ISA 2006 - Rome, Italy

The XIV International Symposium on Atherosclerosis (ISA), under the auspices of the International Atherosclerosis Society (IAS) and the Italian Society for the Study of Atherosclerosis (SISA) and organized by the Giovanni Lorenzini Medical Foundation (Milan-Houston), was held at the Fiera di Roma, a large conference and exhibition centre in Rome, Italy. This important international symposium provided an opportunity to share cutting-edge information and perspectives on the diagnosis, treatment, and prevention of atherosclerosis and related diseases with almost 6,000 attending scientists. The five-day Symposium kicked off on Sunday, June 18 with the Opening Ceremony hosted by the Symposium President, Cesare Sirtori; the Honorary President, Rodolfo Paoletti; the President of the International Atherosclerosis Society, Scott M. Grundy; and the President of the Italian Society for the Study of Atherosclerosis, Elmo Mannarino. The ceremony was followed by a concert by the Band of the famous Italian Military Corps “The Carabinieri”, and by a Welcome Reception.

The meeting format was designed to provide opportunities for intense interaction among participants during the scientific sessions and breaks. The rich scientific program included Plenary Lectures, Sponsored Symposia, Workshops, and Master Lectures on different topics related to atherosclerosis/thrombosis development, complications, dietary and pharmacological management. During the entire meeting, parallel sessions for a total of 519 lectures were held to give participants more choices and to allow time to be dedicated to “hot topics,” usually only covered in more “specific” symposia. The poster sessions included more than 1,914 posters presented mainly by young investigators, providing them the opportunity to share and discuss data with colleagues, as well as with experts in the field.

For a view of the Final Program and the Abstract book, please click here.

The XXXII Lorenzini Annual Lecture, titled “Genetic protection from coronary atherosclerosis: from genes to public health,” was delivered by the invited guest speaker, Dr. H.H. Hobbs from the UT Southwestern Medical Center in Dallas, Texas. The topic was PCSK9, a particular protease able to degrade the LDL receptor, whose activity is a major determinant of plasma LDL-cholesterol levels in humans. In high concentrations, PCSK9 is extremely active in reducing LDL receptor and, therefore, in increasing LDL-cholesterol, which is typical of many atherosclerosis patients. Analyzing the population enrolled in the Dallas Heart Study, Dr. Hobbs and colleagues found that in some African-Americans loss-of-function mutations in the PCSK9 gene cause a lower activity of the protease associated with a 40% reduction in plasma LDL-cholesterol levels. These patients, independent of their life-style, have a 50% lower risk to develop cardiovascular disease (CVD) in comparison to people without the mutation. This gives a real advantage in the long term, achieving low plasma cholesterol for a long time gives higher benefits than in the short run, due to an apparent cumulative advantage. A spectrum of PCSK9 gene sequence variations ranging in frequency and magnitude of effect contribute to inter-individual differences in LDL-cholesterol levels. The potential modulation of the enzyme activity is extremely interesting, and could become an attractive therapeutic target for future LDL-lowering therapies.

Besides the more “traditional” topics in atherosclerosis, such as epidemiology of CVD, vascular biology, pathophysiology of lipids and lipoproteins, drugs affecting lipid metabolism, atherosclerosis/thrombosis risk factors and management, “new” areas were covered. Particular interest was devoted to HDL-targeted therapies, to management of the metabolic syndrome, to the nutritional approach to cardiovascular disease prevention, and to novel technologies for risk determination.

There is limited but compelling clinical trial evidence that raising plasma HDL-cholesterol levels causes a significant reduction of coronary events. Although the mechanisms by which HDL beneficially alters the atherosclerotic disease process are not fully clarified, it is presumed that high levels of HDL can facilitate the efflux of cholesterol from the arterial wall, thereby enhancing the transport of cholesterol and other lipids from the arteries back to the liver for biliary excretion as faecal sterols and bile acids. Current therapies for raising HDL are limited; fibrates produce significant moderate elevations of HDL; the use of niacin, a more powerful HDL-raising drug, is hampered by side effects. Therefore, new therapeutic interventions have been envisioned. CETP inhibitors, which produce remarkable increases of plasma HDL, provide a unique opportunity to prevent CVD through HDL elevation. Alternatively, the infusion of synthetic apolipoprotein A-I (apoA-I)/phospholipid complexes could lead to a rapid facilitation of HDL-mediated cholesterol efflux from the arterial wall. In such a way, HDL therapy could have a subacute therapeutic application to treat CVD acting on the vulnerable, unstable, lipid-rich atherosclerotic plaque. Along these lines, comes the demonstration from Australian studies which have shown in animals that HDL can lead stem cells to repair myocardial lesions. The discovery provides a new indication for the use of HDL to reduce atherosclerotic diseases and it is a remarkable step toward the targets of an effective use of stem cells. “The reason for the present failure of stem cells,” Prof. Cesare Sirtori explained, “is probably due to the fact that these cells, once infused, tend to circulate in the body and hardly reach the damaged sites. On the contrary, HDL has proved to be effective in delivering them to the right target.”

