Akihiko Uehara

Cardiac Autonomic Neuropathy in Patients with Chronic Renal Failure on Hemodialysis

To characterize uremic cardiac autonomic neuropathy, we measured plasma catecholamines, analyzed the 24-hour heart rate variability (HRV), and acquired serial images with 123I-metaiodobenzylguanidine (MIBG) in 44 patients with chronic renal failure on hemodialysis and in 14 controls. Time-domain measures were calculated using the Marquette HRV program. MIBG clearance rates from the heart and lung were evaluated on planar images, and the regional MIBG uptake in the left ventricular myocardium was evaluated with single-photon emission computed tomography. Compared with controls, plasma dopamine and norepinephrine levels were elevated (p < 0.001 and p = 0.03, respectively), and all the time-domain measures of HRV were reduced in the patients (p < 0.001). The MIBG clearance rate from the heart was higher (p < 0.001), that from the lung was lower (p < 0.001), and the myocardial MIBG distribution was more heterogeneous in patients than in controls (total uptake score p ≤ 0.03). These variables were similar between 26 patients without and 18 patients with hypertension. Uremic cardiac autonomic neuropathy may be characterized by high plasma levels of dopamine and norepinephrine, reduced HRV, and abnormal MIBG kinetics in the heart with heterogeneous myocardial MIBG distribution, suggesting cardiac sympathetic overactivity and parasympathetic deterioration. In addition, abnormal MIBG kinetics in the lung may imply pulmonary sympathetic nervous dysfunction and/or endothelial dysfunction in uremic patients.

Post-challenge hyperinsulinaemia rather than hyperglycaemia is associated with the severity of coronary artery disease in patients without a previous diagnosis of diabetes mellitus

Objective: To ascertain the prevalence of abnormal glucose metabolism in patients with coronary artery disease (CAD) but no previous diagnosis of diabetes mellitus (DM) and to examine the relation between the severity of CAD and responses of glucose and insulin to the glucose tolerance test. Methods and results: Abnormalities of glucose metabolism and insulin response were analysed in 144 patients with CAD without a previous diagnosis of DM who underwent both coronary arteriography and 75 g oral glucose tolerance test. The proportions of impaired and diabetic glucose tolerance were very high (39% for impaired and 21% for diabetic glucose tolerance); only 40% had normal glucose tolerance. The parameters of glucose metabolism were not associated with the number of diseased coronary arteries or the presence of previous myocardial infarction (MI). However, the insulin concentration at 60 minutes or 120 minutes after glucose challenge, insulin area, and the ratio of insulin to glucose area were significantly higher in patients with significant coronary stenosis and with previous MI. Fasting glucose concentration and most conventional risk factors did not predict post-challenge hyperinsulinaemia. Conclusion: Patients with CAD without a previous diagnosis of DM had a high prevalence of abnormal glucose tolerance. Post-challenge hyperinsulinaemia was associated with the number of diseased coronary arteries and the presence of previous MI. The insulin response to the glucose challenge test requires further investigation as a potential risk factor for CAD and a potential target for intervention.

Diabetic cardiac autonomic dysfunction: Parasympathetic versus sympathetic

BackgroundDiabetic cardiac autonomic dysfunction often causes lethal arrhythmia and sudden cardiac death.123I-Metaiodobenzylguanidine (MIBG) can evaluate cardiac sympathetic dysfunction, and analysis of heart rate variability (HRV) can reflect cardiac parasympathetic activity. We examined whether cardiac parasympathetic dysfunction assessed by HRV may correlate with sympathetic dysfunction assessed by MIBG in diabetic patients.Methods and ResultsIn 24-hour electrocardiography, we analyzed 4 HRV parameters: high-frequency power (HF), HF in the early morning (EMHF), rMSSD and pNN50. MIBG planar images and SPECT were obtained 15 minutes (early) and 150 minutes (late) after injection and the heart washout rate was calculated. The defect score in 9 left ventricular regions was scored on a 4 point scale (0 = normal ∼ 3 = severe defect). In 20 selected diabetic patients without congestive heart failure, coronary artery disease and renal failure, parasympathetic HRV parameters had a negative correlation with the sum of defect scores (DS) in the late images (R = −0.47 ∼ −0.59, p < 0.05) and some parameters had a negative correlation with the washout rate (R = −0.50 ∼ −0.55, p < 0.05). In a total of 64 diabetic patients also, these parameters had a negative correlation with late DS (R = −0.28 ∼ −0.35, p < 0.05) and early DS (R = −0.27 ∼ −0.32, p < 0.05).ConclusionsThe progress of diabetic cardiac parasympathetic dysfunction may parallel the sympathetic one.

