Atherosclerosis is a progressive disease causally associated with multiple cardiovascular risk factors, including dyslipidemia. Without effective intervention, atherosclerosis becomes evidenced clinically as coronary artery and cerebrovascular disease, both of which remain the leading causes of death worldwide. Multiple lines of investigation indicate a central role for inflammation in atherosclerotic plaque progression, vulnerability and thrombogenicity. Randomized clinical trials have documented the benefit of lipid-lowering therapy for both primary and secondary prevention of cardiovascular events. Statins, a class of drugs that lower cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, have been shown to slow the progression of the atheroma and the frequency of associated clinical events to an extent that cannot be attributed solely to LDL reduction. The non-LDL or pleiotropic effects of statins are attributed to anti-inflammatory activity, enhanced endothelial function, and inhibition of oxidative stress. In this review, we discuss the role of inflammation in atherogenesis along with the effects of statins in slowing this process through LDL-dependent and -independent mechanisms.
Cholesterol ester-laden macrophage foam cells are a hallmark of atherosclerosis. The cycle of esterification and hydrolysis of cholesterol esters is one of the key steps in macrophage cholesterol trafficking. In the process of foam cell formation, excess free cholesterol undergoes esterification by acyl coenzyme A: acylcholesterol transferase 1 (ACAT-1), and fatty acid sterol esters are stored in cytoplasmic lipid droplets. The actions of ACAT-1 are opposed by neutral cholesterol ester hydrolase (nCEH), which generates free cholesterol and fatty acids. The resulting free cholesterol is a preferential source for cholesterol efflux into the extracellular space. Despite the important role of nCEH in protection against foam cell formation and atherosclerosis, the molecular identity of nCEH has long been debated. Although hormone-sensitive lipase (LIPE) has been proposed to be the nCEH in macrophages, recent evidence suggested the existence of other nCEH(s). We have recently identified a novel nCEH, neutral cholesterol ester hydrolase 1 (NCEH1), and demonstrated that NCEH1, in addition to LIPE, primarily mediates the hydrolysis of CE in macrophages. This review focuses on the protective roles of nCEHs in atherosclerosis, with special emphasis on the role of NCEH1.
Aim: We determined the association of lower-body fat mass (LFM) and trunk fat mass (TFM) with cardiometabolic risk factors and adipokines in young, healthy, slim women. Methods: A total of 481 college female students underwent the following: regional body fat distribution as assessed by dual energy X-ray absorptiometry (DXA), a 75g oral glucose tolerance test (OGTT) and fasting blood sampling for measurement of lipids, lipoproteins, apolipoproteins (apo), liver enzymes and adipokines. Results: After adjusting for TFM, LFM was positively associated with HDL cholesterol, adiponectin, pre-heparin lipoprotein lipase and insulin sensitivity, as estimated by the Matsuda index, whereas it was negatively related to triglycerides, apo B, apo B/A1 ratio, small dense LDL, FFA, glucose and insulin at 2h during OGTT, area under the curve of insulin response during OGTT and the white blood cell count. Participants were divided into 9 groups according to tertiles of TFM and LFM. In the middle tertile of TFM, HDL cholesterol and adiponectin increased and triglycerides, apoB/A1 ratio and plasminogen-activator inhibitor-1 decreased from the low to high LFM tertiles. Gamma-glutamyltransferase levels in middle and high LFM tertiles were lower than in the lower LFM tertile. Conclusion: For a given level of trunk fat mass, a higher lower-body fat mass is associated with an advantageous profile of not only blood lipoproteins but also serum adipokines, even in healthy, slim women in early adulthood.
