Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis.

BACKGROUND: Lipoprotein(a) (Lp(a)) is recognized as a causal factor for coronary heart disease (CHD) but its atherogenicity relative to that of low-density lipoprotein (LDL) on a per-particle basis is indeterminate. OBJECTIVES: The authors addressed this issue in a genetic analysis based on the fact that Lp(a) and LDL both contain 1 apolipoprotein B (apoB) per particle. METHODS: Genome-wide association studies using the UK Biobank population identified 2 clusters of single nucleotide polymorphisms: one comprising 107 variants linked to Lp(a) mass concentration, the other with 143 variants linked to LDL concentration. In these Lp(a) and LDL clusters, the relationship of genetically predicted variation in apoB with CHD risk was assessed. RESULTS: The Mendelian randomization-derived OR for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% CI: 1.24-1.33) compared with 1.04 (95% CI: 1.03-1.05) for the same increment in LDL-apoB. Likewise, use of polygenic scores to rank subjects according to difference in Lp(a)-apoB vs difference in LDL-apoB revealed a greater HR for CHD per 50 nmol/L apoB for the Lp(a) cluster (1.47; 95% CI: 1.36-1.58) compared with the LDL cluster (1.04; 95% CI: 1.02-1.05). From these data, we estimate that the atherogenicity of Lp(a) is approximately 6-fold (point estimate of 6.6; 95% CI: 5.1-8.8) greater than that of LDL on a per-particle basis. CONCLUSIONS: We conclude that the atherogenicity of Lp(a) (CHD risk quotient per unit increase in particle number) is substantially greater than that of LDL. Therefore, Lp(a) represents a key target for drug-based intervention in a significant proportion of the at-risk population.

Acute myocardial infarction preferentially alters low-abundant, long-chain unsaturated phospholipid and sphingolipid species in plasma high-density lipoprotein subpopulations.

Aim: High-density lipoprotein (HDL) particles in ST-segment elevation myocardial infarction (STEMI) are deficient in their anti-atherogenic function. Molecular determinants of such deficiency remain obscure. Methods: Five major HDL subpopulations were isolated using density-gradient ultracentrifugation from STEMI patients (n = 12) and healthy age- and sex-matched controls (n = 12), and 160 species of phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, sphingomyelin and ceramide were quantified by LC-MS/MS. Results: Multiple minor species of proinflammatory phosphatidic acid and lysophosphatidylcholine were enriched by 1.7-27.2-fold throughout the majority of HDL subpopulations in STEMI. In contrast, minor phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, sphingomyelin and ceramide species were typically depleted up to 3-fold in STEMI vs. control HDLs, while abundances of their major species did not differ between the groups. Intermediate-to-long-chain phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol species were more affected by STEMI than their short-chain counterparts, resulting in positive correlations between their fold decrease and the carbon chain length. Additionally, fold decreases in the abundances of multiple lipid species were positively correlated with the double bond number in their carbon chains. Finally, abundances of several phospholipid and ceramide species were positively correlated with cholesterol efflux capacity and antioxidative activity of HDL subpopulations, both reduced in STEMI vs controls. KEGG pathway analysis tied these species to altered glycerophospholipid and linoleic acid metabolism. Conclusions: Minor unsaturated intermediate-to-long-chain phospholipid and sphingolipid species in HDL subpopulations are most affected by STEMI, reflecting alterations in glycerophospholipid and linoleic acid metabolism with the accumulation of proinflammatory lysolipids and maintenance of homeostasis of major phospholipid species.

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.

What are the risks associated with lipiodol hysterosalpingography? A literature review.

