The visualization of the remodelling paradox.

In the 1990s, significant efforts and investments were made in the development of imaging technologies with the objective of visualizing and characterizing the atherosclerotic plaque. Although angiography still is the indisputable first choice for the clinical diagnosis of coronary artery luminal narrowing, new imaging modalities are likely to stay to provide surrogate markers for disease progression and treatment efficacy. Since its clinical introduction, an important role has been arrogated to intravascular ultrasound (IVUS) in the diagnosis of coronary artery disease. However, despite the superior information that is provided on plaque and vessel morphology, IVUS has never met the expectations that were raised more than a decade ago, i.e. that IVUS would be routinely used in the cathlab. IVUS did improve our understanding of the natural history of atherosclerotic disease and, more specifically, the impact of geometrical arterial remodelling on luminal stenosis. Plaque formation has long been considered the only determinant of atherosclerotic luminal narrowing. The arterial wall, however, is an organ capable of overall reshaping in response to haemodynamic, mechanical, and biochemical stimuli. Glagov et al. were the first who raised the concept of ‘compensatory enlargement’. They described that the artery can partially or totally compensate for encroachment of atherosclerotic plaques upon the lumen by expansion of the arterial diameter. For a long time it was proposed that all arterial segments that suffered from atherosclerotic lesion formation underwent expansive remodelling and that luminal narrowing occurred when a maximal degree of arterial enlargement was reached. However, the arterial wall may also respond with constrictive remodelling, thereby aggravating the luminal narrowing response. In the same arterial segment one can observe lesions with an identical plaque area but with major differences in percentage luminal stenosis. Scientific interest in the role of arterial remodelling in occlusive arterial disease boomed with the upcoming use of the visualization technique of IVUS. The application of IVUS revealed how ubiquitously remodelling can prevent plaque from encroaching upon the lumen but also how failure of an expansive remodelling response accelerates luminal narrowing in de novo atherosclerosis. The variation of geometrical arterial remodelling in response to plaque formation is currently appreciated but has been traditionally underestimated as a causal factor for arterial occlusive disease. For instance, with IVUS studies it was demonstrated that in 5% of patients eligible for coronary intervention, the plaque mass at the culprit lesion is actually smaller than the plaque size located at the angiographically normal reference site. The latter emphasizes the role of geometry changes of the artery in atherosclerotic luminal narrowing and that the degree of luminal narrowing may be determined by inadequate compensatory enlargement rather than by the increase in plaque mass. One would be easily inclined to think of arterial enlargement as a beneficial response and constrictive remodelling as a harmful response to atherosclerotic plaque formation. The increase in vessel size in response to plaque formation is considered a natural compensatory response to prevent downstream lack of oxygen supply. However, the remodelling response is a coin with two faces and hides a paradox. Histopathological studies clearly demonstrated that expansive remodelling is associated with infiltration of inflammatory cells, expression of pro-inflammatory cytokines, and increased protease activity. These features are recognized as major determinants of plaque destabilization. In addition, collagen and smooth muscle cell content is lower in plaques that undergo expansive remodelling. On the other hand constrictive remodelling may aggravate narrowing of the lumen, but is associated with a stable fibrous plaque phenotype. The histopathological observations were soon followed by clinical IVUS studies that linked the clinical presentation of patients suffering from coronary artery disease with the mode of arterial remodelling. Different studies clearly revealed that unstable coronary syndromes often originated from lesions that revealed expansive remodelling while constrictively remodelled lesions were more frequently observed in patients suffering from stable angina. The aforementioned observations gave rise to the concept that IVUS could be applied to assess plaque characteristics and