Effects of cyclosporin A upon humoral and cellular immune parameters in insulin-dependent diabetes mellitus type I: a long-term follow-up study

Patients who had been included in a randomized double-blind placebo-controlled trial on the efficacy of cyclosporin A (CyA) in producing remissions in insulin-dependent diabetes mellitus (IDDM) type I were investigated for humoral and cellular immunologic parameters. Whereas metabolic derangement before the initiation of insulin treatment led to small but significant decreases in the percentage of CD4-positive lymphocytes as well as of the activity of natural killer (NK) cells and antibody-dependent cellular cytotoxicity (ADCC), the administration of CyA did not influence any of the immunologic parameters tested, which included proliferative lymphocyte responses to mitogens and alloantigens and serum concentrations of immunoglobulins G, A and M. Thus NK cell activity, ADCC as well as the percentage of CD4-positive lymphocytes returned to normal levels in parallel with the normalization of glycosylated haemoglobin (HbAlc), but were not further influenced in their course by the administration of CyA, as compared with patients receiving placebo. Interferon-induced augmentation of NK cell activity did not differ between patients with IDDM on placebo and those under CyA therapy. All other investigated parameters also remained unchanged during the time of CyA therapy. We conclude that metabolic derangement leads to a reversible disturbance of certain cellular immune functions, but their normalization achieved by insulin treatment and their further course remains uninfluenced by the administration of CyA.     

QT dynamicity and sudden death after myocardial infarction: results of a long-term follow-up study

INTRODUCTION: The aim of this study was to determine whether impaired adaptation of the QT interval to changes in heart rate predicts sudden death after an acute myocardial infarction. METHODS AND RESULTS: The Groupe d'Etude du Pronostic de l'Infarctus du Myocarde (GREPI) trial was a prospective multicenter study designed to evaluate the long-term outcome of myocardial infarction. QT dynamicity was evaluated in 265 patients by analyzing 24-hour Holter recordings obtained 9 to 14 days after myocardial infarction. The linear regression slope of QT intervals measured to the apex and to the end of the T wave (QTe) plotted against RR intervals was calculated using a dedicated Holter algorithm. The value of QT/RR in predicting sudden death and total mortality was compared with those of ejection fraction, heart rate variability, and late potentials. Mean follow-up was 81 +/- 27 months. There were 73 deaths, of which 23 were sudden. Of all the parameters, an increased diurnal QTe/RR slope (>0.18) was the strongest independent predictor of sudden death (relative risk 6.07, confidence interval 1.48-24.95, P = 0.01). CONCLUSION: Increased diurnal QTe dynamicity is independently predictive of sudden death among patients with myocardial infarction. This simple parameter may help to stratify risk and select patients who may benefit from antiarrhythmic prophylaxis.     

The value of QT interval dispersion for identification of total mortality risk in non-insulin-dependent diabetes mellitus

Sawicki PT, Kiwitt S, Bender R, Berger M (Heinrich-Heine University of Düsseldorf, Düsseldorf; Germany). The value of QT interval dispersion for identification of total mortality risk in non-insulin-dependent diabetes mellitus. J Intern Med 1998; 243 : 49–56.  

Objectives

To delineate different risk markers including the difference between the maximum and the minimum length of the QT interval in ECG corrected for heart rate (QTc dispersion) as predictors of total, cardiac and cerebrovascular mortality in NIDDM patients.  

Design

Case-control, follow-up study until death or for a period of 15 to 16 years.  

Setting

Tertiary care centre, University Hospital of Düsseldorf, Germany.  

Subjects

216 unselected consecutive NIDDM patients.  

Main outcome measures

Total, cardiac, and cerebrovascular mortality.  

Results

During the follow-up 158 (73%) patients died. In the Cox proportional hazards model QTc dispersion was the most important independent predictor of total mortality (risk ratio (RR) 3.3; difference for RR: 0.05 s^1/2; P = 0.001). Additional independent risk markers were age, male sex, systolic blood pressure, diabetic retinopathy, micro- or macroproteinuria, total serum cholesterol and HDL cholesterol. The QTc dispersion was also an independent predictor of cardiac and cerebrovascular mortality.  

Conclusions

The results of this long-term follow-up study indicate that QT dispersion in a routine ECG is a useful marker to identify NIDDM patients with a high mortality risk.     

