Taku Inoue

Hyperuricemia predicts future metabolic syndrome: a 4-year follow-up study of a large screened cohort in Okinawa, Japan

The aim of this study was to determine whether hyperuricemia could predict future metabolic syndrome (MetS) in a large screened cohort of Japanese male and female subjects. We evaluated 5936 subjects (3144 male subjects, 2792 female subjects; mean age 48.7 years) who underwent health checkup programs in 2006 and 2010, who were MetS free in 2006. At baseline, hyperuricemia was detected in 927 male subjects (29.5%) and 276 female subjects (9.9%). Subjects with baseline hyperuricemia had significantly higher MetS prevalence in 2010 than those without (male subjects: 34.8 vs. 20.6%, P<0.0001; female subjects: 15.6 vs. 4.8%, P<0.0001). Compared with subjects in the first quintile of uric acid levels at baseline, the age-adjusted odds ratios (ORs) for MetS cumulative incidence among subjects in the third, fourth and fifth quintiles were, 1.8 (95% confidence interval (CI): 1.4–2.4: P<0.0001), 2.1 (95% CI: 1.6–2.8: P<0.0001) and 3.2 (95% CI: 2.4–4.1: P<0.0001), respectively, for male subjects and 2.4 (95% CI: 1.3–4.7: P=0.0075), 3.0 (95% CI: 1.6–5.7: P=0.0010) and 4.8 (95% CI: 2.6–8.8: P<0.0001), respectively for female subjects. Multivariable logistic analysis revealed that hyperuricemia was significantly associated with MetS cumulative incidence in male subjects (OR 1.5: 95% CI: 1.3–1.8, P<0.0001) and female (OR 2.0, 95% CI: 1.3–3.0, P<0.0001). In conclusion, hyperuricemia is a significant and independent predictor of MetS in Japanese male and female subjects. For both genders, MetS risk increases with increased serum uric acid levels.

Associations between serum uric acid levels and the incidence of hypertension and metabolic syndrome: a 4-year follow-up study of a large screened cohort in Okinawa, Japan

The purpose of this study was to examine the associations between serum uric acid (SUA) levels and the incidences of hypertension and metabolic syndrome (MetS) in a large screened cohort of Japanese men and women. We evaluated 4812 subjects (males, 2528; females, 2284; mean age, 47.5 years) who underwent health checkups between 2006 and 2010 and were free of hypertension and MetS in 2006. After 4 years, 618 (13%), 764 (16%) and 158 (3%) subjects developed hypertension, MetS and hypertension with MetS, respectively. Increased SUA levels were significantly and positively associated with the incidences of hypertension, MetS and hypertension with MetS. Compared with the first quartile of SUA levels, the odds ratios (95% confidence intervals) for the third and fourth quartiles, respectively, were as follows: 1.5 (1.1–2.1; P=0.0128) and 1.8 (1.2–2.5; P=0.0022) for hypertension, 1.3 (0.9–1.9; P=0.1910) and 1.8 (1.2–2.7; P=0.0039) for MetS and 2.7 (1.1–6.6; P=0.0276) and 3.2 (1.3–8.0; P=0.0115) for hypertension with MetS. In conclusion, increased SUA levels were significantly and independently associated with the incidences of hypertension and MetS in subjects without hypertension or MetS at baseline. Increased SUA levels might also be correlated with the incidence of hypertension with MetS.

Effect of heart rate on the risk of developing metabolic syndrome.

High heart rate and metabolic syndrome are risk factors for cardiovascular morbidity and mortality. The relationship between heart rate and risk of developing metabolic syndrome has not been studied in a large cohort. We examined the relationship between heart rate and the risk of developing metabolic syndrome in individuals who participated in a health evaluation program from 1997 to 2002. Among the 7958 individuals who participated in the program, 1677 were excluded from our study because they were being treated for heart disease or had been diagnosed with metabolic syndrome at baseline examination. A total of 6281 individuals (3789 men and 2492 women, 20–89 years of age) were evaluated. They were categorized according to their baseline heart rate and were followed up for a mean of 47±16 months (range: 7–71 months). Over the 5-year period, 619 individuals (9.9%) developed metabolic syndrome. Men with elevated baseline heart rates were more likely to experience metabolic syndrome than were those with normal heart rates. This was not true for female patients. The odds ratio (95% confidence interval) of developing metabolic syndrome among men in the highest quartile for heart rate was 1.725 (1.282–2.320) compared with those in the lowest quartile. Each increase in the heart rate category led to an approximately 1.2-fold increase in the risk of developing metabolic syndrome for men only, even after adjusting for age and lifestyle. Elevated heart rate is a risk factor for developing metabolic syndrome in men.

Elevated Resting Heart Rate Is Associated With White Blood Cell Count in Middle-Aged and Elderly Individuals Without Apparent Cardiovascular Disease

We investigated the association between resting heart rate (HR) and inflammation markers in a healthy population. White blood cell (WBC) count was used as a surrogate marker of subclinical inflammation. Smoking status, body mass index, resting HR, high-density lipoprotein cholesterol, triglycerides, uric acid, and glycated hemoglobin were significantly associated with WBC in both men and women. Blood pressure and fasting plasma glucose levels, however, were associated with WBC only in women. Logistic regression analysis indicated that for every 10 beats per minute increase in HR, the odds ratio of an increase in the WBC was approximately 1.3 in both men and women. These findings indicate the clinical significance of resting HR for identifying individuals at risk of subclinical inflammation and a future cardiovascular event.

