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.

Dilute Intralesional 5-Fluorouracil for the Treatment of Squamous Cell Carcinomas and Keratoacanthomas: A Case Series.

BACKGROUND: Intralesional 5-fluorouracil (5-FU) is a promising, yet sparsely studied alternative to surgical treatment for nonmelanoma skin cancer (NMSC).1 Previous studies of intralesional 5-FU have reported concentrations ranging from 30 to 50 mg/mL. To the best of our knowledge, this case series represents the first reported use of intralesional 5-FU 10.0 mg/mL and 16.7 mg/mL for NMSC. METHODS: A retrospective chart review identified 11 patients who received intralesional 5-FU 10.0 mg/mL and 16.7 mg/mL for 40 cutaneous squamous cell carcinomas and 10 keratoacanthomas. We describe the characteristics of these patients and calculate the clinical clearance rate of dilute intralesional 5-FU therapy for NMSC at our institution. RESULTS: Dilute intralesional 5-FU successfully treated 96% (48/50) of the study lesions, providing complete clinical clearance in 82% (9/11) of patients across a mean follow-up time of 21.7 months. All patients tolerated their treatments well with no reported adverse effects or local recurrences. DISCUSSION: The use of more dilute preparations of intralesional 5-FU for NMSC may be a means of reducing cumulative dose and dose-dependent adverse reactions while maintaining clinical clearance. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.5058.

Do Atopic Dermatitis Patient-Reported Outcomes Correlate With Validated Investigator Global Assessment? Insights From TARGET-AD Registry.

BACKGROUND: Research examining associations between the clinician-reported validated Investigator Global Assessment for AD (vIGA-AD) and patient-reported disease burden is sparse. This study aims to evaluate the relationship between vIGA-AD with patient-reported disease severity and quality of life (QoL). METHODS: A cross-sectional analysis was conducted using a September 2021 data cut from the TARGET-DERM AD study, a real-world, longitudinal cohort of children, adolescents, and adults with AD enrolled at 44 academic and community dermatology and allergy sites in the US. Clinical AD severity was measured using vIGA-AD while disease severity and QoL were assessed by the Patient Oriented Eczema Measure (POEM) and (Children's) Dermatology Life Quality Index (C/DLQI), respectively. Patient characteristics, clinical- and patient reported-outcomes were assessed by stratified POEM and C/DLQI categories using descriptive statistics. Associations with vIGA-AD were evaluated using unadjusted and adjusted ordinal logistic regression and linear regression models. RESULTS: The analysis cohort (n=1,888) primarily consisted of adults (57%), females (56%), and patients with private insurance (63%). Unadjusted analyses suggest that clinical AD severity was associated with age, with more adolescents and adults having moderate/severe vIGA-AD than pediatric patients. Clinical AD severity was also associated with disease severity, with greater POEM scores observed at greater vIGA-AD severity levels (r = 0.496 and 0.45 for adults and pediatrics, respectively). Clinical AD severity and QoL were positively correlated, with greater CDLQI/DLQI scores at greater vIGA-AD severity levels (r = 0.458 and 0.334 for DLQI and CDLQI, respectively). After adjusting for demographics and other risk factors, vIGA-AD continued to show significant associations with POEM and DLQI/CDLQI. Compared to patients with clear/almost clear disease, adults and pediatrics with moderate-to-severe AD were 8.19 and 5.78 times as likely to be in a more severe POEM category, respectively. Similarly, compared to patients with clear/almost clear disease, adults and pediatrics with moderate/severe AD were 6.69 and 3.74 times as likely to be in a more severe DLQI/CDLQI category. Adjusted linear regression analyses of DLQI in adults showed significant differences by vIGA-AD level, with mild AD and moderate/severe AD associated with a 2.26-point and 5.42-point greater DLQI relative to clear/almost clear AD. CONCLUSIONS: In this real-world study of patients with AD, greater clinician-reported disease severity is positively correlated with higher patient-reported disease severity and lower QoL. J Drugs Dermatol. 2023;22(4): doi:10.36849/JDD.7473 Access Supplementary Material here Citation: Guttman-Yassky E, Bar J, Rothenberg Lausell C, et al. Do atopic dermatitis patient-reported outcomes correlate with validated investigator global assessment? Insights from TARGET-AD registry. J Drugs Dermatol. 2023;22(4):344-355. doi:10.36849/JDD.7473.

