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Technologies for Detection and Therapy of Vascular Plaques

Inflammation and the Vulnerable Plaque (VP)

It is now well-established that atherosclerosis is an inflammatory disease(1,2). The VP is an atherosclerotic plaque that is prone to disruption, causing thrombosis, which often leads to a clinical event (3-9). Autopsy studies have demonstrated that the majority of cases of sudden death are caused by occlusive coronary thromboses that are associated with an underlying ruptured plaque (3, 10-12). From such autopsy studies, much has been learned about the morphological features that are common to VP. Those histologic characteristics include: 1- a thin fibrous cap, 2- an underlying lipid pool, and 3- an abundance of inflammatory cells.

Need For Novel Technologies To Detect Vulnerable Plaques

Even with today’s best available technology,- an unacceptably high incidence of cardiovascular events remains even after aggressive therapy (13). Novel approaches to prevent myocardial infarctions are needed.
Perhaps the most effective method to prevent MI would be to stabilize vulnerable plaque before they rupture. However, currently available systemic therapies are able to lower the risk of plaque rupture by only 20-40%, leaving the vast majority of vulnerable plaques ripe for rupture (13). As such, it is crucial that vulnerable plaques are localized such that local plaque-stabilizing therapies can be delivered. However, currently available technologies are not able to detect vulnerable plaques. This may be due to the fact that available technologies rely on identifying structural criteria to differentiate the common stable plaque from the rupture-prone vulnerable plaque. Indeed, the most commonly employed method for plaque characterization is coronary arteriography, a method which qualifies plaques based on the degree to which they impinge on and thus narrow the vessel lumen. Multiple angiographic studies that have examined ruptured plaques have found that they are most often associated with insignificant luminal narrowing prior to their rupture [14]. Therefore, technologies that rely on identifying luminal narrowing are not able to identify vulnerable plaques with acceptable sensitivity.

Inflammation is Particularly Important in the Development and Progression of Atherothrombosis

It is now well-established that atherosclerosis is an inflammatory disease(1,2). Histopathological data confirmed the critical association of plaque inflammation and rupture. Numerous studies demonstrate an abundance of inflammatory cells (T cells and macrophages) within ruptured plaques (3-11). Moreover, several large studies have shown a strong association between inflammatory biomarkers and subsequent events(12-15).

Conventional Methods for Identifying Plaques:
The ability to identify high-risk plaque features may prove useful in predicting which plaques will rupture and cause a subsequent event. Such information may significantly refine the risk for patients already known to have disease and may identify a subset of patients at increased risk for a clinical event, who by current methodologies are classified as average-risk.
Several technologies are being studied for their ability to refine risk assessment based on identifying high-risk plaques. Intravascular ultrasound (IVUS) can accurately quantify plaque burden (16) measure distensibility of plaques(17,18), and effects of lipid lowering therapy(19,20), and distinguish fibrous, lipid, and calcified regions(21,22). However, this tool is invasive and also dangerous in the carotids and thus will be limited in its ability to be used as risk-stratifying tool. Moreover, it can not detect plaque inflammation.
Noninvasive methods to identify plaque inflammation could prove to be much more useful for following the effect of therapies and as risk stratification tools.
Multi-detector Computed Tomography (MDCT) has shown promise as a non-invasive tool, and may enable the differentiation of non-calcified lipid laden, non-calcified fibrous, and calcified plaques, based on significant differences in XRay attenuation through the tissue. (23-25). However, current MDCT technologies are not capable of identifying plaque inflammation.
Magnetic Resonance Imaging (MRI) has shown significant promise for plaque characterization, can provide information on plaque composition as well as disease burden (26-28) and can be used to monitor changes in plaque area and volume over time (29). Recent studies demonstrate that MRI can distinguish several morphological features believed to be associated with increased risk of plaque rupture. Gadolinium-enhanced MRI is capable of quantitatively measuring the dimensions of the intact fibrous cap and lipid-rich necrotic core(30-32) and preliminary clinical reports (32,33) suggest that ultrasmall superparamagnetic iron oxide (USPIO) particle-enhanced MRI can detect inflamed atherosclerotic plaques. However, there are no detailed clinical investigations focusing on MRI imaging of plaque inflammation.
Although each of these non-invasive tools has shown promise for plaque characterization, none has demonstrated reliable ability to measure plaque inflammation, which is perhaps the most important feature associated with a plaques vulnerability to rupturing. An imaging technology is needed to complement the structural and/or compositional information derived from MDCT, US, or MRI with information about plaque inflammation and biology.

Anticipated Uses Of the Intravascular Beta Ray Detector

Currently, approximately 1.3 million patients per year undergo diagnostic coronary arteriography (cardiac catheterization) while 1 million patients undergo percutaneous interventions (PCI) per year. Coronary arteriography is only modestly effective at determining future risk of MI. Indeed, given the inability of diagnostic coronary catheterization to detect inflamed, vulnerable plaques, current percutaneous interventions fail to prevent future cardiac deaths (they only improve symptoms). If successful, we propose that the intra-vascular beta probe be used as part of routine coronary angiography. In that case, the beta probe can be inserted after the diagnostic angiogram is obtained (through the existing intravascular sheath). Subsequently, PCI can be performed on the vulnerable plaques detected by the beta probe, resulting in a decrease in cardiac deaths.

