Reports and summaries by Jane Stock, Freelance Medical Writer and Journalist
Sponsored Educational Symposia
- Nutritional approaches to prevention of cardiovascular disease: Challenges for the clinician?
Sponsor: Danone. Chair, Prof J. Chapman; speakers, E. Bruckert, S Turley, L Masana, R Carmena
The presentations given in this Symposium are now available to view on-line <here>
Opening Ceremony
At the opening ceremony, Professor John Chapman, EAS President, highlighted the mission of the Society: supporting education into the prevention, diagnosis and treatment of atherosclerosis and cardiovascular disease. Facilitating the exchange of information between basic and clinical researchers is crucial to these aims.
Anitschkow Award Lecture - Professor Michael S. Brown
Nobel prize laureate Professor Michael S. Brown, Genetics Professor and Director of the Center for Genetic Diseases at the University of Texas Southwestern Medical School, USA was awarded the Anitschkow Prize 2010 for his lifelong, outstanding research in the field of lipid metabolism and atherosclerosis.
In the Anitschkow Award lecture How does a cell regulate a lipid embedded entirely in its membrane? Professor Brown eloquently reviewed studies conducted with his colleague and co-Nobel prize laureate Professor Joseph L. Goldstein that led to the unravelling of the molecular basis of familial hypercholesterolemia, identification of the low-density lipoprotein (LDL) receptor, and regulatory mechanisms enabling cells to maintain relatively constant levels of unesterified cholesterol in membranes. More recently, study of Niemann-Pick C disease has provided insights into how cholesterol is transported between different organelles within the cell.
Two genes were identified encoding for separate proteins, NPC1 and NPC2, implying that both were required for LDL-derived cholesterol to exit the lysosomes. The smaller, soluble protein, NPC2, was shown to bind cholesterol via hydrophobic interaction, subsequently confirmed by crystallography studies. However, NPC1 bound cholesterol in the opposite orientation via an N-terminal domain. In contrast to the binding of cholesterol to NPC2, binding to and dissociation from NPC1 was slow. Both processes were accelerated when cholesterol was delivered by NPC2. The NPC1 internal domain was also shown to project beyond the glycocalyx into the lumen of the lysosome.
These data provide the basis for the development of a conceptual model for the transfer of cholesterol from NPC2 to NPC1, in which NPC2 extracts cholesterol from LDL in the lysosome and then transfers it to the N-terminal domain of membrane-bound NPC1, the so-called ‘hydrophobic handoff’ model. In his final conclusion, Professor Brown suggested that similar mechanisms of transmembrane transport may apply to other lipids.
Brown, M. S.: Anitschkow Award Lecture
78th EAS Congress, Hamburg, Germany, 20 June 2010
Plaque biomarkers may offer new potential
‘Initiatives such as Athero-Express offer the possibility of earlier diagnosis of cardiovascular disease and targeted treatment’
Professor Gerard Pasterkamp, UMCU, The Netherlands
New approaches are needed to identify patients at risk of atherosclerotic cardiovascular disease. At the Opening Plenary Session, Professor Gerard Pasterkamp, Professor of Experimental Cardiology, UMCU, The Netherlands presented data from Athero-Express, an atherosclerotic plaque biobank from more than 2500 patients, followed up for 5 years. Patients with evidence of intraplaque thrombosis or neovascularisation were at increased risk of major cardiovascular events (by 1.7-fold, 95% CI, 1.2 to 2.5, and 1.4-fold, 95% CI 1.1 to 1.9), respectively), independent of traditional risk factors.
However, macrophage infiltration, or the presence of a large lipid core, calcifications, collagen and smooth muscle cell infiltration within the plaque were not (1). These data were consistent with those from a retrospective study in which the presence and degree of adventitial vasa vasorum and plaque neovascularization were directly associated with cardiovascular disease (2). Other plaque biomarkers that are predictive of cardiovascular risk have been identified. For example, plaque osteopontin levels increased cardiovascular risk by 3.8-fold (95% CI 2.6-5.9), when levels in the highest versus lowest quartiles were compared (3).