INTRODUCTION: Hysterosalpingography is widely used as a first-line investigation for infertility, and may also be therapeutic, increasing pregnancy rates. Aqueous and oil-based contrast agents can be used. Some studies suggest Lipiodol hysterosalpingography has a greater therapeutic effect on fertility than aqueous contrast, though this is contentious. There are additionally safety concerns surrounding Lipiodol hysterosalpingography. This review summarises the adverse effects associated with Lipiodol hysterosalpingography, particularly on thyroid function. KEY FINDINGS: 331 articles were identified. Of these, 46 met inclusion criteria. 3 further articles were identified from reference lists. Complications typically cited in the literature include pain, intravasation, life-threatening oil embolism, and lipogranuloma formation. Emerging evidence suggests that Lipiodol hysterosalpingography may also impact maternal and neonatal thyroid function. Women may develop hypo- or hyperthyroidism. Thyroid dysfunction is clinically significant as even subclinical hypothyroidism reduces fertility, increases the risk of pregnancy complications including miscarriage, pre-eclampsia and perinatal mortality, and adversely impacts foetal neurodevelopment. One study suggested a possible link with neonatal congenital hypothyroidism. CONCLUSION: There is emerging evidence to suggest that Lipiodol hysterosalpingography can cause hypo- or hyperthyroidism, in addition to known adverse effects of pain, intravasation, oil embolism, and lipogranuloma formation. IMPLICATIONS FOR PRACTICE: Given the significance of these risks, and contention surrounding whether Lipiodol truly increases pregnancy rates compared to aqueous mediums, careful consideration is required in the selection of contrast agent. In particular, Lipiodol hysterosalpingography may not be suitable for women with pre-existing thyroid dysfunction.

Equivalent efficacy of indoor daylight and lamp-based 5-aminolevulinic acid photodynamic therapy for treatment of actinic keratosis.

Background: Photodynamic therapy (PDT) is widely used as a treatment for actinic keratoses (AK), with new sunlight-based regimens proposed as alternatives to lamp-based treatments. Prescribing indoor daylight activation could help address the seasonal temperature, clinical supervision, and access variability associated with outdoor treatments. Objective: To compare the AK lesion clearance efficacy of indoor daylight PDT treatment (30 min of 5-aminolevulinic acid (ALA) pre-incubation, followed by 2 h of indoor sunlight) versus a lamp-based PDT treatment (30 min of ALA preincubation, followed by 10 min of red light). Methods: A prospective clinical trial was conducted with 41 patients. Topical 10% ALA was applied to the entire treatment site (face, forehead, scalp). Patients were assigned to either the lamp-based or indoor daylight treatment. Actinic keratosis lesion counts were determined by clinical examination and recorded for pre-treatment, 1-month, and 6-month follow-up visits. Results: There was no statistical difference in the efficacy of AK lesion clearance between the red-lamp (1-month clearance = 57 ± 17%, 6-month clearance = 57 ± 20%) and indoor daylight treatment (1-month clearance = 61 ± 19%, 6-month clearance = 67 ± 20%). A 95% confidence interval of the difference of the means was measured between -4.4% and 13.4% for 1-month, and -2.2% and +23.6% for 6-month timepoints when comparing the indoor daylight to the red-lamp treatment, with a priori interval of equivalence of ±20%. Limitations: Ensuring an equivalent dose between the indoor and lamp treatment cohorts limited randomisation since it required performing indoor daylight treatments only during sunny days. Conclusion: Indoor-daylight PDT provided equivalent AK treatment efficacy to a lamp-based regimen while overcoming temperature limitations and UV-block sunscreen issues associated with outdoor sunlight treatments in the winter. Clinical trial registration: Clinicaltrials.gov listing: NCT03805737.

Smartphone-based dual radiometric fluorescence and white-light imager for quantification of protoporphyrin IX in skin.

