Journal of clinical lipidology最新文献

This report describes a rare case of lipoprotein glomerulopathy. A 63 year-old man presented with nephrotic syndrome unresponsive to rituximab and tacrolimus. Blood tests showed a mild- to moderate hypertriglyceridemia suggesting familial dysbetalipoproteinemia (FD). Additional diagnostic procedures including lipoprotein ultracentrifugation, fast protein liquid chromatography and agarose gel electrophoresis were performed, which showed increased very-low-density lipoprotein remnants corresponding to the lipid profile observed in FD patients. However, instead of the expected APOE ε2/ε2 genotype, our patient showed APOE ε3/ε4. The APOE gene was sequenced, revealing a c.509C>A:p. (Ala170Asp) variant (also known as APOE Las Vegas), which has been described once in a patient with lipoprotein glomerulopathy. Lipid-lowering therapy was initiated, which resulted in a slight improvement of renal function and lipid profile. This Dutch case further supports the pathogenicity of the APOE Las Vegas variant and emphasizes the importance of timely diagnosis of lipoprotein glomerulopathy to institute appropriate treatment.

Background: Cardiac Allograft Vasculopathy (CAV) is a leading cause of morbidity and mortality after heart transplantation. There are limited contemporary studies examining post-transplant lipid management and cardiometabolic health.

Objective: We study the burden of cardiometabolic derangements post transplantation and its impact on CAV in a modern cohort of heart transplant recipients.

Methods: All heart transplant (HTx) recipients between January 2019 and December 2020, with two lipid assessments and angiographic surveillance were included. Logistic regression was used to assess association of lipid levels with cardiovascular outcomes and CAV.

Results: Among 87 HTx recipients, atherogenic lipids were significantly elevated after Htx. Median LDL-C increased from a baseline level of 69.5 mg/dL to 86.5 mg/dL, p = 0.002, non-HDL-C 91.5 mg/dL to 118 mg/dL, p < 0.001, triglycerides 94.5 mg/dL to 133 mg/dL, p < 0.001, and remnant cholesterol 19 mg/dL to 27 mg/dL, p < 0.001. Increases in non-HDL-C, triglycerides, and remnant cholesterol were significantly associated with increased risk of CAV (Stanford Grade 4 and intimal thickness). Increases in triglycerides and remnant-C were associated with increased risk of composite major adverse cardiovascular events.

Conclusion: We demonstrate a significant increase in atherogenic lipids two years following transplantation with low use (20 %) of high-intensity statin. Increase in atherogenic lipids was associated with increased risk of CAV and increase in triglycerides and remnant cholesterol with increased MACE. Future studies examining cardiometabolic consequences of heart transplantation and optimal treatment strategies to reduce risk of CAV and MACE are needed.

Background: Familial chylomicronemia syndrome (FCS) is an ultrarare inherited disorder. Genetic testing is not always feasible or conclusive. European clinicians developed a "FCS score" to differentiate between FCS and multifactorial chylomicronemia syndrome (MCS), a more common condition with overlapping features. A diagnostic score has not been developed for use in the North American context.

Objective: To develop and validate a diagnostic score for North American patients based on signs, symptoms and biochemical traits of FCS.

Methods: Using the RAND/UCLA modified Delphi process, we convened ten US/Canadian physicians with experience recognizing and treating FCS and one adult patient with FCS. The panel developed and rated 296 scenarios describing patients with FCS. Linear regression analyses used median post-meeting ratings to develop score parameters. We tested the score's sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in patients with classical FCS, functional FCS, and MCS from Western University's Lipid Genetics Clinic's registry.

Results: Numerical scores were attributed based upon the following: age, hypertriglyceridemia onset, body mass index, history of abdominal pain/pancreatitis, presence of secondary factors, triglyceride (TG) levels, ratio of TG/total cholesterol, and apolipoprotein B level. Scores ≥60 indicate definite classical FCS; the score distinguished patients with FCS from MCS in a real-world registry (100.0 % specificity, 66.7 % sensitivity, 100.0 % PPV, 95.5 % NPV). Scores ≥45 were "very likely" to have classical FCS (96.9 % specificity, 88.9 % sensitivity).

