Background

Despite significant progress in the past decade in our understanding of the molecular pathways involved in the atherosclerotic cascade, cardiovascular disease due to atherosclerosis remains the leading cause of mortality and major morbidity in developed countries. To control the rising costs of healthcare, the current focus of cardiovascular medicine is to identify critical cellular and molecular mechanisms of atherosclerotic disease, in order to develop novel preventive and therapeutic strategies . For example, our understanding of the role of cholesterol metabolism and low-density lipoproteins as cardiovascular risk factors has led to considerable therapeutic advances, primarily with the development of statins. However, two out of three patients treated with statins still present with a major coronary event, which presents a significant residual burden of cardiovascular risk .

From the atherosclerotic plaque to the clinical event

For a long time it was believed that most cases of acute atherosclerotic events would arise from advanced atherosclerotic disease causing severe arterial stenosis. More recent studies instead suggest that the lesions responsible for sudden clinical events are frequently angiographically mild . These findings may explain why patients without symptomatic disease are not free from residual risk. In fact, a large number of fatalities due to atherosclerosis occur in apparently healthy individuals, who die suddenly without prior symptoms.

The challenge of identifying atherosclerosis

Almost 20 years ago, some authors highlighted that the challenge for the future would be to develop non-invasive screening methods of detecting atherosclerosis in its earliest stages . If circulating biomarkers and genetic assessment can help to identify high-risk patients within the general population, imaging techniques give the opportunity to identify and evaluate the burden of atherosclerotic disease in such patients. Computed tomography (CT) and magnetic resonance angiography can identify advanced atherosclerotic lesions by quantifying luminal stenosis. Additionally, CT and magnetic resonance imaging (MRI) can also quantify atherosclerotic burden in non-stenotic lesions and characterize plaque composition in terms of lipids, fibrous tissue calcification and microvasculature . However, if the morphological approach of these techniques can eliminate the risk by excluding the presence of atherosclerotic plaque, it is still limited in terms of predicting cardiovascular events . Indeed, major adverse cardiovascular events are most commonly caused by thrombotic occlusion of a high-risk coronary plaque. High-risk atherosclerotic plaque – or vulnerable plaque – represents the susceptibility of a plaque to rupture and its detection has become the goal of new imaging techniques. The morphological approach does not provide information regarding functional variables, such as plaque metabolism and inflammation, which are recognized markers of vulnerability.

Atherosclerotic molecular imaging

Molecular imaging is defined as the in vivo characterization and measurement of biological processes at the cellular, molecular, whole organ or body level . In addition to providing anatomical information, molecular imaging techniques can quantify specific biological processes, thus giving insight into the functional parameters of tissues. These may prove useful not only for detecting subclinical disease before anatomical changes in plaque size occur, but also for assessing the effect of approved and novel treatments, while improving our understanding of the biology of atherosclerosis.

Inflammation is currently regarded as one of the functional features of vulnerable plaques, and is therefore an attractive target for molecular imaging techniques , to measure disease progression and, potentially, the risk of rupture. Some of the key steps involved in the inflammatory cascade are endothelial dysfunction, expression of cellular adhesion molecules, lipid retention, macrophage activation, apoptosis, proteolysis and neoangiogenesis, all of which can be targeted using molecular imaging . Quantification of these features has been possible thanks to the development of high-resolution, high-sensitivity multimodal imaging systems, which can quantify the uptake in atherosclerotic plaques of tracers targeted to specific biological processes. These include ultrasound, single-photon emission CT (SPECT), positron emission tomography (PET), CT, MRI and optical techniques, including fluorescence-mediated tomography and catheter-based sensors . The specificity of these techniques depends on the selectivity of the tracer employed, while sensitivity depends on the intrinsic capabilities and limitations of each modality. For example, optical imaging techniques allow high-specificity by using a customized probe for every target of interest. Currently, these techniques are mainly confined to research, but their application is rapidly expanding in the medical field . Ultrasound has the advantage of being non-invasive, non-ionizing and relatively inexpensive, which makes it a widely available technique. However, the limited penetration depth and the lack of specific molecular probes limit its use in molecular imaging. MRI and CT are widely available techniques that share the advantage of superior spatial resolution compared with other modalities; both can be used alone or in combination, with either non-targeted or targeted contrast agents, to better quantify the features of plaque vulnerability . Both radionuclide imaging techniques – SPECT and PET – have the advantage of being non-invasive with high sensitivity and specificity, which makes them particularly suited for molecular imaging of atherosclerosis . In addition to exposure to ionizing radiation, they have the disadvantage of low spatial resolution and often require advanced radiochemistry techniques if specific tracers have to be used . To exploit the advantages of different techniques at once, the current trend is to develop multimodality imaging systems that integrate molecular, physiological and anatomical information . For example, the high sensitivity of nuclear techniques can be coupled with the high spatial resolution of CT or MRI in multimodality hybrid systems such as SPECT/CT, PET/CT or MRI/PET for superior disease characterization.