Significance: The quantification of protoporphyrin IX (PpIX) in skin can be used to study photodynamic therapy (PDT) treatments, understand porphyrin mechanisms, and enhance preoperative mapping of non-melanoma skin cancers. Aim: We aim to develop a smartphone-based imager for performing simultaneous radiometric fluorescence (FL) and white light (WL) imaging to study the baseline levels, accumulation, and photobleaching of PpIX in skin. Approach: A smartphone-based dual FL and WL imager (sDUO) is introduced alongside new radiometric calibration methods for providing SI-units of measurements in both pre-clinical and clinical settings. These radiometric measurements and corresponding PpIX concentration estimations are applied to clinical measurements to understand mechanistic differences between PDT treatments, accumulation differences between normal tissue and actinic keratosis lesions, and the correlation of photosensitizer concentrations to treatment outcomes. Results: The sDUO alongside the developed methods provided radiometric FL measurements (nW/cm2) with a demonstrated sub nanomolar PpIX sensitivity in 1% intralipid phantoms. Patients undergoing PDT treatment of actinic keratosis (AK) lesions were imaged, capturing the increase and subsequent decrease in FL associated with the incubation and irradiation timepoints of lamp-based PDT. Furthermore, the clinical measurements showed mechanistic differences in new daylight-based treatment modalities alongside the selective accumulation of PpIX within AK lesions. The use of the radiometric calibration enabled the reporting of detected PpIX FL in units of nW/cm2 with the use of liquid phantom measurements allowing for the estimation of in-vivo molar concentrations of skin PpIX. Conclusions: The phantom, pre-clinical, and clinical measurements demonstrated the capability of the sDUO to provide quantitative measurements of PpIX FL. The results demonstrate the use of the sDUO for the quantification of PpIX accumulation and photobleaching in a clinical setting, with implications for improving the diagnosis and treatment of various skin conditions.

What are the experiences of supportive care in people affected by brain cancer and their informal caregivers: A qualitative systematic review.

PURPOSE: To critically synthesise qualitative research to understand experiences of supportive care in people affected by brain cancer and their informal caregivers. METHODS: A qualitative systematic review was conducted according to the Joanna Briggs methodology and has been reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Guidelines. Electronic databases were searched by an expert systematic review librarian for all qualitative studies irrespective of research design. All publications were double screened by two reviewers using a pre-determined exclusion and inclusion criteria. The review was managed using Covidence systematic review software. Methodological quality assessment and data extraction were performed. Qualitative findings accompanied by illustrative quotes from included studies were extracted and grouped into categories, which created the overall synthesised findings. RESULTS: A total of 33 studies were included which represented a total sample of 671 participants inclusive of 303 patients and 368 informal caregivers. There was a total of 220 individual findings included in this review, which were synthesised into two findings (1) caregivers and patients perceived supports which would have been helpful and (2) caregiver and patient experiences of unmet supportive care needs. CONCLUSION: This review highlighted the suffering and distress caused by brain cancer and associated treatments. Both patients and their informal caregivers experienced disconnect from themselves in renegotiating roles, and a profound sense of loneliness as the physical deterioration of the disease progressed. Both patients and informal caregivers reported similar unmet needs within the current service provision for brain cancer. However, what is apparent is that current cancer services are provided solely for patients, with little or no consideration to the support needs of both the patient and their informal caregiver. Service re-design is needed to improve care coordination with individualised informational support, implementation of holistic needs assessments for both the patients and their caregivers, better community support provision, improved opportunities for emotional care with early referral for palliative care services. IMPLICATIONS FOR CANCER SURVIVORS: It is recommended that members of the multidisciplinary brain cancer team reflect on these findings to target holistic needs assessments and develop shared self-management care plans for both the patient and the informal caregiver.

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.

Effective fluence and dose at skin depth of daylight and lamp sources for PpIX-based photodynamic therapy.

