Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in selective excretion of plant sterols from the liver and intestine, leading to failure to prevent absorption of food plant sterols. This disorder has been considered to be extremely rare. However, accumulated clinical data as well as genetics suggest the possibility of a much higher prevalence. Its clinical manifestations resemble those observed in patients with familial hypercholesterolemia (FH), including tendon xanthomas, hyper LDL-cholesterolemia, and premature coronary atherosclerosis. We provide an overview of this recessive genetic disease, diagnostic as well as therapeutic tips, and the latest diagnostic criteria in Japan.

Tangier disease is a genetic disorder characterized by an absence or extremely low level of high-density lipoprotein (HDL)-cholesterol (HDL-C). It is caused by a dysfunctional mutation of the ATP-binding cassette transporter A1 (ABCA1) gene, the mandatory gene for generation of HDL particles from cellular cholesterol and phospholipids, and it appears in an autosomal recessive hereditary profile. To date, 35 cases have been reported in Japan and 109 cases outside Japan. With dysfunctional mutations in both alleles (homozygotes or compound heterozygotes), the HDL-C level is mostly less than 5 mg/dL and there is 10 mg/dL or less of apolipoprotein A-I (apoA-I), the major protein component of HDL. In patients with Tangier disease, major physical findings are orange-colored pharyngeal tonsils, hepatosplenomegaly, corneal opacity, lymphadenopathy, and peripheral neuropathy. Although patients tend to have decreased low-density lipoprotein (LDL)-cholesterol (LDL-C) levels, premature coronary artery disease is frequently observed. No specific curative treatment is currently available, so early identification of patients and preventing atherosclerosis development are crucial. Management of risk factors other than low HDL-C is also important, such as LDL-C levels, hypertension and smoking. Additionally, treatment for glucose intolerance might be required because impaired insulin secretion from pancreatic beta cells has occasionally been reported.

Aims: We aimed to develop and validate risk prediction models to estimate the absolute 10-year risk of death from coronary heart disease (CHD), stroke, and cardiovascular disease (CVD).

Methods: We evaluated a total of 44,869 individuals aged 40–79 years from eight Japanese prospective cohorts to derive coefficients of risk equations using cohort-stratified Cox proportional hazard regression models. Discrimination (C-index) of the equation was examined in each cohort and summarised using random-effect meta-analyses. Calibration of the equation was assessed using Hosmer-Lemeshow chi-squared statistic.

Results: Within a median follow-up of 12.7 years, we observed 765 deaths due to CVD (276 CHDs and 489 strokes). After backward selection, age, sex, current smoking, systolic blood pressure (SBP), proteinuria, prevalent diabetes mellitus, the ratio of total cholesterol to high-density lipoprotein cholesterol (TC/HDLC), interaction terms of age by SBP, and age by current smoking were retained as predictors for CHD. Sex was excluded in the stroke equation. We did not consider TC/HDLC as a risk factor for the stroke and CVD equations. The pooled C-indices for CHD, stroke, and CVD were 0.83, 0.80, and 0.81, respectively, and the corresponding p-values of the Hosmer-Lemeshow tests were 0.18, 0.003, and 0.25, respectively.

Conclusions: Risk equations in the present study can adequately estimate the absolute 10-year risk of death from CHD, stroke, and CVD. Future work will evaluate the system as an education and risk communication tool for primary prevention of CHD and stroke.

Aim: Pneumococcal and influenza infections can cause serious morbidity and mortality in patients with cardiovascular diseases. The purpose of this study was to investigate the safety and efficacy of simultaneous inoculations of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and trivalent influenza vaccine (TIV) in patients with coronary artery disease (CAD).

Methods: This was a prospective, randomized, single-blind, placebo-controlled study. A total of 40 patients with CAD were randomly assigned to the TIV＋PPSV23 (simultaneous inoculations of TIV and PPSV23) and TIV＋Placebo (inoculations of TIV and placebo) groups. Primary outcomes were the safety of simultaneous vaccinations and the changing of circulating cardiovascular biomarkers before, at 4-, and at 12-weeks after vaccinations.