Prevalence of diabetes and pre-diabetes among workers: Japan Epidemiology Collaboration on Occupational Health Study.

AIMS Few studies have examined the prevalence of diabetes using glycated hemoglobin (HbA1c), a newly recommended diagnostic test. We examined the prevalence of diabetes and pre-diabetes using both HbA1c and fasting plasma glucose (FPG) and their associations with risk factors for type 2 diabetes in a large-scale Japanese working population. METHODS Participants were 47,172 men and 8280 women aged 20-69 years who received periodic health checkup in nine companies which participated in the Japan Epidemiology Collaboration on Occupational Health study. Participants were categorized into diabetes (HbA1c≥6.5% (≥48mmol/mol), FPG≥126mg/dl (≥7.0mmol/L), or medication for diabetes), pre-diabetes (HbA1c 6.0-6.4% (42-46mmol/mol) or FPG 110-125mg/dl (6.1-6.9mmol/L) among those without diabetes), and normal glucose regulation. RESULTS The prevalence of diabetes was 8.0% and 3.3% in men and women, respectively. Of individuals with diabetes, approximately 80% were defined by HbA1c≥6.5% (≥48mmol/mol) criterion. The prevalence of pre-diabetes was 14.1% in men and 9.2% in women. Prevalence of these glucose abnormalities increased with advancing age, especially during mid-40s and 50s. Higher body mass index and waist circumference, hypertension, dyslipidemia, and current smoking were each associated with higher prevalence of diabetes in both men and women. CONCLUSIONS Using HbA1c and FPG criteria or current medication, one in 13 men and one in 30 women had diabetes in the present Japanese working population. Interventions targeted for those in an early stage of impaired glucose metabolism would be required to prevent diabetes.

Waist to Height Ratio Is an Independent Predictor for the Incidence of Chronic Kidney Disease

Objective Obesity is a risk factor for chronic kidney disease (CKD) and cardiovascular disease. The association between waist to height ratio (WheiR) and CKD is unclear. This study evaluated the association between WheiR and CKD. Design and Methods In this longitudinal cohort study, 4841 Japanese workers (3686 males, 1155 females) 18 to 67 years of age in 2008 were followed up until 2011. CKD was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2 (by the Modification of Diet in Renal Disease equation for Japanese) or dipstick proteinuria (≥1+). Cox proportional hazards models were used to examine the relationship between WheiR and development of CKD. Results A total of 384 (7.9%) participants (300 men and 84 women) were found to have new CKD. The incidence of CKD was 13.7, 24.2, 37.9 and 43.7 per 1000 person-years of follow-up in the lowest, second, third and highest quartiles of WheiR, respectively. After adjustment for potential confounders, the adjusted hazard ratios (95% confidence interval) for CKD were 1.00 (reference), 1.23 (0.85, 1.78), 1.59 (1.11, 2.26) and 1.62 (1.13, 2.32) through the quartiles of WheiR, respectively. WheiR had a significant predictive value for the incidence of both proteinuria and low estimated glomerular filtration rate. After subdivision according to gender, the relationship between WheiR and the incidence of CKD was statistically significant in the unadjusted model. However, after adjusting for potential confounders, WheiR was significantly associated with the incidence of CKD in females, whereas it was not significant in males. Conclusions WheiR, which is commonly used as an index of central obesity, is associated with CKD. There was a significant gender difference in the relationship between CKD and WheiR.

