The Adventitia - The New Frontier in Coronary Atherosclerosis Imaging

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Citation
ICR 2007;2007:2(1):15-16
DOI
http://dx.doi.org/10.15420/icr.2007.15

Coronary artery adventitia was long considered to be a purely supportive and nutritive tissue, and its role in the natural history of coronaropathy was thus neglected. However, recent studies have highlighted a dynamic role played by the adventitia, and especially by its vasa vasorum (VV), in the genesis of atherosclerosis,1–3 atherothrombotic events4,5 and restenosis following balloon angioplasty.6-9 The adventitia would appear to be an important element to be taken into account in the understanding and study of human atherosclerosis, with a special focus on vulnerable plaque assessment. The role of the adventitia in atherothrombotic coronary evolution, as promoter or mere bystander, now needs to be discussed and evaluated.

Adventitia and Experimental Atherosclerosis

Experimental mini-pig models reveal that isolated VV occlusion without damage to intima or media may nevertheless generate the early stages of atherosclerosis by causing smooth muscle cell intimal proliferation.1 Furthermore, VV distribution has been shown to vary according to the vascular bed, being greater in arteries affected by atherosclerosis (coronary, renal and carotid) than in those, such as the mammaries, that are classically exempt.10 Likewise, a cholesterol-rich diet quickly induces intense neovascularisation of the first- and especially of the second-order VV,2 even before the appearance of the first signs of experimental atherosclerosis in the intima,11,12 which is an observation that also challenges the classical response-to-injury hypothesis. It is noteworthy that this effect can be reduced by simvastatin, probably by reducing the hypoxia induced in the arterial wall, independently of any reduction in cholesterol levels.13

Adventitia and Human Pathology

Many recent anatomopathological studies have highlighted the role of the adventitia in the development of atherosclerosis in humans. Coronary artery adventitia is thicker in cases of negative than of positive remodelling,14,15 especially in the healthy arc.15 VV density increases with the growth of atherosclerotic plaque in asymptomatic patients, and even more so in cases of cardiovascular event16 or plaque rupture.4,17 VV density is four times higher in cases of ruptured plaque compared with complication-free plaque. Moreover, adventitial inflammation was observed to increase as atherosclerotic plaque increases, especially in cases of ruptured plaque.4,5,17 About 80% of aortic plaques showed inflammatory adventitia in case of rupture compared with 62% in cases of non-rupture. Finally, adventitial VV are directly implicated in intraplaque haemorrhage, causing plaque progression and destabilisation.17,18

Adventitia and Vulnerable Plaque

A vulnerable plaque (VP) is an atheromatous plaque that is typically inflammatory, non-stenosing, showing positive remodelling, with a large necrotic core and thin fibrous cap (typically <65μm) and at high risk of evolving towards acute coronary syndrome.19,20 To date, the adventitia and/or its VV are not included in the definition of VP.
However, the adventitia has been very interestingly spotlighted in relation to VP, a lipid core closely associated with adventitial inflammation,21 without associated reduction in cap thickness (the prime morphological aspect of VP).5 Moreover, intraplaque haemorrhage is now recognised as a major factor in necrotic core progression,17 and here again adventitial VV would seem to play a determining role.
Finally, it is clear that there exists a proximal coronary segment cluster in VP development20,22 and a VV increase, predominately in the proximal and medial compared with the distal intracranial vertebral artery (IVA). This was recently demonstrated experimentally in hypercholesterolaemic pigs, and could potentially promote VP progression in those areas.23

In Vivo Detection of Adventitia

A large quantity of experimental and pathological data is currently implicating the adventitia as an early, dynamic and very significant contributor to the genesis and evolution of atherosclerosis via its VV. Therefore, detection in humans is clinically critical. As a surrogate evaluation, the carotid artery was first evaluated by both contrast-enhanced ultrasound24 and magnetic resonance imaging (MRI),25 both of which proved able to evaluate adventitia and neovascularisation. However, for coronary arteries only preliminary data are available.
Various imaging techniques – MRI, computed tomography (CT) and ultrasound, with and without contrast agents – are under assessment,18 but results so far, whether ex vivo2 or in the carotid,24 have been reproduced only under intravascular ultrasound (IVUS). IVUS provides a unique way of studying atherosclerosis in vivo, but the lack of any acoustic interface behind the adventitia notoriously prevents its being analysed. However, careful analysis of IVUS images frequently reveals slight pericardial detachments just to the rear of the artery being explored. This situation creates a new anechogenic acoustic medium at the external edge of the adventitia, setting up a new acoustic interface and thus clearly identifying the adventitial tunica.

Taking advantage of this frequent anatomical situation, which can be observed in about 3cm of explored left anterior descending (LAD) arteries, we recently showed that the adventitia could be easily located and measured in humans in 38 stable coronaropathy patients.26 A complementary pathological study demonstrated that, except insofar as IVUS resolution tended to overestimate the smallest thicknesses, the adventitia values obtained were accurate; thus, in vivo adventitia measurement can be reliable. It was confirmed that the adventitia was thicker in cases of atherosclerosis (353±75μm versus 233±42μm for IVUS-normal LAD). No significant difference was observed in adventitial thickness according to type of arterial remodelling (positive remodelling 353±73μm versus negative remodelling 353±79μm). However, the limited number of plaques explored and the method of calculating the remodelling index, quite different from the pathological definition,15 could explain the absence of correlation between adventitial thickening and negative remodelling.14,15 Obviously, such analysis fails to explore the VV and inflammatory phenomena directly, yet the morphological data, very easily obtained, are certainly a justifiable surrogate endpoint, as VV and inflammation are closely associated with adventitial thickness in pathological studies.14,15
Preliminary IVUS studies27–29 are currently specifically targeting the VV using a microbubble contrast agent. Results, though promising, encounter two major obstacles:
• technically, the US contrast enhancement was rather slight in the analysis area within the adventitia, which is already hyperechogenic, reflective and particularly subject to artifacts induced by US speckling; and • methodologically, no histological correlation exists, so the data available are of purely indicative value. VV analysis represents a further step towards adventitia analysis, the upcoming objective being to associate inflammatory criteria.

Conclusion

The adventitia is the third tunica of the arterial wall and plays a significant, and now widely recognised, role in the evolution and destabilisation of atherosclerosis. Hitherto unamenable to imaging, it will soon be open to routine analysis in humans. The data presented here26–29 are as yet preliminary, focusing on stable coronary pathology, but the field is now open to include unstable coronary pathologies and vulnerable plaques in the quest for further predictive indices of coronary events. Ôûá

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