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Background: Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction, but the molecular mechanisms still remain unclear. Whether exercise training (ET) along with which optimal modality can improve endothelial function is controversial. The present study used a hypertensive, diabetic-driven HFpEF animal model (ZSF1 rats) to determine whether different training modalities (moderate-continuous (MCT) and high-intensity interval training (HIIT)) could reverse endothelial dysfunction and to understand the underlying molecular mechanisms., Methods and Results: The development of HFpEF in ZSF1 obese animals was confirmed by echocardiography and hemodynamic measurements. Thereafter, animals were randomized into following groups: 1) sedentary, 2) 8 weeks of MCT, 3) 8 weeks of HIIT. ZSF1 lean animals served as control. In vitro measurement of endothelial function in aortic rings revealed significantly impaired endothelial-dependent and -independent vasodilation in HFpEF, which was reversed by MCT and HIIT. At the molecular level, the development of endothelial dysfunction was associated with a reduced expression / activation of endothelial nitric oxide synthase (eNOS), an increase in NADPH and activation of c-Jun N-terminal protein kinase (JNK), a reduced collagen I/III ratio and a reduced lining of the vessel wall by endothelial cells. ET primarily decreased NADPH oxidase expression, and JNK activation, elevated collagen I/III ratio while further improving aortic endothelial cell coverage., Conclusions: The present study provides evidence that endothelial dysfunction occurs in experimental HFpEF and that ET, independent of the studied training modality, reverses endothelial dysfunction and specific molecular alterations. ET may therefore provide an important therapeutic intervention for HFpEF patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

For decades, we have known that exercise training exerts beneficial effects on the human body, and clear evidence is available that a higher fitness level is associated with a lower incidence of suffering premature cardiovascular death. Despite this knowledge, it took some time to also incorporate physical exercise training into the treatment plan for patients with cardiovascular disease (CVD). In recent years, in addition to continuous exercise training, further training modalities such as high-intensity interval training and pyramid training have been introduced for coronary artery disease patients. The beneficial effect for patients with CVD is clearly documented, and during the last years, we have also started to understand the molecular mechanisms occurring in the skeletal muscle (limb muscle and diaphragm) and endothelium, two systems contributing to exercise intolerance in these patients. In the present review, we describe the effects of the different training modalities in CVD and summarize the molecular effects mainly in the skeletal muscle and cardiovascular system., (Copyright © 2017 the American Physiological Society.)

Purpose: Cigarette smoking is the main risk factor for chronic obstructive pulmonary disease and emphysema. However, evidence on the extrapulmonary effects of smoke exposure that precede lung impairments remains unclear at present, as are data on nonpharmacological treatments such as exercise training., Methods: Three groups of mice, including control (n = 10), smoking (n = 10), and smoking with 6 wk of high-intensity interval treadmill running (n = 11), were exposed to 20 wk of fresh air or whole-body cigarette smoke. Exercise capacity (peak oxygen uptake) and lung destruction (histology) were subsequently measured, whereas the heart, peripheral endothelium (aorta), and respiratory (diaphragm) and limb (extensor digitorum longus and soleus) skeletal muscles were assessed for in vivo and in vitro function, in situ mitochondrial respiration, and molecular alterations., Results: Smoking reduced body weight by 26% (P < 0.05) without overt airway destruction (P > 0.05). Smoking impaired exercise capacity by 15% while inducing right ventricular dysfunction by ~20%, endothelial dysfunction by ~20%, and diaphragm muscle weakness by ~15% (all P < 0.05), but these were either attenuated or reversed by exercise training (P < 0.05). Compared with controls, smoking mice had normal limb muscle and mitochondrial function (cardiac and skeletal muscle fibers); however, diaphragm measures of oxidative stress and protein degradation were increased by 111% and 65%, respectively (P < 0.05), but these were attenuated by exercise training (P < 0.05)., Conclusions: Prolonged cigarette smoking reduced exercise capacity concomitant with functional impairments to the heart, peripheral endothelium, and respiratory muscle that preceded the development of overt emphysema. However, high-intensity exercise training was able to reverse these smoke-induced extrapulmonary impairments.

