Tuesday June 28 Plenary session

How to find and treat vulnerable plaque: Bridging the gap to clinical practice

Pathology of the vulnerable plaque: what does it look like?

Plaque rupture is the main cause of fatal coronary events. What characterises the vulnerable plaque, and how to detect and treat this was the focus of Tuesday’s Plenary Session. Professor Erling Falk, Aarhus University Hospital, Aarhus, Denmark summarised the key components of the vulnerable plaque. These include a large lipid-rich necrotic core, a thin fibrous cap with accumulation of macrophages, thrombus, angiogenesis, perivascular inflammation, and outward remodelling. The larger the core the more unstable the plaque.¹ ‘While inflammation plays a key role in the development of vulnerable plaque, it is a misconception that ruptured plaques are heavily inflamed. The macrophages are localised to a specific area and play a major role in the rupture of the plaque,’ commented Professor Falk. The other type of event, plaque erosion, more common in women than men, is considerably more difficult to detect. Carotid plaque rupture is an even more frequent cause of stroke, accounting for about 90% of cases, and shares similar characteristics to ruptured plaques in the coronary circulation.

1. Falk E. Pathogenesis of atherosclerosis. J Am Coll Cardiol 2006;47(8 Suppl):C7-12.

Is averting thrombosis a likely strategy?

‘If vulnerable plaques that are likely to rupture could be detected and thrombosis averted, atherosclerosis would be a much more benign disease,’ said Professor Ira Tabas, the Richard J. Stock Professorship, Department of Medicine of Columbia University, New York, USA. Professor Tabas and his group have been interested in the cellular mechanisms underlying the progression of atheromatous plaque to rupture, most recently in understanding the mechanisms underlying necrotic core formation. Throughout the early development of atherosclerotic lesions, intimal macrophages undergo apoptosis and are then cleared via phagocytosis. However, in advanced lesions, this process becomes defective - “efferocytosis”. ‘The concept is that in atheromatous lesions that develop slowly over many years, postapoptotic macrophages build up and coalesce over time to form the necrotic core. There is now direct evidence for this process in the advanced lesion.’

A key issue is understanding the mechanism underlying this defective phagocytic response. Several possible mechanisms might contribute to efferocytosis, including oxidative stress, LP-associated hydrolysis of oxidized phosphatidylserine on the surface of apoptotic cells by phospholipase A2, or protease-mediated cleavage of efferocytosis receptors. Molecular–genetic causation studies in mouse models of advanced atherosclerosis suggest that molecules known to be involved in efferocytosis may play a role in the clearance of apoptotic cells in advanced plaques. The receptor tyrosine kinase Mertk has been a key focus of studies by Professor Tabas’s group.¹

However, macrophages are not the only cells that undergo phagocytosis. Immature dendritic cells have also been shown to be very good efferocytes. Studies showed that about one-third of the cells in lesions have markers of dendritic cells. Why this should be the case is not clear. In terms of functional significance, there is some evidence that lesional dendritic cells present antigen to and activate lesional T cells. Additionally, immature dendritic cells share two properties associated with early lesional macrophages: proliferation and foam cell formation. Using an experimental model, Professor Tabas and his group were able to investigate the dendritic cell maturation process in vivo, and showed that blocking the maturation of dendritic cells resulted in defective phagocytosis or efferocytosis. There remain a number of unanswered questions about the mechanism of this response, and whether this may be used as a model of atherosclerosis. Ultimately, understanding this process may help in delineation of possible therapeutic targets that impact efferocytosis and atherosclerosis progression.

1. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell 2011;145:341-55.