Sphingosine-1-phosphate: metabolism, transport, atheroprotection and effect of statin treatment.

PURPOSE OF REVIEW: To better define the metabolism of sphingosine-1-phosphate (S1P), its transport in plasma and its interactions with S1P receptors on vascular cells, and to evaluate the effect of statin treatment on the subnormal plasma levels of high-density lipoprotein (HDL)-bound S1P characteristic of the atherogenic dyslipidemia of metabolic syndrome (MetS). RECENT FINDINGS: Neither clinical intervention trials targeted to raising high-density lipoprotein-cholesterol (HDL-C) levels nor human genome-wide association studies (GWAS) studies have provided evidence to support an atheroprotective role of HDL. Recently however a large monogenic univariable Mendelian randomization on the N396S mutation in the gene encoding endothelial lipase revealed a causal protective effect of elevated HDL-C on coronary artery disease conferred by reduced enzyme activity. Given the complexity of the HDL lipidome and proteome, components of HDL other than cholesterol may in all likelihood contribute to such a protective effect. Among HDL lipids, S1P is a bioactive sphingolipid present in a small proportion of HDL particles (about 5%); indeed, S1P is preferentially enriched in small dense HDL3. As S1P is bound to apolipoprotein (apo) M in HDL, such enrichment is consistent with the elevated apoM concentration in HDL3. When HDL/apoM-bound S1P acts on S1P1 or S1P3 receptors in endothelial cells, potent antiatherogenic and vasculoprotective effects are exerted; those exerted by albumin-bound S1P at these receptors are typically weaker. When HDL/apoM-bound S1P binds to S1P2 receptors, proatherogenic effects may potentially be induced. Subnormal plasma levels of HDL-associated S1P are typical of dyslipidemic individuals at high cardiovascular risk and in patients with coronary heart disease. International Guidelines recommend statin treatment as first-line lipid lowering therapy in these groups. The cardiovascular benefits of statin therapy are derived primarily from reduction in low-density lipoprotein (LDL)-cholesterol, although minor contributions from pleiotropic actions cannot be excluded. Might statin treatment therefore normalize, directly or indirectly, the subnormal levels of S1P in dyslipidemic subjects at high cardiovascular risk? Our unpublished findings in the CAPITAIN study (ClinicalTrials.gov: NCT01595828), involving a cohort of obese, hypertriglyceridemic subjects (n = 12) exhibiting the MetS, showed that pitavastatin calcium (4 mg/day) treatment for 180days was without effect on either total plasma or HDL-associated S1P levels, suggesting that statin-mediated improvement of endothelial function is not due to normalization of HDL-bound S1P. Statins may however induce the expression of S1P1 receptors in endothelial cells, thereby potentiating increase in endothelial nitric oxide synthase response to HDL-bound S1P, with beneficial downstream vasculoprotective effects. SUMMARY: Current evidence indicates that S1P in small dense HDL3 containing apoM exerts antiatherogenic effects and that statins exert vasculoprotective effects through activation of endothelial cell S1P1 receptors in response to HDL/apoM-bound S1P.

An essential receptor for adeno-associated virus infection.