Use of PET to Detect Inflamed Tissues:
Positron emission tomography (PET) may represent the most promising non-invasive imaging technology for the detection of inflammation in humans. PET imaging with 18F-Flurodeoxyglucose (FDG) has been used extensively in humans to detect metabolically active tissues such as neoplasms, autoimmune disease, and infection(34-44). Numerous studies demonstrate that FDG uptake is increased in inflamed tissues such as tumors and infectious foci(38,42,45-48). Autoradiographic studies show that FDG localizes to macrophage-dense regions within chronic inflammatory lesions (49) and within macrophages surrounding malignant foci (38,50).
Prior studies have demonstrated that 18FDG uptake is greater in inflamed tissues, such as infectious foci and tumors(38,42,45-47), than in non-inflamed tissues. More specifically, autoradiographic studies demonstrate that, in chronic inflammatory lesions(49) and malignancies(38,50), 18FDG uptake is increased in macrophage-dense regions. The relatively high uptake of 18FDG by macrophages is attributed to three main factors. First, macrophages have high metabolic rates(51), which is typically 5-20 fold higher than background tissues(37,49). Second, macrophages are unable to store glycogen, making them more reliant upon external glucose as a source of fuel for the hexose monophosphate shunt pathway(52-54). Third, the rate of glucose utilization of macrophages can increase 50-fold further when activated (55). While the mechanism for this augmentation is not well established, proposed mechanisms include an increase in glycolytic rate(42,51), and an increase in the expression and translocation of glucose transporters(54,56-59).
FDG-PET Characterization of Plaque Inflammation in Animal Models:
Several groups have demonstrated that FDG accumulates in inflamed atherosclerotic specimens in rabbit models of atherosclerosis (60-62). In a study performed with Watanabe heritable hyperlipidemic (WHHL) rabbits, Ogawa, et al. showed that 18F-FDG uptake correlate with the number of macrophages within the atherosclerotic lesions (R = 0.81, P<0001). More recently, our group demonstrated that non-invasive FDG-PET measurements correlate strongly with inflammation in experimental atherosclerotic lesions.
In that study, inflamed atherosclerotic lesions were induced in nine male New Zealand white rabbits via balloon injury of the aorto-iliac arterial segment and exposure to a high cholesterol diet. Ten rabbits fed standard chow served as controls. Three to six months following balloon injury, the rabbits were injected with FDG (1 mCi/kg) after which aortic uptake of FDG was assessed (3 hrs after injection). Biodistribution of FDG activity within aortic segments was obtained using standard well gamma counting. FDG uptake was also determined non-invasively in a subset of six live atherosclerotic rabbits and five normal rabbits, using PET imaging and measurement of standardized uptake values (SUV) over the abdominal aorta. Plaque macrophage and smooth muscle cell density were determined by planimetric analysis of RAM-11 and smooth muscle actin staining, respectively.
Co-registered PET&CT images demonstrated increased uptake of FDG in atherosclerotic aortas compared to control aortas. Further, well counter measurements of FDG uptake were significantly higher within atherosclerotic aortas compared to control aortas (P<0.001). In parallel with these findings, FDG uptake, as determined by PET, was higher in atherosclerotic aortas (0.68±0.06 vs. 0.13±0.01, SUV atherosclerotic vs. control, P<0.001). Moreover, macrophage density, assessed histologically, correlated with well-counter measurements FDG accumulation (r= 0.79, P<0.001) as well as the non-invasive in vivo (PET) measurements of FDG uptake, (r= 0.93, P<0.0001,). Importantly, FDG uptake did not correlate with either smooth muscle cell staining, vessel wall thickness, or plaque thickness of the specimens . These data show that FDG accumulates in macrophage-rich atherosclerotic plaques and demonstrate that vascular macrophage activity can quantified non-invasively with FDG-PET. As such, measurement of vascular FDG uptake with PET holds promise for the non-invasive characterization of vascular inflammation.

7. Studies in Humans Demonstrating Increased Vascular FDG Uptake:
Several groups have observed increased vascular FDG uptake in patients with diseases associated with vessel wall inflammation such as Takayasu's arteritis, giant cell arteritis, polymyalgia rheumatica and nonspecific aortitis (64-67). Others have also reported an association between atherosclerotic disease and increased FDG uptake in patients (68-70).
Rudd and colleagues demonstrated increased carotid FDG uptake in patients with evidence of a recent ischemic cerebrovascular event (71). In a related ex vivo experiment, that same group reported accumulation of deoxyglucose within macrophage-rich areas of excised human carotid arteries that were incubated with tritiated deoxyglucose (71). Recently, Davies et al reported increased FDG uptake measured by PET (co-registered with MRI), in patients with symptomatic carotid disease (72).

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