Degree Of Plaque Calcification Research Articles

Calcification in Atherosclerotic Plaque Vulnerability: Friend or Foe?

Calcification is a clinical marker of atherosclerosis. This review focuses on recent findings on the association between calcification and plaque vulnerability. Calcified plaques have traditionally been regarded as stable atheromas, those causing stenosis may be more stable than non-calcified plaques. With the advances in intravascular imaging technology, the detection of the calcification and its surrounding plaque components have evolved. Microcalcifications and spotty calcifications represent an active stage of vascular calcification correlated with inflammation, whereas the degree of plaque calcification is strongly inversely related to macrophage infiltration. Asymptomatic patients have a higher content of plaque calcification than that in symptomatic patients. The effect of calcification might be biphasic. Plaque rupture has been shown to correlate positively with the number of spotty calcifications, and inversely with the number of large calcifications. There may be certain stages of calcium deposition that may be more atherogenic. Moreover, superficial calcifications are independently associated with plaque rupture and intraplaque hemorrhage, which may be due to the concentrated and asymmetrical distribution of biological stress in plaques. Conclusively, calcification of differential amounts, sizes, shapes, and positions may play differential roles in plaque homeostasis. The surrounding environments around the calcification within plaques also have impacts on plaque homeostasis. The interactive effects of these important factors of calcifications and plaques still await further study.

Criteria for instability of atherosclerotic plaques in carotid arteries

The purpose of the study was to determine the criteria for instability of atherosclerotic plaques in carotid arteries with the use of improved and new diagnostic techniques. The study enrolled a total of 92 patients examined with the help of instrumental methods of diagnosis, including ultrasound triplex scanning, magnetic resonance imaging and multislice computed tomography. All patients were subjected to the operation of carotid endarterectomy in various standard modifications. The specimens of atherosclerotic plaques taken intraoperatively were examined with the help of morphological, immunofluorescent methods, electron paramagnetic resonance, electron microscopy. A multivariate logistic regression analysis demonstrated that the plaques with an area over 90 mm2 (OR 4.05; 95% CI 1.32-13.2; p=0.006), a volume of more than 0.6 cm3 (OR 2.72; 95% CI 1.05-9.58; p=0.04), and the JBA value of not less than 8 mm2 (OR 2.82; 95% CI 1.22-6.23; p=0.02) were statistically significant independent predictors of histologically verified unstable plaques. The results were compared to the findings of histological methods. In patients with the above mentioned ultrasonographic parameters, unstable plaques were encountered in 94% of cases. Immunofluorescent assay demonstrated a significant increase in the number of inflammatory markers (CD68+, CD36+ cells), as well as CD31+ cells as markers of neovasculogenesis in unstable plaques. According to the findings of electron paramagnetic resonance, bivalent manganese is a marker of plaque instability. Further studies will help reveal the mechanisms of plaque calcification. A decrease in the content of manganese correlated with an increase in the degree of plaque calcification (r =-0.69, p<0.01). This serves as indirect evidence of a destabilizing effect of calcification on plaque stability. It was demonstrated that ultrasound elastography makes it possible to significantly extend the capabilities of standard ultrasound examination in detecting instability of atherosclerotic plaques in carotid arteries.

1656 CLINICAL EVALUATION OF TREATMENT OF PEYRONIE'S DISEASE WITH COLLAGENASE CLOSTRIDIUM HISTOLYTICUM: ANALYSIS OF PENILE CURVATURE DEFORMITY BY DURATION OF DISEASE AND PLAQUE CALCIFICATION

