Familial hypercholesterolemia (FH) is the most common and serious form of inherited hyperlipidaemia. Dominantly inherited with high penetrance, untreated FH leads to premature death from coronary artery disease due to accelerated atherosclerosis from birth. Despite its importance, there is still a major shortfall in awareness, detection and treatment of FH worldwide. International models of care for FH have recently been published, but their effective implementation requires the garnering of more knowledge about the condition. The “Ten Countries Study” aims to investigate diagnostic, epidemiological and service aspects, as well as physician practices and patient experiences of FH in several countries in the Asia-Pacific Region and the Southern Hemisphere. Five observational studies are being undertaken that will systematically investigate the following aspects of FH: the phenotypic predictors of low-density lipoprotein receptor mutations, the point prevalence in available community populations, current knowledge and clinical practices among primary care physicians, availability and utilisation of services and facilities, and patient perceptions and personal experiences of the condition. The information gathered will inform better clinical practice and will enable the development of country-specific models of care for FH.
Aim: Recent studies have suggested that metabolic disorders such as obesity and type 2 diabetes are associated with gut microbiota. The association between atherosclerosis and gut microbiota has also been attracting increased attention. Our aim was to specify a characteristic trend of gut microbiota in coronary artery disease (CAD).
Methods: This study included 39 CAD patients, 30 age- and sex-matched no-CAD controls (Ctrls) with coronary risk factors and 50 healthy volunteers (HVs) without coronary risk factors. Bacterial DNA was extracted from their fecal samples and analyzed by terminal restriction fragment length polymorphism.
Results: A characteristic change of gut microbiota was observed in CAD patients, where the order Lactobacillales was increased (CAD, Ctrl vs. HV; 13.6%±12.0%, 6.2%±7.7% vs. 4.1%±5.9%; p＜0.001) and the phylum Bacteroidetes (Bacteroides＋Prevotella) was decreased (CAD, Ctrl vs. HV;35.5%±11.6%, 43.9%±11.2% vs. 47.4%±11.5%; p＜0.001). The CAD group was over-represented in enterotype “others” (III), compared with the Ctrl or HV group (p＜0.001, chi-squared test), although we could not deny the possibility that some drugs affect the gut flora types.
Conclusions: Although this study had some limitations, we demonstrated that the incidence of CAD was linked with an alteration of gut microbiota. A prospective study is desired to clarify a causal relationship between CAD and gut microbiota.
Aim: Diabetic patients with coronary artery disease have a high incidence of cardiovascular events, which was associated with increased coronary plaque volume. Low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) play pivotal roles in the progression of coronary plaque. Several trials have shown that intervention for a single risk factor reduced the development of coronary plaque progression. However, it remained uncertain whether total risk management for LDL-C, BP, and glycosylated Hb (HbA1c) has a beneficial effect on coronary plaque volume in diabetic patients.
Methods: This study was a sub-study of the JAPAN-ACS that was a prospective, randomized, open-label trial that evaluated the impact of intensive lipid-lowering therapy on coronary plaque volume in patients with acute coronary syndrome (ACS). Among a total of 252 patients, 73 diabetic patients were analyzed. We examined the impact of total risk management (LDL-C ＜80 mg/dL, systolic BP ＜130 mmHg, and HbA1c ＜6.5%) on changes in coronary plaque volume. The patients were divided into four groups according to the number of risk factors that achieved the target value.
Results: Baseline characteristics were similar among the groups. The degree of coronary plaque regression was greater in patients who achieved total risk management. The number of risk factors that achieved the target level was associated with the extent of the coronary plaque volume reduction in a dose-dependent manner.
Conclusion: Total risk management that focused on LDL-C, BP, and HbA1c had a beneficial impact on the coronary plaque regression in diabetic patients with ACS.
Aim: Because the prevalence of hyperuricemia is lower in females than in males, the association between hyperuricemia and cardiovascular disease has been frequently reported in females. Increased serum uric acid levels are associated with the presence of cardiovascular risk factors such as hypertension, renal dysfunction, insulin resistance, and metabolic syndrome. However, it is controversial whether hyperuricemia is an independent risk factor for coronary artery disease in both the genders. The purpose of this study was to investigate the relationship between serum uric acid levels and coronary plaque components assessed using integrated backscatter intravascular ultrasound (IB-IVUS) in males and females.
Methods: In total, 385 patients (298 males and 87 females) who underwent percutaneous coronary intervention using IB-IVUS were divided into three groups in each gender according to their serum uric acid levels. We characterized tissue from coronary plaques in culprit lesions.
Results: Serum uric acid levels significantly correlated with percent lipid volume (r=0.37) and inversely correlated with percent fibrous volume (r=－0.35). Multivariate analysis showed that the uric acid level was independently associated with lipid-rich plaques (odds ratio 2.43, 95%, confidence interval 1.75–3.47). The prevalence of lipid-rich plaques increased with increasing uric acid levels in both genders.
