Women, lipids, and atherosclerotic cardiovascular disease:a call to action from the European Atherosclerosis Society

Cardiovascular disease is the leading cause of death in women and men globally, with most due to atherosclerotic cardiovascular disease (ASCVD). Despite progress during the last 30 years, ASCVD mortality is now increasing, with the fastest relative increase in middle-aged women. Missed or delayed diagnosis and undertreatment do not fully explain this burden of disease. Sex-specific factors, such as hypertensive disorders of pregnancy, premature menopause (especially primary ovarian insufficiency), and polycystic ovary syndrome are also relevant, with good evidence that these are associated with greater cardiovascular risk. This position statement from the European Atherosclerosis Society focuses on these factors, as well as sex-specific effects on lipids, including lipoprotein(a), over the life course in women which impact ASCVD risk. Women are also disproportionately impacted (in relative terms) by diabetes, chronic kidney disease, and auto-immune inflammatory disease. All these effects are compounded by sociocultural components related to gender. This panel stresses the need to identify and treat modifiable cardiovascular risk factors earlier in women, especially for those at risk due to sex-specific conditions, to reduce the unacceptably high burden of ASCVD in women

Lipoprotein (a) concentration is associated with plasma arachidonic acid in subjects with familial hypercholesterolemia

Elevated lipoprotein (a) (Lp[a]) is associated with cardiovascular disease (CVD) and is mainly genetically determined. Studies suggest a role of dietary fatty acids (FAs) in the regulation of Lp(a), however, no studies have investigated the association between plasma Lp(a) concentration and omega-6 FAs. We aimed to investigate whether plasma Lp(a) concentration was associated with dietary omega-6 FA intake, and plasma levels of arachidonic acid in subjects with familial hypercholesterolemia (FH). We included FH subjects with (n=68) and without (n=77) elevated Lp(a) defined as ≥75 nmol/L, and healthy subjects (n=14). Total fatty acid profile was analyzed by Gas Chromatography-Flame Ionization Detector analysis, and the daily intake of macronutrients (including the sum of omega-6 FAs: 18:2n-6, 20:2n-6, 20:3n-6 and 20:4n-6) were computed from completed food frequency questionnaires. FH subjects with elevated Lp(a) had higher plasma levels of arachidonic acid (AA) compared to FH subjects without elevated Lp(a) (P=0.03). Furthermore, both FH subjects with and without elevated Lp(a) had higher plasma levels of AA compared to controls (P<0.001). The multivariable analyses showed associations between dietary omega-6 FA intake and plasma levels of AA (P=0.02), and between plasma levels of Lp(a) and AA (P=0.006). Our data suggest a novel link between plasma Lp(a) concentration, dietary omega-6 FAs and plasma AA concentration, which may contribute to explain the small diet-induced increase in Lp(a) levels associated with lifestyle changes. Although the increase may not be clinically relevant, this association may be mechanistically interesting in understanding more of the role and regulation of Lp(a)

Comparison of the characteristics at diagnosis and treatment of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries

Background and aims: For children with heterozygous familial hypercholesterolaemia (HeFH), European guidelines recommend consideration of statin therapy by age 8–10 years for those with a low density lipoprotein cholesterol (LDL-C) >3.5 mmol/l, and dietary and lifestyle advice. Here we compare the characteristics and lipid levels in HeFH children from Norway, UK, Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Methods: Fully-anonymized data were analysed at the London centre. Differences in registration and on treatment characteristics were compared by standard statistical tests. Results: Data was obtained from 3064 children. The median age at diagnosis differed significantly between countries (range 3–11 years) reflecting differences in diagnostic strategies. Mean (SD) LDL-C at diagnosis was 5.70 (±1.4) mmol/l, with 88% having LDL-C>4.0 mmol/l. The proportion of children older than 10 years at follow-up who were receiving statins varied significantly (99% in Greece, 56% in UK), as did the proportion taking Ezetimibe (0% in UK, 78% in Greece). Overall, treatment reduced LDL-C by between 28 and 57%, however, in those >10 years, 23% of on-treatment children still had LDL-C>3.5 mmol/l and 66% of those not on a statin had LDL-C>3.5 mmol/l. Conclusions: The age of HeFH diagnosis in children varies significantly across 8 countries, as does the proportion of those >10 years being treated with statin and/or ezetimibe. Approximately a quarter of the treated children and almost three quarters of the untreated children older than 10 years still have LDL-C concentrations over 3.5 mmol/l. These data suggest that many children with FH are not receiving the full potential benefit of early identification and appropriate lipid-lowering treatment according to recommendations

Comparison of the characteristics at diagnosis and treatment of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries

Background and aims: For children with heterozygous familial hypercholesterolaemia (HeFH), European guidelines recommend consideration of statin therapy by age 8–10 years for those with a low density lipoprotein cholesterol (LDL-C) &gt;3.5 mmol/l, and dietary and lifestyle advice. Here we compare the characteristics and lipid levels in HeFH children from Norway, UK, Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Methods: Fully-anonymized data were analysed at the London centre. Differences in registration and on treatment characteristics were compared by standard statistical tests. Results: Data was obtained from 3064 children. The median age at diagnosis differed significantly between countries (range 3–11 years) reflecting differences in diagnostic strategies. Mean (SD) LDL-C at diagnosis was 5.70 (±1.4) mmol/l, with 88% having LDL-C&gt;4.0 mmol/l. The proportion of children older than 10 years at follow-up who were receiving statins varied significantly (99% in Greece, 56% in UK), as did the proportion taking Ezetimibe (0% in UK, 78% in Greece). Overall, treatment reduced LDL-C by between 28 and 57%, however, in those &gt;10 years, 23% of on-treatment children still had LDL-C&gt;3.5 mmol/l and 66% of those not on a statin had LDL-C&gt;3.5 mmol/l. Conclusions: The age of HeFH diagnosis in children varies significantly across 8 countries, as does the proportion of those &gt;10 years being treated with statin and/or ezetimibe. Approximately a quarter of the treated children and almost three quarters of the untreated children older than 10 years still have LDL-C concentrations over 3.5 mmol/l. These data suggest that many children with FH are not receiving the full potential benefit of early identification and appropriate lipid-lowering treatment according to recommendations. © 2019 The Author

Tracking insulin secretion and sensitivity in children who subsequently develop diabetes:a seven year study

In the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) trial, the benefits of adding nifedipine GITS to the treatment of patients with stable symptomatic coronary artery disease were particularly apparent in those with concomitant hypertension. This further analysis has assessed whether or not the addition of nifedipine GITS is particularly beneficial in the treatment of patients with the combination of diabetes mellitus and chronic stable angina

Comparison of the mutation spectrum and association with pre and post treatment lipid measures of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries

Background and aims: Familial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Methods: Differences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests. Results: Data were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p &amp;lt; 2.2 × 10−16). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p=0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p &amp;lt; 2.2 × 10−16) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l). Conclusions: The most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR-FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB-FH. © 2021 Elsevier B.V

Article T cells with increased responsiveness cause obesity in mice without diet intervention

Obesity is a complex multicausal disease that can cause morbidity and mortality, and there is need for improved knowledge on the underlying mechanisms. Using a mouse model of increased T cell responsiveness, we show that development of obesity can be driven by immune cells. This was confirmed with bone marrow transplantation and adoptive T cell transfer to several recipient mouse models. Single-cell RNA sequencing and CyTOF analysis showed that the mice display altered composition of circulating T cells and increased T cell activation in visceral adipose tissue, suggesting activated T cells as critical players in the increased fat mass. In this study, we provide evidence that obesity can be driven by immune cell activity and in particular by T cells, which could have broad implications for prevention and treatment of this condition.Metabolic health: pathophysiological trajectories and therap

The hCOMET project: International database comparison of results with the comet assay in human biomonitoring. Baseline frequency of DNA damage and effect of main confounders

The alkaline comet assay, or single cell gel electrophoresis, is one of the most popular methods for assessing DNA damage in human population. One of the open issues concerning this assay is the identification of those factors that can explain the large inter-individual and inter-laboratory variation. International collaborative initiatives such as the hCOMET project a COST Action launched in 2016 represent a valuable tool to meet this challenge. The aims of hCOMET were to establish reference values for the level of DNA damage in humans, to investigate the effect of host factors, lifestyle and exposure to genotoxic agents, and to compare different sources of assay variability. A database of 19,320 subjects was generated, pooling data from 105 studies run by 44 laboratories in 26 countries between 1999 and 2019. A mixed random effect log-linear model, in parallel with a classic meta-analysis, was applied to take into account the extensive heterogeneity of data, due to descriptor, specimen and protocol variability. As a result of this analysis interquartile intervals of DNA strand breaks (which includes alkali-labile sites) were reported for tail intensity, tail length, and tail moment (comet assay descriptors). A small variation by age was reported in some datasets, suggesting higher DNA damage in oldest age-classes, while no effect could be shown for sex or smoking habit, although the lack of data on heavy smokers has still to be considered. Finally, highly significant differences in DNA damage were found for most exposures investigated in specific studies. In conclusion, these data, which confirm that DNA damage measured by the comet assay is an excellent biomarker of exposure in several conditions, may contribute to improving the quality of study design and to the standardization of results of the comet assay in human populations.(c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

Background and aims: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. Methods: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. Results: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ∼2/3 countries. Lipoprotein-apheresis is offered in ∼60% countries, although access is limited. Conclusions: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed. © 2018 Elsevier B.V