Prognostic value of plasma MR-proADM vs NT-proBNP for heart failure in people with type 2 diabetes: the SURDIAGENE prospective study

Aims/hypothesis

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is the gold standard prognostic biomarker for diagnosis and occurrence of heart failure. Here, we compared its prognostic value for the occurrence of congestive heart failure with that of plasma mid-region pro-adrenomedullin (MR-proADM), a surrogate for adrenomedullin, a vasoactive peptide with vasodilator and natriuretic properties, in people with type 2 diabetes.

Methods

Plasma MR-proADM concentration was measured in baseline samples of a hospital-based cohort of consecutively recruited participants with type 2 diabetes. Our primary endpoint was heart failure requiring hospitalisation.

Results

We included 1438 participants (age 65?±?11 years; 604 women and 834 men). Hospitalisation for heart failure occurred during follow-up (median 64 months) in 206 participants; the incidence rate of heart failure was 2.5 (95% CI 2.2, 2.9) per 100 person-years. Plasma concentrations of MR-proADM and NT-proBNP were significantly associated with heart failure in a Cox multivariable analysis model when adjusted for age, diabetes duration, history of coronary heart disease, proteinuria and baseline eGFR (_adjHR [95%CI] 1.83 [1.51, 2.21] and 2.20 [1.86, 2.61], respectively, per 1 SD log₁₀ increment, both p?<?0.001). MR-proADM contributed significant supplementary information to the prognosis of heart failure when we considered the clinical risk factors (integrated discrimination improvement [IDI, mean ± SEM] 0.021?±?0.007, p?=?0.001) (Table 3). Inclusion of NT-proBNP in the multivariable model including MR-proADM contributed significant complementary information on prediction of heart failure (IDI [mean ± SEM] 0.028?±?0.008, p?<?0.001). By contrast, MR-proADM did not contribute supplementary information on prediction of heart failure in a model including NT-proBNP (IDI [mean ± SEM] 0.003?±?0.003, p?=?0.27), with similar results for heart failure with reduced ejection fraction and preserved ejection fraction.

Conclusions/interpretation

MR-proADM is a prognostic biomarker for heart failure in people with type 2 diabetes but gives no significant complementary information on prediction of heart failure compared with NT-proBNP.

     

Effect of long-term treatment with rosiglitazone on arterial elasticity and metabolic parameters in patients with Type 2 diabetes mellitus: a 2-year follow-up study.

AIMS: Thiazolidinediones may influence the atherogenic process by improving cardiovascular risk factors. The present study was designed to determine the long-term effect of rosiglitazone on arterial compliance and metabolic parameters in patients with Type 2 diabetes. METHODS: In an open-label, prospective study, 65 diabetic patients received rosiglitazone orally (4-8 mg/day) for 6 months. After 6 months, the patients continued an open follow-up study and were divided into two groups: group 1 included patients continuing rosiglitazone for 2 years, group 2 included patients discontinuing rosiglitazone and receiving other oral glucose-lowering agents. Lipid profile, glycated haemoglobin (HbA1c), insulin, C-peptide, fibrinogen, high-sensitivity-CRP and homeostasis model assessment-insulin resistance were measured. Arterial elasticity was assessed using pulse wave contour analysis. RESULTS: In patients treated with rosiglitazone for 2 years: the large artery elasticity index (LAEI) increased from 10.0 +/- 4.6 to 13.9 +/- 4.7 ml/mmHg x 100 after 2 years (P = 0.003). The small artery elasticity (SAEI) index increased significantly from 3.2 +/- 1.2 to 5.1 +/- 1.9 (P < 0.0001). In patients who discontinued rosiglitazone: LAEI did not change after 6 months, but decreased from 12.1 +/- 5.4 to 8.9 +/- 3.9 ml/mmHg x 10 (P < 0.0001) at the end of 2 years. SAEI increased during the first 6 months of treatment, from 3.9 +/- 1.8 to 5.1 +/- 1.5 ml/mmHg x 100 (P < 0.0001) and decreased after discontinuation of rosiglitazone (P = 0.042). CONCLUSIONS: Prolonged treatment with rosiglitazone improved arterial elasticity. However, significant deterioration in LAEI and SAEI was observed in patients who discontinued rosiglitazone. The beneficial vascular effect of rosiglitazone on arterial elasticity was independent of glycaemic control.     

