Necrotic cores

Fig. 8.2 (A) Intravascular ultrasound (IVUS) image of a coronary artery using Revolution 45 MHz IVUS imaging catheter. (B) Plaque composition imaging using volcano VH IVUS system. Green areas represent Fibrous plaque. Yellow is fibro-fatty areas. Red is the necrotic core and white represents areas of dense calcium...

At autopsy, a ruptured plaque features a thin fibrous cap overlying cell-rich regions with a lipid-rich necrotic core (<3 mm ) containing cell debris. The indicators for plaque instability include an inflammatory infiltrate with lipid-rich macrophages (foam-cells) and a decreased collagen and smooth muscle cell (SMC) content in the fibrous caps as well as at the shoulders of the atheroma, respectively. Therefore, one of the challenges of modern medicine is the design of... 

The situation is much more complicated for multilayers of cells on microcarriers or for cells that grow in clumps or spheroids. The specific growth rate in such systems is normally a function of cell location. For example, cells at the outside of tumour cell spheroids generally prohferate rapidly, while those further in are quiescent. For spheroids with a radius larger than about ten cell diameters, there is normally a necrotic core of dead cells. In these complex systems it is only possible to determine apparent growth rates. These can be expressed in terms of total cell numbers, viable cell numbers or spheroid volume. Another difficulty with these systems is that accurate cell counts are hindered by cell clumps that resist dissociation with trypsin. One way around this is to lyse the cells with surfactant and count the nuclei released (Lin et al, 1991). However, analysis is complicated because the nuclei from recently dead cells are preserved, while those from cells dead for long periods are lost. 

Necrotic core (atheroma) cholesterol clefts, lipid, foam cells and necrotic debris... 

Conceptual description of an avascular tumor growth model. Tumor growth is represented as a layered structure consisting of an outer proliferating rim, quiescent band, and necrotic core. The model treats the proliferating, quiescent, and necrotic cells as a continuum under the influence of environmental factors such as nutrient/growth factors from underl)dng tissues, and cell movement in terms of migration and contact inhibition. 

Induction of Cell Death and Expansion of the Necrotic Core.322... 

INDUCTION OF CELL DEATH AND EXPANSION OF THE NECROTIC CORE... 

Moreover, as described in this chapter, it has been fully established that oxysterols also exert a pro-apoptotic stimuli agaiust the various types of vascular cells, thus likely contributing to the expansion of the necrotic core of the lesion and to its instability. Conversely, a possible antiapoptotic action of oxysterols may be only speculated since it has not been experimentally supported so far. 

Apoptosis of VSMC may contribute to the plaque necrotic core, cap rupture, and thrombosis. In human VSMC, moderately oxidized LDL, with its high lipid hydroperoxide content, rather than mildly or highly oxidized LDL, causes apoptosis. 

Erosion and rupture of vulnerable atherosclerotic plaque is the cause of most acute coronary syndromes [32, 33]. Plaque mpture leads to the formation of an intracoronary thrombus, which produces an obstruction that acutely limits coronary artery blood flow, resulting in myocardial ischemia or necrosis. Multiple clinical and autopsy studies have confirmed the pathogenic role of coronary thrombus in cases of acute MI, unstable angina and sudden cardiac death [33, 34]. The lesions that harbor vulnerable plaques are often mildly stenotic on angiographic examination and, consequently, their stability cannot be assessed. The stability of atherosclerotic plaques is related to histological composition Figure 17.2. Unstable plaques typically comprise thin (<65 pm) fibrous caps infiltrated with macrophages that encapsulate lipid-rich necrotic cores with adjacent microcalcification [33, 34]. 

In vivo identification of plaque eomposition with suffieient resolution should enable the detection of vulnerable plaque before rupture enabling some local treatment. Being able to image vulnerable plaques may lead to the detection of the eharacteristics of a vulnerable plaque that could allow the development of predietive models to assess the risk that a vulnerable plaque poses to the patient [33]. Current state-of-the-art IVUS systems, sueh as those that use VH from Volcano Corporation, do not measure the thin fibrous cap explicitly as the axial resolution is too poor to detect the thin caps. Rather, when a necrotic core is with in 125 microns of the lumen, it is assumed to be covered by a thin fibrous cap and is deemed vulnerable [29,51]. 

Figure 13.2 Representation of two hypothetical conditions of abnormal cellular death (Apoptosis Caspase-3 active, PARP-1 Necrosis Caspase-3 inactive, PARP-1 hyper-activated). The example on the left consists of a large area of necrosis surrounded by a small penumbra of apoptosis. This condition would benefit greater from treatment with a PARP-1 inhibitor. The condition on the right consists of a large area of apoptosis surrounding a small necrotic core. This condition would benefit more from treatment with either a pancaspase inhibitor or a selective inhibitor of caspase-3.

This condition is referred to as ischemia-reperfusion injury. Several studies in animal models of ischemia-reperfusion injury have shown that the principal cause of cellular death is necrosis (11-13). However, other smdies have shown that cellular death consisted of a necrotic core surrounded by a peri-necrotic area that displayed properties consistent with apoptosis (11,14-18). Therefore, it is likely that cellular death resulting from ischemia-reperfusion injury can consist of a mixture of apoptosis and necrosis, depending on the extent and duration of the ischemia prior to reperfusion. Other disease conditions where evidence demonstrating both apoptosis and necrosis occur includes diabetic cardiomyopathy, sepsis, stroke, and the neurodegenerative disorders Alzheimer s disease and Parkinson s disease. The development of a noninvasive imaging technique capable of measuring apoptosis and necrosis independently could provide valuable information on the balance between apoptosis and necrosis, and if there is a temporal shift in the balance of these mechanisms of cellular death, in a wide variety of pathological conditions. 

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