Sven Waßmann

The ESC/ESH Guidelines represent the views of the ESC and ESH and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating. The ESC and ESH are not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the ESC/ESH Guidelines and any other official

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National Cardiac Societies document reviewers: listed in Addenda The content of these European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC. Other ESC entities having participated in the development of this document: Associations: Acute Cardiovascular Care Association (ACCA), European Association for Cardiovascular Prevention & Rehabilitation (EACPR), European Association of Cardiovascular Imaging (EACVI), European Heart Rhythm Association (EHRA), Heart Failure Association of the ESC (HFA). Working groups: Working Group on Cardiac Cellular Electrophysiology, Working Group on Cardiovascular Magnetic Resonance, Working Group on Cardiovascular Pharmacology and Drug Therapy, Working Group on Cardiovascular Surgery, Working Group on Coronary Pathophysiology and Microcirculation, Working Group on Nuclear Cardiology and Cardiac Computed Tomography, Working Group on Peripheral Circulation, Working Group on Thrombosis, Working Group on Valvular Heart Disease. Councils: Council for Cardiology Practice, Council on Cardiovascular Primary Care, Council on Cardiovascular Nursing and Allied Professions. Disclaimer 2014: The ESC/EACTS Guidelines represent the views of the ESC and of the EACTS and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating. The ESC and the EACTS are not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC/EACTS Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC/EACTS Guidelines fully into account when exercising their clinical judgment as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC/EACTS Guidelines do not in any way whatsoever override the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and, where appropriate and/or necessary, in consultation with that patient and the patient's care provider. Nor do the ESC/EACTS Guidelines exempt health professionals from giving full and careful consideration to the relevant official, updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient's case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional's responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

BACKGROUND: The molecular mechanisms by which physical training improves peripheral and coronary artery disease are poorly understood. Bone marrow-derived endothelial progenitor cells (EPCs) are thought to exert beneficial effects on atherosclerosis, angiogenesis, and vascular repair. METHODS AND RESULTS: To study the effect of physical activity on the bone marrow, EPCs were quantified by fluorescence-activated cell sorter analysis in mice randomized to running wheels (5.1+/-0.8 km/d, n=12 to 16 per group) or no running wheel. Numbers of EPCs circulating in the peripheral blood of trained mice were enhanced to 267+/-19%, 289+/-22%, and 280+/-25% of control levels after 7, 14, and 28 days, respectively, accompanied by a similar increase of EPCs in the bone marrow and EPCs expanded from spleen-derived mononuclear cells. eNOS-/- mice and wild-type mice treated with N(G)-nitro-l-arginine methyl ester showed lower EPC numbers at baseline and a significantly attenuated increase of EPC in response to physical activity. Exercise NO dependently increased serum levels of vascular endothelial growth factor and reduced the rate of apoptosis in spleen-derived EPCs. Running inhibited neointima formation after carotid artery injury by 22+/-2%. Neoangiogenesis, as assessed in a subcutaneous disc model, was increased by 41+/-16% compared with controls. In patients with stable coronary artery disease (n=19), moderate exercise training for 28 days led to a significant increase in circulating EPCs and reduced EPC apoptosis. CONCLUSIONS: Physical activity increases the production and circulating numbers of EPCs via a partially NO-dependent, antiapoptotic effect that could potentially underlie exercise-related beneficial effects on cardiovascular diseases.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert direct effects on vascular cells and beneficially influence endothelial dysfunction. Because reactive oxygen species (ROS) may lead to vascular damage and dysfunction, we investigated the effect of atorvastatin on ROS production and the underlying mechanisms in vitro and in vivo. Cultured rat aortic vascular smooth muscle cells were incubated with 10 micromol/L atorvastatin. Angiotensin II-induced and epidermal growth factor-induced ROS production were significantly reduced by atorvastatin (dichlorofluorescein fluorescence laser microscopy). Atorvastatin downregulated mRNA expression of the NAD(P)H oxidase subunit nox1, whereas p22phox mRNA expression was not significantly altered (reverse transcription-polymerase chain reaction, Northern analysis). Membrane translocation of rac1 GTPase, which is required for the activation of NAD(P)H oxidase, was inhibited by atorvastatin (Western blot). mRNA expression of superoxide dismutase isoforms and glutathione peroxidase was not modified by atorvastatin, whereas catalase expression was upregulated at mRNA and protein levels, resulting in an increased enzymatic activity. Effects of atorvastatin on ROS production and nox1, rac1, and catalase expression were inhibited by L-mevalonate but not by 25-hydroxycholesterol. In addition, spontaneously hypertensive rats were treated with atorvastatin for 30 days. ROS production in aortic segments was significantly reduced in statin-treated rats (lucigenin chemiluminescence). Treatment with atorvastatin reduced vascular mRNA expression of p22phox and nox1 and increased aortic catalase expression. mRNA expression of superoxide dismutases, glutathione peroxidase, and NAD(P)H oxidase subunits gp91phox, p40phox, p47phox, and p67phox remained unchanged. Translocation of rac1 from the cytosol to the cell membrane was also reduced in vivo. Thus, atorvastatin exerts cellular antioxidant effects in cultured rat vascular smooth muscle cells and in the vasculature of spontaneously hypertensive rats mediated by decreased expression of essential NAD(P)H oxidase subunits and by upregulation of catalase expression. These effects of atorvastatin may contribute to the vasoprotective effects of statins.