Long- but not short-term multifactorial intervention with focus on exercise training improves coronary endothelial dysfunction in diabetes mellitus type 2 and coronary artery disease.

AIMS: Patients with type 2 diabetes mellitus (T2DM) suffer from accelerated coronary artery disease. We assessed the effects of a multifactorial intervention with focus on exercise training on coronary endothelial function, vascular structure, and inflammation in serum and skeletal muscle biopsies, including mRNA expression of diabetes candidate genes. METHODS AND RESULTS: Twenty-three patients were randomized to either 4 weeks in-hospital exercise training (6 x 15 min bicycle/day, 5 days/week) and a hypocaloric diet, followed by a 5 months ambulatory program (30 min ergometer/day, 5 days/week, plus 1 h group exercise/week), or a control group. At the beginning of the study, at 4 weeks, and after 6 months changes in diameter of coronary arteries in response to acetylcholine and mean peak flow velocity were invasively measured; intramural plaques were assessed by intravascular ultrasound. Six months of intervention led to significant improvement of coronary endothelial function, whereas intramural plaque burden remained unchanged. After 4 weeks, endothelial function remained unchanged, however, lowest values for fasting glucose, HbA1c, high-sensitive C-reactive protein, total and LDL-cholesterol, and highest values for mRNA expression in skeletal muscle of p22, gp91, haem oxygenase 1, peroxisome proliferator activator receptor (PPAR) alpha and gamma were observed. There was a continuous increase for AdipoR1, AdipoR2, Glut4, interleukin-6, endothelial nitric oxide synthase, and PPARgamma-coactivator-1alpha mRNA expression in skeletal muscle. CONCLUSION: This is the first study to demonstrate improvement in coronary endothelial function by a multifactorial intervention which focused on exercise training in patients with T2DM. This coincided with improved markers of hyperglycaemia, insulin sensitivity, and inflammation both in serum and skeletal muscle biopsies.

Effect of increased exercise in school children on physical fitness and endothelial progenitor cells: a prospective randomized trial.

BACKGROUND: The aim of this prospective, randomized study was to examine whether additional school exercise lessons would result in improved peak oxygen uptake (primary end point) and body mass index-standard deviation score, motor and coordinative abilities, circulating progenitor cells, and high-density lipoprotein cholesterol (major secondary end points). METHODS AND RESULTS: Seven sixth-grade classes (182 children, aged 11.1+/-0.7 years) were randomized to an intervention group (4 classes with 109 students) with daily school exercise lessons for 1 year and a control group (3 classes with 73 students) with regular school sports twice weekly. The significant effects of intervention estimated from ANCOVA adjusted for intraclass correlation were the following: increase of peak o(2) (3.7 mL/kg per minute; 95% confidence interval, 0.3 to 7.2) and increase of circulating progenitor cells evaluated by flow cytometry (97 cells per 1 x 10(6) leukocytes; 95% confidence interval, 13 to 181). No significant difference was seen for body mass index-standard deviation score (-0.08; 95% confidence interval, -0.28 to 0.13); however, there was a trend to reduction of the prevalence of overweight and obese children in the intervention group (from 12.8% to 7.3%). No treatment effect was seen for motor and coordinative abilities (4; 95% confidence interval, -1 to 8) and high-density lipoprotein cholesterol (0.03 mmol/L; 95% confidence interval, -0.08 to 0.14). CONCLUSIONS: Regular physical activity by means of daily school exercise lessons has a significant positive effect on physical fitness (o(2)max). Furthermore, the number of circulating progenitor cells can be increased, and there is a positive trend in body mass index-standard deviation score reduction and motor ability improvement. Therefore, we conclude that primary prevention by means of increasing physical activity should start in childhood. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Identifier: NCT00176371.

Does dysfunction of the autonomic nervous system affect success of renal denervation in reducing blood pressure?