Chronic hepatitis C and type II diabetes mellitus: a prospective cross-sectional study

An epidemiologic link between chronic hepatitis C (HCV) and type II diabetes mellitus (DM) has been established. Our aims were to prospectively determine the prevalence of DM in interferon-naive patients with HCV in comparison with the general population, and to determine the association between DM and impaired fasting glucose (IFG) with histological stage in patients with HCV. A consecutive sample of 179 patients was included in this prospective cross-sectional study. The crude percentage of DM for the cohort was 14.5%, different from the crude rate of 7.8% for the general population (p= 0.0008) and from the rate of 7.3% observed in a matched control group with non-HCV liver disease. The prevalence of DM and IFG (DM/IFG) was higher among HCV-infected patients with advanced versus those with early histological disease (p= 0.0004). Advanced histological disease predicted DM/IFG after controlling for other identified risk factors for DM. Family history was the only other independent predictor of DM/IFG in HCV-infected patients. In conclusion, patients with HCV had a higher prevalence of DM compared to the general population. The presence of advanced histological disease in genetically predisposed HCV-patients is associated with a higher prevalence of DM/IFG. DM and IFG were not associated with anthropomorphic markers of obesity in HCV patients, suggesting a unique multifactorial pathogenesis of DM in HCV.     

QT interval analysis in patients with chronic liver disease: a prospective study

In previous studies, it has been shown that QT interval prolongation is related to an increased mortality rate in chronic liver disease (CLD). But QT dispersion (QTd) and its clinical significance in CLD has not been well studied. The objectives of this study were to investigate the relation between QTd and severity of the disease and determine its prognostic value in cirrhotic patients. Thirty-three consecutive patients with cirrhosis and 35 sex- and age-matched healthy subjects were studied. QT intervals and QT dispersions were measured on admission, and all intervals were corrected for heart rate according to Bazett's formula. The authors analyzed the potential relationship between QT parameters and the disease severity according to Child-Pugh classification and compared these values between survivors and nonsurvivors after a 3-year follow-up. Child-Pugh classification is used to assess liver function in cirrhosis. Corrected QT (QTc) prolongations were found in 32% of patients with cirrhosis and 5.7% of the healthy controls (p <0.001). The prevalence of increased (>70 ms) corrected QT dispersion (QTcd) was 45% in patients with cirrhosis. According to Child-Pugh criteria: QTd, maximum QT interval (QTmax), corrected QTmax (QTcmax), and QTcd in class C were significantly higher than those of class A and B (p <0.05, for all comparison). But there was no significant difference between class A and B in QTmax, QTcmax, QTd, and QTcd. There were 10 (30%) deaths from all causes during 3-year follow-up in the study group. Cox regression analysis showed that QTd and QTcd were better mortality indicators than QTmax and QTcmax, and Child's classification was the best predictor for mortality among all variables. In conclusion, QT dispersion and corrected QT dispersion parameters were better mortality indicators than other QT interval parameters and also may give additional prognostic information in patients with chronic liver disease.     

QT<Subscript>c</Subscript> interval and resting heart rate as long-term predictors of mortality in type 1 and type 2 diabetes mellitus: a 23-year follow-up

Aims/hypothesis We evaluated the association of QT interval corrected for heart rate (QT_c) and resting heart rate (rHR) with mortality (all-causes, cardiovascular, cardiac, and ischaemic heart disease) in subjects with type 1 and type 2 diabetes. Methods We followed 523 diabetic patients (221 with type 1 diabetes, 302 with type 2 diabetes) who were recruited between 1974 and 1977 in Switzerland for the WHO Multinational Study of Vascular Disease in Diabetes. Duration of follow-up was 22.6 ± 0.6 years. Causes of death were obtained from death certificates, hospital records, post-mortem reports, and additional information given by treating physicians. Results In subjects with type 1 diabetes QT_c, but not rHR, was associated with an increased risk of: (1) all-cause mortality (hazard ratio [HR] 1.10 per 10 ms increase in QT_c, 95% CI 1.02–1.20, p = 0.011); (2) mortality due to cardiovascular (HR 1.15, 1.02–1.31, p = 0.024); and (3) mortality due to cardiac disease (HR 1.19, 1.03–1.36, p = 0.016). Findings for subjects with type 2 diabetes were different: rHR, but not QT_c was associated with mortality due to: (1) all causes (HR 1.31 per 10 beats per min, 95% CI 1.15–1.50, p < 0.001); (2) cardiovascular disease (HR 1.43, 1.18–1.73, p < 0.001); (3) cardiac disease (HR 1.45, 1.19–1.76, p < 0.001); and (4) ischaemic heart disease (HR 1.52, 1.21–1.90, p < 0.001). Effect modification of QT_c by type 1 and rHR by type 2 diabetes was statistically significant (p < 0.05 for all terms of interaction). Conclusions/interpretation QT_c is associated with long-term mortality in subjects with type 1 diabetes, whereas rHR is related to increased mortality risk in subjects with type 2 diabetes.     