Introduction and Objective: Three phase 3 studies have been conducted to examine the safety and efficacy of collagenase clostridium histolyticum (CCH) in subjects with Peyronie’s disease (PD). The effect of CCH on change in penile curvature deformity from baseline to end of study was analyzed by the subjects’ duration of disease or degree of plaque calcification. Methods: All subjects within the phase 3 studies (2 randomized, doubleblind, placebo-controlled; 1 open-label [interim data]) and who were treated with CCH received up to 8 injections of CCH (0.58 mg) with 2 injections per cycle separated by about 24 to 72 hours, with the second injection followed 24 to 72 hours later by plaque modeling. A maximum of up to 4 cycles each was allowed, with each cycle separated by a 6-week interval. Penile x-ray or ultrasound findings were used to determine the degree of plaque calcification (no calcification, non-contiguous stippling, and contiguous calcification that did not interfere with the injection). Results: CCH-treated subjects (N=775) were stratified by duration of disease: 1-2 years (n=280), >2 to ≤4 years (n=266), and >4 years (n=229). Change in mean curvature deformity by duration of disease is shown in Figure 1 and by degree of plaque calcification in Figure 2. Duration of disease had no relationship to the degree of calcification (no calcification=3.8 years, non-contiguous stippling=4.2 years, and contiguous calcification that did not interfere with the injection=3.3 years). Conclusions: Treatment with CCH resulted in improvements in curvature deformity regardless of duration of disease or level of plaque calcification; although small differences were noted within the subgroups, they are not expected to be clinically meaningful. The observation that the duration of disease had no relationship with the degree of calcification in this population warrants further exploration. Presented at the American Urological Association’s 2013 Annual Meeting, May 4 8, 2013, San Diego, CA. • CCH is approved for treatment of adults with Dupuytren’s contracture (DC) with a palpable cord.7 Two identical, randomized, doubleblind, placebo-controlled, pivotal, phase 3 clinical trials (IMPRESS I and II) were conducted to investigate the use of CCH (followed by a modeling procedure) in subjects with PD – A recently published analysis of this data showed that CCHtreated subjects had a significantly greater improvement in penile curvature deformity compared with placebo subjects (34% vs 18.2%; P<0.0001)8 – Significant improvements in the PD symptom bother domain score for CCH-treated subjects compared with placebo subjects were also observed (-2.8±3.8 vs -1.8±3.5; P=0.0037)

Expression of NPP1 is regulated during atheromatous plaque calcification

Mutations of the ENPP1 gene encoding ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) are associated with medial calcification in infancy. While the inhibitory role of matrix proteins such as osteopontin (OPN) with respect to atherosclerotic plaque calcification has been established, the role of NPP1 in plaque calcification is not known. We assessed the degree of plaque calcification (computed tomography), NPP1 and OPN localization (immunohistochemistry) and expression (RT-PCR) in a cohort of 45 patients undergoing carotid endatherectomy for significant stenosis of the internal carotid artery and in normal arteries (N= 50). We correlated NPP1 and OPN expression levels to the degree of plaque calcification, to pro-atherogenic factors and statin therapy. NPP1 was demonstrated in the base and in the shoulder of atherosclerotic plaques. Compared to normal arteries and non-calcified plaques, in calcified plaques NPP1 mRNA was decreased (P < 0.0001). OPN mRNA levels were up-regulated in carotid atheroma. NPP1 and OPN expression levels positively correlated with the degree of plaque calcification (R= 0.54, P= 0.00019 and R= 0.46, P= 0.017, respectively) and with risk factors of atherosclerosis. Expression of the calcification inhibitor NPP1 is down-regulated in calcified atherosclerotic plaques. Our correlation data point to a counter-active mechanism, which in the end turns out to be insufficient to prevent further progression of calcification.

Editorial: Imaging of Cerebral Arterial Occlusive Disease: Do We Really Look for the Right Things?