Background: As adolescents rarely experience cardiovascular events, surrogate markers of atherosclerosis are useful to justify and monitor effects of primary prevention and therapy of risk factors. Endothelial function assessed by reactive hyperemic peripheral arterial tonometry (RH-PAT) resulting in a reactive hyperemic index (RHI) is a noninvasive method with limited data for use in children and adolescents., Methods and results: We performed a total of 931 RHI measurements in 445 high-school students, aged 10-17 years, over a time period of 5 years. Students were randomized by class to 60 min physical exercise (PE) at school daily (intervention group), or 2 units of 45-min PE weekly (control group). To characterize the factors influencing the RHI, anthropometry, cardiopulmonary exercise testing, blood cholesterol and quality of life were assessed and used to build mixed linear models. Main influential factors were age, with an increase of RHI from 1.53±0.42 in the youngest to 1.96±0.59 in the oldest students, sex, with higher values in girls, and physical activity. This increase adjusted by age and sex was estimated as 0.11 [0.08, 0.14] per year. RHI was higher in the intervention group by 0.09 [-0.05, 0.23] in comparison with the control group., Conclusions: If RH-PAT is used in research or as a clinical tool in adolescents, the shown age- and sex-dependence of RHI have to be taken in account.

Background: A reduction in number and function of endothelial progenitor cells (EPCs) occurs in both physiologic aging and chronic heart failure (CHF). We assessed whether disease and aging have additive effects on EPCs or whether beneficial effects of exercise training are diminished in old age., Methods: We randomized 60 patients with stable CHF and 60 referent controls to a training or a control group. To detect possible aging effects we included subjects below 55 (young) and above 65 years (older). Subjects in the training group exercised four times daily at 60% to 70% of VO2max for four weeks under supervision. At baseline and after the intervention the number and function of EPCs were assessed., Results: As compared with young referent controls, older referent controls showed at baseline a reduced EPC number (young: 190 ± 37 CD34/KDR positive cells/ml blood; older: 131 ± 26 CD34/KDR positive cells/ml blood; p < 0.05) and function (young: 230 ± 41 migrated cells/1000 plated cells; older: 185 ± 28 cells/1000 plated cells; p < 0.05). In young and older CHF patients EPC-number (young: 85 ± 21 CD34/KDR positive cells/ml blood; older: 78 ± 20 CD34/KDR positive cells/ml blood) and EPC-function (young: 113 ± 26 cells/1000 plated cells; older: 120 ± 27 cells/1000 plated cells) were impaired. As a result of exercise training, EPC function improved by 24% in older referent controls (p < 0.05), while it remained unchanged in young training referent controls and controls respectively. In young and older patients with CHF four weeks of exercise training resulted in a significant improvement in EPC numbers and EPC function (young: number +66% function +43%; p < 0.05; older: number +69% function +36%; p < 0.05). These results were accompanied by a significant increase in flow mediated dilatation in the training groups of young/older CHF patients and in older referent controls., Conclusions: Four weeks of exercise training are effective in improving EPC number and EPC function in CHF patients. These training effects were not impaired among older patients, emphasizing the potentials of rehabilitation interventions in a patient group where CHF has a high prevalence., (© The European Society of Cardiology 2015.)