Results: The baseline characteristics between the two groups were identical. The prevalence of injection-site pain, swelling, and reddening were 47%, 37%, and 37% in the TIV＋PPSV23 group, and 10%, 5%, and 0% in the TIV＋Placebo group, respectively. All reactions were self-limited. Body temperature ＞37.0℃ or serious injection-related reaction was not observed. The levels of white blood cells, high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, pentraxin-3, and malondialdehide-modified low-density lipoprotein (LDL), were not significantly different between the two groups before and after vaccinations. The levels of anti-oxidized LDL were significantly and step-wisely decreased from baseline, to 4-, and 12-weeks vaccinations in the both groups. No significant changes of other markers were observed in both groups at each time point.

Conclusion: Simultaneous inoculations of TIV and PPSV23 were safety in patients with CAD, suggesting that dual vaccinations can be considered even in patients with CAD.

Aim:The clinically meaningful coronary stenosis is diagnosed by trained interventional cardiologists. Whether artificial intelligence (AI) could detect coronary stenosis from CAG video is unclear.

Methods: The 199 consecutive patients who underwent coronary arteriography (CAG) with chest pain between December 2018 and May 2019 was enrolled. Each patient underwent CAG with multiple view resulting in total numbers of 1,838 videos. A multi-layer 3-dimensional convolution neural network (CNN) was trained as an AI to detect clinically meaningful coronary artery stenosis diagnosed by the expert interventional cardiologist, using data from 146 patients (resulted in 1,359 videos) randomly selected from the entire dataset (training dataset). This training dataset was further split into 109 patients (989 videos) for derivation and 37 patients (370 videos) for validation. The AI developed in derivation cohort was tuned in validation cohort to make final model.

Results: The final model was selected as the model with best performance in validation dataset. Then, the predictive accuracy of final model was tested with the remaining 53 patients (479 videos) in test dataset. Our AI model showed a c-statistic of 0.61 in validation dataset and 0.61 in test dataset, respectively.

Conclusion: An artificial intelligence applied to CAG videos could detect clinically meaningful coronary atherosclerotic stenosis diagnosed by expert cardiologists with modest predictive value. Further studies with improved AI at larger sample size is necessary.

Aim: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders associated with metabolic syndrome, and its prevalence has been on the rise. The pathogenesis of NAFLD has not yet been sufficiently elucidated due to the multifactorial nature of the disease, although the activation of macrophages/Kupffer cells is considered to be involved. We previously reported an animal model of NAFLD using Microminipigs^TM (µMPs) fed high-fat diets containing cholesterol with or without cholic acid. The aim of this study was to investigate the phenotypic changes of macrophages that occur during the development of NAFLD.

Methods: Immunohistochemistry of macrophages, lymphocytes, and stellate cells was performed using liver samples, and the density of positive cells was analyzed.

Results: The number of Iba-1-positive macrophages increased with increasing cholesterol content in the diet. The numbers of CD163-positive macrophages and CD204-positive macrophages also increased with increasing cholesterol content in the diet; however, the proportion of CD204-positive macrophages among Iba-1-positive macrophages was significantly reduced by cholic acid supplementation.

Conclusion: The results suggest that lipid accumulation induced macrophage recruitment in swine livers, and that the number of M2-like macrophages increased at the early stage of NAFLD, while the number of M1-like macrophages increased at the late stage of NAFLD, resulting in a liver condition like non-alcoholic steatohepatitis. We provide evidence of the phenotypic changes that occur in macrophages during the development of NAFLD that has never been reported before using µMPs.

Aims: Stress is known to be a potential contributor to the development of diabetes and hypertension. However, the biological mechanisms underlying the association between cardiometabolic risk markers and the biological stress response have not yet been determined. Therefore, we examined salivary alpha-amylase and heart rate variability in relation to cardiometabolic status in a sample of healthy Japanese men and women.