New imaging possibilities

Undoubtedly, inflammation is one of the key drivers of plaque destabilisation. However, most imaging modalities cannot readily measure this. The exceptions to this are positron emission tomography (PET) and computed tomography (CT). Dr James Rudd, Senior Lecturer and Consultant in Cardiology at Addenbrooke's Hospital and the University of Cambridge, UK overviewed findings from his research aimed at visualising the early vulnerable plaque using PET with 2-[18]-fluoro-2-deoxy- D-glucose PET (PET/FDG) FDG is an analogue of glucose which accumulates in all cells that actively metabolise glucose, including macrophages in atherosclerosis, and can be used to visualise inflammation. Studies have shown that FDG uptake correlates with macrophage infiltration in human carotid atheroma, and also reflects inflammatory gene expression. The question is whether this modality can be applied translationally to inform about biology, measure the change in inflammation with therapy and predict heart attack and stroke.

In respect of the first challenge, there is clear evidence that vascular inflammation is highly correlated across arterial beds, and that FDG uptake correlates with inflammation. In a recent study, cartotid plaque inflammation was associated with cerebral micro-emboli with uptake by FDG a good surrogate marker of carotid plaque inflammation. FDG is also a surrogate marker of vascular risk in the coronary arteries, with higher FDG uptake in patients with ACS.

FDG PET may also have application in evaluation of the early efficacy of anti-atheroma drugs. In a recent study, 18-F FDG PET-CT was a surrogate marker in the assessment of changes in vascular inflammation associated with treatment with losmapimod.¹ Active calcification imaging, currently tested in oncology patients,² may offer an alternative approach, especially in the visualisation of vulnerable plaque in high-risk patients. ‘Future platforms may involve the integration of imaging with more specific tracers of hypoxia, calcification or macrophages.’

1. Elkhawad M, Rudd JH, Sarov-Blat L et al. Abstract 16936: Inhibition of p38 Mitogen-Activated Protein Kinase Attenuates Vascular and Systemic Inflammation in Patients with Atherosclerosis as Assessed by 18-F Fluorodeoxyglucose PET-CT. American Heart Association 2010.

2. Rominger A, Saam T, Vogl E et al. In vivo imaging of macrophage activity in the coronary arteries using 68Ga-DOTATATE PET/CT: correlation with coronary calcium burden and risk factors. J Nucl Med 2010;51:193-7.

Plaque inflammation at the crossroads: evaluating new therapeutic agents

Atherosclerosis is a chronic inflammatory condition evolving over several decades, and culminating in the rupture of a vulnerable atherosclerotic plaque precipitating the clinical event. Current therapies predominantly focus on the management of cardiovascular risk factors including smoking cessation, diet, physical activity, and management of lipids, hypertension and blood glucose, which act at several points of this pathway. Undoubtedly lowering LDL cholesterol with a statin reduces the risk of cardiovascular disease, and may stabilise plaque. However, even with aggressive LDL cholesterol reduction, there is a clear need for additional approaches. ‘This is especially relevant in a progressively older population who are increasingly obese and sedenatary,’ commented Professor Peter Libby, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, USA.

The use of biomarkers of inflammatory status suggests the potential of anti-inflammatory therapy as a treatment for atherosclerosis. However, trials of conventional anti-inflammatory treatments have been largely unsuccessful or even have aggravated atherosclerosis. What of the new therapeutic possibilities?

Two randomized, placebo-controlled trials are testing the hypothesis that anti-inflammatory agents normally used in other indications may be relevant as cardiovascular therapeutic agents in the secondary prevention setting. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) is evaluating canakinumab, an antibody that inhibits the endogenous pro-inflammatory protein interleukin-1-beta (IL-1β) in patients with stable coronary artery disease. IL-1 promotes atherothrombosis and also plays a role in the autoimmune process that causes insulin resistance. The primary endpoint is major cardiovascular events, defined as recurrent MI, stroke and cardiovascular-associated death. A secondary endpoint is new-onset diabetes. The second trial, the Cardiovascular Inflammation Reduction Trial (CIRT) is evaluating the use of low-dose methotrexate on top of the current standard of care (including high-dose statin therapy) in stable post-MI patients.

‘There have been substantial advances in the diagnosis and treatment of vulnerable plaque. However there are still considerable challenges in translate experimental findings to bridge the gap to clinical practice.’

Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011;473:317-25.