Background: The noninvasive measurement of endothelial function is a very powerful tool to assess cardiovascular disease. Especially in children this is not an easy task, and therefore an easy method like the Endo-Pat device is helpful. Due to the still existing uncertainties of the validity of endothelial measurement by the Endo-PAT device in children, we thought to analyze the correlation between endothelial functional measurement by Endo-PAT, and the capability of HDL to modify nitric oxide (NO) production by phosphorylation of endothelial nitric oxide synthase at the stimulatory site (Ser(1177)) and the inhibitory site (Thr(495))., Methods: The reactive hyperemic index (RHI) was measured in 11 school children by the Endo-PAT device. HDL was isolated by ultracentrifugation, and the capability to stimulate eNOS phosphorylation was assessed in cell culture., Results: A close correlation between the RHI and the eNOS-Ser(1177) phosphorylation (r=0.66, p=0.02) and the eNOS-Thr(495) phosphorylation (r=-0.60, p=0.04) was detected., Conclusion: The results obtained in our limited study performed in healthy children supports the validity of endothelial function measurement in children using the Endo-PAT device. Nevertheless, studies measuring FMD and the RHI index need to confirm the strength of the Endo-Pat device also in children., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Exercise training partially corrects endothelial dysfunction in patients with coronary artery disease (CAD). Growth factors like vascular endothelial growth factor (VEGF) as well as erythropoietin (EPO) are known to modulate the bioavailability of nitric oxide and, thereby, contribute to the maintenance of a normal vascular tone. The aim of the present study was to determine the impact of 4 weeks of exercise training on circulating growth factors and to elucidate their involvement in the training-induced changes in vasomotion in patients with CAD., Methods and Results: A total of 39 patients were enrolled (training group: n = 20; control group: n = 19). At start of study and after 4 weeks, average peak flow velocity (APV) of the left internal mammary artery (LIMA) in response to acetylcholine was measured invasively in the treatment and control groups. Serum concentrations of VEGF and EPO were determined by enzyme-linked immunosorbent assay. After exercise training, LIMA APV in response to acetylcholine was increased by 93% (from 69 ± 17% at start of study to 133 ± 16% at 4 weeks, p < 0.01 vs. start of study and control). At start of study, there was no association between any of the vascular growth factors and endothelial function. However, after exercise training a close correlation was apparent between the acetylcholine-induced change in APV and EPO (r = 0.69, p < 0.01) and VEGF (r = 0.76, p < 0.01) serum concentrations. In the control group, these correlations were not evident and there was no change in endothelial function either., Conclusion: Exercise training improves agonist-mediated endothelium-dependent vasodilatation in CAD, partially through a restoration of the endothelial response to EPO and VEGF.

Background: The full impact of statins on patients with chronic heart failure (CHF) is unknown. Therefore, we aimed to evaluate the pleiotropic effects of rosuvastatin on vascular and tissue regeneration, its impact on endothelial function and hemodynamics in CHF., Methods: Forty-two patients with CHF (LVEF 30±1%) were randomized to 12 weeks of oral rosuvastatin (40 mg/d) or placebo. At baseline and at 12 weeks, VEGF and oxidized LDL (oxLDL) were assessed by ELISA. Circulating endothelial progenitor cells (CPCs) were quantified using FACS. CPC function was determined by matrigel assay. Number of CD34(+) stem cells and capillary density were measured in skeletal muscle (SM). Flow-mediated dilatation (FMD) and left ventricular (LV) function were determined by ultrasound., Results: Rosuvastatin increased VEGF by +43% (p=0.004 vs. placebo) and decreased oxLDL by -27% (p=0.04 vs. placebo). This was associated with an elevation in CPC count by +224% (p=0.04 vs. placebo) and an augmentation of CPC integrative capacity by +91% (p=0.03 vs. placebo). Capillary density increased by +14% (p<0.001 vs. placebo), which was associated with an enhanced homing of CD34(+) stem cells. Rosuvastatin improved FMD by +163% (p<0.001 vs. placebo) and enhanced ejection fraction by +27% (p<0.001 vs. placebo)., Conclusion: In CHF, rosuvastatin activates CPCs that contribute to neovascularisation and to the enhancement of endothelial function. Correction of vascular abnormalities leads in part to an increase in LV function. Therefore, rosuvastatin's non-lipid effects may have the potential to promote endogenous tissue regeneration and improve LV performance in CHF., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Attenuated peripheral perfusion in patients with advanced chronic heart failure (CHF) is partially the result of endothelial dysfunction. This has been causally linked to an impaired endogenous regenerative capacity of circulating progenitor cells (CPC). The aim of this study was to elucidate whether exercise training (ET) affects exercise intolerance and left ventricular (LV) performance in patients with advanced CHF (New York Heart Association class IIIb) and whether this is associated with correction of peripheral vasomotion and induction of endogenous regeneration., Methods and Results: Thirty-seven patients with CHF (LV ejection fraction 24+/-2%) were randomly assigned to 12 weeks of ET or sedentary lifestyle (control). At the beginning of the study and after 12 weeks, maximal oxygen consumption (Vo(2)max) and LV ejection fraction were determined; the number of CD34(+)/KDR(+) CPCs was quantified by flow cytometry and CPC functional capacity was determined by migration assay. Flow-mediated dilation was assessed by ultrasound. Capillary density was measured in skeletal muscle tissue samples. In advanced CHF, ET improved Vo(2)max by +2.7+/-2.2 versus -0.8+/-3.1 mL/min/kg in control (P=0.009) and LV ejection fraction by +9.4+/-6.1 versus -0.8+/-5.2% in control (P<0.001). Flow-mediated dilation improved by +7.43+/-2.28 versus +0.09+/-2.18% in control (P<0.001). ET increased the number of CPC by +83+/-60 versus -6+/-109 cells/mL in control (P=0.014) and their migratory capacity by +224+/-263 versus -12+/-159 CPC/1000 plated CPC in control (P=0.03). Skeletal muscle capillary density increased by +0.22+/-0.10 versus -0.02+/-0.16 capillaries per fiber in control (P<0.001)., Conclusions: Twelve weeks of ET in patients with advanced CHF is associated with augmented regenerative capacity of CPCs, enhanced flow-mediated dilation suggestive of improvement in endothelial function, skeletal muscle neovascularization, and improved LV function. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00176384.