Pasterkamp, G.: Vascular Biomarkers
78th EAS Congress, Hamburg, Germany, 21 June 2010
Multi-modal imaging technologies
‘The challenge for the future is whether this technology can be used to identify patients at risk of cardiovascular events to guide therapeutic management’
Professor Martin Bennett, University of Cambridge, UK
New imaging technologies enable visualisation of the arterial vessel wall, as outlined by Professor Martin Bennett, British Heart Foundation Chair of Cardiovascular Sciences, University of Cambridge, UK. He overviewed the relevance of three complementary techniques: invasive intravascular ultrasound VH (IVUS VH), and non-invasive dual-source computed tomography (CT) and positron emission tomography-FDG (PET-FDG).
IVUS‑VH uses advanced spectral analysis techniques to allow simplified interpretation of ultrasound images and provide detailed information on the composition of the atherosclerotic plaque. Results from the landmark PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) trial (4) showed that IVUS technology could be successfully used to classify plaque lesions for risk of a cardiovascular event. The technology is superior to angiography as it allows identification of lesions likely to progress to clinical events, as well as lesions in locations often missed by angiography. Understanding the risk of each lesion type is paramount to minimizing the occurrence of future events. Both dual-source CT and PET-FDG offer applicability in the assessment of plaque vulnerability in clinical research, with preliminary trials in in aortic aneurysm.
Bennett, M. R.: Unstable Plaque Biology and Detection
78th EAS Congress, Hamburg, Germany, 21 June 2010
Cytokine networks
Cytokine evaluation could identify biomarkers for plaque development and stability, as reviewed by Professor Alain Tedgui, Director, PARCC (Paris-Cardiovascular Research Center)-Inserm U970, France. Specifically, study of T-helper responses showed that Th1 was atherogenic, whereas Th2 responses, mediated by interleukin-5 (IL-5) were protective against atherosclerosis. More recently, a third member of the T-helper set, IL-17-producing T-cells (Th17), were shown to play an important role in autoimmune diseases, and potentially a protective role in atherosclerosis, mediated by the SOCS3 protein. CD4+CD25+ regulatory T-cells which limit the development of atherosclerosis may be a promising anti-atherosclerotic strategy to limit inflammation.
Tedgui, A.: Immunoregulation in Atherosclerosis
78th EAS Congress, Hamburg, Germany, 21 June 2010
Genome wide genetic studies
‘For the future, we need to look at the network of loci and how these changes in individual patients. Understanding the mechanisms involved may provide new targets for treatment’
Professor Schunkert, Direktor der Medizinischen Klinik II - Campus Lübeck, Germany
Genome-wide studies such as the CARDIoGRAM Consortium offer the possibility of identifying common alleles associated with coronary artery disease risk, as discussed by Professor Heribert Schunkert, Direktor der Medizinischen Klinik II - Campus Lübeck, Germany. CARDIoGRAM is an example of the globalisation of research, as it brings together an enormous wealth of GWAs data on risk for coronary artery disease (CAD) and myocardial infarction (MI). The data currently comprise more than 22,000 well-characterized cases with CAD and more than 60,000 controls mostly from population-based studies. CARDIoGRAM offers the potential for identifying novel genetic loci for cardiovascular disease, not associated with traditional risk factors. The challenge for the future will be to understand the underlying mechanisms and identifying new targets for disease.
Schunkert, H.: What are we learning from Genome-wide Studies?
