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Our mission is to promote excellence in research, practice, education and policy in cardiovascular health, primary and secondary prevention.
Our mission is to reduce the burden of cardiovascular disease through percutaneous cardiovascular interventions.
Improving the quality of life and reducing sudden cardiac death by limiting the impact of heart rhythm disturbances.
Our mission is to improve quality of life and longevity, through better prevention, diagnosis and treatment of heart failure, including the establishment of networks for its management, education and research.
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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Dr. Zeljko Reiner,
The first speaker of the symposium was Valentin Fuster (New York, USA) who explained how plaque progression/regression can be evaluated by different imaging techniques, of which those used more recently consider not only morphological but also biological imaging. He stressed the significance of some imaging modalities to identify morphological features of coronary plaque instability and presented the results of evaluating the effects of recombinant ApoA-1 MIlano on atherosclerotic plaque regression by MRI in rats as well as of imaging atherosclerotic inflammation with PET and PET/CT in humans. He discussed the results obtained with IVUS in patients from the ILLUSTRATE study with torcetrapib showing no effect on progression of coronary atherosclerosis despite HDL-C raising. He also discussed the results of Dal-PLAQUE study with dalcetrapib on plaque structure obtained with MRI and PET/CT in the context of the observation that early increases in arterial inflammation are associated with subsequent increases in atherosclerotic burden. He also stressed that functional changes in HDL are more important than plasma concentration of HDL-cholesterol and presented the results showing that dalcetrapib incresed HDL-C with modest but significant increases in cholesterol efflux as a measure of HDL functionality. Increases in efflux in turn were associated with directionally beneficial changes in arterial wall parameters.
The next speaker was Ulf Landmesser (Zurich, Switzerland) who, after reaffirming the concept of low HDL-C as predictor of CV events in patients with low LDL-C, discussed the proposed endothelial-protective and potential anti-atherogenic effects of HDL apart from reverse cholesterol transport: effects on endothelial NO production and therefore on leukocyte and platelet adhesion and inflitration-aggregation, endothelial repair, anti-inflammatory, anti-apoptotic and anti-thrombotic effects. He presented his results showing that HDL from patients with CHD or ACS do not increase endothelial NO production unlike those from healthy subjects, that anti-inflammatory capacity of HDL in CHD is lower and that no endothelial repair effect of HDL from CHD patients can be proved. So stressing the importance of HDL functionality and not only HDL-C quantity, he addressed the question of which changes of HDL are mediating these differences in HDL's vascular effects. Again he presented his own results showing that the answer might be impaired protection from lipid oxydation, (paraoxonase-1 inactivation) and alteration in the HDL proteome (Apo CIII, clusterin) and concluded that HDL-target therapies may need to take ino account the effects on HDL function and not only quantity.
The third presenter was Jane Armitage (Oxford, Great Britain) who presented the results of the studies with reconstituted HDL. The aim of this treatment is to mimic the actions of HDL in vivo. Recombinant ApoA1 Milano caused only small improvements, CSL-111 (preparation of reconstituted HDL) in the ERASE study did not show any significant impact on vascular function in ACS patients, autologous delipidated HDL showed no changes in % plaque volume after 2 weeks, Apo AI mimetic peptides promote cholesterol efflux in animals, improve endothelial function and inflammatory markers while RVX-208, an oral stimulator of Apo AI gene expression increases HDL-C in CAD patients but also increases transaminases. Considering that no data on outcomes exist and limitations of rHDL therapies at the moment, they could have a role in the context of ACS but clinical data are needed.
Philip Barter (Sydney, Australia) tried to answer why should we continue the development of CETP inhibitors after the failures of torcetrapib and dalcetrapib. The reason for developing CETP inhibitors as agents to reduce CVD risk is justified by the facts that inhibiting CETP in rabbits one can inhibit atherosclerosis, that genetic variants of CETP in humans are accompanied by higher HDL-C, lower LDL-C and reduced CV risk and that inhibition of CETP in humans increases HDL-C and, in some cases, decreases LDL-C. Adverse off-target effects of torcetrapib in the ILLUMINATE trial unrelated to CETP inhibition may have been responsible for the adverse outcome. Dal-OUTCOMES trial with dalcetrapib has been recently terminated on the basis of futility. The explanations might be that the increase in HDL-C concentration induced by dalcetrapib was not accompanied by an enhancement of the protective functions of HDL or that the inverse relationship between HDL-C concentration and CV risk observed in population studies is an epiphenomenon rather than being reflective of an ability of HDL to protect against CVD. A possible explanation might also be that CETP inhibition is not effective in patients treated soon after an acute coronary event as was the case with Dal-OUTCOMES. He concluded that there is a compelling case for conducting new clinical outcome trials with CETP inhibitors like anacetrapib and evacetrapib that do not have the off-target adverse effects of torcetrapib and are much more effective than dalcetrapib.
"From bench to practice: dyslipidemia; is high-density lipoprotein our next treatment target?"
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