SIGNIFICANCE: Skin-based photodynamic therapy (PDT) is used for the clinical treatment of actinic keratosis (AKs) and other skin lesions with continued expansion into the standard of care. Due to the spectral dependency of photosensitizer activation and skin optical fluence, there is a need for more accurate methods to estimate the delivered dose at depth from different PDT light sources and treatment regimens. AIM: Develop radiometric methods for calculating photosensitizer-effective fluence and dose at depth and determine differences between red-lamp, blue-lamp, and daylight-based PDT treatments. METHODS: Radiometric measurements of FDA-approved PDT lamp sources, outdoor daylight, and indoor daylight were performed for clinically relevant AK treatments. The protoporphyrin IX (PpIX) equivalent irradiance, fluence, and dose for each light source were calculated from the PpIX absorption spectrum and a 7-layer skin fluence model. The effective fluence and dose at depth was estimated by combining the spectral attenuation predicted at each wavelength and depth with the source fluence at each wavelength. RESULTS: The red-lamp source had the highest illuminance (112,000 lumen/m2), but lowest PpIX-effective irradiance (9.6 W/m2), and highest effective fluence at depth (10.8 W/m2 at 500 µm). In contrast, the blue light source had the lowest illuminance (2300 lumen/m2), but highest PpIX effective irradiance (37.0 W/m2), and ultimately the lowest effective fluence at depth (0.18 W/cm2 at 500 µm). The daylight source had values of (outdoor | indoor) illuminance of (49,200 | 37,800 lumen/m2), effective irradiance of (19.2 | 10.7 W/m2), and effective fluence of (1.50 | 1.08 W/m2 at 500 µm). The effective fluence and dose at depth facilitated the comparison of treatment regimens, for example, calculating an equivalent dose for a 2 hr indoor daylight treatment and a 10 min red-light treatment for the 300-1000 µm depth range. CONCLUSIONS: The consideration of PpIX-effective fluence at varying depths is necessary to provide adequate comparisons of the delivered dose from PDT light sources. Methods for calculating radiometric fluence and delivered dose at depth were introduced, with open source MATLAB code, to help overcome the limitations of commonly used photometric and irradiance-based reporting.

Validation of an ELISA method for quantification of the major Timothy grass pollen allergen Phl p 5a (BSP090).

Progress towards standardisation of allergen products has been made in recent years. Nevertheless, no standardised test method to quantify the allergen content of grass pollen allergen products is available at present. One aim of the BSP090 project was to validate a quantitative assay for a major Timothy grass (Phleum pratense) pollen allergen, Phl p 5. Qualification of a candidate ELISA system was performed with regard to range, robustness and cross-reactivity in preliminary studies. The assay specifically detected Phl p 5 with a quantification range from 3.9 ng/mL to 62.5 ng/mL. Suitability to quantify recombinant and natural Phl p 5 was further assessed in a collaborative study including 14 laboratories in Europe and the USA. Precision and accuracy of the assay was satisfactory with 93% of calculated Phl p 5 concentrations and 100% of total recoveries being within the ± 30% acceptance range. Similar results were obtained for spike recoveries, with exclusion of the lowest concentration spike, showing spike recoveries exceeding the acceptance range for six laboratories. Inter-assay (repeatability) and inter-laboratory (reproducibility) variability were satisfactory, in the format used in the present study. Robustness towards different statistical methods for data analysis was demonstrated. In conclusion, the assay can easily be established in routine testing and results of the preliminary testing and collaborative study support the proposal of the assessed Phl p 5-specific ELISA as a European Pharmacopoeia general method.

Cholesterol crystals and atherosclerotic plaque instability: Therapeutic potential of Eicosapentaenoic acid.

