Inflammation with macrophage infiltration is a key feature of atherosclerosis. Although the mechanisms had been unclear, emerging evidence unveiled that NLRP3 inflammasomes, which regulate caspase-1 activation and subsequent processing of pro-IL-1β, trigger vascular wall inflammatory responses and lead to progression of atherosclerosis. NLRP3 inflammasomes are activated by various danger signals, such as cholesterol crystals, calcium phosphate crystals, and oxidized low-density lipoprotein in macrophages, to initiate inflammatory responses in the atherosclerotic lesion. Recent studies have further clarified the regulatory mechanisms and the potential therapeutic agents that target NLRP3 inflammasomes. In this study, we reviewed the present state of knowledge on the role of NLRP3 inflammasomes in the pathogenesis of atherosclerosis and discussed the therapeutic approaches that target NLRP3 inflammasomes.
We have learned that low-density lipoprotein (LDL) cholesterol is the cause of atherosclerosis from various aspects, including a single case with familial hypercholesterolemia, other cases with different types of Mendelian dyslipidemias, large-scale randomized controlled trials using LDL cholesterol lowering therapies, and Mendelian randomization studies using common as well as rare variants associated with LDL cholesterol levels. There is no doubt that determinations of genotypes in lipid-associated genes have contributed not only to the genetic diagnosis for Mendelian dyslipidemias but also to the discoveries of novel therapeutic targets. Furthermore, recent studies have shown that such genetic information could provide useful clues for the risk prediction as well as risk stratification in general and in particular population. We provide the current understanding of genetic analyses relating to plasma lipids and coronary artery disease.
Even though it is only a little over a decade from the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a plasma protein that associates with both high and low cholesterol syndromes, a rich body of knowledge has developed, and drugs inhibiting this target have been approved in many markets. While the majority of research in recent years has focused on the impact of therapeutic antagonism of this molecule, important lines of investigation have emerged characterizing its unique physiology as it relates to cholesterol metabolism and atherosclerosis. The PCSK9 story is unfolding rapidly but is far from complete. One chapter that is of particular interest is the possible direct link between PCSK9 and atherosclerosis. This review specifically examines this relationship drawing from data produced from experimental models of plaque biology and inflammation, atherosclerosis imaging studies, and observational epidemiology.
Aim: To investigate the relationship between intravascular ultrasound (IVUS) findings and restenosis after stent implantation for long occlusive femoropopliteal (FP) lesions using the intraluminal approach.
Methods: This was a single-center retrospective study of 45 patients (49 lesions) with de novo long occlusive FP lesions treated with bare metal stents implanted using the intraluminal approach under IVUS guidance from April 2007 to December 2014. All patients were followed up at least 12 months. The preprocedural and postprocedural IVUS findings were compared for patients with and without restenosis, which was defined as a peak systolic velocity ratio of ＞2.4 on duplex ultrasonography or ＞50% diameter stenosis on angiography.
Results: Within 12 months, 13 patients (14 lesions) developed restenosis, whereas 32 patients (35 lesions) did not (restenosis rate=29%). The male: female ratio and the prevalence of diabetes mellitus, hemodialysis, and critical limb ischemia were similar between the two groups. No significant differences were observed in lesion length, chronic total occlusion (CTO) length, and the percentage of involving popliteal lesion between the two groups. A whole intraplaque route was gained in 15 lesions (31%). Multivariate analysis revealed that the within-CTO intramedial route proportion and the distal lumen cross-sectional area (CSA) were independent predictors of restenosis. Receiver operating characteristic analysis showed that the best cutoff values of these parameters were 14.4% and 17.7 mm2, respectively.
Conclusions: In patients with long occlusive FP lesions undergoing stent placement using the intraluminal approach, a whole intraplaque route was gained in 31%. Restenosis is more likely if IVUS shows a within-CTO intramedial route proportion of ＞14.4% or distal lumen CSA of ＜17.7 mm2.
Aims: Previous studies have shown that aortic valve calcification (AVC) was associated with cardiovascular events and mortality. On the other hand, periprocedural myocardial injury (PMI) in percutaneous coronary intervention (PCI) is a well-known predictor of subsequent mortality and poor clinical outcomes. The purpose of the study was to assess the hypothesis that the presence of AVC could predict PMI in PCI.
Methods: This study included 370 patients treated with PCI for stable angina pectoris. AVC was defined as bright echoes ＞1 mm on one or more cusps of the aortic valve on ultrasound cardiography (UCG). PMI was defined as an increase in high-sensitivity troponin T level of ＞5 times the upper normal limit (＞0.070 ng/ml) at 24 hours after PCI.
Results: AVC was detected in 45.9% of the patients (n=170). The incidence of PMI was significantly higher in the patients with AVC than in those without AVC (43.5% vs 21.0%, p＜0.001). The presence of AVC independently predicted PMI after adjusting for other significant variables (odds ratio 2.26, 95% confidence interval 1.37–3.74, p=0.002). Other predictors were male sex, age, estimated glomerular filtration rate, and total stent length. Furthermore to predict PMI, adding AVC to the established risk factors significantly improved the area under the receiver operating characteristic curves, from 0.68 to 0.72, of the PMI prediction model (p=0.025).
Conclusion: The presence of AVC detected in UCG could predict the incidence of PMI.
