White adipose tissue (WAT) stores energy as triacylglycerol in preparation for fasting state. In contrast, brown adipose tissue (BAT) consumes energy and produces heat in a cold environment. One of the major differences between these two adipose tissues is the morphology of the intracellular lipid droplet (LD), which is large and unilocular in WAT and small and multilocular in BAT. Although the fat-specific protein 27 alpha (FSP27α), belonging to the cell death-inducing DNA fragmentation factor A (DFFA)-like effector (Cide) family, was known to be indispensable for large unilocular LD formation in WAT, the mechanism that regulated small multilocular LD formation in BAT remained unknown. We recently uncovered that FSP27β, a novel isoform of FSP27 abundantly expressed in BAT, plays a crucial role in small multilocular LD formation by inhibiting the homodimerization of CideA in BAT. We speculate that unilocular LD formation is ideal for efficient lipid storage in WAT because lipolysis from the LD surface is restricted due to the minimum LD surface area. In addition, hydrolyzed free fatty acid (FFA) and glycerol can efficiently flow out into the circulation from the cell surface. In contrast, small multilocular LD formation is ideal for efficient intracellular lipolysis from the LD surface and the subsequent facilitation of FFA transport to mitochondria that are adjacent to LDs for β-oxidation in BAT. Thus, intracellular LD morphology is closely related to the functions and characteristics of adipose tissues. Given that the browning of adipose tissue leads to enhanced energy expenditure and the prevention of obesity, clarification of the mechanism with respect to intracellular LD formation is very meaningful.

The adoption of the Western-style diet, with decreased fish intake and lack of exercise, has increased the prevalence of cardiovascular disease (CVD) in Japan. Statin treatment has been established to reduce the risk of cardiovascular events; however, 60%–70% of these events occur despite its use. Thus, the residual risk for CVD should be identified and resolved to reduce further cardiovascular events. The serum levels of n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid and docosahexaenoic acid, are reportedly associated with an increased incidence of cardiovascular events and mortality, whereas the addition of n-3 PUFA treatment to the statin treatment decreases cardiovascular events. Similar to statins, n-3 PUFAs have pleiotropic effects in addition to lipid-modifying effects. Pre-clinical and clinical studies have shown that n-3 PUFAs prevent cardiovascular events by ameliorating endothelial function and attenuating lipid accumulation, vascular inflammation, and macrophage recruitment, thereby causing coronary plaque development and rupture. Taken together, n-3 PUFAs are comprehensively able to attenuate the atherogenic response. Therefore, n-3 PUFA intake is recommended to prevent cardiovascular events, particularly in patients with multiple cardiovascular risk factors.

Aim: Polyunsaturated fatty acids (PUFAs) take part in various biological events linked to the pathogenesis of venous thromboembolism (VTE), including inflammation, endothelial dysfunction, and hypercoagulability. Several studies have demonstrated the association between PUFAs and the occurrence of VTE. However, the role of PUFAs in the pathogenesis of VTE remains unclear.

Methods: We enrolled 45 patients with acute VTE and 37 age-, gender-, and body mass index-matched healthy volunteers to examine their PUFA levels. Serum omega 3 (eicosapentaenoic acid: EPA and docosahexaenoic acid: DHA) and omega 6 (dihomogammalinolenic acid: DGLA and arachidonic acid: AA) fatty acids levels were measured within 24 h of admission.

Results: Patients with VTE showed significantly higher AA and lower EPA levels, and lower EPA/AA ratios than the controls. Multivariate analysis revealed that AA was an independent marker for VTE. In addition, we divided the patients based on their median age (58 years old). The younger patients with VTE showed significantly lower EPA/AA levels than their age-matched controls, whereas older patients with VTE showed a significantly higher AA/DGLA levels than the older controls.

Conclusions: High serum AA levels and low EPA levels are associated with the development of acute VTE, suggesting that the imbalance of PUFAs may be a potential therapeutic target for preventing acute VTE.

Aim: To examine the association between the serum endostatin levels and subclinical atherosclerosis independent of traditional risk factors in a healthy Japanese population.

Methods: Among 1,057 residents who attended free public physical examinations between 2010 and 2011, we evaluated the data of 648 healthy residents for whom the serum endostatin level and common carotid intima-media thickness (IMT) were successfully measured.

Results: The median endostatin level was 63.7 ng/mL (interquartile ranges: 49.7–93.2 ng/mL), and the mean carotid IMT was 0.68±0.12 mm. Residents with above median endostatin had significantly higher carotid IMT than did those with below median endostatin (0.71±0.14 vs. 0.65±0.09 mm, P＜0.001). Multiple linear regression analysis demonstrated that increased serum endostatin is significantly associated with carotid IMT (above vs. below median endostatin level; beta=0.11, P=0.03), independent of the known covariates of age, sex, body mass index, drinking and smoking status, systolic blood pressure, diastolic blood pressure, hemoglobin A1c, low density lipoprotein cholesterol, estimated glomerular filtration rate, and log-transformed high sensitive C-reactive protein.