Proteinuria as a significant determinant of hypertension in a normotensive screened cohort in Okinawa, Japan.

To evaluate the influence of proteinuria on the development of hypertension in normotensive screened subjects. We studied 4,428 normotensive subjects without heart disease (2,888 men, 1,540 women, age 19–89 years) who were participants in a 1-day health evaluation in both 1997 and 2000. The 3-year frequency of developing hypertension was 6.0% in subjects without proteinuria, and 13.5% in subjects with proteinuria. The odds ratio for developing hypertension by age (year) increased approximately 1.6%. Obesity was associated with an approximately 40% increased risk of hypertension; proteinuria increased the risk of hypertension 2-fold. Proteinuria was a significant predictor of developing hypertension. Age, obesity, and initial blood pressure level also contributed to the development of hypertension. In conclusion, proteinuria is a powerful predictor of developing hypertension. Age and obesity are also associated with increased risk of hypertension. Lifestyle modification might thus be necessary, particularly in subjects with proteinuria.

Heart rate as a possible therapeutic guide for the prevention of cardiovascular disease

Epidemiologic evidence indicates that an elevated heart rate (HR) is an independent predictor of all-cause and cardiovascular (CV) mortality. Ivabradine, a pure HR-lowering agent, reduces CV events in patients with coronary artery disease (CAD) and chronic heart failure, and indicate that an HR greater than 70 b.p.m. is hazardous. These findings demonstrate not only that an elevated HR is an epiphenomenon of CV risk status but also that an elevated HR itself should be a therapeutic target. In addition, recent epidemiologic evidence demonstrates that the in-treatment HR or HR change predicts subsequent all-cause and CV mortality, independent of the HR-lowering strategy. Characteristics of the in-treatment HR or HR change are also important as possible therapeutic guides for risk management. However, there have been concerns regarding deleterious effects on CV event prevention owing to β-blocker-derived pharmacologic HR reduction. The potential role of HR and its modulation should be considered in future guidance documents.

Heart Rate as a Therapeutic Target for the Prevention of CardiovascularDisease

Evidence from epidemiologic studies demonstrates that resting Heart Rate (HR) is an independent risk factor for Cardiovascular (CV) event. In addition, recent studies indicate that follow-up HR adds prognostic information over and above baseline HR. Elevated resting HR represents sympathetic over-activation leading to cardiometabolic deterioration and is also associated with subclinical inflammation and target organ damage. In addition, elevated resting HR might modify the local hemodynamic environment and contribute to atherosclerosis formation. A pure HR-lowering drug, Ivabradine, reduces CV event in patients with coronary artery disease and chronic heart failure. These findings indicate that elevated resting HR is not just as an epiphenomenon representing “poor conditioning” but a therapeutic target. The potential role of HR and its modulation should be considered in the future guidance documents.

Pivotal role of elevated heart rate in the cardiovascular continuum

We congratulate Custodis et al. for demonstrating that elevated eart rate (HR) plays a pivotal role in the vascular pathophysioogy of the cardiovascular continuum [1]. An elevated HR promotes therosclerosis via not only sympathetic overactivation, but also by odulating the local hemodynamic environment. An elevated HR ncreases the exposure of the endothelium to systolic low shear tress (SS), attenuates the diastolic SS, and increases local tenile stress, which change the arterial structure in patients with ardiovascular risks. Thereby, HR lowering might act specifically n atherosclerosis-prone lesions, contributing to a residual risk eduction [2]. The prognostic benefit of blockers in patients ith stable coronary artery disease has been called into quesion [3]. These findings might be due in part to inadequate R control [4], indicating that the physician did not use a locker in a HR-guided manner, because no optimal HR level is escribed in the guideline documentation. The SIGNIFY study will eveal the prognostic significance of HR lowering for stable CAD atients [5].

103 BLOOD CELLS’ RHOA IS TRANSCELLULARLY DELIVERED VIA MICROPARTICLES TO ENDOTHELIAL CELLS TO GET ACTIVATED THEREIN

Background: Eukaryotic organism releases fine vesicles called microparticles (MPs) from plasma membrane. Recent literatures show that MPs represent the state of the original cells with its amount, inclusions or membrane molecules, and play a role in transcellular signal transduction. There has also been shown that downstream of Rho is activated in various tissues with cardiovascular diseases. We examine whether circulating RhoA in the MPs derived from blood cells is transferred to ECs to activate Rho signalling in the ECs. Methods: Human blood MPs (bMPs) were isolated from healthy volunteers by sequences of centrifuging the plasma as reported previously. MPs from isolated platelets (PLMPs) and cultured bovine ECs (ECMPs) were also collected, and RhoA expression in each MPs were examined. Isolated bMPs or PLMPs or thrombin (positive control) was applied to ECs for 15 minutes, and the ECs were fractionated into cytosol and plasma membrane to assess active RhoA. In cell lysate before fractionation phosphorylation of MYPT1, downstream of RhoA, was evaluated. Results: RhoA expression was seen in bMPs and PLMPs but not in ECMPs, suggesting RhoA in bMPs is derived from blood cells. Applying thrombin or bMPs or PLMPs to ECs showed significant RhoA distribution in plasma membrane and also enhanced phosphorylation of MYPT1 in ECs lysates, indicating RhoA signalling is activated in ECs. Conclusion: Blood cells’ RhoA could be transcellularly delivered to ECs through circulating microparticles derived from blood cells, and be activated in ECs. This would be a new concept on Rho signalling in cardiovascular system.