78th EAS Congress, Hamburg, Germany, 21 June 2010
Managing socio-economic risk factors
‘Health inequality represents an urgent challenge. Doctor visits cannot compensate for a lifetime of social inequality. Perhaps a change in the emphasis of healthcare policy from efficacy to equity would achieve reduction in coronary heart disease mortality across the social spectrum’
Dr Eric Brunner, UCL, London
Despite enormous advances in improving life expectancy in developed countries, people in lower socio-economic groups remain at increased risk of coronary heart disease (CHD) death than those in higher groups (5,6). These socioeconomic inequalities in health do not appear to be fully accounted for by differences in well-known risk factors, such as smoking. (5,6). As physical functioning declines faster with age in lower socioeconomic groups, such inequalities will become an important public health issue as the population ages.
There needs to be new approaches in healthcare policy to redress this balance, as discussed by Dr Eric Brunner, University College London, UK. In the 21st century, there has been a re-evaluation of the importance of lifestyle intervention to reduce cardiovascular risk. Yet despite such overwhelming evidence, there has been little sociological impact. Researchers at University College London used a multiple logistic modelling approach to show that successful implementation of best-practice interventions (i.e., reduction of systolic blood pressure by 10 mm Hg, of total cholesterol by 2 mmol/L, and of blood glucose by 1 mmol/L in pre-diabetic people; halving the prevalence of type 2 diabetes; and complete cessation of cigarette smoking) could prevent more than 50% of events in lower socio-economic groups (7). However, such an approach is representative of almost universal medication, and is clearly unrealistic from ethical, clinical and economic perspectives.
Brunner, E.: Risk Factors Raised by Socioeconomic Deprivation that Doctors Can Manage.
78th EAS Congress, Hamburg, Germany, 21 June 2010
Managing environmental risk factors
Eating less meat can prevent cancer, heart disease and reduce global warming, as proposed by Professor Ole Faergeman, Aarhus Amtssygehus University Hospital, Denmark. The EAS, together with other expert societies, can play a key role in changing this unsustainable relationship.
Increased consumption of meat has been associated with about 30% increase in the risk of cardiovascular events (8), although a more recent systematic analysis suggests that this may be restricted to consumptionof processed meat (9). Global demand for meat has increased over the last decade, especially in developing regions, such as South East Asia. However, raising livestock for meat production is an inefficient process which contributes substantially to global greenhouse gases. The environmental impact of raising livestock and growing animal feed is profound in terms of deforestation, energy use and the production of greenhouse gases. Dietary guidelines also need to change to reflect both dietary and ecological perspectives.
There is a clear need for a serious debate regarding the lack of sustainability of this approach, from environmental, health and economic perspectives. Professor Faergeman suggested that this should be led by key societies, such as the European Atherosclerosis Society.
Faergeman, O.: Environmental and Nutritional Factors – What Can Doctors Do?
78th EAS Congress, Hamburg, Germany, 21 June 2010.
Targeting metabolic risk factors: new priorities
‘From a practical perspective, probably the combination of both body mass index and waist circumference or waist/hip ratio is the best measure of abdominal obesity’
Professor Luc Van Gaal, Antwerp University Hospital, Antwerp, Belgium.
The Second Plenary Session discussed the potential for new metabolic factors as therapeutic targets, especially relevant with the ongoing obesity pandemic. The association between increased abdominal obesity and cardiovascular risk is already recognized. Most recently in INTERSTROKE, a case-control study including 3000 first acute-stroke cases and 3000 controls from 22 countries (81% from Southeast Asia, India, or Africa), abdominal obesity was associated with a population attributable risk for ischaemic stroke of 26.5 (18.8-36.0), when comparing patients in the second and first tertiles (10). Sustained exposure to lipids is also deleterious for pancreatic islet function, promoting beta-cell apoptosis and increased risk for diabetes.
Ectopic fat releases a large number of bioactive mediators that impact the development of insulin resistance and atherosclerosis. In the heart, accumulation of ectopic fat in the myocytes increases myocardial triglyceride levels, promotes re-modelling of the myocardium and contributes to the pathogenesis of cardiac dysfunction and atherosclerosis via secretion of various pro-inflammatory cytokines. In the muscle, accumulation of ectopic fat in the muscle has been associated with an increase in serum retinol-binding protein (RBP4), an adipocyte-derived 'signal' (11), which may represent a potential target for future intervention.