Conclusion: Given its simplicity and high specificity for distinguishing patients with FCS from MCS, the NAFCS Score could be used in lieu of - or while awaiting - genetic testing to optimize treatment.

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease of low-density lipoprotein cholesterol (LDL-C) metabolism. Despite the devastating effect of this disease on atherosclerotic cardiovascular health, the disease phenotype and severity are more heterogeneous than previously thought. The predictors of atherosclerotic cardiovascular disease (ASCVD) in HoFH patients have never been systematically studied.

Objective: To investigate the univariate and multivariate predictors of ASCVD in HoFH patients.

Methods: Patients from the Canadian HoFH Registry were included in the present retrospective longitudinal study. Data for these patients were collected using a standardized questionnaire between 2019 and 2022 in 19 academic sites across Canada. Predictors of ASCVD were evaluated using Cox proportional hazards models.

Results: Among 48 HoFH patients, 26 (54 %) of them had at least one ASCVD event. The average age at baseline was 19 ± 15 years and women represented 56 % of the cohort. The independent predictors of ASCVD events were male sex (HR 2.57 (1.13-5.84)), diabetes (HR 16.22 (3.38-77.97)), and LDL-C above the median of 14.45 mmol/L [559 mg/dL] (HR 3.10 (1.24-7.76)). When performing subgroup analysis according to sex, the presence of LDL-C above median was associated with a significantly higher probability of ASCVD (88 % vs. 43 %, p = 0.005) in women, but not in men (100 % at age 40 in both groups, p = 0.98).

Conclusion: This study reported for the first time the univariate and multivariate predictors of ASCVD in HoFH patients. We demonstrate that predictors of ASCVD in HoFH differ in males and females with respect to LDL-C levels.

Pseudohypertriglyceridemia is an overestimation of serum triglyceride levels, potentially leading to an inaccurate diagnosis of hypertriglyceridemia. This can result from hyperglycerolemia, which interferes with enzymatic measurement methods. Hyperglycerolemia may arise from drugs or genetic glycerol kinase defects. We present a case of a severely burned patient with very high triglyceride levels (up to 5,696 mg/dL) that was resistant to lipid-lowering treatment, identified during the work up for pancreatitis associated with elevated lipase levels. Despite the very high triglyceride levels reported in the laboratory results, the standing plasma showed clear plasma, with no significant peak of pre-beta lipoprotein observed on serum lipoprotein electrophoresis. Serum apolipoprotein B levels were low, and urine triglyceride levels were high. This case confirms that very high serum glycerol levels caused the falsely elevations of triglyceride and lipase levels, resulting from hyperglycerolemia induced by the massive topical application of silver sulfadiazine cream (containing glycerine and glyceryl stearate) to the severely burned wound, which interfered with the laboratory assays. Triglyceride and lipase levels dramatically decreased after reducing the dose of silver sulfadiazine cream. No genetic defects related to glycerol kinase deficiency were identified.

Background: The genetic basis of hypertriglyceridemia (HTG) is complex and includes variants in Lipase Maturation Factor 1 (LMF1), an endoplasmic reticulum (ER)-chaperone involved in the post-translational activation of lipoprotein lipase (LPL).

Objective: The objective of this study was to identify and functionally characterize biallelic LMF1 variants in patients with HTG.

Methods: Genomic DNA sequencing was used to identify biallelic LMF1 variants in HTG patients without deleterious variants in LPL, apolipoprotein C-II (APOC2), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) or apolipoprotein A-V (APOA5). LMF1 variants were functionally evaluated by in silico analyses and assessing their impact on LPL activity, LMF1 protein expression and specific activity in transiently transfected HEK293 cells.

Results: We identified four homozygous LMF1 variants in patients with severe HTG: two novel rare variants (p.Asn147Lys and p.Pro246Arg) and two low-frequency variants (p.Arg354Trp and p.Arg364Gln) previously reported at heterozygosity. We demonstrate that all four variants reduce the secretion of enzymatically active LPL by impairing the specific activity of LMF1, whereas p.Asn147Lys also diminishes LMF1 protein expression.