Occurrence of endothelial dysfunction is primarily the result of a reduction in nitric oxide bioavailability. Besides pharmacological approaches, lifestyle interventions with various forms of exercise training have the potential to partially correct endothelial dysfunction in many cardiovascular diseases. A normal endothelial function also depends on the balance between loss of endothelial cells and regeneration by circulating progenitor cells that are released from the bone-marrow. Nevertheless, exercise training also has the potential to increase the amount of endothelial progenitor cells and improve their migratory capacity, hence rejuvenating the endothelium. This review focuses on lifestyle interventions to correct endothelial dysfunction in different cardiovascular diseases.

The number of circulating stem cells with endothelial progenitor capacity (EPCs) inversely correlates with the number of cardiovascular risk factors. In this study we sought to investigate the effects of vascular H(2)O(2) on circulating EPC levels. In C57BL/6 mice 3 weeks of freely moving or forced physical activity or voluntary exercise failed to increase circulating EPCs defined as double positive for Flk-1 and CD34, CD133 or Sca-1. Likewise, neither insertion of additional genes encoding for catalase (cat(++)) or eNOS nor eNOS knock-out changed EPCs in resting mice. In striking contrast, inhibition of catalase by aminotriazole strongly reduced circulating EPCs in sedentary cat(++) and their transgen-negative littermates (cat(n)), while forced or voluntary exercise training of cat(++) mice significantly increased the number of circulating EPCs. The latter effect was completely inhibitable by aminotriazole. These data suggest that endogenous vascular H(2)O(2) likely contributes to the impairment of important stem cell-induced vascular repair mechanisms in cardiovascular 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.

Aims: Endothelial destruction and calcification primarily occur at the aortic side of the calcified aortic valves (AVs). This study investigated whether degenerative AV stenosis (AS) is associated with the presence of valvular endothelial senescence and a reduction in the number and function of endothelial progenitor cells (EPCs)., Methods and Results: Fifteen patients with severe AS and 18 age-matched control subjects were enrolled. Senescence-associated beta-galactosidase activity was mostly localized on the valvular endothelial cells (ECs) of the explanted AVs and highly coincided with the calcified lesion at the aortic side. The number (9.3 +/- 8.3 vs. 20.5 +/- 9.0 cells per 10(6) mononuclear cells; P < 0.01) and the migratory capacity (107.8 +/- 54.6 vs. 185.0 +/- 68.8 cells per 1000 cells; P < 0.01) of EPCs evaluated by FACS analysis or migration assay were significantly reduced in AS when compared with control. As possible mechanisms of alterations in EPCs, caspase-3 activity was significantly increased, whereas telomere-repeating factor-2 expression quantified by western blot was significantly reduced in EPCs from AS when compared with control., Conclusion: Reduced regenerative capacity of valvular ECs due to senescence and decreased levels of EPCs might be, at least in part, a pathological link for the destruction of valvular ECs, resulting in progression of degenerative AS.

