Volker Adams

Regular Physical Exercise Corrects Endothelial Dysfunction and Improves Exercise Capacity in Patients With Chronic Heart Failure

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 endotheli...

Regular Physical Activity Improves Endothelial Function in Patients With Coronary Artery Disease by Increasing Phosphorylation of Endothelial Nitric Oxide Synthase

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 &Dgr; 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.

Anti-inflammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure

OBJECTIVES The aim of this study was to assess the effects of regular physical exercise on local inflammatory parameters in the skeletal muscle of patients with chronic heart failure (CHF). BACKGROUND Inflammatory activation with increased serum cytokine levels and expression of inducible nitric oxide synthase (iNOS) in the myocardium and peripheral skeletal muscles has been described in CHF. METHODS Twenty male patients with stable CHF (left ventricular ejection fraction 25 +/- 2%; age 54 +/- 2 years) were randomized to a training group (n = 10) or a control group (n = 10). At baseline and after six months, serum samples and vastus lateralis muscle biopsies were obtained. Serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1-beta levels were measured by enzyme-linked immunosorbent assay, local cytokine, and iNOS expression by real-time polymerase chain reaction. RESULTS Exercise training improved peak oxygen uptake by 29% in the training group (from 20.3 +/- 1.0 to 26.1 +/- 1.5 ml/kg. min; p < 0.001 vs. control group). While serum levels of TNF-alpha, IL-6, and IL-1-beta remained unaffected by training, local skeletal muscle TNF-alpha decreased from 1.9 +/- 0.4 to 1.2 +/- 0.3 relative U (p < 0.05 for change vs. control group), IL-6 from 71.3 +/- 16.5 to 41.3 +/- 8.8 relative U (p < 0.05 vs. begin), and IL-1-beta from 2.7 +/- 1.1 to 1.4 +/- 0.6 relative U (p = 0.02 vs. control group). Exercise training also reduced local iNOS expression by 52% (from 6.3 +/- 1.2 to 3.0 +/- 1.0 relative U; p = 0.007 vs. control group). CONCLUSIONS Exercise training significantly reduced the local expression of TNF-alpha, IL-1-beta, IL-6, and iNOS in the skeletal muscle of CHF patients. These local anti-inflammatory effects of exercise may attenuate the catabolic wasting process associated with the progression of CHF.

Increase of Circulating Endothelial Progenitor Cells in Patients with Coronary Artery Disease After Exercise-Induced Ischemia

Objectives—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-&agr;, 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; &Dgr;VEGF and &Dgr;EPC 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.

Transplantation of Blood-Derived Progenitor Cells After Recanalization of Chronic Coronary Artery Occlusion First Randomized and Placebo-Controlled Study

Transplantation of blood-derived circulating progenitor cells (CPC) has been shown to improve myocardial regeneration after myocardial infarction. It remains unclear whether CPC transplantation exerts beneficial effects also in patients with chronic myocardial ischemia. We initiated a randomized, double-blind, placebo-controlled study evaluating the impact of intracoronary infusion of CPCs on coronary vasomotion and left ventricular (LV) function in patients after recanalization of chronic coronary total occlusion (CTO). After recanalization of CTO, 26 patients (age, 63±2 years; LV ejection fraction, 53±2%) were randomly assigned to the treatment (intracoronary transplantation of CPCs) or control group. Coronary flow reserve in response to adenosine (2.4 mg/min) was measured in the target vessel at the beginning of the study and after 3 months. LV function and infarct size were assessed by MRI and metabolism by 18F deoxyglucose positron emission tomography. CPC application resulted in an increase in coronary flow reserve by 43% from 2.3±0.3 to 3.3±0.5 (P<0.05 versus beginning and control). At 3 months, the number of hibernating segments in the target region (from 2.9±0.6 to 2.0±0.6 segments, P<0.05 versus beginning and control) had declined in the treatment group, whereas no significant changes were observed in the control group. MRI revealed a reduction in infarct size by 16% and an increase in LV ejection fraction by 14% in the treatment group (from 51.7±3.7 to 58.9±3.2%; P<0.05 versus beginning and control) because of an augmented wall motion in the target region. Hence, intracoronary transplantation of CPCs after recanalization of CTO results in an improvement of macro- and microvascular function and contributes to the recruitment of hibernating myocardium.

