Day 1 :
Imperial College London, UK
Time : 09:05-09:40
Peter Sever is Professor of Clinical Pharmacology at the National Heart and Lung Institute, Imperial College London. He graduated from the University of Cambridgernand has a PhD from the University of London. He is Past President of the British Hypertension Society, current Joint Chief Editor of the Journal of thernRenin-Angiotensin Aldosterone System and Honorary Fellow, Trinity Hall, Cambridge. His research interests include the aetiology and pathophysiology of vascularrndisease and clinical trials of cardiovascular disease prevention. He has published more than 350 papers in peer review journals.
As many as one in three adults would benefit from lipid-lowering with a statin. Current guidelines advocate statin usernfor all patients with established atherosclerotic disease and, in primary prevention, for those at an estimated 10 yearrn cardiovascular risk of 7.5-10%. In clinical practice, reports in the medical and lay press of the high frequency of putative adverse reactions to statins have influenced the uptake of statins by patients, not only in secondary prevention, but also in primary prevention, thereby exposing an increasing number of patients to the risk of preventable cardiovascular disease. Inrndouble-blind, randomized, trials adverse events are reported equally by those assigned statin or placebo, however, in open observational studies up to 20% of patients claim that adverse events, particularly muscle related symptoms, are associated with statin use. In order to further investigate this apparent discrepancy, the unique opportunity provided by over 10,000 patients participating in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid-lowering Arm was used to compare adversere events associated with blinded use of statin in the first 3 years of the trial, with adverse events during open label statin usernover the 2 year extension of the trial, using characterization and classification of events according to the Medical Dictionaryrnfor Regulatory Activities (MedRA) for the coding of reports. The results of these observations, which it is anticipated will have a major impact on clinical practice, including the prescribing of statins and their acceptability to patients, will be published shortly, and will be discussed in the presentation.
Yale University School of Medicine, USA
Time : 09:40-10:15
Jeffrey R. Bender graduated from the University of California, San Francisco School of Medicine in 1979. He works in New Haven, CT and specializes in Cardiovascular Disease. Jeffrey R. Bender is affiliated with Yale New Haven Hospital.
Cardiovascular physiology and pathology involves the expression of angiogenic, proteolytic and inflammatory genes in arnwide variety of contexts. Many of the RNA transcripts encoding these gene products are very labile, leading to minimal gene expression, unless the mRNA is protected from degradation (stabilized). Leukocyte recruitment to, and localization in, many tissues requires the engagement of integrin adhesion receptors, promoting leukocyte adhesion to the endothelium and transmigration into tissues. In both innate (monocyte/macrophage) and adaptive (T lymphocyte) immune cells, engagement of the beta2 integrin LFA-1 results in the rapid and dramatic modulation of an important mRNA-binding protein, HuR, leading to protection of labile transcripts from degradation, and prolongation of their half-lives with enhanced gene expression. Monocyte/macrophages are important producers of the key angiogenic/arteriogenic factor VEGF-A, which is encoded by a transcript that is intrinsically unstable. Integrin engagement in human and mouse macrophages results in marked, HuR dependent stabilization of the VEGF-A mRNA. The signal transduction cascade downstream of integrin engagement includes activation of the small Rho family GTPase Rac2, and its consequent interaction with the non-muscle myosin IIA (MyIIA). Using the murine model of hindlimb ischemia, a powerful model for the study of arteriogenic responses to ischemia, and targeting either Rac2 or MyIIA selectively in macrophages, we showed that a complete revascularizing, arteriogenic response to ischemia requires macrophage Rac2 and MyIIA. Animals with either of these genes deleted in a myeloid-specific fashionrnhave impaired arteriogenic responses to ischemia, as detected by laser Doppler flow imaging. This was not due to failed tissue localization of macrophages, but to their inability to produce angiogenic factors at sufficient levels. Using a different model of inflammation, the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, which involves profound CNS immune/inflammatory reactions mediated largely by the Th17 subset of T lymphocytes, we showed that CNS production of a potent pro-inflammatory cytokine, IL-17A, requires integrin-mediated, HuR-dependent stabilization of its transcript. Mice with Th17-targeted deletion of HuR are completely protected against the development of EAE, with greatly reduced CNS levels of IL-17A mRNA and protein, despite equal numbers of localizing immune cells. In this presentation, a major molecular switch for the production of angiogenic, immune and proteolytic genes in vascular and target organ inflammatory environments is described. This defines a new therapeutic target for the inflammatory component of cardiovascular disease.