Adeno-associated virus (AAV) vectors are currently the leading candidates for virus-based gene therapies because of their broad tissue tropism, non-pathogenic nature and low immunogenicity. They have been successfully used in clinical trials to treat hereditary diseases such as haemophilia B (ref. 2), and have been approved for treatment of lipoprotein lipase deficiency in Europe. Considerable efforts have been made to engineer AAV variants with novel and biomedically valuable cell tropisms to allow efficacious systemic administration, yet basic aspects of AAV cellular entry are still poorly understood. In particular, the protein receptor(s) required for AAV entry after cell attachment remains unknown. Here we use an unbiased genetic screen to identify proteins essential for AAV serotype 2 (AAV2) infection in a haploid human cell line. The most significantly enriched gene of the screen encodes a previously uncharacterized type I transmembrane protein, KIAA0319L (denoted hereafter as AAV receptor (AAVR)). We characterize AAVR as a protein capable of rapid endocytosis from the plasma membrane and trafficking to the trans-Golgi network. We show that AAVR directly binds to AAV2 particles, and that anti-AAVR antibodies efficiently block AAV2 infection. Moreover, genetic ablation of AAVR renders a wide range of mammalian cell types highly resistant to AAV2 infection. Notably, AAVR serves as a critical host factor for all tested AAV serotypes. The importance of AAVR for in vivo gene delivery is further highlighted by the robust resistance of Aavr(-/-) (also known as Au040320(-/-) and Kiaa0319l(-/-)) mice to AAV infection. Collectively, our data indicate that AAVR is a universal receptor involved in AAV infection.

Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society.

Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD.

Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial.

BACKGROUND: Alirocumab, an antibody that blocks PCSK9 (proprotein convertase subtilisin/kexin type 9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). In this study, higher baseline levels of low-density lipoprotein cholesterol (LDL-C) predicted greater benefit from alirocumab treatment. Recent studies indicate high polygenic risk scores (PRS) for coronary artery disease (CAD) identify individuals at higher risk who derive increased benefit from statins. We performed post hoc analyses to determine whether high PRS for CAD identifies higher-risk individuals, independent of baseline LDL-C and other known risk factors, who might derive greater benefit from alirocumab treatment. METHODS: ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled trial comparing alirocumab or placebo in 18 924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. The primary endpoint (MACE) comprised death of CAD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. A genome-wide PRS for CAD comprising 6 579 025 genetic variants was evaluated in 11 953 patients with available DNA samples. Analysis of MACE risk was performed in placebo-treated patients, whereas treatment benefit analysis was performed in all patients. RESULTS: The incidence of MACE in the placebo group was related to PRS for CAD: 17.0% for high PRS patients (>90th percentile) and 11.4% for lower PRS patients (≤90th percentile; P<0.001); this PRS relationship was not explained by baseline LDL-C or other established risk factors. Both the absolute and relative reduction of MACE by alirocumab compared with placebo was greater in high versus low PRS patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6.0% and 1.5%, respectively, and a relative risk reduction by alirocumab of 37% in the high PRS group (hazard ratio, 0.63 [95% CI, 0.46-0.86]; P=0.004) versus a 13% reduction in the low PRS group (hazard ratio, 0.87 [95% CI, 0.78-0.98]; P=0.022; interaction P=0.04). CONCLUSIONS: A high PRS for CAD is associated with elevated risk for recurrent MACE after acute coronary syndrome and a larger absolute and relative risk reduction with alirocumab treatment, providing an independent tool for risk stratification and precision medicine.

Topical Imiquimod for Lentigo Maligna: Survival Analysis of 103 Cases With 17 Years Follow-up.

Topical imiquimod 5% cream has been investigated as off-label primary or adjuvant treatment for melanoma in situ, lentigo maligna type (LM). Herein, we present the largest known case series of lentigo maligna treated with topical imiquimod, with up to 17 years of follow-up, and include a recurrence-free survival analysis. In this case series, 103 lesions were retrospectively evaluated for treatment response and recurrence following a course of topical imiquimod with or without tazarotene gel 0.1% pretreatment between January 1, 2002 and March 31, 2019, and prospectively followed through November 15, 2019. Over median follow-up of 5.1 years (mean = 6.2 years, S = 5.2 years, range, 0.08–17.1 years), including 29.1% LM with >10 years follow-up, we observed a response rate of 97.1% (100/103), with 8 local recurrences (8/100, 8.0%) developing at mean 2.9 years (SD: 2.7 years). Local recurrence was significantly associated with a history of failed excision (P= 0.001), <60 applications of imiquimod (P= 0.04) and partial clinical clearance (P= 0.0003). Recurrence-free survival analysis demonstrated significant risk-stratification for low and high-risk groups (P= 0.0001). Long term risk for recurrence showed significant differences among low- and high-risk cases, with low-risk cases demonstrating favorable long-term outcomes, comparable to conventional and staged surgery. Our observed low recurrence in a large case series with long-term follow-up suggests the efficacy of topical 5% imiquimod for LM and emphasizes the need for randomized control trials comparing imiquimod with, or as an adjunct to, surgical treatment. J Drugs Dermatol. 2021;20(3):346-348. doi:10.36849/JDD.5660.