Conclusion: Increased serum uric acid levels were associated with larger lipid content plaques in both genders.
Aim: Atherosclerotic diseases are the leading cause of death worldwide. Longitudinal changes in carotid intima-media thickness (IMT) and plaque are being increasingly used as markers of atherosclerosis progression and may predict future cardiovascular events. This study aimed to investigate the predictors of carotid IMT and plaque progression in a Chinese population and to determine whether these predictors differ by gender.
Methods: Segment-specific carotid IMT and plaque were measured in 712 stroke- and myocardial infarction-free subjects at baseline and after an average interval of 4.3±0.9 years. Multivariate linear regression and logistic regression analyses were conducted to investigate the predictive effect of age, gender, and cardiovascular risk factors on carotid IMT and plaque progression. Gender-specific analyses were also performed.
Results: Overall, age and smoking were predictors of common carotid artery IMT progression (adjusted p＜0.001 and p=0.045, respectively). Age, hypertension, and use of antihypertensive medication were predictors of bifurcation IMT progression (adjusted p＜0.001, p=0.033, and p＜0.001, respectively). The use of antihypertensive medication was associated with less annual IMT progression in hypertensive subjects than in those who did not take medication, which was most prominent in the bifurcation segment. In addition, most predictors of IMT progression were identified in women in a gender-specific analysis. For plaque progression, age and gender were independent predictors.
Conclusions: The predictors of carotid atherosclerosis progression were gender and segment specific. The detection and control of hypertension may prevent atherosclerosis progression, particularly in women.
Aim: Although the underlined mechanisms are still unknown, metabolic/coagulation alterations related to childhood obesity can induce vascular impairments. The aim of this study was to investigate the relationship between metabolic/coagulation parameters and endothelial function/vascular morphology in overweight/obese children.
Methods: Thirty-five obese/overweight children (22 pre-pubertal, mean age: 9.52±3.35 years) were enrolled. Body mass index (BMI), homeostasis model assessment index (HOMAIR), metabolic and coagulation parameters, [adiponectin, fibrinogen, high molecular weight adiponectin (HMW), endothelin-1, and vonWillebrand factor antigen] ultrasound early markers of atherosclerosis [flow-mediated dilatation (FMD), common carotid intima-media thickness (C-IMT), and anteroposterior diameter of infra-renal abdominal aorta (APAO)] were assessed.
Results: APAO was related to anthropometric (age: r=0.520, p=0.001; height: r=0.679, p＜0.001; weight: r=0.548, p=0.001; BMI: r=0.607, p＜0.001; SBP: r=0.377, p=0.026) and metabolic (HOMAIR: r=0.357, p=0.035; HMW: r=－0.355, p=0.036) parameters. Age, height, and systolic blood pressure were positively related to increased C-IMT (r=0.352, p=0.038; r=0.356, p=0.036; r=0.346, p=0.042, respectively). FMD was not related to any clinical and biochemical characteristics of the pediatric population. Age, HOMAIR, fasting glucose levels, and HMW were independent predictors for APAO increase. Each unit decrease in HMW concentrations (1 μg/ml) induced a 0.065 mm increase in APAO.
Conclusion: High molecular weight adiponectin is related to cardiovascular risk in overweight/obese children.
Aim: The aryl hydrocarbon receptor (AhR), a ligand-inducible transcription factor mediating toxic effects of dioxins and uremic toxins, has recently emerged as a pathophysiological regulator of immune-inflammatory conditions. Indoxyl sulfate, a uremic toxin, is associated with cardiovascular disease in patients with chronic kidney disease and has been shown to be a ligand for AhR. The aim of this study was to investigate the potential role of AhR in indoxyl sulfate-induced leukocyte–endothelial interactions.
Methods: Endothelial cell-specific AhR knockout (eAhR KO) mice were produced by crossing AhR floxed mice with Tie2 Cre mice. Indoxyl sulfate was administered for 2 weeks, followed by injection of TNF-α. Leukocyte recruitment to the femoral artery was assessed by intravital microscopy. Vascular endothelial cells were transfected with siRNA specific to AhR (siAhR) and treated with indoxyl sulfate, followed by stimulation with TNF-α.
Results: Indoxyl sulfate dramatically enhanced TNF-α-induced leukocyte recruitment to the vascular wall in control animals but not in eAhR KO mice. In endothelial cells, siAhR significantly reduced indoxyl sulfate-enhanced leukocyte adhesion as well as E-selectin expression, whereas the activation of JNK and nuclear factor-κB was not affected. A luciferase assay revealed that the region between －153 and －146 bps in the E-selectin promoter was responsible for indoxyl sulfate activity via AhR. Mutational analysis of this region revealed that activator protein-1 (AP-1) is responsible for indoxyl sulfate-triggered E-selectin expression via AhR.