Aim: A positive association between metabolic syndrome (MetS) and periodontal status has recently been noted. However, no study has evaluated the relationship by sex and in a general urban population using the uniform definition proposed in the 2009 Joint Interim Statement. The aim of this study was to clarify the relationship between MetS and periodontal status using the uniform definition in a general urban Japanese population.
Methods: A total of 1,856 Japanese men and women (mean age: 66.4 years) were studied using data from the Suita study. Periodontal status was evaluated by the Community Periodontal Index (CPI). MetS was defined using the 2009 Joint Interim Statement. The associations of the MetS and its components with periodontal disease were investigated using multiple logistic regression analysis adjusting for age, drinking, and smoking.
Results: Among the components of the MetS, low HDL cholesterol level was significantly associated with periodontal disease in men and women [odds ratios (OR)=2.39 and 1.53; 95% confidence intervals=1.36–4.19 and 1.06–2.19]. Furthermore, the risk of periodontal disease showed 1.43-, 1.42-, and 1.89-fold increases in those with 2, 3, and ≥4 components, respectively, compared with those having no components (Ptrend ＜0.001). For the analysis by sex, the risk of periodontal disease was increased 2.27- and 1.76-fold in those with ≥4 components in men and women, respectively (both Ptrend=0.001).
Conclusion: These findings suggest that MetS and lower HDL cholesterol are associated with periodontal disease. Subjects with two or more MetS components had a significantly higher prevalence of periodontal disease.
Aim: Previous studies demonstrated that endothelin-1 (ET-1) can significantly increase the cell size and stimulate adiponectin expression in cultured human cardiomyocytes (HCM). The aim of the present study was to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor-α (PPARα) activator, on cell hypertrophy and adiponectin expression in vitro and in a rat model of daunorubicin-induced cardiomyopathy.
Methods: The cultured human cardiomyocytes (HCM) were stimulated with or without ET-1. The cell size and the protein expressions of PPARα and adiponectin were tested by confocal Immunofluorescence study and Western blot, respectively. To study the effects of PPARα activation on ET-1-induced cell hypertrophy and adiponectin protein synthesis, HCM were pretreated with fenofibrate or small interfering RNA (siRNA) of PPARα. Echocardiographic parameters were measured and immunohistochemistry study of myocardial adiponectin expression was conducted in the in vivo study.
Results: ET-1 significantly increased the cell size, dose-dependently suppressed the expression of PPARα, and enhanced the expression of adiponectin; whereas, such an increase of cell size and enhancement of adiponectin expression were inhibited by the pre-treatment with fenofibrate. Addition of siRNA of PPARα abolished the effects of fenofibrate. Moreover, we found that fenofibrate treatment can significantly improve the left ventricular function and reverse the myocardial expression of adiponectin.
Conclusions: Our study shows that fenofibrate may protect against ET-1-induced cardiomyocyte hypertrophy and enhanced adiponectin expression through modulation of PPARα expression in vitro and limitation of daunorubicin cardiotoxicity in vivo, suggesting a novel mechanistic insight into the role of PPARα and adiponectin in cardiac hypertrophy and heart failure.
Aim: Data for long-term trends in blood pressures, body mass index (BMI), and their relations are needed to set future intervention priorities for prevention of cardiovascular disease. The objective of this study was to investigate these trends revealed by repeated cross-sectional surveys conducted from 1963 to 2013 in a Japanese community.
Methods: Men and women aged 40-79 years who participated in annual cardiovascular checkups were enrolled, and the number of participants ranged between 1,776 and 2,366 with consistently high participation rates for both sexes aged 60-69 years. Sex- and age-specific mean systolic and diastolic blood pressures were calculated using mixed effects modeling for repeated measurement, and the prevalence of hypertension with and without obesity (BMI ≥ 25 kg/m2) were also calculated.
Results: Sex- and age-specific mean systolic and diastolic blood pressures declined irrespective of antihypertensive medication use in both men and women from 1963-1966 to 2009-2013, while mean BMI increased among men of all ages and women of ages 60-69 and 70-79 years. For both sexes aged 60-69 years, the prevalence of hypertension with obesity increased, but the prevalence of hypertension without obesity was still higher that with obesity.
Conclusions: Despite the transition to increased BMI levels, targeting non to obese hypertension remains important in addition to targeting obese hypertension for cardiovascular disease prevention.
Aim: Collagen tripeptide (CTP) is a functional food with a high content of Gly-X-Y tripeptides derived from collagen. The objective of this study was to evaluate the effect of CTP administration on the development of atherosclerosis in healthy individuals.
Methods: The present study was conducted in the form of an open-label, single-dose trial for 6 months. All subjects ingested CTP twice daily: at breakfast and supper (total intake per day: 16 g). The effect of CTP on atherosclerosis was verified by measuring several indices, including serum lipid levels, toxic advanced glycation end-products (TAGE), and the cardio-ankle vascular index (CAVI), at baseline and 6 months.
Results: The low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio (LDL-C/HDL-C ratio) was significantly reduced in patients with an initial ratio of ≥2.5 (p=0.025). A significant reduction in TAGE was observed in all the subjects (p=0.031) and in the high-risk group (p=0.024). A significant reduction in CAVI was observed in all the subjects (right side: p=0.048, left side: p=0.047). As a result of multiple regression analysis, a significant relationship between the change in CAVI and that in each factor was not observed. No adverse events were observed during the study period.
Conclusions: The results of the present study indicate that CTP contributes to the prevention and treatment of atherosclerosis in healthy humans (UMIN000018525).
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