OBJECTIVES: Renal denervation is an interventional approach aiming to reduce high blood pressure. Its efficacy is subject of controversial debate. We analyzed autonomic function in patients undergoing renal denervation to identify responders. METHODS: A total of 21 patients with treatment-resistant hypertension scheduled for renal denervation were included. Heart rate variability, pupillary function and sympathetic skin response were examined prior to intervention. Before and 1 or 3 months after intervention, 24-h ambulatory blood pressure readings were taken. RESULTS: Patients were stratified according to sympathetic nervous system function. Sympathetic activity was reduced in 12 participants (group 1) and normal or enhanced in nine patients (group 2). The mean of daytime systolic blood pressure decreased in groups 1 and 2 from 168 to 157 mmHg (95% confidence interval for difference, 1-21 mmHg, p = 0.035) and from 166 to 145 mmHg (8-34 mmHg, p = 0.005), respectively. In a linear model, blood pressure reduction was 11.3 mmHg (0.3-22 mmHg) greater in group 2 than in group 1 (p = 0.045). CONCLUSION: Patients with preexisting reduced activity of the sympathetic nervous system benefited less from renal denervation.

Randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension.

UNLABELLED: Few data are available with regard to the effectiveness of renal sympathetic denervation in patients with resistant hypertension yet only mildly elevated blood pressure (BP). Patients with resistant hypertension and slightly elevated BP (day-time systolic pressure, 135-149 and diastolic pressure, 90-94 mm Hg on 24-hour ambulatory measurement) were randomized in a 1:1 ratio to renal sympathetic denervation with the Symplicity Flex Catheter (Medtronic) or an invasive sham procedure. The primary efficacy end point was the change in 24-hour systolic BP at 6 months between groups in the intention to treat population. A total of 71 patients underwent randomization. Baseline day-time systolic BP was 144.4±4.8 mm Hg in patients assigned to denervation and 143.0±4.7 mm Hg in patients randomized to the sham procedure. The mean change in 24-hour systolic BP in the intention to treat cohort at 6 months was -7.0 mm Hg (95% confidence interval, -10.8 to -3.2) for patients undergoing denervation and -3.5 mm Hg (95% confidence interval, -6.7 to -0.2) in the sham group (P=0.15). In the per protocol population, the change in 24-hour systolic BP at 6 months was -8.3 mm Hg (95% confidence interval, -11.7 to -5.0) for patients undergoing denervation and -3.5 mm Hg (95% confidence interval, -6.8 to -0.2) in the sham group (P=0.042). In patients with mild resistant hypertension, renal sympathetic denervation failed to show a significant reduction in the primary end point of 24-hour systolic BP at 6 months between groups in the intention to treat analysis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01656096.

Effect of cocoa products on blood pressure: systematic review and meta-analysis.

BACKGROUND: Cocoa products such as dark chocolate and cocoa beverages may have blood pressure (BP)-lowering properties due to their high content of plant-derived flavanols. METHODS: We performed a meta-analysis of randomized controlled trials assessing the antihypertensive effects of flavanol-rich cocoa products. The primary outcome measure was the change in systolic and diastolic BP between intervention and control groups. RESULTS: In total, 10 randomized controlled trials comprising 297 individuals were included in the analysis. The populations studied were either healthy normotensive adults or patients with prehypertension/stage 1 hypertension. Treatment duration ranged from 2 to 18 weeks. The mean BP change in the active treatment arms across all trials was -4.5 mm Hg (95% confidence interval (CI), -5.9 to -3.2, P < 0.001) for systolic BP and -2.5 mm Hg (95% CI, -3.9 to -1.2, P < 0.001) for diastolic BP. CONCLUSIONS: The meta-analysis confirms the BP-lowering capacity of flavanol-rich cocoa products in a larger set of trials than previously reported. However, significant statistical heterogeneity across studies could be found, and questions such as the most appropriate dose and the long-term side effect profile warrant further investigation before cocoa products can be recommended as a treatment option in hypertension.

Low vs. higher-dose dark chocolate and blood pressure in cardiovascular high-risk patients.

BACKGROUND: Dark chocolate may have blood pressure-lowering properties. We conducted a prospective randomized open-label blinded end-point design trial to study a potential dose dependency of the presumed antihypertensive effect of dark chocolate by directly comparing low vs. higher doses of dark chocolate over the course of 3 months. METHODS: We enrolled a total of 102 patients with prehypertension/stage 1 hypertension and established cardiovascular end-organ damage or diabetes mellitus. Patients were randomly assigned to receive either 6 or 25 g/day of flavanol-rich dark chocolate for 3 months. The difference in 24-h mean blood pressure between groups was defined as the primary outcome measure. RESULTS: Significant reductions in mean ambulatory 24-h blood pressure were observed between baseline and follow-up in both groups (6 g/day: -2.3 mm Hg, 95% confidence interval -4.1 to -0.4; 25 g/day: -1.9 mm Hg, 95% confidence interval -3.6 to -0.2). There were no significant differences in blood pressure changes between groups. In the higher-dose group, a slight increase in body weight was noted (0.8 kg, 95% confidence interval 0.06 to 1.6). CONCLUSIONS: The findings are consistent with the hypothesis that dark chocolate may be associated with a reduction in blood pressure (BP). However, due to the lack of a control group, confounding may be possible and the results should be interpreted with caution.