Conclusions: A higher serum endostatin level reflected subclinical atherosclerosis in this Japanese population.

Aim: Fetuin-A plays a role in insulin resistance and cardiovascular disease. This study aims to determine the relationship between fetuin-A levels and cardiometabolic risk factors, as well as to investigate the effect of serum fetuin-A on insulin resistance indices to determine whether fetuin-A is an additional marker for insulin resistance in prepubertal children.

Methods: A total of 99 prepubertal Korean children (59 males) aged from 6.0 to 10.0 years was included in this study. Subjects were divided into underweight/normal-weight and overweight/obese groups. Serum fetuin-A levels were measured using an enzyme-linked immunosorbent assay and were natural logarithm (ln)-transformed.

Results: Serum fetuin-A concentrations were significantly elevated in overweight/obese children as compared with underweight/normal-weight children (P=0.029). Ln serum fetuin-A was significantly positively correlated with body mass index (BMI) standard deviation scores (SDSs) (r=0.239, P=0.017), triglyceride levels (r=0.285, P=0.004), ln insulin (r=0.377, P＜0.001), systolic blood pressure (BP) (r=0.274, P=0.006), and diastolic BP (r=0.304, P=0.006) and was significantly inversely correlated with high-density lipoprotein cholesterol (HDL-C) levels (r=−0.236, P=0.019). In univariate linear regression analysis, ln fetuin-A was significantly positively associated with the homeostasis model assessment of insulin resistance (HOMA-IR) (r=0.356, P＜0.001) and significantly inversely associated with the quantitative insulin sensitivity check index (QUICKI) (r=−0.309, P=0.002). Following adjustment for age, gender, BMI, and lipid profiles in multivariate linear regression analysis, fetuin-A was significantly positively associated with HOMA-IR (P=0.048) and marginally inversely associated with QUICKI (P=0.054).

Conclusions: Our results suggest that fetuin-A can be an alternative marker for insulin resistance and cardiovascular risk in prepubertal children.

Aims: The pleiotropic effects of statins on recurrent stroke remain unclear. We investigated the effects of pravastatin on high-sensitivity C-reactive proteins (Hs-CRP) in ischemic stroke, and explored the impact of Hs-CRP on recurrent stroke and vascular events.

Methods: This randomized open-label trial was ancillary to the J-STARS trial. One thousand and ninety-five patients with non-cardiogenic ischemic stroke were assigned to the pravastatin (n=545) or control groups (n=550). The primary and secondary endpoints were serum Hs-CRP reduction and stroke recurrence, including both ischemic and hemorrhagic ones, respectively. Onset of vascular events and each stroke subtype in relation to Hs-CRP levels were also determined.

Results: In the pravastatin treatment group, Hs-CRP levels (median 711 µg/L, IQR 344–1500) significantly decreased 2 months later (median 592 µg/L, IQR 301–1390), and they remained significantly lower until the end of the study. However, in the control group, baseline Hs-CRP levels were similar to those 2 months later. The reduction of Hs-CRP levels from the baseline to 2 months in the pravastatin group was statistically significant compared with the control (p=0.007). One SD increase in log-transformed Hs-CRP increased the risk of stroke recurrence (HR 1.17, 95% CI 0.97–1.40) and vascular events (HR 1.30, 95% CI 1.12–1.51). With an Hs-CRP cut-off of 1000 µg/L, higher Hs-CRP significantly increased the risk of recurrent stroke (HR 1.50, 95% CI 1.03–2.17)and vascular events (HR 1.68, 95% CI 1.23–2.29).

Conclusion: In non-cardiogenic ischemic stroke, pravastatin treatment may reduce vascular inflammation as assessed by Hs-CRP, and higher Hs-CRP levels appeared to increase the risk of recurrent stroke and vascular events.

Aim: The effect of nitroglycerin on proper arterial stiffness of the arterial tree has not been fully clarified. The cardio-ankle vascular index (CAVI), which is an application of the stiffness parameter β theory on the arterial tree from the origin of the aorta to the ankle, was developed recently. Furthermore, the stiffness of the aorta (heart-thigh β (htBeta)) and of the femoral-tibial arteries (thigh to ankle β (taBeta)) could be monitored by applying the same theory. The effects of nitroglycerin on CAVI, htBeta, and taBeta were studied comparing the values of healthy people and those of arteriosclerotic patients.

Methods: The subjects were healthy people (CAVI ＜7.5, n=25) and arteriosclerotic patients (CAVI ＞9, n=25). Nitroglycerin (0.3 mg) was administrated sublingually, and various arterial stiffness indices were measured at one-minute intervals for a period of 20 minutes using Vasera VS-1500 (Fukuda Denshi, Tokyo).

