Shinichi Hitsumoto

Heart Rate Variability, Insulin Resistance, and Insulin Sensitivity in Japanese Adults: The Toon Health Study

Background Although impaired cardiac autonomic function is associated with an increased risk of type 2 diabetes in Caucasians, evidence in Asian populations with a lower body mass index is limited. Methods Between 2009–2012, the Toon Health Study recruited 1899 individuals aged 30–79 years who were not taking medication for diabetes. A 75-g oral glucose tolerance test was used to diagnose type 2 diabetes, and fasting and 2-h-postload glucose and insulin concentrations were measured. We assessed the homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt’s insulin sensitivity index (ISI). Pulse was recorded for 5 min, and time-domain heart rate variability (HRV) indices were calculated: the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive difference (RMSSD). Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power, and the LF:HF ratio. Results Multivariate-adjusted logistic regression models showed decreased SDNN, RMSSD, and HF, and increased LF:HF ratio were associated significantly with increased HOMA-IR and decreased ISI. When stratified by overweight status, the association of RMSSD, HF, and LF:HF ratio with decreased ISI was also apparent in non-overweight individuals. The interaction between LF:HF ratio and decreased ISI in overweight individuals was significant, with the odds ratio for decreased ISI in the highest quartile of LF:HF ratio in non-overweight individuals being 2.09 (95% confidence interval, 1.41–3.10). Conclusions Reduced HRV was associated with insulin resistance and lower insulin sensitivity. Decreased ISI was linked with parasympathetic dysfunction, primarily in non-overweight individuals.

High-density Lipoprotein Subclasses and Risk of Stroke and its Subtypes in Japanese Population The Circulatory Risk in Communities Study

Background and Purpose— High-density lipoprotein (HDL) cholesterol is an established protective factor for ischemic stroke. However, the contribution of HDL subclasses to stroke risk and its subtypes is uncertain. Methods— A prospective nested case–control study of 40- to 85-year-old Japanese was undertaken using frozen serum samples collected from 5280 men and 7524 women. They participated in cardiovascular risk surveys from 1985 to 1999 (1 community) and 1989 to 1998 (2 communities) under Circulatory Risk in Communities Study. HDL cholesterol subclasses were classified by high-performance liquid chromatography into 3 subgroups: S-HDL (very small or small HDL), M-HDL (medium HDL), and L-HDL (large or very large HDL) cholesterol. One control subject per case was matched by sex, age, community, serum storage year, and fasting status. Results— In 2005, we identified 241 strokes (155 ischemic and 86 hemorrhagic). S-HDL and M-HDL cholesterol levels were inversely associated with total stroke risk, ischemic stroke, specifically lacunar infarction, and hemorrhagic stroke. After adjustment for cardiovascular risk factors, these associations remained statistically significant. Multivariable conditional odds ratios (95% confidence interval) for 1 SD (0.12 mmol/L) increment of S-HDL cholesterol levels were 0.34 (0.23–0.52) for total stroke, 0.38 (0.23–0.63) for ischemic stroke, 0.33 (0.18–0.61) for lacunar infarction, 0.30 (0.14–0.65) for hemorrhagic stroke, and 0.30 (0.12–0.77) for intraparenchymal hemorrhage. The respective multivariable odds ratios for 1SD (0.10 mmol/L) increment of M-HDL cholesterol levels were 0.56 (0.41–0.75), 0.63 (0.45–0.88), 0.59 (0.40–0.87), 0.41 (0.21–0.80), and 0.38 (0.16–0.90). No associations were found between L-HDL cholesterol levels and risk of total stroke and its subtypes. Conclusions— Small- to medium-sized HDL, not large HDL, cholesterol levels were inversely associated with total stroke risk.