Effects of extended-release niacin on lipid profile and adipocyte biology in patients with impaired glucose tolerance.

BACKGROUND: Low high-density lipoprotein cholesterol (HDL-C) serum concentrations are independent risk factors for the development of coronary artery disease. In patients with the metabolic syndrome, low HDL-C can contribute to premature atherosclerosis. Extended-release (ER) niacin increases HDL-C and was shown to slow the progression of atherosclerosis. Adipose tissue is an important site of niacin action. Here we sought to determine potential pleiotropic effects of ER niacin on adipose tissue biology in patients with impaired glucose tolerance (IGT). METHODS AND RESULTS: Thirty patients with IGT (mean age=45.2+/-3.9 years), low HDL-C serum concentrations (HDL-C <1.0 mmol/l), but no additional comorbidities were treated once-daily with ER niacin (1000 mg) in a randomized open-label controlled (n=30) study for 6 months. During the first 4 weeks, daily dose was increased from 375 to 1000 mg in weekly intervals. At baseline and after 6 months, subcutaneous adipose tissue biopsies were taken, body fat mass, insulin sensitivity (euglycemic-hyperinsulinemic clamp), and adipokine serum concentrations were measured. After 6 months of ER niacin treatment, HDL-C increased significantly by 24% and adiponectin by 35%. In addition, ER niacin significantly reduced circulating lipoprotein (a) by 38% (p<0.001) and fasting triglycerides by 12% (p<0.05). Whole-body insulin sensitivity increased in the ER niacin treatment group, although this trend was not statistically significant (p=0.085). Six months ER niacin led to a significant reduction in mean adipocyte size associated with increased insulin sensitivity in isolated adipocytes and gene expression changes including increased adiponectin, C/EBPalpha, C/EBPdelta, PPARgamma and decreased carnitine palmitoyl transferase 2, hormone sensitive lipase, nicotinic acid receptor (GPR109B) and fatty-acid synthase mRNA expression. CONCLUSION: Treatment with ER niacin significantly improves atherogenic lipid profile in patients with IGT. These beneficial effects could at least in part be due to pleiotropic niacin effects in adipose tissue, characterized by decreased mean adipocyte size, increased insulin sensitivity and altered mRNA expression profile.

Exercise training but not rosiglitazone improves endothelial function in prediabetic patients with coronary disease.

BACKGROUND: Impaired glucose tolerance (IGT) is associated with endothelial dysfunction and upregulation of inflammatory markers, which is potentially reversible by adequate treatment. It was our aim to compare the impact of exercise training with that of rosiglitazone on endothelial function and inflammatory markers in patients with IGT and coronary artery disease (CAD). METHODS: Patients with IGT and CAD were randomly assigned to either exercise training (n=13), rosiglitazone (8 mg; n=11), or a control group (n=10). During the first week, exercise training consisted of 6 x 15 min/d followed by three weeks of 30 min/d submaximal ergometer exercise. In addition, group exercise training of 1 h was performed twice per week. RESULTS: After 4 weeks, triglycerides and uric acid were significantly lower in the exercise group whereas fasting glucose, HbA1c, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, C-reactive protein, fibrinogen, and body mass index did not differ between groups. In the exercise group, exercise capacity (123+/-33 vs. 144+/-31 W; P=0.006) and endothelium-dependent, flow-mediated vasodilatation (P<0.01) increased significantly, whereas in the rosiglitazone group and in the control group (P=n.s.) no changes were seen. CONCLUSION: In patients with IGT and CAD, 4 weeks of exercise training exert significant and superior improvement of endothelium-dependent vasodilatation as compared with rosiglitazone therapy or usual care. This finding should be seen as an even further encouragement to recommend and, where available, prescribe exercise training to our patients.

Long-term exercise training decreases interleukin-6 (IL-6) serum levels in subjects with impaired glucose tolerance: effect of the -174G/C variant in IL-6 gene.