Methods: Participants (473 men and 1,029 women aged 30-84) underwent a 75 g oral glucose tolerance test after a 10-hr fast. The homeostasis model assessment index for insulin resistance was based on fasting and 2-hr postload glucose and insulin concentrations. Sitting blood pressure was measured twice after rest. A saliva sample was collected in the morning and salivary alpha-amylase was assayed. A 5-min heart rate variability recording was evaluated using time-domain indices of standard deviations of normal-to-normal intervals and root mean square of successive differences. Multivariate linear regression models were used to estimate associations between salivary alpha-amylase and each outcome measure.

Results: Salivary alpha-amylase was associated with fasting glucose (β=0.008; 95% CI=0.002, 0.014), 2-hr postload glucose (β=0.023; 95% CI=0.004, 0.041), homeostasis model assessment index for insulin resistance (β=0.032; 95%CI=0.000, 0.064), systolic (β=1.603; 95% CI=0.479, 2.726) and diastolic (β=0.906; 95% CI=0.212, 1.600) blood pressures among women. These associations remained significant after further adjustment for heart rate variability measures.

Conclusions: The elevation of salivary alpha-amylase may reflect a dysfunction of the sympathetic nervous system associated with cardiometabolic abnormalities in women.

Aim: We examined the effects of active learning education on arterial stiffness and physical activity of community-dwelling older adults with low health literacy.

Methods: This study is a secondary analysis of randomized controlled trial of 60 participants aged 65 and older with low health literacy. The intervention group (n=30) participated in a weekly 90-minute active learning program session for 24 weeks, which addressed health promotion in older age. The control group (n=30) attended a 90-minute health education class in a didactic manner. The outcomes were measured at baseline and in week 24. The degree of arterial stiffness was assessed based on the cardio-ankle vascular index (CAVI) using the VS-1500 device (Fukuda Denshi Co., Ltd., Tokyo, Japan). The shortened version of the self-reported International Physical Activity Questionnaire was used to assess the amount of total physical activity determined by the metabolic equivalent hours per week. We used analysis by intention-to-treat, with multiple imputation for missing data.

Results: Seven participants (11.7%) dropped out prior to the post-intervention assessment. The multiple imputation analysis revealed that the intervention group showed significant improvement in CAVI [between-groups difference (95% confidence interval)=-0.78 (-1.25 to -0.31), Cohen’s d=0.82] and physical activity [32.5 (0.3 to 64.7), Cohen’s d=0.57] as compared with the control group. The sensitivity analysis for the complete cases showed similar results.

Conclusion: Active learning health education may be effective in improving arterial stiffness and physical activity in older adults with low health literacy.

Aim: The efficacy and safety of ticagrelor and clopidogrel in patients with stable coronary artery disease (SCAD) undergoing percutaneous coronary intervention (PCI) remain uncertain. Thus, this study aimed to compare the efficacy and safety of ticagrelor and clopidogrel in patients with SCAD treated with PCI.

Methods: A total of 9,379 patients with SCAD undergoing PCI who received dual antiplatelet therapy (DAPT) were consecutively enrolled in two groups, namely, ticagrelor (n=1,081) and clopidogrel (n=8,298) groups. Major adverse cardiovascular and cerebrovascular events (MACCEs) and bleeding events according to ticagrelor or clopidogrel use were compared.

Results: After propensity matching (n=1,081 in each group), ticagrelor was associated with fewer MACCEs compared with clopidogrel (3.6% vs. 5.7%, hazard ratio [HR]=0.62, 95% confidence interval [CI] 0.41–0.93, p=0.019), and the difference between ticagrelor and clopidogrel for bleeding events was nonsignificant (4.0% vs. 3.2%, HR=1.24, 95% CI 0.79-1.93, p=0.356). On the other hand, the difference between ticagrelor and clopidogrel for net adverse clinical events was significant (4.1% vs. 6.0%, HR=0.67, 95% CI 0.46–0.98, p=0.039). In a multivariate analysis, the use of ticagrelor, number of stents, previous history of diabetes, previous history of smoking, and ACC/AHA type B2 or C lesions were considered independent predictors of MACCEs, while radial artery access, previous history of stroke, and weight ＜60kg were independent predictors of bleeding events.

Conclusions Ticagrelor was associated with a lower incidence of MACCEs without an increased risk of bleeding events in patients with SCAD receiving PCI.