Targeting dietary factors is one approach to address this issue. For example, replacing fructose, which has adverse effects on the selective deposition of visceral and ectopic fat, lipid metabolism, de novo lipogenesis, blood pressure and insulin sensitivity, with glucose is worthy of consideration. Additionally, evidence from studies involving the use of prebiotics and probiotics (12) indicates that changing the composition of the gut flora may impact the development of metabolic diseases associated with obesity.
Van Gaal, L.: Obesity as a Risk Factor.
78th EAS Congress, Hamburg, Germany, 22 June 2010
Influencing intracellular metabolic regulation
‘Activation of brown adipose tissue by cold exposure might be important in terms of energy expenditure in humans, and could offer a new target for future therapies’
Professor Nuutila, Turku University Hospital, Finland
Targeting pathways that impact mitochondrial metabolic capacity and energy homeostasis offers therapeutic potential. New data presented by Professor Pirjo Nuutila, Turku University Hospital, Finland suggest a role for targeting brown fat. In contrast to white adipose tissue, brown fat is mitochondria-dense and therefore highly metabolically active. It was previously thought that brown fat is only present in infants, disappearing in later life. However, more recent studies have disputed this. In a study in healthy volunteers (13), exposure to cold resulted in a 15-fold increase in glucose utilization, mediated by increased expression of an uncoupling protein in the membrane (UPC1), involved in an alternative pathway for energy production, distinct from oxidative phosphorylation.
Other research has shown that fasting, exercise or administration of resveratrol, a component of red wine, can modulate mitochondrial function, resulting in increased energy expenditure. These adaptive effects appear to be transcriptionally regulated by the nuclear factor proliferator-activated receptor γ co-activator (PGC1-α), mediated via reversible acetylation. Regulation of intracellular levels of nicotinamide adenine dinucleotide (NAD+) is crucial to this process (14). Future studies with agents that mimic the effects of resveratrol will help to show whether activation of this pathway may have potential beneficial effects on cardiovascular disease.
Nuutila, P.
78th EAS Congress, Hamburg, Germany, 22 June 2010
‘PGC1-α appears to be the master regulator of mitochondria. Since altered signalling by nuclear receptors and cofactors contributes to the pathogenesis of type 2 diabetes, obesity and atherosclerosis, this research may offer the potential for novel therapeutic strategies’
Professor Johan Auwerx, Ecole Polytechnique Fédérale de Lausanne, Switzerland.
PGC1-α is also implicated in the regulation of metabolic pathways which play a role in diabetic cardiomyopathy. Mice over-expressing cardiac-specific fatty acid-activated nuclear receptor peroxisome proliferator-activated receptor-γ (myosin heavy chain [MHC]-PPARalpha mice), an experimental model of the diabetic heart, was been used to explore this further. When crossed with mice deficient for cardiac lipoprotein lipase, there was evidence of improved cardiac function, no propensity for myocardial accumulation of triglycerides and normalisation of the activity of the cardiac PPARalpha gene regulatory pathway. Mitochondrial capacity was shown to be key to rescue of cardiac function, with PGC1-α implicated in transcriptional regulation of the metabolic cascade (15).
Auwerx, J.: Transcriptional Cofactors and NAD+ in the Control of Metabolism.
78th EAS Congress, Hamburg, Germany, 22 June 2010
How does HDL protect against atherosclerosis?
HDL was a focus of discussions at one Workshop during the Congress. Professor Kerry-Anne Rye, Heart Research Institute, Sydney reviewed evidence that HDL have important atheroprotective functions beyond reverse cholesterol transport, including anti-oxidant, anti-inflammatory, anti-apoptotic, antithrombotic, anti-infectious and vasodilatory properties.