Conclusion: AhR mediates indoxyl sulfate-enhanced leukocyte–endothelial interactions through AP-1 transcriptional activity, which may constitute a new mechanism of vascular inflammation in patients with renal disease.
Aim: Hyperlipidemia and diabetic retinopathy increase the risk of cardiovascular disease (CVD). The standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study examines whether intensive lipid-lowering therapy is superior to standard therapy in reducing the incidence of cardiovascular events in patients with hyperlipidemia and diabetic retinopathy, but without a history of coronary artery disease.
Methods: Patients who had elevated low-density lipoprotein cholesterol (LDL-C) and diabetic retinopathy without a history of coronary artery disease were eligible for the study. Patients were randomly assigned in a 1:1 ratio to receive intensive or standard therapy. Patients are being treated with monotherapy with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) for a maximum of 5.5 years to achieve the following LDL-C target: ＜70 mg/dL for the intensive therapy group or ≥100 and ＜120 mg/dL for the standard therapy group. The primary endpoint is a composite of incidence of CVD and death from CVD.
Results: Between May 2010 and October 2013, 5,995 patients were assessed for eligibility, and 5,144 were assigned to the study treatment (2,571 and 2,573 in the intensive and standard therapy groups, respectively), and baseline data were analyzed from 5,107 (2,550 in the intensive therapy group and 2,557 in the standard therapy group).
Conclusions: This is the first study assessing the benefits of intensive statin therapy in patients with hypercholesterolemia and diabetic retinopathy in a primary prevention setting. Furthermore, this study evaluates the appropriateness of the treat-to-target approach because all patients are treated to achieve specific LDL-C targets by titrating statin therapy.
Clinical Trial Registration Number: UMIN000003486.
Aims: Several guidelines propose target levels (TLs) of atherosclerotic risk factors (ARFs) to reduce atherosclerotic cardiovascular diseases; however, few data are available regarding the attainment statuses of TLs in Japan. In this study, utilizing the data obtained from the annual “Specific Health Check and Guidance in Japan” conducted from 2008 to 2011 (approximately 280,000 subjects each year), we determined TL attainments of ARFs in cardiovascular high-risk subjects.
Methods: Those who had suffered from cerebrovascular disease (pCVD) or coronary heart disease (pCHD) or were receiving diabetes mellitus treatment (DM) were selected, and the rates of subjects that attained TLs of blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and glycated hemoglobin (HbA1c) were analyzed.
Results: Approximately 70% of pCVD or pCHD and 35% of subjects with DM attained TLs of BP. With regard to HbA1c, ＞90% of pCVD or pCHD and approximately 50% of subjects with DM attained TLs. With regard to LDL-C, ＜25% of pCHD females and approximately 35% of pCHD males and 50%–55% of subjects with pCVD or DM attained TLs. The TL-attainment rates of HDL-C and TGs were approximately 90% and 75%, respectively, for the three diseases. Analyses of time course changes in their attainment statuses revealed that the attainment rates of BP and LDL-C significantly improved in all the diseases.
Conclusions: TL-attainment rates of BP and LDL-C were not as high as those for HDL-C, TGs, and HbA1c; however, they both showed highly significant improvements during the study period.
Aim: Pulse wave velocity (PWV) has been regarded as the “gold standard” measurement of arterial stiffness (AS), but it is still only used in the assessment of central and peripheral arteries. We constructed a new method to evaluate cerebral AS by measuring PWV using transcranial Doppler (TCD).
Methods: In all, 90 healthy subjects who received annual health screening were consecutively enrolled in this study between January 2011 and June 2013. Data on clinical characteristics, brachium–ankle (ba) PWV, and carotid–cerebral (cc) PWV measured with our newly constructed method by two experienced operators were recorded. cc PWV was calculated as the distance between two points in the common carotid artery and proximal part of ipsilateral middle cerebral artery, which was divided by the pulse transit time between these two points where the pulse was measured using TCD.
Results: The value of cc PWV was 499.3±78.6 cm/s. Correlation between cc PWV and ba PWV in the assessment of AS was r=0.794 (P＜0.001). The concordance between both the above mentioned methods was good. Interobserver and intraobserver reliability using interclass correlation for measuring cc PWV were 0.815 (P＜0.001) and 0.939 (P＜0.001), respectively. In multivariable analysis, older age (β=4.51, P＜0.001) and increased diastolic blood pressure (β=2.39, P＜0.001) were independently associated with higher cc PWV.
Conclusion: cc PWV measured using TCD may be a promising method for the assessment of human cerebral AS, which is independently associated with age and diastolic blood pressure.