The first speaker of the session, Dr Virmani (Gaithersburg, USA) gave an excellent overview of the current insights in human cardiovascular pathology. Insights that, according to her, are essential for appreciating the significance of markers for vulnerable patients. The features of stable, vulnerable and ruptured plaques were defined, showing that with progressive disease the cap becomes increasingly thinner and inflammatory while plaques are growing almost devoid of smooth muscle cells. Only 11% of observed ruptures occurred on plaques that had never undergone rupture before: apparently rupture is a rather frequent and generally nonfatal event. Dr Virmani proposed that rupture may be a critical step in expansive plaque growth. Furthermore, she showed recent data to support the notion that intraplaque haemorrhage and rupture are interrelated. In fact, the majority of ruptured plaques contained more than 5 haemorrhages, as compared to 0.5 for stable plaques. IPH (intra plaque haemorrhage) by itself may lead to expansive plaque growth and increment of the necrotic core, thus contributing to plaque vulnerability. She showed that vasa vasorum are most common in coronary arteries carrying plaques > 0.5 mm, pointing to a key role of hypoxia in their formation. Interestingly, vasa vasorum are much less frequently observed in plaques of femoral and carotid arteries.
The next speaker, Dr De Bruyn (Aalst, Belgium), presented a review of finished and ongoing longitudinal studies on the predictive value of vascular imaging. Angiography appeared not to be very helpful in predicting future adverse cardiovascular events. Moreover, PCI of vascular segments with non critical stenosis (FFR<0.75) did not improve the incidence of future AMI or cardiac death. These data were basically confirmed in the DEFER study showing that the death and AMI rate in patients that received a PCI on lesions with a FFR<0.75 was 7.6% while that in the case of FFR >0.75 lesions was only 2.5%. The most predictive imaging procedure was IVUS palpography: the number of high strain spots was seen to correlate quite considerably with the future risk of adverse events. Palpography therefore is at present the method of choice to identify high risk plaques, but the need for a clinically relevant definition of a vulnerable plaque remains.
The third speaker, Dr Van der Wall (Amsterdam, Netherlands) brought the focus back to pathology and his presentation centered on thrombus formation in culprit plaques. Thrombi may form as a result of acute plaque rupture, plaque dissection (intramural and lumenal) or microvessel rupture (intramural). Only a low percentage of all ruptures seems to be fatal, raising the question on the actual fate of nonfatal lumenal thrombi. The latter thrombi are partly resolved in situ. Often microembolisation of distal tissue occurs which may cause microinfarctions that may eventually culminate in loss of cardiac function. Thrombosuction or the use of a distal scavenging device during PCI may help to reduce the risk of such phenomena.
The majority of thrombi are re-organised and may in this way lead to further plaque growth and neovascularisation of the intima. While most thrombi are either resolved or reorganised, a most surprising finding is that the time span between thrombus formation and its clinical manifestation often extends to days or even one week. This has major implications for interventional strategies.
The final speaker of this workshop, Dr Pasterkamp (Utrecht, Netherlands), questioned the value of markers of plaque vulnerability based on histological features. He proposed that it would make more sense to identify markers for vulnerable patients either systemically (by sero-epidemiology) or at the level of the plaque (plaque analysis). Hereto, Dr Pasterkamp and coworkers have established a large, well described longitudinal biobank of plaque material, which will allow the identification of plaque biomarkers that are predictive of future events. As an illustration, he showed that MMP2 and MMP9, two major metalloproteases deemed critical in plaque rupture, behave differently in that MMP2 activity is highest in stable SMC rich plaques whereas MMP9 is typical of vulnerable macrophage rich plaques. Another factor that was identified in proteomic analysis, caveolin-1, was seen to be inversely related to the incidence of future events in particular at short term. Caveolin-1 levels also correlated with those of MMP-9; which is conceivable when realising that MMP-9 is inhibited by caveolin-1.