Stroke is the main cause of disability in adults and represents the secondmost prevalentcause of death in the Western world. Cerebral arterial occlusive disease (CAOD) of the internal carotid artery (ICA) has been identified as a major trigger for stroke. Based on large-scale randomized trials published in the 1990s, the basis for determining the appropriate therapeutic approach and regimen for this disease is exact ICA stenosis grading, even though only 20% to 30% of strokes stem from high-grade stenoses. In those studies, digital subtraction angiography (DSA) served as the gold standard. Since then, numerous studies have compared all novel imaging techniques, such as color-coded Doppler sonography, magnetic resonance (MR) angiography, and computed tomographic (CT) angiography, as noninvasive alternatives to DSA. In general, it is accepted that these techniques provide high sensitivity and specificity for the detection and exact grading of ICA stenosis. However, for almost 20 years we have put our focus almost entirely on the morphological grading of ICA stenoses, despite the fact that most of the strokes arise from embolic material from the plaque and not from hypoperfusion due to the grade of the stenosis. A few years ago, modern imaging techniques began to be used to explore atherosclerotic plaques because correlations between plaque composition and final outcome in thesepatients had been reported. All available modalities have been used for this purpose, and small case series have initially reported enthusiastic results. However, no high-grade evidence trial has ever confirmed these preliminary results. To date, the real value of plaque imaging is still a matter of debate, mainly because actual techniques are not yet able to provide detailed information on the plaque composition with an image resolution acceptable for clinical use. An interesting approach to risk stratification is the calcium scoring of the ICA and the circle of Willis. Analogous to coronary plaque assessment, a higher degree of plaque calcification detected on CT without contrast medium would suggest a higher risk for potential cardiovascular or cerebrovascular events. The value of this approach is not yet determined, as data are not complete for coronary arteries let alone for the carotid arteries. Risk stratification for stroke should also include the hemodynamic effects caused by ICA stenosis. The evaluation of contrast enhancement in the brain can be performed by CT or MR imaging, yielding data regarding cerebral blood volume, cerebral blood flow, mean transit time, and time to peak mapping. The acquired information details the hemodynamic effects of ICA stenoses and offers a prognosis of therapeutic success in symptomatic patients based on the concept of cerebral hypoperfusion. Additionally, the diffusion-perfusion mismatch in symptomatic patients represents an interesting concept in clinical application. In theory, areas of reduced perfusion without diffusion flow voids are considered to be ideal for revasculariza-

Noninvasive Phenotypes of Atherosclerosis

To the Editor: The otherwise excellent review by Manolio et al1 seems to have misinterpreted some points in our recent article about noninvasive phenotypes of atherosclerosis.2 We showed that 2 different ultrasound traits, specifically carotid plaque area and percent carotid stenosis, were only modestly correlated with each other and had different associations with risk factors, including genetic determinants.2 By focusing on intima-media thickness (IMT), Manolio et al have overlooked the looming impact of new ultrasound traits, such as carotid plaque area and volume and percent stenosis. Furthermore, by treating IMT as synonymous with “atherosclerosis,” these authors perpetuate the outmoded idea that IMT, which is widely used mainly because of convention and practicality, bears some unique relationship with atherogenesis. In reality, newer quantitative ultrasound measures, including plaque area or volume, percent stenosis, degree of plaque calcification, and other manifestations each, like IMT, says something fundamental, and distinctive, about the process of …

Degree of carotid plaque calcification in relation to symptomatic outcome and plaque inflammation

Objective We undertook this study to quantitate differences in the degree of calcification between symptomatic and asymptomatic plaques removed at carotid endarterectomy (CEA) and to determine associated extent of plaque macrophage infiltration, a histopathologic feature of plaque instability. Methods CEA plaques (n = 48) were imaged at 1.25-mm intervals with spiral computed tomography (CT; 10-15 images per plaque). Indications for CEA were transient ischemic attack (n = 16), stroke (n = 5), amaurosis (n = 4), and critical asymptomatic stenosis (n = 23). The percent area calcification for each plaque was determined in spiral CT serial sections and averaged for each plaque. In 31 of 48 plaques macrophage infiltration was quantitated in corresponding histologic sections with immunohistochemical techniques. Results The mean (± SD) age of patients with symptomatic and asymptomatic plaques was 66 ± 7 years vs 71 ± 7 years, respectively, and degree of stenosis was 76% versus 82%, respectively ( P = .05). Atherosclerosis risk factors were similar between groups. Percent plaque area calcification was twofold greater in asymptomatic versus symptomatic plaques (48% ± 19% vs 24% ± 20%, respectively; P < .05). At receiver operating characteristic curve analysis, 80% of symptomatic plaques were below and 87% of asymptomatic plaques were above a cutoff point of 30% plaque area calcification. Macrophage burden was greater in the symptomatic plaques than in the asymptomatic plaques (52% vs 23%; P < .03). A strong inverse relationship between the degree of plaque calcification and macrophage infiltration was found in critical carotid stenoses ( r = −0.87; P < .001). Conclusions Symptomatic plaques are less calcified and more inflamed than asymptomatic plaques. Regardless of clinical outcome, a strong inverse correlation was found between the extent of carotid plaque calcification and the intensity of plaque fibrous cap inflammation as determined by the degree of macrophage infiltration. Carotid plaque calcification is associated with plaque stability, and is a potential spiral CT in vivo quantitative marker for cerebrovascular ischemic event risk.