- Anti-inflammatory and anti-oxidant properties of HDL
The anti-inflammatory properties of HDL and their main apolipoprotein, apolipoprotein A-I (apoA-I), are now well established. In one study, chow-fed rabbits were given daily infusions of reconstituted HDL, apoA-I, and phospholipid- small unilamellar vesicles prior to insertion of a peri-arterial collar. All treatments were shown to inhibit early pro-oxidant and proinflammatory changes induced by the collar, i.e., increases in vascular wall reactive oxygen species, dense infiltration of the arterial wall by polymorphonuclear leukocytes, and endothelial expression of VCAM-1, ICAM-1 and MCP-1 (16). The anti-inflammatory properties of apoA-I were impaired by non-enzymatic glycation, attributed to a reduced ability to inhibit nuclear factor-kappaB activation and reactive oxygen species formation (17).
- Effect of HDL on beta-cell function
There is also new evidence that HDL may be involved in maintaining normal beta-cell function (18). Min6 cells and primary islets from rats were incubated in the presence and absence of physiologically relevant concentrations of apoA-I or apoA‑II, in lipid free-form or as a constituent of discoidal reconstituted HDL, or with HDL isolated from human plasma. Cells were incubated in basal glucose (2.8 mmol/L) and high-glucose (25 mmol/L) concentrations. Lipid-free and lipid-associated apoA-I and apoA-II increased insulin secretion under both basal and high-glucose conditions. This effect was calcium-dependent. Under high-glucose conditions (but not low-glucose conditions), the effect of apoA-I and apoA-II was also KATP channel and glucose metabolism-dependent. These data therefore raise the possibility that therapeutic intervention aimed at raising HDL levels may also offer the possibility of improving beta-cell function and glycaemic control, with potential implications for the treatment or prevention of type 2 diabetes.
- Does therapeutic intervention to raise HDL also influence HDL function?
Niacin is the most effective agent currently available for raising HDL cholesterol levels. In patients with type 2 diabetes, niacin has been shown to have beneficial vasoprotective effects independent of lipid-modifying effects in type 2 diabetes (19). Most recently, niacin was shown to protect against experimentally induced endothelial dysfunction and inhibit vascular inflammation, independent of changes in plasma lipid levels in an animal model (20). Rabbits were fed a normal chow diet with or without supplementation with niacin (0.6% or 1.2%, weight/weight) for 14 days before insertion of a non-occlusive periarterial carotid collar. At this time, there were no significant differences in plasma lipid levels between the control or niacin groups.
After 24 hours, the collar induced acute vascular inflammation in the control animals; however, this response was attenuated among the niacin-treated groups. Additionally, in collared carotid artery rings taken from rabbits that received niacin, vasorelaxation was improved relative to what was observed in the collared control animals. Niacin was also shown to protect against endothelial dysfunction induced by myeloperoxidase-derived oxidants such as HOCL. These beneficial effects were associated with improved vascular redox state and increased vascular content of reduced glutathione, a scavenger of reactive oxygen species.
Despite the fact that niacin has been in clinical use for over 30 years, the metabolic pathways that it influences have still not been fully defined. These latest studies provide new insights, showing that niacin markedly inhibits acute vascular inflammation and protects against endothelial dysfunction, independent of any lipid-modifying effects of niacin.
Diabetes and cardiovascular risk – is lower better?
The Third Plenary Session focused on the role of intensive glycaemic and blood pressure in patients with diabetes. Professor Marja-Riitta Taskinen, Biomedicum, Helsinki, Finland overviewed evidence from recent major clinical trials: Action to Control Cardiovascular Risk in Diabetes (ACCORD) (21), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) (22) and Veteran Administration Diabetes Trial (VADT) (23) (Table 1). None of these studies showed significant reduction in cardiovascular risk with intensive versus conventional glycaemic control; in fact, in ACCORD the intensive glycaemic arm was prematurely discontinued due to an excess in death (all-cause and cardiovascular) and patients continued on conventional glycaemic control.