Total and high molecular weight adiponectin levels and risk of cardiovascular disease in individuals with high blood glucose levels

OBJECTIVE The association of adiponectin levels with cardiovascular disease (CVD) may vary by age and health condition. It is unknown whether adiponectin predicts CVD events among individuals with high blood glucose levels. METHODS We conducted a nested case-control study among 15,566 men and women aged 40-85 years from four communities, who were free of CVD at baseline. During 192,181 person-years of follow-up, 117 individuals subsequently developed coronary heart disease or ischemic stroke and had high plasma glucose concentrations (fasting/nonfasting ≥ 5.6/7.2 mmol/L or treated) at baseline. Controls were randomly selected at a 2:1 ratio and matched for sex, age, blood glucose, year of survey, fasting conditions, and community (n = 234). Baseline total and high molecular weight (HMW) adiponectin and their ratio were examined for total subjects and the association with CVD was compared between ages of 40-69 and 70-85 years. RESULTS After adjustment for matched variables and traditional risk factors, total and HMW adiponectin and their ratio were not associated with overall risk of CVD. However, significant interactions of the associations between the age groups were found. The highest quartile for HMW adiponectin and HMW/total adiponectin ratio decreased risk of CVD compared with the lowest quartile among middle-aged individuals (multivariable-adjusted odds ratio = 0.33 [95%CI, 0.13-0.83] and 0.47 [0.22-0.98], respectively), while this association was not seen among the elderly. CONCLUSIONS High HMW adiponectin levels may decrease the risk of CVD in middle-aged adults with high blood glucose.

An association between central aortic pressure and subclinical organ damage of the heart among a general Japanese cohort: Circulatory Risk in Communities Study (CIRCS).

BACKGROUND This study aimed to investigate associations between central aortic pressure (CAP) and subclinical organ damage of the heart amongst the general population. METHODS We conducted a cross-sectional study in a community-based population, consisting of 3002 men and women aged between 40 and 79 years. The CAP was measured using the HEM-9000AI device, an automated tonometer. Electrocardiograms (ECG) were read according to the Minnesota Code. Subclinical organ damage in the heart was defined as measurable left high amplitude R waves (LHAR), major and minor ST-T abnormalities, and left ventricular hypertrophy (LVH). RESULTS Age- and sex-adjusted prevalence of LHAR, major and minor ST-T abnormalities, and LVH was higher for subjects in the highest tertile of CAP levels than those in the lowest tertile. After further adjustments for other cardiovascular risk factors, these associations did not change substantially. The multivariable odds ratios (ORs) (95% CI) of LHAR, major and minor ST-T abnormalities, and LVH for the highest tertile of CAP levels compared to the lowest tertile were 2.7(1.9-3.9), 1.8(1.1-2.9), 1.7(1.3-2.3) and 3.2(1.3-8.1), respectively. The positive associations with LHAR and minor ST-T abnormalities were observed primarily among non-hypertensive subjects. The respective corresponding ORs were 2.8(1.7-4.6) and 1.7(1.2-2.4) for non-hypertensive subjects, and 1.7(0.9-3.3) and 1.1(0.7-1.8) for hypertensive subjects. CONCLUSION CAP levels were associated with subclinical organ damage of the heart independent of cardiovascular risk factors, and these associations were primarily seen in non-hypertensive subjects.

Association of hematological parameters with insulin resistance, insulin sensitivity, and asymptomatic cerebrovascular damage: The J-SHIP and Toon Health Study