Aim: Phytosterolemia is an inherited disorder characterized by hypercholesterolemia and premature atherosclerosis, together with increased inflammatory states in some cases. The underlying mechanisms of atherogenesis in phytosterolemia, however, have not been completely elucidated. In this study, we investigated whether phytosterols would affect inflammatory reactions in macrophages and macrophage cell lines. Methods:We incubated RAW264.7 cells (RAW) and mouse peritoneal macrophages (MPMs) with sitosterol (Sito), campesterol (Camp) or cholesterol (Chol) at low (8 µM, 16 µM) or high (160 µM) concentrations, and investigated their effects on LPS-induced secretion of IL-6 and TNF-α. We also analyzed their effects on endoplasmic reticulum (ER) stress in both cells, and on the cell proliferation of RAW. Results: At low sterol concentrations, only Chol resulted in a tendency toward the increased secretion of TNF-α from MPMs. At high concentrations, Chol induced a significant increase in TNF-α secretions from both cells; however, Sito resulted in a non-significant increase in TNF-α secretion. The effects on IL-6 secretions of Sito were also significantly less than those of Chol. Camp increased the secretions of both cytokines from MPMs; however, the extent of these increases was less pronounced than that of Chol. Augmentation of ER stress was greatest with Chol among the sterols, and the proliferation of RAW cells was inhibited only with Chol. Conclusion: The lesser degree of inflammatory reactions and toxicity in macrophages with phytosterols than with cholesterol suggests that plant sterols themselves might not be primarily responsible for atherogenesis in phytosterolemia.
Aim: Although statins have been well documented to induce the regression of thoracic aortic plaques, a similar effect of statins on abdominal aortic plaques has not been observed.We aimed to explore whether a statin in combination with a bisphosphonate was effective in the regression of abdominal aortic plaques, which are more likely to be calcified. Methods: Eighty-seven patients with hypercholesterolemia were assigned to the atorvastatin (ATR)+etidronate (ETD) group (n = 45) or ATR group (n = 42). A total of 98 thoracic and 107 abdominal aortic plaques were detected in the ATR+ETD group, and 86 thoracic and 102 abdominal plaques in the ATR group at baseline, as measured by magnetic resonance imaging (MRI). The primary endpoint was the change of maximal vessel wall thickness (Max-VWT) in atherosclerotic lesions after 1 year, as assessed by MRI. Results: ATR+ETD and ATR groups reduced the low density lipoprotein cholesterol level (−42% and −43%, p < 0.001 vs. baseline for both groups), and Max-VWT in thoracic lesions (−15% and −14%, p < 0.001 vs. baseline for both groups). ATR+ETD group reduced Max-VWT in abdominal lesions (−14%, p < 0.001 vs. baseline), whereas ATR group did not (−1%, p =0.958 vs. baseline). Conclusion: The results suggest that ATR+ETD treatment for 12 months significantly reduces both thoracic and abdominal aortic plaques, while ATR treatment reduces only thoracic aortic plaques.(Clinical trial registry no. UMIN 000003756)
Aims: To examine and evaluate the association between psychological distress and metabolic syndrome (MetS). Methods: Between 2005 and 2006, 1,613 men and women aged 30-79 participated in annual health examinations at Takarazuka City Health Promotion Center in Takarazuka, Japan. Psychological stress was assessed with the General Health Questionnaire (GHQ) and MetS was evaluated using three criteria based on those of the Japanese Society of Internal Medicine as the Japanese counterpart of the third report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Cholesterol in Adults (NCEP/ATPIII) and the International Diabetes Federation (IDF). Results: The mean depression score after adjustment for age, smoking, alcohol intake and serum total cholesterol levels was higher for men with than without MetS as defined by Japanese criteria as well as for men with than without fasting glucose ≥ 110 mg/dL. Multivariable-adjusted, odds ratio associated with increments of one standard deviation in the depression score was 1.48 (1.19-1.84) for MetS, and anxiety and depression scores were 1.32 (1.08-1.61) and 1.24 (1.03-1.50) for fasting glucose ≥ 110 mg/dL, respectively. Similar trends were observed for the depression score and MetS as defined by NCEP/ATPIII and IDF. For women, somatic symptoms, anxiety, and depression were not associated with MetS and its components. Conclusions: Depressive symptoms are considered to be associated with MetS and, more specifically, glucose abnormality among urban Japanese men.