Profound reductions in first and total cardiovascular events with icosapent ethyl in the REDUCE-IT trial: why these results usher in a new era in dyslipidaemia therapeutics.

The aims of this clinical review are to: (i) highlight the importance of elevated baseline triglycerides (TG) in the setting of well-controlled low-density lipoprotein cholesterol (LDL-C) on statins as a major contributor to residual atherosclerotic cardiovascular disease (ASCVD) risk, particularly among patients with type 2 diabetes mellitus, metabolic syndrome, and obesity whose distinctive lipid phenotype cannot be optimally treated with LDL-C reduction therapy alone; (ii) describe the findings and clinical implications of the landmark REDUCE-IT trial in which ethyl eicosapentaenoic acid significantly improved ASCVD outcomes. While many genetic studies have shown that elevated TG are an independent causal factor for ASCVD, prior placebo-controlled trials using niacin, fibrates, omega-3 fatty acids, and dietary supplement fish oil preparations have failed to demonstrate significant CV event reduction when added to statin therapy. In contrast, the REDUCE-IT trial in 8179 participants showed convincingly that the administration of 4 g daily of icosapent ethyl (an ethyl ester of eicosapentaenoic acid) in patients at high risk for ASCVD with increased levels of baseline TG [median value, 2.44 mmol/L (216.0 mg/dL)] but well-controlled LDL-C [median value, 1.94 mmol/L (75.0 mg/dL)] reduced significantly incident events across both the trial primary endpoint and multiple prespecified secondary endpoints, including cardiovascular death, as well as both subsequent and total primary endpoint and key secondary endpoint events. Icosapent ethyl unequivocally contributed to ASCVD event reduction over and above statin therapy. The REDUCE-IT trial results should alter our approach to managing a growing population of hypertriglyceridaemic patients whose lipid phenotype requires more intensive treatment beyond LDL-C lowering alone.

Remnant lipoproteins: are they equal to or more atherogenic than LDL?

PURPOSE OF REVIEW: To critically appraise new insights into the biology of remnant lipoproteins and their putative role in the pathophysiology of atherosclerotic cardiovascular disease, and to compare the atherogenicity of remnant particles with that of low-density lipoproteins (LDL). RECENT FINDINGS: New in-vivo stable isotope tracer studies of the kinetics of apoB48 and apoB100-containing lipoproteins in postprandial conditions have revealed that apoB48-containing very low-density lipoproteins (VLDL) accumulated markedly in hypertriglyceridemic patients. These intestinally-derived particles were cleared slowly, and represented up to 25% of circulating VLDL; as part of the remnant particle population, they may increase cardiovascular risk. Importantly, the PCSK9 inhibitor, evolocumab, was shown to reduce remnant levels (-29%) during the postprandial period in diabetic patients on statin therapy - an effect which may be additive to that of LDL-cholesterol reduction in conferring cardiovascular benefit. In recent Mendelian randomization studies, the effect of lowering triglyceride-rich lipoproteins or LDL-cholesterol translated to similar clinical benefit per unit of apoB. Finally, in randomized trials involving statin-treated patients with atherosclerotic cardiovascular disease, remnant cholesterol levels were associated with coronary atheroma progression independently of LDL-cholesterol. SUMMARY: Overall, data from observational studies in large cohorts, Mendelian randomization studies, meta-regression analyses, and post-hoc analyses of randomized trials are consistent with the contention that remnants are highly atherogenic particles and contribute to the atherosclerotic burden in an equivalent manner to that of LDL.