Objectives: Polymorphisms of endothelial nitric oxide synthase (eNOS) gene in the promoter (T-786C) and exon 7 (G894T) have been suggested to attenuate endothelial function. As it is unknown whether these polymorphisms, on top of classical risk factors, further deteriorate endothelium-dependent vasomotion, we aimed to elucidate the impact of both polymorphisms on the ex-vivo vasomotor function of left internal mammary artery rings from patients with coronary artery disease (CAD) undergoing coronary bypass surgery (CABG)., Methods: Mammary artery rings from 51 consecutive patients with CAD were obtained during elective CABG. Endothelium-dependent ring relaxation was measured in vitro in an organ chamber using acetylcholine (10 to 3 x 10 mol/l). Polymorphisms were determined by polymerase chain reaction restriction length polymorphism., Results: Thirty-three per cent of patients were positive for the T-786C polymorphism, 25% for the G894T polymorphism, and 18% carried mutated alleles in both loci. Maximal acetylcholine-induced ring relaxation was 46.7+/-3.2% in T-786C, 59.6+/-4.2% in G894T, and 66.7+/-7.4% in T-786C/G894T compared with 94.9+/-2.0% in wild-type subjects (P<0.05 versus T-786C, G894T, T-786C/G894T). Patients positive for an eNOS polymorphism with more than three cardiovascular risk factors displayed a further attenuation of acetylcholine-mediated relaxation (45+/-6 %) compared with having up to three risk factors (59+/-3%, P<0.05)., Conclusion: In patients with CAD, in-vitro assessed endothelium-dependent relaxation of mammary arteries was significantly impaired in those positive for the T-786C or the G894T eNOS polymorphism. These results suggest that the presence of either one of the eNOS polymorphisms deteriorated endothelium-dependent vasodilatory capacity of large conduit vessels on top of classical risk factors in patients with CAD.

Background: Regular exercise training has emerged as a powerful tool to improve endothelium-dependent vasorelaxation. However, little is known about the magnitude of change and the permanence of exercise-induced adaptations in endothelial function., Design: Rats were randomized to either 6 weeks of regular exercise or one bout of exercise. Rats were then sacrificed 0, 6, 12, 24, 48, 96 or 192 h post-exercise, and vascular responsiveness to acetylcholine was determined., Methods: Endothelium-dependent dilation was assessed by exposure to accumulating doses of acetylcholine in ring segments of the abdominal aorta from female Sprague-Dawley rats that either exercised regularly for 6 weeks or performed a single bout of exercise., Results: A single exercise session improved endothelium-dependent vasodilatation for about 48 h. Six weeks of regular exercise induced a significantly larger improvement that lasted for about 192 h. Sensitivity to acetylcholine was twofold higher in chronically trained animals than in those exposed to a single bout of exercise. The decay after a single bout of exercise was about eightfold faster than that after 6 weeks of training., Conclusion: The present data extend our concept of exercise-induced adaptation of endothelium-dependent vasodilatation in two regards: (1) a single bout of exercise improves endothelium-dependent dilation for about 2 days, with peak effect after 12-24 h; (2) regular exercise further improves adaptation and increases the sensitivity to acetylcholine approximately fourfold, which slowly returns to sedentary levels within a week of detraining.

