lmf1 gene are unable to generate active EL, but they regain this capacity after reconstitution with the Lmf1 wild type. Furthermore, we show that cellular EL copurifies with Lmf1, indicating their physical interaction in the ER. Finally, we determined that post-heparin phospholipase activity in a patient with the LMF1(W464X) mutation is reduced by more than 95% compared with that in controls. Thus, our study indicates that EL is critically dependent on Lmf1 for its maturation in the ER and demonstrates that Lmf1 is a required factor for all three vascular lipases, LPL, HL, and EL.

Context: Lipase maturation factor 1 (LMF1) gene is a novel candidate gene in severe hypertriglyceridemia. Lmf1 is involved in the maturation of lipoprotein lipase (LPL) and hepatic lipase in endoplasmic reticulum. To date only one patient with severe hypertriglyceridemia and related disorders was found to be homozygous for a nonsense mutation in LMF1 gene (Y439X)., Objective: The objective of the study was to investigate LMF1 gene in hypertriglyceridemic patients in whom mutations in LPL, APOC2, and APOA5 genes had been excluded., Results: The resequencing of LMF1 gene led to the discovery of a novel homozygous nonsense mutation in one patient with severe hypertriglyceridemia and recurrent episodes of pancreatitis. The mutation causes a G>A substitution in exon 9 (c.1395G>A), leading to a premature stop codon (W464X). LPL activity and mass were reduced by 76 and 50%, respectively, compared with normolipidemic controls. The proband over the years has shown a good response to treatment. The proband's son, heterozygous for the W464X, shows normal plasma triglyceride levels., Conclusions: We identified the second novel pathogenic mutation in LMF1 gene in a patient with severe hypertriglyceridemia. LPL deficiency in our patient was milder than in the carrier of the Y439X previously described.

Triglyceride-rich lipoproteins generated during the postprandial phase are atherogenic. Large very low-density lipoproteins (LDLs) or chylomicrons (CMs) are not as atherogenic as their remnants (Rem). Small and dense LDLs are associated with cardiovascular disease. Low-density lipoprotein size is partly under genetic control and is considered as a relatively stable LDL feature. In this article, we present data on retinyl palmitate kinetics correlated with the modification of LDL features in terms of size, density, and in vitro receptor binding affinity after an oral fat load. Six nondiabetic, hypertriglyceridemic (HTG) patients and 6 healthy controls were examined. Low-density lipoprotein size was assessed by gradient gel electrophoresis, and LDL density by density gradient ultracentrifugation. Low-density lipoprotein binding affinity was tested by in vitro competition binding assay on normal human skin fibroblasts (HSFs) and hepatoma cells (HepG2). Kinetic parameters were estimated in CM and Rem fractions by compartmental modeling. Hypertriglyceridemic patients showed significantly higher triglyceride area and a slower CM fractional catabolic rate. Postprandial LDL density increased both in HTG patients and in the control group with a significant difference between groups at 6 hours. Fasting LDL size was lower in HTG patients vs controls but decreased similarly in the postprandial phase. Low-density lipoprotein size and density postprandial modifications were not correlated with any investigated parameter. Postprandial LDLs were internalized more efficiently by HSF than baseline LDL only in the HTG group. In conclusion, postprandial LDLs are smaller and denser compared with fasting LDLs after an oral fat load. Postprandial LDLs also slightly increased their affinity to the HSF cell receptors.

Post-prandial profiles of plasma lipids and apoproteins have been studied in 13 hypertriglyceridaemic patients and in 24 normolipidaemic subjects who acted as controls. Triglyceride curves were different in the two groups: type IV patients reached the peak later than the controls (7-h vs 4 1/2-h) and cleared plasma triglycerides more slowly. The magnitude of post-prandial response was found to be higher in hypertriglyceridaemic patients. Positive correlations were also found between triglycerides response and fasting levels of triglycerides, apo B, apo C-II, apo C-III and apo E levels and negative correlations (not significant) with HDL-C levels in both hypertriglyceridemics and controls. In normolipidaemic subjects the triglyceride increase area was also correlated with age, BMI and total cholesterol, while in type IV patients with apo A-I and apo A-II levels. These data confirm that the magnitude of post-prandial phase is influenced by fasting levels of triglycerides-rich lipoproteins and that HDL are important determinants in the control of the post-prandial response. The most relevant finding in this study was the difference of the post-prandial profile of apoproteins C-II, C-III and E. These apoproteins significantly decreased nine hours after meal in the controls, while in hypertriglyceridaemics these apoproteins showed a rise over time. On the contrary apo A-I, apo A-II and apo B curves presented a similar profile in both groups. Possible mechanisms have been discussed, but further studies are necessary to understand the metabolic defects responsible for this behaviour in hypertriglyceridaemia.

Thirty-three patients with chronic renal failure (CRF) and uremic hypertriglyceridemia (HTG) on hemodialysis were compared with 33 type IV hyperlipoproteinemic patients matched for age, body mass index (BMI), and triglyceride (TG) levels. The two forms of hypertriglyceridemia showed different apolipoprotein profiles: apo AI, AII, and B levels and apo CII:CIII and TG:apo CIII ratios of CRF-HTG patients were lower and apo CIII levels were higher than the levels of type IV subjects.