LDL subclass lipidomics in atherogenic dyslipidemia: effect of statin therapy on bioactive lipids and dense LDL.

Atherogenic LDL particles are physicochemically and metabolically heterogeneous. Can bioactive lipid cargo differentiate LDL subclasses, and thus potential atherogenicity? What is the effect of statin treatment? Obese hypertriglyceridemic hypercholesterolemic males [n = 12; lipoprotein (a) <10 mg/dl] received pitavastatin calcium (4 mg/day) for 180 days in a single-phase unblinded study. The lipidomic profiles (23 lipid classes) of five LDL subclasses fractionated from baseline and post-statin plasmas were determined by LC-MS. At baseline and on statin treatment, very small dense LDL (LDL5) was preferentially enriched (up to 3-fold) in specific lysophospholipids {LPC, lysophosphatidylinositol (LPI), lysoalkylphosphatidylcholine [LPC(O)]; 9, 0.2, and 0.14 mol per mole of apoB, respectively; all P < 0.001 vs. LDL1-4}, suggesting elevated inflammatory potential per particle. In contrast, lysophosphatidylethanolamine was uniformly distributed among LDL subclasses. Statin treatment markedly reduced absolute plasma concentrations of all LDL subclasses (up to 33.5%), including LPC, LPI, and LPC(O) contents (up to -52%), consistent with reduction in cardiovascular risk. Despite such reductions, lipotoxic ceramide load per particle in LDL1-5 (1.5-3 mol per mole of apoB; 3-7 mmol per mole of PC) was either conserved or elevated. Bioactive lipids may constitute biomarkers for the cardiometabolic risk associated with specific LDL subclasses in atherogenic dyslipidemia at baseline, and with residual risk on statin therapy.

Laboratory biomarkers associated with COVID-19 severity and management.

The heterogeneous disease course of COVID-19 is unpredictable, ranging from mild self-limiting symptoms to cytokine storms, acute respiratory distress syndrome (ARDS), multi-organ failure and death. Identification of high-risk cases will enable appropriate intervention and escalation. This study investigates the routine laboratory tests and cytokines implicated in COVID-19 for their potential application as biomarkers of disease severity, respiratory failure and need of higher-level care. From analysis of 203 samples, CRP, IL-6, IL-10 and LDH were most strongly correlated with the WHO ordinal scale of illness severity, the fraction of inspired oxygen delivery, radiological evidence of ARDS and level of respiratory support (p ≤ 0.001). IL-6 levels of ≥3.27 pg/ml provide a sensitivity of 0.87 and specificity of 0.64 for a requirement of ventilation, and a CRP of ≥37 mg/l of 0.91 and 0.66. Reliable stratification of high-risk cases has significant implications on patient triage, resource management and potentially the initiation of novel therapies in severe patients.

Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM.

The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), LDL cholesterol (LDLC), and calculated non-HDLC (=total - HDLC) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDLC is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDLC shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a) [Lp(a)]-cholesterol is part of measured or calculated LDLC and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDLC declines poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDLC or apolipoprotein B (apoB), especially in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L). Non-HDLC includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apoB measurement can detect elevated LDL particle (LDLP) numbers often unidentified on the basis of LDLC alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20-100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds.

Efficacy and safety of icosapent ethyl in hypertriglyceridaemia: a recap.