Aim: Bilirubin has antioxidant properties and may protect against atherosclerosis and coronary heart disease (CHD). Further, in patients with metabolic syndrome, hyperbilirubinemia is associated with attenuation of insulin resistance. The aim of the present study was to determine the relationship between serum bilirubin concentration and coronary endothelial function in overweight patients. Methods: The study population consisted of 107 patients without CHD who underwent coronary flow studies. Vascular reactivity was examined by intra-coronary administration of papaverine and nitroglycerin. Coronary endothelial function was evaluated by assessing the change in coronary artery diameter to papaverine [percent change in flow-mediated dilatation (%FMD)] and nitroglycerin (%NTG). Serum total bilirubin, high-sensitivity C-reactive protein (hs-CRP), high density lipoprotein-cholesterol (HDL-C), fasting plasma glucose and immunoreactive insulin levels were also measured, and the homeostasis model assessment insulin resistance (HOMA-IR) index was calculated. Patients were divided into two groups according to body mass index (BMI): an overweight group (BMI ≥ 25; n = 36) and a normal weight group (BMI < 25; n = 71). Results: In the overweight group, univariate analysis revealed that log-transformed total bilirubin was positively correlated with %FMD and HDL-C (r = 0.38, p< 0.05; r = 0.30, p < 0.05, respectively) and was inversely correlated with log-transformed hs-CRP and HOMA-IR (r = −0.45, p < 0.01; r = −0.45, p< 0.05, respectively). Multivariate analysis revealed that log-transformed hs-CRP was the only independent predictor of log-transformed total bilirubin (p< 0.05). Conclusions: These results suggest that a high bilirubin level was associated with favorable coronary endothelial function in overweight patients. Further, the anti-inflammatory effects of bilirubin may mediate this effect.
Aims: The single nucleotide polymorphism (SNP) rs11066001 of BRAP has been shown to be associated with myocardial infarction (MI), coronary atherosclerosis and carotid atherosclerosis, but it is not clear whether it also plays a role in peripheral artery disease (PAD). The ankle-brachial index (ABI) is often used as a non-invasive measure of PAD; therefore, the aim of this study was to test for a relationship between the SNP rs11066001 and ABI. Methods: A total of 537 high-risk subjects with a family history of MI or stroke completed a health survey, including a physical examination, blood test and measurement of ABI. Among them, 523 subjects had the genotypes. Association analyses between the genotype of BRAP and ABI were performed by multiple linear and logistic regressions with adjustment for covariates. Results: We found that the GG genotype is significantly associated with a lower ABI value. For the lowest ABI tertile, the GG genotype had an OR of 2.87 (p =0.018) when compared with the middle ABI tertile, and OR of 2.92 (p =0.015) when compared to the highest ABI tertile. Women with the GG genotype had a lower ABI value than men with the same genotype (p =0.012). Accordingly, women carrying this GG risk genotype may have a higher risk for PAD. Conclusion: Our findings provide additional evidence that support the genetic effect of BRAP on diverse cardiovascular phenotypes.
A 65-year-old man with rheumatic combined valvular heart disease showed a persistent fever after cardiac catheterization. He was diagnosed with cholesterol embolism due to multiple mobile plaques in the descending thoracic aorta by transesophageal echocardiography (TEE) along with persistent eosinophilia, deteriorating renal function, and blue toe sign. He was treated with intensive cholesterol-lowering therapy for 3 years, resulting in marked regression of the aortic plaque on TEE.
We report the case of an 82-year-old Sardinian woman affected by “favism” (i.e. intolerance to fava beans) with chest pain associated with persistent massive ST elevation in V2-V6 leads, admitted to our department after transfer from a rural hospital without catheterization facilities. On immediate transfer to the catheterization laboratory for primary percutaneous intervention (PCI), coronary angiogram showed proximal left anterior descending (LAD) thrombotic occlusion. In consideration of her history of glucose-6 phosphate dehydrogenase deficiency and “loss of consciousness” at a young age after taking aspirin, which contraindicated aspirin therapy, we treated this patient using a new, two-step strategy, with an emergency minimalist intervention using manual thrombectomy and intracoronary glycoprotein IIb/IIIa (GPIIbIIIa) inhibition with abciximab. Subsequent angiography control confirmed the persistence of Thrombolysis in Myocardial Infarction Trial (TIMI) grade 3 flow and the presence of an intermediate proximal LAD coronary lesion, which was not treated, also due to the persisting contraindication to aspirin. In our opinion, minimalist intervention with a thrombectomy device (especially in patients characterized by a high intracoronary thrombus burden) and/or with the use of a small balloon or gentle dilation, sustained by maximized antithrombotic therapy may represent an interesting and rational approach, allowing interventionalists to postpone stenting in the setting of primary PCI in special cases.