Multidisciplinary approach to patients with poorly controlled type 2 diabetes mellitus: a prospective,randomized study

Abstract. Practicing physicians as well as diabetes specialists are confronted with the often-frustrating experience of dealing with patients with poorly controlled diabetes. It is not always obvious why these patients fail to improve. The aims of this study were two-fold: (a) to determine if the interdisciplinary approach offered by the Western Negev Mobile Clinic Diabetes Program (WNMDCP) is of benefit in patients with poorly controlled type 2 diabetes and (b) to more fully characterize patients refractory to treatment. Two primary-care clinics of the Western Negev were randomly selected as control and intervention. All patients from both clinics with hemoglobin (HbA_1C) 10% (tested during June-July 2000) were studied for 6 months. Patients from the control clinic continued the usual treatment. Patients from the intervention clinic received the interdisciplinary approach offered by WNMCDP. The rate of improvement of diabetes control, measured as a decrease in HbA_1C values of at least 0.5%, and compliance to treatment were determined. Overall, 48 of 258 patients in the intervention clinic and 34 of 179 patients in the control clinic met the inclusion criteria. At the 6-month follow-up, we observed significant improvements in plasma glucose (-1.5 mmol/l; p=0.003) and HbA_1C (-1.8%; p=0.00001) in the intervention group but not in the control group. The compliance and response rates were 85% and 71% for the intervention group and 32% and 35% for the control group, respectively. Patients from the intervention clinic showed significant improvement in the endpoints compared to patients from the control clinic. More than 70% of patients with poorly controlled diabetes mellitus responded to the interdisciplinary treatment approach offered by WNMDCP. The group of non-responders comprised patients with poor compliance (15%) and those with serious concomitant diseases or limitations of mobility.     

Increased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus

OBJECTIVES: To study effects of insulin-induced hypoglycaemia on the cardiac repolarization, using QT interval measurements, in patients with type 2 diabetes. DESIGN: Hypoglycaemia was induced by an i.v. insulin-infusion and blood glucose was clamped at 2.7 mmol L-1 for 60 min (T = 90-150 min) in two experiments, with (+GLIB) and without (-GLIB) glibenclamide. In a third experiment, with similar hyperinsulinaemia, glucose was clamped at a euglycaemic level (;5 mmol L-1). ECG was continuously recorded for arrhythmia-monitoring, and 12-lead ECGs were recorded at T = 0 and 150 min. QT intervals were measured, and we determined QT dispersion (difference between the maximum and the minimum QT interval) reflecting interlead variability of repolarization. SUBJECTS: Thirteen patients with type 2 diabetes, on combined insulin and glibenclamide treatment, were studied during hypoglycaemia, and eight of them participated in the euglycaemic experiment. RESULTS: No significant arrhythmias were seen during hypoglycaemia but the mean QT intervals and QT dispersion increased significantly (P < 0.001), with no differences between -GLIB and +GLIB. During the euglycaemic clamp all QT measurements remained unchanged. Serum potassium decreased significantly (P < 0.001) during all three clamps, but the decrease was more pronounced during hypoglycaemia. The change in potassium was not correlated to the degree of QT prolongation or QT dispersion. CONCLUSIONS: Significant changes in the repolarization of the heart can be seen during hypoglycaemia in patients with type 2 diabetes, indicating an increased risk of arrhythmia at low blood glucose levels.     

老年2型糖尿病患者长期随访期间糖化血红蛋白控制达标的影响因素

目的 探讨老年2型糖尿病患者长期随访期间糖化血红蛋白(HbA1c)控制达标的影响因素。方法 选择2007年1月至2011年1月于中国人民解放军总医院第二医学中心住院,行动态血糖监测的200例老年男性2型糖尿病患者为研究对象。根据年龄(60岁≤年龄<70岁57例、70岁≤年龄<80岁51例、年龄≥80岁92例)、糖尿病病程(病程<10年57例、10年≤病程<20年89例、病程≥20年54例)、基线HbA1c(HbA1c<6.5%74例、6.5%≤HbA1c<7.5%72例、HbA1c≥7.5%54例)分别将患者分为3组。比较不同组别患者长期随访期间HbA1c水平的差异。采用SPSS 13.0统计软件进行数据分析。根据数据类型,分别采用方差分析或χ²检验进行组间比较。采用logistic回归分析随访期间HbA1c控制达标的影响因素。结果 平均随访12.5年。不同年龄组随访期间HbA1c均值、HbA1c控制达标率差异无统计学意义(P＞0.05);与糖尿病病程<10年组比较,糖尿病病程≥20年组随访期间HbA1c均值升高(P<0.01),HbA1c控制达标率降低(P<0.05);随着基线HbA1c增加,随访期间HbA1c均值逐渐增加(P<0.01),HbA1c控制达标率逐渐降低(P<0.01)。单因素logistic回归分析显示,糖尿病病程、基线HbA1c、空腹血糖、餐后2h血糖、血糖波动、胰岛素治疗是随访期间HbA1c控制达标的影响因素(P<0.01)。非条件多因素logistic回归分析提示,基线HbA1c(OR=5.73,95%CI 3.02~10.88,P<0.001)是随访期间HbA1c控制达标最重要的影响因素。结论 糖尿病病程、基线HbA1c、空腹血糖、餐后2h血糖、血糖波动、胰岛素治疗是老年2型糖尿病随访期间HbA1c控制达标的影响因素,其中基线HbA1c是最重要的影响因素。     