Although low-density lipoprotein cholesterol lowering is effective in atherosclerotic cardiovascular disease (ASCVD) prevention, considerable 'lipid-associated' residual risk remains, particularly in patients with mild-to-moderate hypertriglyceridaemia (2-10 mmol/L; 176-880 mg/dL). Triglyceride (TG)-rich lipoproteins carry both TGs and cholesterol (remnant-cholesterol). At TG levels >5 mmol/L (440 mg/dL) vs. <1 mmol/L (88 mg/dL) or remnant-cholesterol >2.3 mmol/L (89 mg/dL) vs. <0.5 mmol/L (19 mg/dL), risk is ∼1.5-fold elevated for aortic stenosis, 2-fold for all-cause mortality, 3-fold for ischaemic stroke, 5-fold for myocardial infarction (MI), and 10-fold for acute pancreatitis. Furthermore, Mendelian randomization studies indicate that elevated TG-rich lipoproteins are causally related to increased risk of ASCVD and even all-cause mortality. While genetic and epidemiological data strongly indicate that TG-rich lipoproteins are causally linked to ASCVD, intervention data are ambiguous. Fibrates, niacin and low-dose omega-3 fatty acids have all been used in outcome trials, but have failed to demonstrate clear benefit in combination with statins. Whether the lack of additional benefit relates to methodological issues or true failure is indeterminate. Importantly, a recent intervention trial evaluating a high dose of eicosapentaenoic-acid showed clear benefit. Thus, REDUCE-IT evaluated the effect of icosapent ethyl (4 g/day) on cardiovascular outcomes in 8179 high-risk patients with moderate TG elevation on statin therapy. Over a median duration of 4.9 years, the relative risk for the primary endpoint (composite of cardiovascular death, non-fatal MI, non-fatal stroke, coronary revascularization, or unstable angina) was reduced by 25% (absolute risk 17.2% vs. 22.0%; P < 0.0001; number needed to treat 21). High-dose icosapent ethyl intervention therefore confers substantial cardiovascular benefit in high-risk patients with moderate hypertriglyceridaemia on statin therapy.

Beyond cardiovascular medicine: potential future uses of icosapent ethyl.

The REDUCE-IT trial demonstrated that icosapent ethyl, an ethyl ester of eicosapentaenoic acid (EPA), reduced cardiovascular events in an at-risk population by a substantial degree. While the cardiovascular protective properties of this compound are now proven, several other potential uses are being actively explored in clinical studies. These areas of investigation include cancer, inflammatory bowel disease, infections, Alzheimer's disease, dementia, and depression. The next decade promises to deepen our understanding of the beneficial effects that EPA may offer beyond cardiovascular risk reduction.

Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes.

BACKGROUND: Pharmacologic inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) are being evaluated in clinical trials for the treatment of cardiovascular disease. The effect of lowering low-density lipoprotein (LDL) cholesterol levels by inhibiting PCSK9 on the risk of cardiovascular events or diabetes is unknown. METHODS: We used genetic scores consisting of independently inherited variants in the genes encoding PCSK9 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR; the target of statins) as instruments to randomly assign 112,772 participants from 14 studies, with 14,120 cardiovascular events and 10,635 cases of diabetes, to groups according to the number of LDL cholesterol-lowering alleles that they had inherited. We compared the effects of lower LDL cholesterol levels that were mediated by variants in PCSK9, HMGCR, or both on the risk of cardiovascular events and the risk of diabetes. RESULTS: Variants in PCSK9 and HMGCR were associated with nearly identical protective effects on the risk of cardiovascular events per decrease of 10 mg per deciliter (0.26 mmol per liter) in the LDL cholesterol level: odds ratio for cardiovascular events, 0.81 (95% confidence interval [CI], 0.74 to 0.89) for PCSK9 and 0.81 (95% CI, 0.72 to 0.90) for HMGCR. Variants in these two genes were also associated with very similar effects on the risk of diabetes: odds ratio for each 10 mg per deciliter decrease in LDL cholesterol, 1.11 (95% CI, 1.04 to 1.19) for PCSK9 and 1.13 (95% CI, 1.06 to 1.20) for HMGCR. The increased risk of diabetes was limited to persons with impaired fasting glucose levels for both scores and was lower in magnitude than the protective effect against cardiovascular events. When present together, PCSK9 and HMGCR variants had additive effects on the risk of both cardiovascular events and diabetes. CONCLUSIONS: In this study, variants in PCSK9 had approximately the same effect as variants in HMGCR on the risk of cardiovascular events and diabetes per unit decrease in the LDL cholesterol level. The effects of these variants were independent and additive. (Funded by the Medical Research Council and the National Heart, Lung, and Blood Institute.).