Interestingly, carriers of a particular mutation of apoAI (the mutant gene A-IMilano carriers), beside being protected from CVD despite their low plasma HDL levels, have been shown also to have a reduced accumulation of lipids inside the retina and appear to be protected from blindness. This could be related to the mutant gene ability in binding and removing very effectively fats, especially cholesterol and phospholipids, from intra- and extra-cellular deposits, as has already been demonstrated in vitro, in animals and men.

The incidence of the metabolic syndrome is increasing all over the world. The metabolic sndrome is characterized by 3 out of 5 factors: increased waist circumference, low HDL levels, high blood pressure, hyperglycemia, and high triglyceride levels. Among these risk factors, visceral obesity may partly be a marker of a dysmetabolic state and partly a cause of the metabolic syndrome. This model would explain why molecules promoting a selective deposition of subcutaneous fat such as thiazolidinediones improve the metabolic profile of patients with the metabolic syndrome by promoting the creation of a subcutaneous “metabolic sink.” Another therapeutic option is to induce abdominal fat loss. The influence of the endocannabinoid system on excessive fat has been discovered very recently: in obese people the system is hyper-activated in a permanent way, not transitorily as in normal weight people. In the light of these data, a new class of target and drugs have been introduced: the inhibitors of endocannabinoid active on abdominal fat. The first of this new class, rimonabant, has proved to reduce both weight and waist circumference and the altered lipoprotein levels. The international, multicenter, double-blind studies RIO (Rimonabant In Obesity)-Lipids and RIO-Europe, carried out respectively for 1 and 2 years on more than 2,500 overweight or obese people in Europe and the US, have highlighted, when comparing patients treated with rimonabant and those treated with placebo, a waist circumference reduction as well as a 20% increase of HDL cholesterol levels.

Changes in the diet have been shown to reduce CVD, but the question still remains open on the optimal diet to achieve this goal. Products based on phytosterols, soybean and lupin proteins are among the non-pharmaceutical options that can act like drugs by effectively reducing atherosclerotic risk. A number of human studies have shown that regular consumption of phytosterol-enriched low-fat or non-fat food products significantly lower total and LDL-cholesterol. The cholesterol-lowering effect of phytosterols does not depend on a particular food matrix or on the fat content of the food. Moreover, modern food industry offers dietary products with great potentialities. “Starting with soy proteins and omega-3 fatty acids, still essential in anti-atherosclerotic diets,” Prof. Cesare Sirtori explained, “we have recently arrived to the use of lupin, a vegetable protein of Mediterranean origin which was the nutritional basis of ancient Roman soldiers. Lupin can decrease cholesterol almost as much as soy, adding the benefit of an appreciable antihypertensive and antidiabetic activities.”

Finally, in the search for good diagnostic tools, imaging biomarkers can serve as valid surrogates for clinical endpoints. Of the noninvasive techniques available, carotid intima-media thickness (IMT) measured by B mode ultrasound is the most established method for measuring atherosclerosis progression and regression. The measurement of intima-media thickness was proposed for the first time 20 years ago by an Italian team of researchers including Drs. Pignoli, Paoletti, Poli, Sirtori and Tremoli. Several large observational studies have shown a graded response between raised IMT and increased risk of incident CVD events. None of the studies published so far has, however, been able to address, on a prospective basis, whether IMT-progression, that is the end point of pharmacological studies, may effectively predict the occurrence of cardiovascular events. A long-term study by Dr. O’Leary from Boston carried out on 5,858 patients monitored with the IMT measurements, clearly indicated that an increased wall thickness corresponds to a higher risk of myocardial infarction and stroke. To address the same issues the European “IMPROVE” study was designed by Drs Tremoli and Baldassarre. This study is a currently ongoing prospective multicenter, longitudinal, long-term, observational study funded by the European Community and carried out in 5 countries on more than 3,600 patients at high cardiovascular risk. The major objective of the IMPROVE study is to evaluate the association between IMT, IMT-progression, and the rate of new vascular events in European patients at high risk of atherosclerosis for the presence of at least three vascular risk factors. Although the final results are expected by the end of 2007, the study has already shown a correlation between IMT and common cardiovascular risk factors (smoking and high cholesterol, triglycerides, and blood pressure), confirming the relevance of IMT as an indicator for cardiovascular risk. The IMPROVE study will, in addition, highlight the importance of clinical data distribution in the different countries.

During the Symposium, eighty investigators 35 year old or less, among those who presented abstracts selected for poster presentation, were chosen as semi-finalists in the Young Investigators Poster Awards. Among these, 20 awards were given to recognize scientific merit and outstanding research achievements, based on originality, importance of accomplished work, quality of experimental design and methodology, strength and reliability of data, and means of expression.
Hundreds of Registration Fees and Hotel/Travel Grants were made available by ISA 2006 Symposium to young investigators 35 year old or less, with limited financial resources, whose abstracts were selected for oral or poster presentation. Other awards were made available by the European Atherosclerosis Society and by the Japan Atherosclerosis Society.

This very well-attended Symposium brought together diverse disciplines within the atherosclerosis, thrombosis, and vascular biology research fields allowing young, and more “seasoned.” investigators to explore areas of cross-disciplinary interest and encompass a broader view of the field.