Objective: The concept of neovascularization in response to tissue ischemia has been extended by the finding of postnatal vasculogenesis initiated by endothelial progenitor cells (EPCs). The aim of this study was to analyze whether a maximal stress test in patients with coronary artery disease (CAD) increases the number of circulating EPCs., Methods and Results: Blood concentration of EPCs was analyzed by FACS and cell culture assay in CAD patients with (n=16) or without (n=12) exercise-induced myocardial ischemia and in healthy subjects (n=11) for up to 144 hours after maximal stress test. Plasma concentrations of vascular endothelial growth factor (VEGF), basic fibroblast growth factor, tumor necrosis factor-alpha, and granulocyte macrophage-colony stimulating factor were determined by ELISA. EPCs increased significantly in ischemic patients, with a maximum after 24 to 48 hours (cell culture: 3.3+/-0.5-fold increase; FACS: 3.1+/-0.6-fold increase) and returned to baseline within 72 hour. In nonischemic patients and healthy subjects, no EPC increase was detectable. VEGF levels in ischemic patients increased significantly after 2 to 6 hours (maximum after 2 hours; 4.0+/-1.1-fold increase) and no change was observed in nonischemic patients and healthy subjects; DeltaVEGF and DeltaEPC correlated significantly (r=0.66)., Conclusions: Patients with symptomatic CAD respond to a single episode of exercise-induced myocardial ischemia with a time-dependent increase in circulating EPCs. This increase may be related to and preceded by an increase in plasma VEGF.

Unlabelled: Background- Polymorphisms in the promoter (T-786C) and exon 7 (G894T) of the endothelial nitric oxide synthase (eNOS) gene were shown to be associated with reduced vascular NO production or increased proteolytic cleavage of eNOS. Therefore, we aimed to determine the effects of these polymorphisms on endothelial function and endothelial response to physical exercise in patients with coronary artery disease (CAD)., Methods and Results: Sixty-seven patients were randomized to either a training or a control group. At the beginning and after 4 weeks, acetylcholine-induced changes in average peak velocity (APV) of a coronary or mammary artery were invasively assessed by Doppler velocimetry. Polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism. At the beginning, in subjects with the wild-type (WT) variant, APV increased by 88+/-7% in response to acetylcholine. This response was significantly blunted in patients who were positive for the promoter (44+/-7%) or the exon 7 (62+/-9%) polymorphism. Four weeks of exercise training resulted in augmentation of an endothelium-dependent increase in APV by +36+/-12% in promoter polymorphism-positive patients but by +81+/-18% and +91+/-15% in WT variant- and exon 7 polymorphism-positive subjects, respectively., Conclusions: These results suggest that the presence of either one of the polymorphisms attenuates endothelium-dependent vasodilatation in CAD patients. Only the promoter polymorphism might have an adverse effect on training-induced improvement in endothelial function.

Background: Endothelial dysfunction has been described in patients with coronary artery disease (CAD) or chronic heart failure (CHF). Vitamin C administration leads to an improvement of endothelial function by reducing elevated levels of reactive oxygen species. It remains unclear, however, whether the degree of endothelial dysfunction caused by oxidative stress differs between CAD and CHF because of ischemic (ICM) or dilated cardiomyopathy (DCM)., Methods: In patients with CAD (n = 9; left ventricular ejection fraction [LVEF], 64% +/- 3%), ICM (n = 9; LVEF, 25% +/- 4%), DCM (n = 9; LVEF, 25% +/- 3%), and healthy subjects (HS; n = 5; LVEF, 66% +/- 5%) a change in internal radial artery diameter in response to acetylcholine (Ach; 15 and 30 microg/min) was measured with high-resolution ultrasound scanning during a co-infusion of normal saline or vitamin C (25 mg/min)., Results: Ach-mediated vasodilation was blunted in patients with CHF (DCM, 90 +/- 20 microm; ICM, 86 +/- 20 microm) and patients with CAD (336 +/- 20 microm) as compared with HS (496 +/- 43 microm; P <.05 vs patients with DCM, ICM, CAD). Vitamin C co-infusion increased Ach-mediated vasodilation by 180 +/- 35 microm (to 270 +/- 30 microm) in DCM (P <.05 vs CAD, HS) and by 294 +/- 40 microm (to 380 +/- 20 microm) in ICM (P <.05 vs DCM, CAD, HS). In patients with CAD, vitamin C increased Ach-mediated vasodilation by 146 +/- 35 microm to normal values, whereas vascular diameter remained unchanged in HS (14 +/- 20 microm; P = not significant)., Conclusions: Acute vitamin C administration restored peripheral endothelial function in patients with CAD to normal values, whereas endothelial function remained attenuated in CHF, in particular in patients with DCM. These results suggest that in patients with CHF, factors other than oxidative stress (eg, cytokines) contribute to the pathologic endothelial function.