Identification of Cystic Lesions by Secondary Screening of Familial Pancreatic Cancer (FPC) Kindreds Is Not Associated with the Stratified Risk of Cancer.

OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are associated with risk of pancreatic ductal adenocarcinoma (PDAC). It is unclear if an IPMN in individuals at high risk of PDAC should be considered as a positive screening result or as an incidental finding. Stratified familial pancreatic cancer (FPC) populations were used to determine if IPMN risk is linked to familial risk of PDAC. METHODS: This is a cohort study of 321 individuals from 258 kindreds suspected of being FPC and undergoing secondary screening for PDAC through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Computerised tomography, endoscopic ultrasound of the pancreas and magnetic resonance imaging were used. The risk of being a carrier of a dominant mutation predisposing to pancreatic cancer was stratified into three even categories (low, medium and high) based on: Mendelian probability, the number of PDAC cases and the number of people at risk in a kindred. RESULTS: There was a median (interquartile range (IQR)) follow-up of 2 (0-5) years and a median (IQR) number of investigations per participant of 4 (2-6). One PDAC, two low-grade neuroendocrine tumours and 41 cystic lesions were identified, including 23 IPMN (22 branch-duct (BD)). The PDAC case occurred in the top 10% of risk, and the BD-IPMN cases were evenly distributed amongst risk categories: low (6/107), medium (10/107) and high (6/107) (P = 0.63). CONCLUSIONS: The risk of finding BD-IPMN was independent of genetic predisposition and so they should be managed according to guidelines for incidental finding of IPMN.

Are singleton pregnancies after assisted reproduction technology (ART) associated with a higher risk of placental anomalies compared with non-ART singleton pregnancies? A systematic review and meta-analysis.

BACKGROUND: Placental anomalies (placenta praevia, placental abruption, morbidly adherent placenta and cord insertion anomalies) are associated with maternal and fetal morbidity and mortality. It has been suggested these might be more prevalent in pregnancies after assisted reproduction technology (ART). OBJECTIVES: To determine whether ART singleton pregnancies are associated with an increased risk of placental anomalies compared with non-ART singleton pregnancies. SEARCH STRATEGY: MEDLINE, EMBASE, CENTRAL, Web of Science and Scopus (January 2018). SELECTION CRITERIA: Cohort studies reporting placental anomalies in ART and non-ART singleton pregnancies. DATA COLLECTION AND ANALYSIS: We report pooled odds ratios (OR) for the comparisons: (1) ART versus SC (spontaneously conceived), (2) ART versus non-ART (unspecified), (3) FET-ART (frozen-embryo transfer) versus SC, (4) ART versus non-ART (subfertile patients). Study quality was assessed using a modified Newcastle -Ottawa scale. MAIN RESULTS: 33 low/moderate quality studies evaluated 124 215 ART and 6 054 729 non-ART singleton pregnancies. Risk of placenta praevia, placental abruption and morbidly adherent placenta was higher in ART than SC pregnancies: odds ratio (OR) (OR 3.76, 95% CI 3.09-4.59); (OR 1.87, 95% CI 1.70-2.06) and (OR 2.27, 95% CI 1.79-2.87) respectively. Risk of placenta praevia and placental abruption was higher in ART than in non-ART (subfertile patients): (OR 2.51, 95% CI 2.12-2.98) and (OR 1.61, 95% CI 1.33-1.95) respectively. Results were similar when comparing ART with unspecified non-ART pregnancies. Risk of placenta praevia was higher, but not significantly so, in FET-ART than in SC pregnancies (OR 2.42, 95% CI 0.63-9.30). CONCLUSIONS: Singleton ART pregnancies are associated with an increased risk of placental anomalies compared with non-ART singleton pregnancies. TWEETABLE ABSTRACT: A review of over 6 million singleton pregnancies finds increased risk of placental anomalies after ART.