BACKGROUND Elevated hematocrit levels have been suggested to be an independent determinant of insulin resistance and type 2 diabetes. To clarify the diagnostic significance of hematocrit level, we investigated the association with hemodynamic profiles, insulin resistance and insulin sensitivity, arterial properties, and asymptomatic cerebrovascular damage in a general Japanese population. METHODS This study included 1,978 participants from two independent cohorts. Insulin sensitivity was assessed by the oral 75 g glucose tolerance test. Carotid ultrasonography was performed to evaluate atherosclerosis and wall shear stress. Periventricular hyperintensity and lacunar infarction were assessed by brain magnetic resonance imaging. RESULTS Hematocrit quartile showed a stepwise association with insulin sensitivity (Q1: 2.2±0.7, Q2: 2.0±0.7, Q3: 1.9±0.7, Q4: 1.8±0.6, p<0.001) and insulin resistance (1.0±0.6, 1.2±0.7, 1.3±0.8, 1.5±1.0, p<0.001). Multiple linear regression analysis adjusted for possible covariates identified hematocrit as an independent determinant of insulin sensitivity (β=-0.074, p=0.019) and insulin resistance (β=0.115, p<0.001). However, this association was lost after further adjustment for visceral fat area and plasma alanine aminotransferase level. Further, no significant association was observed between hematocrit and carotid intima-media thickness (p=0.306) where as wall shear stress was inversely associated with the carotid atherosclerosis (r=-0.250, p<0.001). In contrast, a low hematocrit level was independently associated with periventricular hyperintensity (odds ratio 0.87 (95% CI 0.80-0.95), p=0.001). CONCLUSION Hematocrit was positively associated with insulin resistance and insulin sensitivity. This association was epiphenomenon of visceral and hepatic adiposity. Conversely, low hematocrit was a significant risk factor for periventricular hyperintensity independent of insulin resistance.

Association Between TSLP Polymorphisms and Eczema in Japanese Women: the Kyushu Okinawa Maternal and Child Health Study

We examined the association between thymic stromal lymphopoietin (TSLP) single nucleotide polymorphisms (SNPs) and eczema in young adult Japanese women. Cases were 188 women who met the criteria of the International Study of Asthma and Allergies in Childhood (ISAAC) for eczema. Controls were 565 women without eczema according to the ISAAC criteria, who had not been diagnosed with asthma, atopic eczema, and/or allergic rhinitis by a doctor and who had no asthma as defined by the European Community Respiratory Health Survey criteria and no rhinoconjunctivitis according to the ISAAC criteria. Compared with women with the TT genotype of SNP rs1837253, those with the TC or CC genotype had a significantly increased risk of eczema after adjustment for age and smoking, although this association was not significant in crude analysis. There were no relationships between SNP rs3806933 or rs2289276 and eczema. The TC and CC genotypes combined of SNP rs1837253 may be significantly positively associated with eczema.

Long‐Term Prognosis of Brugada‐Type ECG and ECG With Atypical ST‐Segment Elevation in the Right Precordial Leads Over 20 Years: Results From the Circulatory Risk in Communities Study (CIRCS)

Background Brugada syndrome is recognized as being associated with sudden cardiac death; however, the prevalence of non–type 1 Brugada‐type ECG (BrS) or atypical ST‐segment elevation in the right precordial leads (STERP) and the long‐term prognosis for those patients remain unknown. Methods and Results We analyzed standard 12‐lead ECGs of 7178 apparently healthy participants (age range 40–64 years) who underwent health checkups from 1982 to 1986 in the Circulatory Risk in Communities Study, a prospective, large, community‐based cohort study in Japan. ECGs with J point amplitude ≥0.2 mV in the right precordial leads were divided into 3 groups: (1) type 1 BrS, (2) type 2 or 3 BrS (non‐type 1 BrS), and (3) STERP. The others served as the non–ST‐segment elevation group. We identified 8 participants (0.1%) with type1 BrS, 84 (1.2%) with non–type 1 BrS, and 228 (3.2%) with STERP. During a median follow‐up of 18.7 years (133 987.0 person‐years), sudden cardiac death was observed in no participants (0.0%) with type 1 BrS, in 1 (1.2%) with non–type 1 BrS, in 7 (3.1%) with STERP, and in 50 (0.7%) with non–ST‐segment elevation. Participants with STERP had a markedly elevated risk of sudden cardiac death (multivariable hazard ratio 3.9, 95% CI 1.7–9.0). Conclusions STERP was associated with an elevated risk of sudden cardiac death in a middle‐aged population.