Results: After the administration of nitroglycerin in healthy people, CAVI decreased significantly after 5 min. [from 6.76(6.32-7.27) to 5.50(4.70-6.21), P＜0.05], and recovered after 15 min. htBeta [from 5.10(4.76-5.76) to 3.96(3.35-4.79), P＜0.05], and taBeta [from 14.41(10.80-16.33) to 10.72 (9.19-13.01), P＜0.05] also decreased significantly. In arteriosclerotic patients, CAVI decreased after 5 min. [from 10.47(9.67-11.29) to 9.71(8.74-10.57), P＜0.05] and recovered after 15 min. htBeta did not significantly change [from 12.00(11.46-13.21) to 11.81(10.14-13.83), ns], but taBeta decreased significantly [from 18.55(12.93-23.42) to 12.37(9.68-16.99), P＜0.05].

Conclusion: These results indicate that a nitroglycerin-induced decrease of arterial stiffness is more prominent in muscular arteries than in elastic arteries, and this effect was preserved much more prominently in arteriosclerotic patients than in healthy people.

Aims: Tartrate-resistant acid phosphatase (TRACP)-5b and osteoprotegerin (OPG) are specific and sensitive markers of bone resorption in patients with rheumatoid arthritis (RA) and chronic kidney disease (CKD). The TRACP-5b level is associated with the severity of RA and CKD, while the OPG level is associated with the severity of coronary atherosclerosis and calcification, and can predict a poor outcome in patients with coronary artery disease (CAD). However, the impact of TRACP-5b on coronary atherosclerosis in CAD patients remains unclear.

Methods: A total of 71 CAD patients (57 men, 14 women; mean age: 69.0±9.7 years) and 28 age- and gender- matched healthy subjects were investigated. The number of diseased vessels (a marker of the severity of coronary atherosclerosis) and the Gensini score (a marker of the extent of coronary atherosclerosis), as well as the OPG and TRACP-5b levels were measured in CAD patients. The TRACP-5b levels were classified into quartiles.

Results: The TRACP-5b levels were significantly higher in CAD patients than in healthy subjects. Patients with higher TRACP-5b levels had higher OPG levels and Gensini scores than those with lower TRACP-5b levels. Higher TRACP-5b levels were associated with an increased number of diseased vessels. A multivariate linear regression analysis showed that the OPG level and the number of diseased vessels or the Gensini score were significantly and independently associated with the TRACP-5b level.

Conclusions: These data indicate that the TRACP-5b level is significantly associated with the OPG level and with the severity and extent of coronary atherosclerosis in CAD patients.

Aim: We have conducted medical surveys on two Japanese populations (Japanese Americans living in the US and native Japanese living in Japan) to investigate the impact of westernization of lifestyles on diseases in Japanese people. A 1998 survey revealed that the progression of carotid intima-media wall thickness (IMT) was faster by approximately 20 years in Japanese Americans than in native Japanese. In this study, we compared the progression of atherosclerosis in native Japanese versus that in Japanese Americans using carotid IMT data from medical examinations conducted in the 2010s.

Methods: This study included 115 native Japanese living in Hiroshima who underwent a medical examination in 2014 and 112 Japanese Americans living in Hawaii who underwent a medical examination in 2012, excluding those receiving medication for diabetes mellitus (DM) or dyslipidemia. Carotid IMT was compared between the two Japanese populations.

Results: Serum total and low-density lipoprotein cholesterol levels were significantly higher in native Japanese than in Japanese Americans. The median carotid IMT was significantly greater in Japanese Americans than in native Japanese [median (25^th-75^th percentile): 1.27 (0.86-2.02) mm vs. 1.00 (0.80-1.30) mm, P =0.001]. Regression curves showed that the age at which IMT exceeded 1.1 mm was estimated at ＞50 years in Japanese Americans and at approximately 60 years in native Japanese.

Conclusions: According to surveys conducted in 2012 and 2014, carotid IMT was still greater in Japanese Americans than in native Japanese. However, a comparison with data from the 1998 survey showed that current native Japanese had higher serum lipid levels and more advanced atherosclerosis.

Familial Hypercholesterolemia (FH) is the most common and serious monogenic disorder of lipoprotein metabolism that leads to premature coronary heart disease. There are over 65,000 people estimated to have FH in Australia, but many remain undiagnosed. Patients with FH are often under-treated, but with early detection, cascade family testing and adequate treatment, patient outcomes can improve. Patient registries are key tools for providing new information on FH and enhancing care worldwide. The development and design of the FH Australasia Network Registry is a crucial component in the comprehensive model of care for FH, which aims to provide a standardized, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes. Informed by stakeholder engagement, the FH Australasia Network Registry was collaboratively developed by government, patient and clinical networks and research groups. The open-source, web-based Rare Disease Registry Framework was the architecture chosen for this registry owing to its open-source standards, modular design, interoperability, scalability and security features; all these are key components required to meet the ever changing clinical demands across regions. This paper provides a high level blueprint for other countries and jurisdictions to help inform and map out the critical features of an FH registry to meet their particular health system needs.