Impact of Regular Physical Activity on the NAD(P)H Oxidase and Angiotensin Receptor System in Patients With Coronary Artery Disease

Background—In patients with stable coronary artery disease, physical exercise training (ET) improves endothelial dysfunction. A potential mechanism mediating the enhanced vasomotor function is a reduced breakdown of endothelium-derived nitric oxide by reactive oxygen species (ROS). The aim of the present study was to analyze the impact of ET on sources of ROS generation in the left internal mammary artery of patients with symptomatic coronary artery disease. Methods and Results—In left internal mammary artery rings sampled during bypass surgery from 45 patients randomized to either a training (n=22) or an inactive control (n=23) group, the mRNA expression of NAD(P)H oxidase subunits, NAD(P)H oxidase activity, and ROS production were assessed. In addition, endothelial function, expression of angiotensin II (Ang II) receptor type 1 and 2 (AT1-R and AT2-R), and Ang II-mediated vasoconstriction were determined. ET resulted in a significant lower expression of gp91phox (23.1±0.5 versus 69.1±18.1 arbitrary units, training versus control), p22phox (0.7±0.3 versus 2.0±0.5 arbitrary units), and Nox4 (2.7±1.2 versus 5.4±1.0 arbitrary units). Enzymatic activity (2.1±0.3 versus 4.9±0.4 mU/mg) and ROS generation (0.02±0.01 versus 0.06±0.02 arbitrary units) were significantly lower in the training compared with the control group. On a functional level, ET resulted in improved acetylcholine-mediated vasodilatation and a 49% reduction in Ang II–induced vasoconstriction, accompanied by lower AT1-R (3.7±0.8 versus 16.6±5.7 arbitrary units, training versus control) and higher AT2-R (7.8±2.5 versus 1.6±0.7 arbitrary units) mRNA expression. Conclusions—ET reduces vascular expression of NAD(P)H oxidase and AT1-R, resulting in decreased local ROS generation. These molecular effects converge in a reduced Ang II–mediated vasoconstriction.

Effects of Exercise and Ischemia on Mobilization and Functional Activation of Blood-Derived Progenitor Cells in Patients With Ischemic Syndromes Results of 3 Randomized Studies

Background—Exercise training (ET) has been shown to improve regional perfusion in ischemic syndromes. This might be partially related to a regeneration of diseased endothelium by circulating progenitor cells (CPCs) or CPC-derived vasculogenesis. The aim of the present study was to determine whether ischemic stimuli during ET are required to promote CPC mobilization in patients with cardiovascular diseases. Methods and Results—Patients with peripheral arterial occlusive disease (PAOD) were randomized to 4 weeks of daily ischemic ET or control (group A). Successfully revascularized patients with PAOD were randomized to 4 weeks of daily nonischemic ET or control (group B). Patients with stable coronary artery disease were subjected to 4 weeks of subischemic ET or control (group C). At baseline and after 4 weeks, the number of KDR+/CD34+ CPCs was determined by fluorescence-activated cell sorting analysis. Levels of vascular endothelial growth factor (VEGF) were measured by ELISA. A Matrigel assay was used to quantify CPC integration into vascular structures. Expression of the homing factor CXCR4 was determined by reverse transcription-polymerase chain reaction. In group A only, ischemic ET increased VEGF levels by 310% (P<0.05 versus control) associated with an increase in CPCs by 440% (P<0.05 versus control), increased CXCR4 expression, and enhanced integration of CPCs into endothelial networks. In contrast, subischemic ET in groups B and C increased CXCR4 expression and CPC integration. Conclusions—In training programs, symptomatic tissue ischemia seems to be a prerequisite for CPC mobilization. However, ischemic and subischemic ET programs affect CXCR4 expression of CPCs, which might lead to an improved CPC integration into endothelial networks.

Cardiovascular Effects of Exercise Training Molecular Mechanisms

In the natural habitat of our ancestors, physical activity was not a preventive intervention but a matter of survival. In this hostile environment with scarce food and ubiquitous dangers, human genes were selected to optimize aerobic metabolic pathways and conserve energy for potential future famines.1 Cardiac and vascular functions were continuously challenged by intermittent bouts of high-intensity physical activity and adapted to meet the metabolic demands of the working skeletal muscle under these conditions. When speaking about molecular cardiovascular effects of exercise, we should keep in mind that most of the changes from baseline are probably a return to normal values. The statistical average of physical activity in Western societies is so much below the levels normal for our genetic background that sedentary lifestyle in combination with excess food intake has surpassed smoking as the No. 1 preventable cause of death in the United States.2 Physical activity has been shown to have beneficial effects on glucose metabolism, skeletal muscle function, ventilator muscle strength, bone stability, locomotor coordination, psychological well-being, and other organ functions. However, in the context of this review, we will focus entirely on important molecular effects on the cardiovascular system. The aim of this review is to provide a birds-eye view on what is known and unknown about the physiological and biochemical mechanisms involved in mediating exercise-induced cardiovascular effects. The resulting map is surprisingly detailed in some areas (ie, endothelial function), whereas other areas, such as direct cardiac training effects in heart failure, are still incompletely understood. For practical purposes, we have decided to use primarily an anatomic approach to present key data on exercise effects on cardiac and vascular function. For the cardiac effects, the left ventricle and the cardiac valves will be described separately; for the vascular effects, we will follow the arterial vascular …

