Coronary artery remodelling in atherosclerosis: unfortunately unpredictable.

Coronary heart disease is the main cause of mortality and morbidity worldwide, and occurs because of the growth and complications of coronary atherosclerosis. Therefore, efforts in the understanding of how atherosclerotic plaques grow and undergo complications, and in identifying predictors of such dramatic events are welcome and worthwhile. Atherosclerosis has long been considered a relentless process by which the accumulation of lipids and extracellular matrix leads to progressive lumen encroachment. Two notions in the past 20 years have dramatically altered this conception. One is that most cases of myocardial infarction likely derive from acute plaque complications (plaque fissuring in most instances), and not from progressive lumen stenosis. The other is that the growth of atherosclerotic plaques is not necessarily towards the lumen, but may also occur towards the outer vessel layers, leading to an actual overall enlargement of the vessel, contrary to the previous tenet that atherosclerosis is similar to the encrustation of metal pipes in a building. This second aspect, although less appreciated in current literature than the burgeoning plethora of investigations on mechanisms of plaque rupture, is also fertile of important clinical consequences. In a series of human histopathological observations, Glagov et al. were the first to identify a significant direct correlation between the plaque area—calculated as the area defined externally by the internal elastic lamina (internal elastic membrane, IEM) and internally by the vessel lumen (intimal area) and the potential lumen area— i.e. the area circumscribed by the internal elastic lamina, taken as a measure of the area of the arterial lumen if no plaque had been present and the intima remained a virtual space. This finding indicated that, in general, the larger the plaque, the larger the vessel, and allowed the inference that plaques also grow towards the outside (‘positive remodelling’). These results have been subsequently validated in a number of investigations both by histopathology and by intravascular ultrasound (IVUS), clearly demonstrating that the evaluation of lumen area (and, by comparison with adjacent vessel segments, lumen stenosis, as routinely performed by angiography), may grossly underestimate the volume of the plaque, and that acute plaque complications (plaque rupture in most cases), may occur even in the total absence of any lumen reduction. Another interesting part of Glagov’s original findings has spurred further research. In correlating lumen area with the plaque burden, calculated as the percent of plaque area out of the IEM area, the authors found that lumen area was not related to the plaque burden for a range of percent plaque areas between 0 and 40; but an important significant negative relationship existed for plaque areas .40%. The inference at that time was that early plaque growth occurs preferentially towards the outside, because of the occurrence of positive remodelling, whereas further growth of the plaque, beyond a value estimated at 40% of the total potential lumen area, leads to lumen encroachment, and therefore, potentially, to a limitation of the coronary reserve. Two important theoretical limitations of Glagov’s analysis, on which the hypothesis was based were that: (1) the estimate of the relationship between lumen area and plaque burden is biased by the fact that one term of the relationship (lumen area) is arithmetically related to the other (plaque burden 1⁄4 % plaque area/IEM area, with IEM area 1⁄4 lumen areaþ plaque area); and (2) Glagov’s original findings were correlations in a snapshot of a sample of coronary arteries, and not dynamic estimates or the actual progression of the two parameters (plaque burden and lumen area) over time. The introduction of IVUS in the clinical routine has more recently allowed the in vivo imaging of the vessel area, as IVUS can identify the external elastic membrane (EEM) and may document the presence of atheromas otherwise undetectable by standard angiography. Lesions localized in the left main stem and detected by IVUS, but not by angiography have a clear clinical relevance, as they predict one-year clinical events. Moreover, IVUS is repeatable and allows serial measurements. One example of such