Background: In stable coronary artery disease (CAD), exercise training has well-documented positive effects on arterial endothelial function. NO derived from endothelial NO synthase (eNOS) is regarded as a protective factor against atherosclerosis. The aim of the present study was to investigate the effects of exercise training on the endothelial function in relation to the expression of eNOS and Akt-dependent eNOS phosphorylation in the left internal mammary artery (LIMA) of patients with stable CAD., Methods and Results: In 17 training patients (T) and 18 control patients (C), endothelium-dependent vasodilation and average peak flow velocity (APV) in response to acetylcholine were measured invasively at study beginning and after 4 weeks in the LIMA. In LIMA tissue sampled during bypass surgery, eNOS expression and content of pospho-eNOS-Ser1177, Akt, and phospho-Akt were determined by Western blot and quantitative reverse transcriptase-polymerase chain reaction. After exercise training, LIMA APV in response to acetylcholine was increased by 56+/-8% (from +48+/-8% at beginning to +104+/-11% after 4 weeks, P<0.001). Patients in T had a 2-fold higher eNOS protein expression (T 1.0+/-0.7 versus C 0.5+/-0.3 arbitrary units, P<0.05) and 4-fold higher eNOS Ser1177-phosphorylation levels in LIMA-endothelium (1.2+/-0.9 versus 0.3+/-0.2 arbitrary units, P<0.01). A linear correlation was confirmed between Akt phosphorylation and phospho-eNOS levels (R=0.80, P<0.05) and between phospho-eNOS and Delta APV (R=0.59, P<0.05)., Conclusions: Exercise training in stable CAD leads to an improved agonist-mediated endothelium-dependent vasodilatory capacity. The change in acetylcholine-induced vasodilatation was closely related to a shear stress-induced/Akt-dependent phosphorylation of eNOS on Ser1177.

Background: The purpose of this study was to determine the effects of systemic exercise training on endothelium-mediated arteriolar vasodilation of the lower limb and its relation to exercise capacity in chronic heart failure (CHF). Endothelial dysfunction is a key feature of CHF, contributing to increased peripheral vasoconstriction and impaired exercise capacity. Local handgrip exercise has previously been shown to enhance endothelium-dependent vasodilation in conduit and resistance vessels in CHF., Methods and Results: Twenty patients were prospectively randomized to a training group (n=10, left ventricular ejection fraction [LVEF] 24+/-4%) or a control group (n=10, LVEF 23+/-3%). At baseline and after 6 months, peak flow velocity was measured in the left femoral artery using a Doppler wire; vessel diameter was determined by quantitative angiography. Peripheral blood flow was calculated from average peak velocity (APV) and arterial cross-sectional area. After exercise training, nitroglycerin-induced endothelium-independent vasodilation remained unaltered (271% versus 281%, P=NS). Peripheral blood flow improved significantly in response to 90 microg/min acetylcholine by 203% (from 152+/-79 to 461+/-104 mL/min, P<0.05 versus control group) and the inhibiting effect of L-NMMA increased by 174% (from -46+/-25 to -126+/-19 mL/min, P<0.05 versus control group). Peak oxygen uptake increased by 26% (P<0.01 versus control group). The increase in peak oxygen uptake was correlated with the endothelium-dependent change in peripheral blood flow (r=0.64, P<0. 005)., Conclusions: Regular physical exercise improves both basal endothelial nitric oxide (NO) formation and agonist-mediated endothelium-dependent vasodilation of the skeletal muscle vasculature in patients with CHF. The correction of endothelium dysfunction is associated with a significant increase in exercise capacity.