Association of Cardiorespiratory Fitness and Overweight with Risk of Type 2 Diabetes in Japanese Men

Objective Existing evidence is limited on what extent fitness can counterbalance type 2 diabetes mellitus (T2DM) risk associated with obesity. We investigated the joint association of weight status and estimated VO2max, a marker of fitness, with the risk of developing T2DM among Japanese men using haemoglobin A1c and fasting glucose criterion. Methods The present study included 3,523 male employees aged 18–61 years without diabetes who provided health check-up and fitness data in Japan in 2003–2005. We calculated hazard ratios and 95% confidence intervals for incident diabetes using the Cox regression model. Results During a mean follow-up of 6.0 years, 199 men developed diabetes. Multivariable-adjusted hazard ratios (95% confidence interval) of diabetes were 1.00 (reference), 1.44 (1.01–2.07), and 1.48 (1.03–2.13) for the highest through the lowest tertile of fitness (P for trend  = 0.04). Additional adjustment for body mass index largely attenuated the association of fitness with diabetes. Joint analysis showed that adjusted hazard ratios of diabetes were 1.00, 1.32, 2.94, and 1.83 in normal weight high-fit men, normal weight low-fit men, overweight high-fit men, and overweight low-fit men, respectively. Conclusion The results suggest that weight control is more important than fitness in prevention of type 2 diabetes in Japanese men.

Development of Risk Score for Predicting 3-Year Incidence of Type 2 Diabetes: Japan Epidemiology Collaboration on Occupational Health Study

Objective Risk models and scores have been developed to predict incidence of type 2 diabetes in Western populations, but their performance may differ when applied to non-Western populations. We developed and validated a risk score for predicting 3-year incidence of type 2 diabetes in a Japanese population. Methods Participants were 37,416 men and women, aged 30 or older, who received periodic health checkup in 2008–2009 in eight companies. Diabetes was defined as fasting plasma glucose (FPG) ≥126 mg/dl, random plasma glucose ≥200 mg/dl, glycated hemoglobin (HbA1c) ≥6.5%, or receiving medical treatment for diabetes. Risk scores on non-invasive and invasive models including FPG and HbA1c were developed using logistic regression in a derivation cohort and validated in the remaining cohort. Results The area under the curve (AUC) for the non-invasive model including age, sex, body mass index, waist circumference, hypertension, and smoking status was 0.717 (95% CI, 0.703–0.731). In the invasive model in which both FPG and HbA1c were added to the non-invasive model, AUC was increased to 0.893 (95% CI, 0.883–0.902). When the risk scores were applied to the validation cohort, AUCs (95% CI) for the non-invasive and invasive model were 0.734 (0.715–0.753) and 0.882 (0.868–0.895), respectively. Participants with a non-invasive score of ≥15 and invasive score of ≥19 were projected to have >20% and >50% risk, respectively, of developing type 2 diabetes within 3 years. Conclusions The simple risk score of the non-invasive model might be useful for predicting incident type 2 diabetes, and its predictive performance may be markedly improved by incorporating FPG and HbA1c.

Multivessel coronary thrombosis, acute myocardial infarction, and no reflow in a patient with essential thrombocythaemia

Essential thrombocythaemia (ET) has been reported rarely to cause coronary thrombosis, but the management is still undefined. A 63 year old woman with multivessel coronary thrombosis, acute myocardial infarction (MI), and no reflow in reperfused coronary artery in association with ET is presented. The patients platelet count was only moderately raised at the onset of MI, but peripheral blood smear and bone marrow evaluation revealed clumping giant platelets and numerous large hyperploid megakaryocytes. Long term prophylaxis with antiplatelet agents in patients with ET is recommended, even if the platelet count is not largely raised. Cytoreductive treatment may also be effective for secondary prevention when thrombotic complications occur.

Hba1c, Blood Pressure, and Lipid Control in People with Diabetes: Japan Epidemiology Collaboration on Occupational Health Study.