Smoking cessation predicts amelioration of microalbuminuria in newly diagnosed type 2 diabetes mellitus: a 1-year prospective study

The objective of the study was to assess the effect of smoking cessation on microalbuminuria in subjects with newly diagnosed type 2 diabetes mellitus (DM). From 500 smokers newly diagnosed with type 2 DM and microalbuminuria, only 193 (96 men/97 women; age, 56.4 ± 7.8 years) agreed to participate and were educated on smoking cessation, diet, and exercise. Pharmacological interventions were not different among the studied groups. All subjects were contacted by phone monthly with emphasis on smoking cessation. Anthropometric, biochemical parameters and urine specimens were obtained at baseline and at 12-month follow-up. Microalbuminuria was defined as an albumin to creatinine ratio of 30 to 299.9 μg/mg creatinine. Ankle brachial pressure index was determined by ultrasound. A total of 120 (62.2%) subjects quit smoking. Prevalence of microalbuminuria was reduced at 1 year to 72.6% in the subjects who quit smoking and to 22.5% in those who continued smoking (P = .015). Multivariate logistic regression analysis demonstrated that independently associated with the reduction in albumin to creatinine ratio (84.8 vs 28.7 μg/mg creatinine) were amelioration of glycemic control (P < .001), blood pressure (P = .02), dyslipidemia (P = .02), and insulin resistance (P = .05). Smoking cessation also reduced the prevalence of peripheral vascular disease (P = .03) and neuropathy (P = .04). From the pharmacological and lifestyle interventions, smoking cessation had the highest and an independent contribution to the reduction of microalbuminuria (P < .001). Smoking cessation in newly diagnosed type 2 DM patients is associated with amelioration of metabolic parameters, blood pressure, and the reduction of microalbuminuria. Stricter counseling about the importance of quitting smoking upon type 2 DM diagnosis is necessary to protect against the development of diabetic nephropathy and vascular complications.     

QT interval dispersion analysis in patients with aortic valve stenosis: a prospective study

BACKGROUND AND AIM OF THE STUDY: QT interval dispersion (QTd) was analyzed in patients with aortic valve stenosis, and the relationship investigated between QTd, age, gender, hypertension, presence of significant coronary artery stenosis and left ventricular (LV) hypertrophy assessed by echocardiography. Results were also compared between survivors and patients who had cardiac arrest or died before, during or soon after cardiac surgery. METHODS: The group comprised 535 consecutive patients (217 women, 318 men; mean age 59 +/- 11 years; range: 20-81 years) with significant aortic valve stenosis before valve replacement. The control group comprised 35 healthy subjects (12 women, 23 men; mean age 51 +/- 11 years; range: 28-74 years). RESULTS: Mean QTd was 29 +/- 10 ms in controls and 59 +/- 24 ms in patients (p < 0.001). Gender had no impact on QTd. QTd was increased in men with significant coronary artery stenosis, and independently related strongly with ECG parameters (QTmax, heart rate) and weakly with age and degree of LV hypertrophy. In patients with cardiac arrest or those who died (n = 14), QTd was increased compared to that in survivors (71 +/- 22 versus 59 +/- 24 ms; p = 0.05), and QTd >70 ms was observed more frequently (p = 0.02; odds ratio 3.4, 1.16-10.0). CONCLUSION: QTd is abnormally increased in two-thirds of patients with aortic valve stenosis, and is increased in men with concomitant coronary artery disease. QTd >70 ms significantly increased the risk of cardiac arrest or death perioperatively. QTd was only weakly related with age and degree of LV hypertrophy, but QTmax and heart rate had a greater impact. QT dispersion analysis has limited clinical value in patients with aortic stenosis.