However, the studies warrant closer inspection to investigate reasons for these findings. First, the primary outcome differed across the trials limiting comparison. In VADT the primary outcome included a wide range of end points: MI, stroke, cardiovascular death, new or worsening heart failure, revascularisation and inoperable coronary artery disease and amputation for ischaemic gangrene, whereas in both ACCORD and ADVANCE, the major cardiovascular outcome was more consistent (nonfatal MI, nonfatal stroke and CVD death). Second, the nature of the patient populations differed in terms of median HbA1C, duration of diabetes at study entry and the proportion of patients on insulin at study close (see Table 1). Both US trials also showed a substantial weight gain with intensive glycaemic control, as well as a higher incidence of hypoglycemia (16-21% versus 2.7% in ADVANCE).
To resolve this controversy, recent meta-analyses have investigated the relationship between intensive lowering of HbA1c and cardiovascular risk. However, even the results of these meta-analyses have been conflicting. A meta-analysis of five trials (n=33,040) showed that intensive glycaemic control led to 0.9% reduction in HbA1c which was associated with 17% reduction in non-fatal MI and a 15% reduction in CHD events, although there was no significant effect on stroke or all-cause mortality (24). However, the UKPDS data strongly weighted the results of this analysis. A second meta-analysis showed that while more intensive glycaemic control was associated with 15% reduction in risk for MI, the risk of hypoglycaemia was more than 2-fold higher (25). Finally, a retrospective cohort study comparing outcomes in patients treated with oral combination therapy or insulin-based therapy showed a U‑shaped association for HbA1c and all-cause mortality, with mortality higher at both low and high mean HbA1c values (26).
Taking these findings into account, consensus suggests that an individualised approach to glycaemic management, taking into account both HbA1c and the risk of hypoglycaemia is more appropriate. Emphasis should be given to earlier initiation of treatment, as well as multifactorial intervention targeting all cardiovascular risk factors.
Does lower blood pressure provide greater CV risk reduction?
According to Professor Guiseppe Mancia, Head of the Division and Department of Internal Medicine at the San Gerardo Hospital, Monza, Italy, this issue is controversial. Taking account of recent clinical trial evidence, he suggested the need for a more cautious approach. In the ACCORD Blood Pressure Trial (27), there was no significant difference in cardiovascular risk reduction between patients treated to a target systolic BP (SBP) <120 mmHg compared with those treated to SBP <140 mmHg. Additionally, a retrospective analysis of the INVEST (International Verapamil SR-Trandolapril) (28) study, published this month in the Journal of the American Medical Association adds support. In INVEST, patients achieving a SBP of 130-140 mm Hg (usual care) had a better outcome than those with values >140 mm Hg. However, there did not appear to be any additional benefit at SBP below 130 mmHg. Although these studies had slightly different patient populations, the results give a similar message.
The effects of blood pressure lowering on renal disease and stroke are also relevant, with studies showing incremental benefits with greater blood pressure lowering. In the ACCORD Blood Pressure Trial, intensive blood pressure lowering was associated with significant reduction in stroke by 41%, (p=0.01) and nonfatal stroke by 37% (p=0.03) versus standard therapy. These findings are, however, limited by few patients and need to be weighed against an increased incidence of adverse events (3.3% versus 1.3%, p<0.001) (27). In addition, ADVANCE demonstrated significant renoprotective effects directly related to the degree of reduction in SBP (29). These findings may be due to better autoregulation of blood flow in these tissues with improved glycaemic control.
There remain a number of outstanding questions. For example, studies are needed to evaluate treatment effects in Caucasian versus Asian patients, especially given the higher cardiovascular risk in the latter group, as well as in patients with a history or cerebral or renovascular disease. In concluding remarks, Professor Mancia highlighted that from a clinical practice perspective, such issues are academic, given that in most diabetic patients, blood pressure control is difficult to achieve.
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