Antioxidative Effects of Exercise Training in Patients With Chronic Heart Failure Increase in Radical Scavenger Enzyme Activity in Skeletal Muscle

Background—In chronic heart failure (CHF), cross-talk between inflammatory activation and oxidative stress has been anticipated in skeletal muscle (SM). The role of the radical scavenger enzymes superoxide dismutase (SOD), catalase (Cat), and glutathione peroxidase (GPX), which remove oxygen radicals, has never been assessed in the SM in this context. Moreover, it remains unknown whether exercise training augments the activity of these enzymes in CHF. Methods and Results—Twenty-three patients with CHF were randomized to either 6 months of exercise training (T) or a sedentary lifestyle (C); 12 age-matched healthy subjects (HS) were studied in parallel. Activity of Cat, SOD, and GPX was assessed in SM biopsies before and after 6 months (6 months). Oxidative stress was determined by measuring nitrotyrosine formation. SOD, Cat, and GPX activity was reduced by 31%, 57%, and 51%, respectively, whereas nitrotyrosine formation was increased by 107% in SM in CHF (P<0.05 versus HS). In CHF, exercise training augmented GPX and Cat activity in SM by 41% (P<0.05 versus before and group C) and 42% (P<0.05 versus before and group C), respectively, and decreased nitrotyrosine production by 35% (from 3.8±0.4% tissue area before to 2.5±0.3% after 6 months; P<0.05 versus before). Conclusions—The reduced activity of major antioxidative enzymes in the SM of CHF patients is associated with increased local oxidative stress. Exercise training exerts antioxidative effects in the SM in CHF, in particular, due to an augmentation in activity of radical scavenger enzymes.

Clinical Recommendations for Cardiopulmonary Exercise Testing Data Assessment in Specific Patient Populations

From an evidence-based perspective, cardiopulmonary exercise testing (CPX) is a well-supported assessment technique in both the United States (US) and Europe. The combination of standard exercise testing (ET) (ie, progressive exercise provocation in association with serial electrocardiograms [ECG], hemodynamics, oxygen saturation, and subjective symptoms) and measurement of ventilatory gas exchange amounts to a superior method to: 1) accurately quantify cardiorespiratory fitness (CRF), 2) delineate the physiologic system(s) underlying exercise responses, which can be applied as a means to identify the exercise-limiting pathophysiologic mechanism(s) and/or performance differences, and 3) formulate function-based prognostic stratification. Cardiopulmonary ET certainly carries an additional cost as well as competency requirements and is not an essential component of evaluation in all patient populations. However, there are several conditions of confirmed, suspected, or unknown etiology where the data gained from this form of ET is highly valuable in terms of clinical decision making.1 Several CPX statements have been published by well-respected organizations in both the US and Europe.1–5 Despite these prominent reports and the plethora of pertinent medical literature which they feature, underutilization of CPX persists. This discrepancy is at least partly attributable to the fact that the currently available CPX consensus statements are inherently complex and fail to convey succinct, clinically centered strategies to utilize CPX indices effectively. Likewise, current CPX software packages generate an overwhelming abundance of data, which to most clinicians are incomprehensible and abstract. Ironically, in contrast to the protracted scientific statements and dense CPX data outputs, the list of CPX variables that have proven clinical application is concise and uncomplicated. Therefore, the goal of this writing group is to present an approach of CPX in a way that assists in making meaningful decisions regarding a patient’s care. Experts from the European Association for Cardiovascular Prevention and Rehabilitation and American Heart Association have joined in this effort to distill easy-to-follow guidance on CPX interpretation based upon current scientific evidence. This document also provides a series of forms that are designed to highlight the utility of CPX in clinical decision-making. Not only will this improve patient management, it will also catalyze uniform and unambiguous data interpretation across laboratories on an international level. The primary target audience of this position paper is clinicians who have limited orientation with CPX but whose caregiving would be enhanced by familiarity and application of this assessment. The ultimate goal is to increase awareness of the value of CPX and to increase the number of healthcare professionals who are able to perform clinically meaningful CPX interpretation. Moreover, this document will hopefully lead to an increase in appropriate patient referrals to CPX with enhanced efficiencies in patient management. For more detailed information on CPX, including procedures for patient preparation, equipment calibration, and conducting the test, readers are encouraged to review other publications that address these and other topics in great detail.1–5