Atherosclerosis plus最新文献

Background

Cognitive function has an important role in determining the quality of life of older adults. Cardiovascular disease (CVD) is common in older people and may compromise cognitive performance; however, the extent to which this is related to carotid atherosclerosis is unclear.

Aim

We investigated associations between carotid atherosclerosis and cognitive function and neuroimaging markers of brain health in a UK multi-ethnic community-based sample including older people of European, South Asian, and African-Caribbean ethnicity.

Methods

Carotid plaques and intima-media thickness (cIMT) were assessed using ultrasound in 985 people (mean age 73.2y, 56 % male). Associations of carotid atherosclerosis with cognitive function (memory, executive function, language and CSI-D, a global measure of cognitive state) and neuroimaging measures (total brain volume, hippocampal volume, white matter (WM) lesion volume and coalescence score) were analysed using regression analyses, with and without adjustment for potential confounders using two models: 1) adjustment for age, sex, and ethnicity; 2) model 1 plus education, physical activity category, body mass index, hypertension, diabetes, total and high density lipoprotein cholesterol, atrial fibrillation, smoking, previous CVD, alcohol consumption, and presence of chronic kidney disease.

Results

People with carotid plaque or higher cIMT had lower CSI-D score, poorer memory poorer executive function and higher WM lesion volume and coalescence. Language was poorer in people with plaque but was not correlated with cIMT. Associations with plaque were preserved after full adjustment (model 2) but relationships for cIMT were attenuated. Associations with other plaque characteristics were generally unconvincing after adjustment.

Conclusions

This multi-ethnic cohort study provides evidence that presence of carotid plaque, is associated with poorer cognitive function and brain health.

Background and aims

Statin-associated muscle symptoms (SAMS) is a prevalent cause of statin discontinuation. It is challenging and time-consuming for clinicians to assess whether symptoms are caused by the statin or not, and diagnostic biomarkers are requested. Atorvastatin metabolites have been associated with SAMS. We aimed to compare atorvastatin pharmacokinetics between coronary heart disease (CHD) patients with and without clinically statin intolerance and statin-dependent histopathological alterations in muscle tissue. Secondarily we aimed to assess genetic variants relevant for the observed pharmacokinetic variables.

Methods

Twenty-eight patients with CHD and subjective SAMS were included in the exploratory MUSE biomarker study in 2020. Participants received atorvastatin 40 mg/day for seven weeks followed by no statins for eight weeks. Muscle biopsies and blood were collected at the end of each period. Four patients were categorized as clinically intolerant to ≥3 statins prior to study start whereas four patients had signs of muscle cell damage during treatment.

Results

We found significantly lower levels of atorvastatin acids, and higher lactone/acid ratios in the statin intolerant, both in muscle and plasma. With optimal cut-off, the combination of 2-OH-atorvastatin acid and the 2-OH-atorvastatin lactone/acid ratio provided sensitivity, specificity, and predictive values of 100 %. Patients with variants in UGT1A1 and UGT1A3 had higher lactone metabolite levels than those with wild type, both in muscle and plasma.

Conclusion

Atorvastatin metabolites appear promising as biomarkers for the identification of clinical statin intolerance in patients with self-perceived SAMS, but the findings have to be confirmed in larger studies.

Background and aims

C–C motif chemokine ligand 2 (CCL2) is a pro-inflammatory chemokine important for monocyte recruitment to the arterial wall and atherosclerotic plaques. Global knockout of Ccl2 reduces plaque formation and macrophage content in mice, but the importance of different plaque cell types in mediating this effect has not been resolved. Smooth muscle cells (SMCs) can adopt a potentially pro-inflammatory function with expression of CCL2. The present study aimed to test the hypothesis that SMC-secreted CCL2 is involved in early atherogenesis in mice.

Methods

SMC-restricted Cre recombinase was activated at 6 weeks of age in mice with homozygous floxed or wildtype Ccl2 alleles. Separate experiments in mice lacking the Cre recombinase transgene were conducted to control for genetic background effects. Hypercholesterolemia and atherosclerosis were induced by a tail vein injection of recombinant adeno-associated virus (rAAV) encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and a high-fat diet for 12 weeks.