Aims The control of blood glucose levels, blood pressure (BP), and low-density lipoprotein cholesterol (LDL-C) levels reduces the risk of diabetes complications; however, data are scarce on control status of these factors among workers with diabetes. The present study aimed to estimate the prevalence of participants with diabetes who meet glycated hemoglobin (HbA1c), BP, and LDL-C recommendations, and to investigate correlates of poor glycemic control in a large working population in Japan. Methods The Japan Epidemiology Collaboration on Occupational Health (J-ECOH) Study is an ongoing cohort investigation, consisting mainly of employees in large manufacturing companies. We conducted a cross-sectional analysis of 3,070 employees with diabetes (2,854 men and 216 women) aged 20–69 years who attended periodic health examinations. BP was measured and recorded using different company protocols. Risk factor targets were defined using both American Diabetes Association (ADA) guidelines (HbA1c < 7.0%, BP < 140/90 mmHg, and LDL-C < 100 mg/dL) and Japan Diabetes Society (JDS) guidelines (HbA1c < 7.0%, BP < 130/80 mmHg, and LDL-C < 120 mg/dL). Logistic regression models were used to explore correlates of poor glycemic control (defined as HbA1c ≥ 8.0%). Results The percentages of participants who met ADA (and JDS) targets were 44.9% (44.9%) for HbA1c, 76.6% (36.3%) for BP, 27.1% (56.2%) for LDL-C, and 11.2% (10.8%) for simultaneous control of all three risk factors. Younger age, obesity, smoking, and uncontrolled dyslipidemia were associated with poor glycemic control. The adjusted odds ratio of poor glycemic control was 0.58 (95% confidence interval, 0.46–0.73) for participants with treated but uncontrolled hypertension, and 0.47 (0.33–0.66) for participants with treated and controlled hypertension, as compared with participants without hypertension. There was no significant difference in HbA1c levels between participants with treated but uncontrolled hypertension and those with treated and controlled hypertension. Conclusion Data from a large working population, predominantly composed of men, suggest that achievement of HbA1c, BP, and LDL-C targets was less than optimal, especially in younger participants. Uncontrolled dyslipidemia was associated with poor glycemic control. Participants not receiving antihypertensive treatment had higher HbA1c levels.

Smoking, Smoking Cessation, and the Risk of Type 2 Diabetes among Japanese Adults: Japan Epidemiology Collaboration on Occupational Health Study

Aims To examine the association of smoking status, smoking intensity, and smoking cessation with the risk of type 2 diabetes (T2D) using a large database. Methods The present study included 53,930 Japanese employees, aged 15 to 83 years, who received health check-up and did not have diabetes at baseline. Diabetes was defined as fasting plasma glucose ≥126 mg/dl, random plasma glucose ≥200 mg/dl, HbA1c ≥6.5% (≥48 mmol/mol), or receiving medication for diabetes. Cox proportional-hazards regression models were used to investigate the association between smoking and the risk of diabetes. Results During 3.9 years of median follow-up, 2,441 (4.5%) individuals developed T2D. The multivariable-adjusted hazard ratios (95% CI) for diabetes were 1 (reference), 1.16 (1.04 to 1.30) and 1.34 (1.22 to 1.48) for never smokers, former smokers, and current smokers, respectively. Diabetes risk increased with increasing numbers of cigarette consumption among current smokers (P for trend <0.001). Although the relative risk of diabetes was greater among subjects with lower BMIs (< 23 kg/m2), attributable risk was greater in subjects with higher BMIs (≥ 23 kg/m2). Compared with individuals who had never smoked, former smokers who quit less than 5 years, 5 to 9 years, and 10 years or more exhibited hazards ratios for diabetes of 1.36 (1.14 to 1.62), 1.23 (1.01 to 1.51), and 1.02 (0.85 to 1.23), respectively. Conclusions Results suggest that cigarette smoking is associated with an increased risk of T2D, which may decrease to the level of a never smoker after 10 years of smoking cessation.