Spontaneous Hair Repigmentation in an 80-Year-Old Man: A Case of Melanoma-Associated Hair Repigmentation and Review of the Literature.

Spontaneous hair repigmentation of physiologically white or gray hair is a rare occurrence that may be associated with melanoma in elderly individuals. We present the first case of this phenomenon in a man. A gray-haired, 80-year-old man presented to dermatology clinic with a 3-cm lock of black hair on his vertex scalp that developed over 1 year. Punch biopsies showed an increase in junctional dendritic melanocytes with rare pagetoid cells and extension along the follicular outer root sheath epithelium and interfollicular epidermis, associated with prominent dendritic melanocytic hyperplasia and pigment-containing melanocytes within the hair bulbs. Although the findings on the biopsies were not diagnostic of melanoma in situ, an irregular interfollicular distribution of melanocytes was concerning for an adjacent atypical process. A complete excision was performed and revealed melanoma in situ, lentigo maligna type. Rare reports describe spontaneous hair repigmentation as a harbinger of lentigo maligna in women. Repigmentation can occur in the setting of proliferation of malignant pigment-producing melanocytes or by paracrine stimulation of benign bulbar melanocytes through receptor tyrosine kinase KIT activation. Presence of prominent dendritic melanocytic hyperplasia and pigment-containing melanocytes within the hair bulbs in our patient's biopsies was suggestive of paracrine or physiologic stimulation of bulbar melanocytes. Given the importance of early melanoma detection and the low visibility of the scalp, this report raises awareness of an extraordinary presentation of lentigo maligna and exemplifies the importance of close clinicopathologic correlation to ensure optimal clinical management and patient outcome.

No evidence of neurocognitive adverse events associated with alirocumab treatment in 3340 patients from 14 randomized Phase 2 and 3 controlled trials: a meta-analysis of individual patient data.

Aims: Despite patient reports of neurocognitive disorders with lipid-lowering treatments (LLTs), large clinical trials have found no significant association between neurocognitive disorders and LLTs. We assessed incidence of neurocognitive treatment-emergent adverse events (TEAEs) from 14 Phase 2 and 3 trials of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab. Methods and results: Patients (most on background maximally tolerated statin) received alirocumab 75/150 mg every 2 weeks (n = 3340; 4029 patient-years of exposure), placebo (n = 1276), or ezetimibe (n = 618). Data were pooled by the control used. Neurocognitive TEAEs were reported by 22 (0.9%) alirocumab-treated patients vs. 9 (0.7%) with placebo in placebo-controlled trials [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.57-2.68] and 10 (1.2%) with alirocumab vs. 8 (1.3%) with ezetimibe in ezetimibe-controlled trials (HR 0.81, 95% CI 0.32-2.08). Rates of neurocognitive TEAEs were similar in patients receiving alirocumab with LDL cholesterol (LDL-C) levels <25 mg/dL (<0.65 mmol/L; n = 5/839; 0.6%; 0.5/100 patient-years) vs. ≥25 mg/dL (n = 26/2501; 1.0%; 0.8/100 patient-years). One patient (0.1%; ezetimibe-controlled pool) receiving alirocumab had a neurocognitive TEAE leading to discontinuation vs. two (0.2%) patients receiving placebo and three (0.4%) patients receiving ezetimibe. Neurocognitive TEAE incidence was also similar between alirocumab and controls when stratified by age. Conclusions: Neurocognitive TEAE incidences were low (≤1.2%), with no significant differences between alirocumab vs. controls up to 104 weeks. No association was found between neurocognitive TEAEs and LDL-C <25 mg/dL based on the completed Phase 2 and 3 trials examined, although long-term effects of very low LDL-C levels induced by PCSK9 inhibitors are currently unknown.