OBJECTIVE: Exercise training has been shown to have anti-inflammatory effects in patients with type 2 diabetes. Changes in interleukin-6 (IL-6) serum concentrations in response to training could contribute to these beneficial effects. However, there are heterogeneous data on whether circulating IL-6 is altered by exercise training. We therefore hypothesize that genetic factors modify the individual changes in IL-6 levels after long-term training. RESEARCH DESIGN AND METHODS: The -174G/C variant in the IL-6 gene was genotyped in 60 subjects with impaired glucose tolerance. For a 12-month interventional study, patients were randomized into three groups: a control group (n=16) was compared with one group, which underwent a standardized training program (n=24) and another group, which was treated with 4 mg rosiglitazone once daily (n=20). At baseline, after 1, 6, and 12 months, we measured anthropometric parameters and serum concentration of IL-6 and, at baseline and after 12 months, we determined glucose tolerance and fitness level. RESULTS: Only in subjects carrying the SNP -174C allele did long-term exercise training result in significantly reduced IL-6 serum concentrations. Multivariate linear regression analysis identified the IL-6 genotype as a significant predictor of changes in IL-6 serum concentrations independent of age, gender and improvement in body mass index, hemoglobin (Hb)A(1c), and fitness level in response to training. CONCLUSIONS: Genetic variants in the IL-6 gene significantly modify changes in IL-6 serum concentrations in response to long-term exercise training programs. Our data suggest that genetic factors are important determinants for the individual response to anti-inflammatory effects of exercise training.

Increasing physical education in high school students: effects on concentration of circulating endothelial progenitor cells.

AIMS: Levels of endothelial progenitor cells (EPCs), that can be increased by regular exercise, correlate with vascular function. In the context of primary prevention, the impact of regular physical activity on the amount and function of EPC has not yet been investigated in school children. METHODS: Four sixth grade classes of high school students (n=92) were randomly assigned to either the intervention group (IG) with daily physical exercise (45 min) at school or to the control group (CG) with conventional physical education (PE) (2 h/week). In addition, one sixth grade class at a high school focused on competitive sports (PE) served as a reference group. After 1 school year, exercise capacity and the amount and function of EPCs were evaluated. RESULTS: After 1 year, a significantly higher Vo2max was evident in the intervention group. Nevertheless, exercise capacity did not reach the level of children from PE. In addition, exercise intervention was successful in increasing the amount of EPCs but failed to increase the migratory capacity of the cells. CONCLUSION: The result of this study shows, that intensified, supervised school sports leads to an increase in exercise capacity and EPCs in children. Nevertheless, its effect on primary prevention in cardiovascular disease has to be proven in further longitudinal studies.

High, but not moderate frequency and duration of exercise training induces downregulation of the expression of inflammatory and atherogenic adhesion molecules.

BACKGROUND: Lifestyle changes which include daily exercise training have been shown to slow the progression of coronary artery disease. We designed a study to examine the effects of a multifactorial intervention on atherogenic adhesion molecules on the surface of monocytes in patients with coronary artery disease. METHODS: We randomized 39 patients with coronary artery disease to (i) an intervention program which consisted of 4 weeks of daily 6x15 min ergometer training at submaximal intensity in addition to a 1 h/week group exercise session, followed by 5 months of home-based ergometer training of 30 min/day again in addition to a 1 h/week group exercise session or (ii) conventional therapy. All patients received a statin. Monocyte-bound cellular adhesion molecules LFA-1 (CD11a), MAC-1 (CD11b), VLA-4 (CD49d) and L-selectin (CD62L) were assessed by fluorescence activated cell sorting analysis. RESULTS: After 4 weeks the multifactorial intervention led to a significant improvement of maximal work capacity, lipid profile, body mass index, blood pressure, fasting glucose and hemoglobin A1c. This was associated with a reduced expression of MAC-1 and VLA-4. After 5 months of a home-based intervention the beneficial effects of the cardiovascular risk profile were still apparent, whereas the effects on the expression of adhesion molecules were blunted. CONCLUSION: In patients treated with statins, 4 weeks of high frequency and long duration exercise training led to a diminished expression of atherogenic adhesion molecules MAC-1 und VLA-4. After 5 months of home-based exercise training of moderate frequency and duration, these effects were blunted. Our data suggest that our patients in cardiac rehabilitation programs might further benefit from the antiatherogenic effects of an even higher amount of exercise training.