Early identification of coronary atherosclerotic pathogenic mechanisms is useful for predicting the risk of coronary heart disease (CHD) and future cardiac events. Epigenome changes may clarify a significant fraction of this “missing hereditability”, thus offering novel potential biomarkers for prevention and care of CHD. The rapidly growing disciplines of systems biology and network science are now poised to meet the fields of precision medicine and personalized therapy. Network medicine integrates standard clinical recording and non-invasive, advanced cardiac imaging tools with epigenetics into deep learning for in-depth CHD molecular phenotyping. This approach could potentially explore developing novel drugs from natural compounds (i.e. polyphenols, folic acid) and repurposing current drugs, such as statins and metformin. Several clinical trials have exploited epigenetic tags and epigenetic sensitive drugs both in primary and secondary prevention. Due to their stability in plasma and easiness of detection, many ongoing clinical trials are focused on the evaluation of circulating miRNAs (e.g. miR-8059 and miR-320a) in blood, in association with imaging parameters such as coronary calcifications and stenosis degree detected by coronary computed tomography angiography (CCTA), or functional parameters provided by FFR/CT and PET/CT. Although epigenetic modifications have also been prioritized through network based approaches, the whole set of molecular interactions (interactome) in CHD is still under investigation for primary prevention strategies.

Aim: The incidence of sudden death and its risk factors in patients on hemodialysis remain unclear. This study aimed to clarify the incidence of sudden death and its risk factors in Japanese patients on hemodialysis.

Methods: A total of 3505 patients on hemodialysis aged ≥ 18 years were followed for 10 years. Multivariate-adjusted hazard ratio (HR) with 95% confidence interval (95% CI) of each risk factor of sudden death were calculated using a Cox proportional hazards model.

Results: During the 10-year follow-up, 1735 patients died, including 227 (13%) sudden deaths. The incidence rate of sudden death was 9.13 per 1000 person-years. In multivariable-adjusted Cox analysis, male sex (HR 1.67; 95% CI 1.20–2.33), age (HR 1.44; 95% CI 1.26–1.65 per 10-year higher), the presence of diabetes (HR 2.45; 95% CI 1.82–3.29), history of cardiovascular disease (HR 1.85; 95% CI 1.38–2.46), cardiothoracic ratio (HR 1.21; 95% CI 1.07–1.39 per 5% higher), serum C-reactive protein (HR 1.11; 95% CI 1.03–1.20 per 1-mg/dL higher), and serum phosphate (HR 1.15; 95% CI 1.03–1.30 per 1-mg/dL higher) were independent predictors of sudden death. A subgroup analysis stratified by sex or age showed that lower serum corrected calcium levels, not using vitamin D receptor activators in women, and a shorter dialysis session length in men or older people (≥ 65 years) increased the risk for sudden death.

Conclusions: This study clarified the incidence of sudden death and its specific predictors in Japanese patients on hemodialysis.

Aims: Small dense low-density lipoprotein cholesterol (sdLDL-C) and remnant-like particle cholesterol (RLP-C) are the novel atherosclerotic risk factors and might be strongly associated with inflammation. The basic evidence supports that sdLDL and RLP have some different mechanisms inducing an inflammatory response. Many studies have focused on the mechanism of inflammation of sdLDL-C or RLP-C per se, with limited data on the association between sdLDL-C and RLP-C in the real-world, population-based setting. Thus, the aim of this study was to investigate the association between sdLDL-C and RLP-C with inflammation.

Methods: We examined the baseline cross-sectional data of participants from the Jichi Medical School-II Cohort Study. In total, 5,305 participants (2,439 men and 2,866 women) were included in this study.

Results: Of all quartiles of sdLDL-C, the fourth had the highest high-sensitivity C-reactive protein (hs-CRP) level. Once adjusted for age, sex, smoking status, homeostasis model assessment of insulin resistance, antidyslipidemic and antihyperglycemic medication use, and RLP-C, sdLDL-C was significantly and positively associated with hs-CRP (geometric mean, 95% confidence interval (CI), 0.36 mg/L (0.34–0.38 mg/L), 0.37 mg/L (0.35–0.39 mg/L), 0.40 mg/L (0.37–0.42 mg/L) versus 0.44 mg/L (0.42–0.47 mg/L), P＜0.001 for trend). After stratifying the participants into four sdLDL-C×four RLP-C categories, the group in the fourth sdLDL-C quartile and the forth RLP-C quartile had the highest hs-CRP level (geometric mean, 95% CI, 0.52 mg/L, 0.48–0.57 mg/L, interaction P=0.75).

Conclusions: SdLDL-C and RLP-C had different associations with inflammation. Our results support sdLDL-C as the potential novel factor of cardiovascular disease, independently of RLP-C.

Aim: Our study investigated the association between soluble endoglin and carotid subclinical atherosclerosis.

Methods: We used endoglin as an adjunct to atherosclerotic cardiovascular disease (ASCVD) risk, in recognition of carotid clinical atherosclerosis, in order to explore a new model to refine risk assessment. Out of 3,452 participants, 978 subjects with detected soluble endoglin were enrolled in a cross-sectional investigation in Fujian Province were enrolled. Soluble endoglin concentration in serum samples was evaluated using an enzyme-linked immunosorbent assay method. Carotid ultrasonography was used to detect intima-media thickness and carotid plaque.