Atherosclerotic plaques associated with acute coronary syndromes (ACS), i.e. culprit lesions, frequently feature a ruptured fibrous cap with thrombotic complications. On imaging, these plaques exhibit a low attenuation, lipid-rich, necrotic core containing cholesterol crystals and are inherently unstable. Indeed, cholesterol crystals are causally associated with plaque vulnerability in vivo; their formation results from spontaneous self-assembly of cholesterol molecules. Cholesterol homeostasis is a central determinant of the physicochemical conditions leading to crystal formation, which are favored by elevated membrane free cholesterol content in plaque endothelial cells, smooth muscle cells, monocyte-derived macrophages, and foam cells, and equally by lipid oxidation. Emerging evidence from imaging trials in patients with coronary heart disease has highlighted the impact of intervention involving the omega-3 fatty acid, eicosapentaenoic acid (EPA), on vulnerable, low attenuation atherosclerotic plaques. Thus, EPA decreased features associated with unstable plaque by increasing fibrous cap thickness in statin-treated patients, by reducing lipid volume and equally attenuating intraplaque inflammation. Importantly, atherosclerotic plaques rapidly incorporate EPA; indeed, a high content of EPA in plaque tissue is associated with decreased plaque inflammation and increased stability. These findings are entirely consistent with the major reduction seen in cardiovascular events in the REDUCE-IT trial, in which high dose EPA was administered as its esterified precursor, icosapent ethyl (IPE); moreover, clinical benefit was proportional to circulating EPA levels. Eicosapentaenoic acid is efficiently incorporated into phospholipids, where it modulates cholesterol-enriched domains in cell membranes through physicochemical lipid interactions and changes in rates of lipid oxidation. Indeed, biophysical analyses indicate that EPA exists in an extended conformation in membranes, thereby enhancing normal cholesterol distribution while reducing propagation of free radicals. Such effects mitigate cholesterol aggregation and crystal formation. In addition to its favorable effect on cholesterol domain structure, EPA/IPE exerts pleiotropic actions, including antithrombotic, antiplatelet, anti-inflammatory, and proresolving effects, whose plaque-stabilizing potential cannot be excluded. Docosahexaenoic acid is distinguished from EPA by a higher degree of unsaturation and longer carbon chain length; DHA is thus predisposed to changes in its conformation with ensuing increase in membrane lipid fluidity and promotion of cholesterol aggregation into discrete domains. Such distinct molecular effects between EPA and DHA are pronounced under conditions of high cellular cholesterol content and oxidative stress. This review will focus on the formation and role of cholesterol monohydrate crystals in destabilizing atherosclerotic plaques, and on the potential of EPA as a therapeutic agent to attenuate the formation of deleterious cholesterol membrane domains and of cholesterol crystals. Such a therapeutic approach may translate to enhanced plaque stability and ultimately to reduction in cardiovascular risk.

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.

Reducing residual cardiovascular risk in Europe: Therapeutic implications of European medicines agency approval of icosapent ethyl/eicosapentaenoic acid.

Atherosclerotic cardiovascular disease (ASCVD) and its atherothrombotic complications impose a substantial disease burden in Europe, representing a cost of €210 billion per year for the European Union. Hypertriglyceridemia, a major risk factor for premature ASCVD, is present in more than 20% of the European population, and is a key feature of atherogenic dyslipidemia. Recent findings from the Progression of Early Subclinical Atherosclerosis (PESA) cohort in Spain showed that even in apparently healthy, middle-aged individuals without a history of cardiovascular (CV) risk, elevated triglyceride levels are associated with subclinical atherosclerosis and arterial inflammation. Emerging evidence from epidemiologic and genetic studies supports an independent causative role of triglycerides, triglyceride-rich lipoproteins, and their remnants in this pathology. Icosapent ethyl (IPE) is a highly purified, stable ethyl ester of eicosapentaenoic acid (EPA) that was initially approved by the United States Food and Drug Administration to treat severe hypertriglyceridemia, and subsequently received an expanded indication to reduce the risk of CV events in adult statin-treated patients. Approval was based on the pivotal, randomized, placebo-controlled, double-blind Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), which showed that high-dose IPE (4 g/day) significantly reduced the risk of primary and secondary composite endpoints comprising major CV events and CV death relative to placebo. In 2021, the European Medicines Agency (EMA) approved IPE to reduce the risk of CV events in adult statin-treated patients at high CV risk with elevated triglyceride levels (≥1.7 mmol/L [≥150 mg/dL]) and established CV disease, or diabetes and at least one other CV risk factor. Clinical studies in Europe, which included patients with acute myocardial infarction, coronary artery disease, and those undergoing cardiac rehabilitation, established that 12.5% to 23.3% of these high-risk populations may benefit from treatment with IPE. Such clinical benefit may in part result from the moderate triglyceride-lowering properties of IPE/EPA; equally however, concentrations of atherogenic remnant particle-cholesterol are markedly reduced. Furthermore, IPE/EPA exerts pleiotropic actions beyond its lipid-lowering properties, which include modulation of endothelial function, attenuation of intra-plaque inflammation and oxidative stress, and reduction in macrophage accumulation. Plasma phospholipids, into which EPA is primarily incorporated and transported, appear to serve as precursors for a series of anti-inflammatory metabolites involving the resolvins RvE1 to RvE3, a pathway which may confer cardioprotective benefits. In addition, plaque imaging data from the Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy (EVAPORATE) and the Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography (CHERRY) trials show that plaque stabilization may be favorably affected. These factors may act synergistically to stabilize atherosclerotic plaques and reduce CV risk. In addition to robust efficacy data, multiple cost-utility studies across several countries indicate that IPE/EPA is a cost-effective treatment option that is favorably situated relative to some common willingness-to-pay thresholds. This review will evaluate the relevance of hypertriglyceridemia to residual ASCVD burden in statin-treated dyslipidemic patients, the potential of IPE/EPA to reduce the risk of ASCVD and cardiovascular mortality in high-risk patient populations, and the mechanisms which may underlie these effects. Finally, the clinical implications of the EMA label for IPE will be critically appraised in light of the updated 2019 European Society of Cardiology/European Atherosclerosis Society guidelines on the management of dyslipidemia and the recent European Atherosclerosis Society consensus statement on triglyceride-rich lipoproteins and their remnants, together with considerations of its cost-effectiveness across several countries.