Results

Unexpectedly, mice with SMC-specific Ccl2 deletion developed higher levels of plasma cholesterol and larger atherosclerotic plaques with more macrophages compared with wild-type littermates. When total cholesterol levels were incorporated into the statistical analysis, none of the effects on plaque development between groups remained significant. Importantly, changes in plasma cholesterol and atherosclerosis remained in mice lacking Cre recombinase indicating that they were not caused by SMC-specific CCL2 deletion but by effects of the floxed allele or passenger genes.

Conclusions

SMC-specific deficiency of Ccl2 does not significantly affect early plaque development in hypercholesterolemic mice.

Background and aims

– Pseudoxanthoma elasticum (PXE) is a rare genetic disease caused by pathogenic mutations in the ABCC6 gene, resulting in low values of inorganic pyrophosphate (PPi). While low PPi is thought to contribute to arterial calcification, it remains unclear whether this fully explains premature calcification in PXE. It has been hypothesized that the ABCC6 gene could be related to dyslipidemia, which could contribute to vascular calcification seen in PXE. The aim of this study is to evaluate the relation between PXE and plasma lipid concentrations in a large cohort of PXE patients compared with reference values for the general population and compared with non-PXE controls.

Methods

– The plasma concentrations of total cholesterol, HDL-cholesterol, tiglycerides, and LDL-cholesterol of 312 PXE patients were compared to age- and sex-matched modeled data of the general Dutch population. Differences in median lipid levels were compared with Mann-Whitney-U test. Secondly, plasma lipid concentrations of 44 PXE patients were compared to 44 not-genetically related relatives (spouses or friends), with linear models adjusted for age, sex and BMI.

Results

– Total cholesterol in PXE patients was 5.6 [IQR 4.6–6.4] mmol/L versus 5.3 [IQR 4.7–6.0] mmol/L (p < 0.01) in the general population; triglycerides were 1.1 [IQR 0.9–1.7] mmol/L versus 1.0 [0.7–1.4] mmol/L (p < 0.01); HDL-c was 1.4 [IQR 1.2–1.7] mmol/L versus 1.5 [IQR 1.2–1.8] mmol/L (p = 0.03) and LDL-c was 3.3 [IQR 2.7–4.1] mmol/L versus 3.2 [IQR 2.7–3.8] mmol/L (p = 0.01). In the patient control analysis with 44 pairs and age, sex and BMI adjusted, comparison with the non-PXE controls only triglycerides were significantly different (mean difference: 0.38 (0.13–0.63)).

Conclusion

–The lipid profiles of PXE patients are marginally different from the general population or compared to a matched control group, but the differences are unlikely to be clinically relevant. It is therefore unlikely that plasma lipids contribute to the premature vascular calcifications in PXE patients.

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.

Familial hypercholesterolemia (FH) is one of the most common genetically inherited disorders in the world. Children with severe heterozygous FH (HeFH), i.e. untreated low-density lipoprotein cholesterol (LDL-C) levels above the 90th percentile for age and sex among FH mutation carriers, can have LDL-C levels that overlap levels of children with homozygous FH (HoFH), but treatment regimen and cardiovascular follow-up to prevent cardiovascular disease are less intensive in children with severe HeFH. In children with HoFH, subclinical atherosclerosis can already be present using computed tomography coronary angiography (CTCA). The question remains whether this is also the case in children with severe HeFH who have a high exposure to elevated LDL-C levels from birth onwards as well. We calculated the cumulative LDL-C exposure (CE_total [mmol]) in four children with severe HeFH and performed computed tomography coronary angiography (CTCA). These children, aged 13, 14, 15 and 18 years, had CE_total of 71.3, 97.8, 103.6 and 136.1 mmol, respectively. None of them showed abnormalities on cardiovascular imaging, despite high LDL-C exposure. The results of this study, do not give us an indication to recommend performing CTCA routinely in children with severe HeFH.