Results: The mean 10-year ASCVD risk by the new Pooled Cohort Equations accounted for 10.04% (±12.35). The mean soluble endoglin level was 15.35 ng/ml (±6.64). Multivariable regression demonstrated that age, systolic blood pressure, diastolic blood pressure, total cholesterol, high density lipoprotein cholesterol, and serum uric acid were independent determinants of soluble endoglin. Adding tests of ASCVD and endoglin together, in parallel, will increase the sensitivity and decrease specificity in recognizing carotid subclinical atherosclerosis. Evaluating the added value of endoglin to the ASCVD risk model showed significantly improved discrimination with analysis of C-statistics, continuous net reclassification index and integrated discrimination index. Both ASCVD risk and soluble endoglin showed positively linear correlation with carotid intima-media thickness (cIMT) (β=0.006, P＜0.001; β=0.485, P＜0.001). Even with adjustment for other factors, the relationship between log-transformed soluble endoglin with cIMT was still significant (β=0.369, P＜0.001).

Conclusions: The combination of ASCVD risk and endoglin levels increases carotid atherosclerosis recognition.

Aim: Obesity is a social problem due to the prevalence of the Western lifestyle. In particular, visceral fat accumulation, which is a main component of metabolic syndrome, is closely associated with the progression of atherosclerosis. This study aimed to investigate the relationships of obesity-related indices and metabolic syndrome with subclinical atherosclerosis in middle-aged untreated workers.

Methods: Employees undergoing their periodic health check-up but without previous cardiovascular events or cardiovascular medications were enrolled in this study (n=7,750). Body mass index (BMI), percent body fat, waist circumference, and visceral fat area were evaluated as obesity-related indices. Assessment of visceral fat area was performed by computed tomography (CT). Subclinical atherosclerosis was assessed by measuring arterial stiffness using cardio-ankle vascular index (CAVI) and by ultrasound examination of carotid intima-media thickness (IMT).

Results: Obesity-related indices were significantly correlated with each other and were positively associated with carotid IMT but negatively associated with CAVI in multivariate regression analysis. In a logistic regression analysis including CAVI and carotid IMT simultaneously, CAVI was negatively associated, but carotid IMT was positively associated, with obesity defined by each obesity-related index. In contrast, both CAVI and carotid IMT were positively associated with the presence of metabolic syndrome based on visceral fat accumulation.

Conclusions: Obesity-related indices were negatively associated with CAVI and positively associated with carotid IMT in middle-aged untreated workers, while both CAVI and carotid IMT were worsened in the presence of metabolic syndrome.

Aim: Atypical hemolytic uremic syndrome (aHUS), characterized by thrombotic microangiopathy (TMA), is a genetic, life-threatening disease which needs many differential diagnoses. This study aimed to reveal coagulation and fibrinolysis profiles in aHUS and secondary TMA patients. Furthermore, we investigated whether aHUS patients progress to, and meet, disseminated intravascular coagulation (DIC) criteria.

Methods: The acute phase samples were available in 15 aHUS and 20 secondary TMA patients. We measured PT-ratio, activated partial thromboplastin time (APTT), fibrinogen, fibrin degradation product (FDP), fibrin monomer complex (FMC), antithrombin (AT), plasmin-α2 plasmin inhibitor complex (PIC), and von Willebrand factor antigen (VWF:Ag). We examined and compared these tests among aHUS, secondary TMA patients, and healthy volunteer (HV), and evaluated whether patients with aHUS and secondary TMA met DIC criteria.

Results: PT-ratio, APTT, FDP, FMC and PIC in patients with aHUS and secondary TMA were higher than those in HV. Fibrinogen and AT showed no significant difference among three groups. VWF:Ag was higher in only aHUS patients. No tests showed significant difference between aHUS and secondary TMA patients. Three aHUS patients out of 15 met DIC criteria.

Conclusion: We revealed the profiles and distributions of coagulation and fibrinolysis tests of aHUS and secondary TMA patients. All tests were enhanced compared to HV; however, our results showed the no specificities in distinguishing aHUS from secondary TMA patients. We also clarified that some aHUS patients fulfilled DIC diagnostic criteria, indicating that DIC itself cannot be an exclusion criterion of aHUS.

Aim: A positive association between non-high-density lipoprotein cholesterol (non-HDL-C) and coronary heart disease (CHD) has been established; however, associations between non-HDL-C and stroke subtypes have not been determined.

Methods: We conducted a prospective study of 30,554 individuals aged 40–69 yrs with no history of cardiovascular disease (CVD) in Japan. Sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of stroke subtypes and CHD were estimated according to quintiles of non-HDL-C, using Cox proportional hazard models adjusted for other established risk factors.

Results: We identified 1,705 stroke and 296 CHD events over a median 15 yrs of follow-up. The fractional polynomials analysis revealed a U-shaped association between non-HDL-C and stroke risk in men. When analyzed for stroke subtypes, the data revealed an inverse relationship between non-HDL-C and intracerebral hemorrhage (ICH), primarily with lobar ICH, and a positive association between non-HDL-C and large-artery occlusive infarction in men [adjusted HR 0.55 (95% CI, 0.35–0.87) and 2.05 (95% CI, 1.07–3.93) for the highest and lowest quintile of non-HDL-C, respectively]. The lowest risk of ICH in women was observed in the fourth quintile, and the lowest risk of embolic infarction was observed in the third quintile. In contrast, non-HDL-C was positively associated with CHD in both sexes.

Conclusions: In Japanese men, lower non-HDL-C levels were associated with a decreased risk of large-artery occlusive infarction and an increased risk of ICH, particularly lobar ICH.