HDL functionality in type 1 and type 2 diabetes: new insights.

PURPOSE OF REVIEW: To critically appraise new insights into HDL structure and function in type 1 diabetes (T1DM) and type 2 diabetes (T2DM). RECENT FINDINGS: In young T1DM patients with early renal impairment and a high inflammatory score, both HDL antioxidative activity and endothelial vasodilatory function were impaired, revealing a critical link between HDL dysfunction, subclinical vascular damage, systemic inflammation and end organ damage. HDL may inhibit development of T2DM by attenuating endoplasmic reticulum (ER) stress and apoptotic loss of pancreatic ß-cells, an effect due in part to ABC transporter-mediated efflux of specific oxysterols with downstream activation of the hedghehog signalling receptor, Smoothened. The apoM-sphingosine-1-phosphate complex is critical to HDL antidiabetic activity, encompassing protection against insulin resistance, promotion of insulin secretion, enhanced ß-cell survival and inhibition of hepatic glucose production. Structure-function studies of HDL in hyperglycemic, dyslipidemic T2DM patients revealed both gain and loss of lipidomic and proteomic components. Such changes attenuated both the optimal protective effects of HDL on mitochondrial function and its capacity to inhibit endothelial cell apoptosis. Distinct structural components associated with individual HDL functions. SUMMARY: Extensive evidence indicates that both the proteome and lipidome of HDL are altered in T1DM and T2DM, with impairment of multiple functions.

The reconstruction of invasion histories with genomic data in light of differing levels of anthropogenic transport.

Unravelling the history of range shifts is key for understanding past, current and future species distributions. Anthropogenic transport of species alters natural dispersal patterns and directly affects population connectivity. Studies have suggested that high levels of anthropogenic transport homogenize patterns of genetic differentiation and blur colonization pathways. However, empirical evidence of these effects remains elusive. We compared two range-shifting species (Microcosmus squamiger and Ciona robusta) to examine how anthropogenic transport affects our ability to reconstruct colonization pathways using genomic data. We first investigated shipping networks from the 18th century onwards, cross-referencing these with regions where the species have records to infer how each species has potentially been affected by different levels of anthropogenic transport. We then genotyped thousands of single-nucleotide polymorphisms from 280 M. squamiger and 190 C. robusta individuals collected across their extensive species' ranges and reconstructed colonization pathways. Differing levels of anthropogenic transport did not preclude the elucidation of population structure, though specific inferences of colonization pathways were difficult to discern in some of the considered scenario sets. We conclude that genomic data in combination with information of underlying introduction drivers provide key insights into the historic spread of range-shifting species. This article is part of the theme issue 'Species' ranges in the face of changing environments (part I)'.