Conclusion: This study extends the role of LMF1 as a genetic determinant in severe HTG and demonstrates that rare and low-frequency LMF1 variants can underlie this condition through distinct molecular mechanisms. The clinical phenotype of patients affected by partial loss of LMF1 function is consistent with Multifactorial Chylomicronemia Syndrome (MCS) and suggests that secondary factors and additional genetic determinants contribute to HTG in these subjects.

Context: Lorlatinib is an anaplastic lymphoma kinase (ALK) inhibitor, which is currently used for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). Previous reports have noticed an association between lorlatinib and hyperlipidemia, however the specific mechanisms for this side effect remain unknown. Some investigators have reported nephrotic syndrome to be the underlying cause of lorlatinib-induced hyperlipidemia.

Case report: A 59-year-old female with NSCLC presented with marked elevation of lipid levels, including total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C), after initiation of lorlatinib therapy. Despite high dose atorvastatin and ezetimibe, lipid levels remained elevated. A 24-hour urine collection revealed only 226 mg of protein excretion.

Conclusions: Lorlatinib induced a complex dyslipidemia in our patient with elevations of both LDL-C and HDL-C. The underlying mechanism of lorlatinib-induced hyperlipidemia remains unknown and is unlikely to be secondary to nephrotic syndrome in many patients.

Background: The timing of the clinical benefit of intensive lipid-lowering therapy in reducing major adverse cardiovascular events (MACE) in individuals with established cardiovascular disease (CVD), both before and after the advent of novel medications (proprotein convertase subtilisin/kexin type 9 inhibitor [PCSK9i] and ezetimibe) in 2010, is unclear.

Objective: To evaluate the time to benefit (TTB) from intensive lipid-lowering therapy.

Methods: The investigators systematically searched for randomized controlled trials evaluating intensive lipid-lowering therapy. The primary outcome was MACEs. Utilizing reconstructed individual participant data, Weibull survival curves were fitted to estimate the TTB for specific absolute risk reduction thresholds (0.002, 0.005, and 0.01).

Results: Seven trials randomizing 92,180 adults aged between 58.2 and 63.6 years were identified. A TTB of 19.6 months (95 % confidence interval [CI]: 12.3 to 31.4) of intensive lipid-lowering was needed to prevent 1 MACE per 100 patients. Before 2010, when statin as the only option, a TTB for high-intensity statin therapy of 15.2 months (95 % CI: 6.52 to 35.5) was needed. After 2010, the TTB for PCSK9i-based, ezetimibe-based intensive lipid-lowering on a background of statin therapy was 17.7 (95 % CI: 12.2 to 25.6) and 47.3 (95 % CI: 20.4 to 110) months, respectively.

Conclusions: In contemporary practice, to prevent 1 MACE in 100 individuals with established CVD, a TTB of 17.7 and 47.3 months was needed for PCSK9i-based and ezetimibe-based intensive lipid-lowering therapy on a background of statin therapy, respectively. The observed variations across different drug regimens highlight the need for a personalized approach to treatment decisions.

Dietary guidance is based on a robust evidence base that includes high-quality clinical trials, of which some have been designed to establish causal relationships between dietary interventions and ASCVD risk reduction. However, the complexity associated with conducting these trials has resulted in criticism of nutrition and dietary recommendations because the strength and quality of evidence falls short of that for some pharmaceutical interventions. In this paper, we aim to promote greater awareness of the nutrition-related clinical trials that have been conducted showing ASCVD benefits and how this evidence has contributed to dietary recommendations. Compared to clinical trials of pharmaceutical agents, nutrition-related clinical trials have several unique considerations, including complexities of intervention design, challenges related to the blinding of participants to treatment, modest effect magnitudes, variability in baseline dietary exposures, absence of objective dietary adherence biomarkers, achieving sustained participant adherence, and the significant timeline for endpoint responses. Evidence-based dietary recommendations are made based on multiple lines of evidence including that from randomized controlled trials, epidemiological studies, as well as animal and in vitro studies. This research has provided foundational evidence for the role of diet in prevention, management, and treatment of ASCVD. Based on the clinical trials that have been conducted, a strong consensus has evolved regarding the key elements of healthy dietary patterns that decrease ASCVD risk. Going forward, implementation research is needed to identify effective translation approaches to increase adherence to evidence-based dietary recommendations.