Necrotic Volume Research Articles

Thyroid hormones can increase astrocyte fatty acid oxidation and survival; a possible mechanism for decreased tissue necrosis after cerebral stroke

Enhancement of astrocyte metabolism in mice significantly decreases lesion size after stroke. This was achieved after purinergic stimulation, but we know that thyroid hormones (TH) can also increase mitochondrial metabolism. Acute treatment with triiodothyronine (T3) increases long‐chain fatty acid oxidation (FAO) in several tissues to improve metabolism. Because astrocytes also use fatty acids for energy, we hypothesized that THs increase astrocyte FAO and improve survival after oxidative stress or stroke.ResultsNanomolar concentrations of either diiodothyronine (T2) or T3 increase astrocyte FAO of [3H]palmitate into 3H2O by over 30% (p<0.01). The astrocyte mitochondrial membrane potential was measured using the potential sensitive dye tetramethyl rhodamine methyl ester. Acute T2 treatment (15 minutes) tripled the dye intensity (p<0.05), indicating improved mitochondrial membrane potential. These data are consistent with increased energy production upon TH treatment. Astrocytes were stressed with hydrogen peroxide, and viability was measured using the vital dye calcien‐AM. T2 and T3 each increased astrocyte viability 25% (p<0.01). To test if TH is protective in vivo, we induced focal ischemia in mice. Administration of T2 decreased the necrotic volume in the brain by half (p=0.02) 24 hours post‐stroke. Future testing will determine if TH‐mediated survival of astrocytes is dependent on FAO.

Impact of Microbubble-Enhanced Ultrasound on Liver Ethanol Ablation

Ethanol ablation (EA) is a safe and effective method for treating small liver cancer. However, the ethanol is rapidly washed out by blood perfusion, preventing its accumulation within tumors. Microbubble-enhanced ultrasound (MEUS) is capable of disrupting tumor and liver circulation. We hypothesized that this disruption could be used to enhance EA of normal liver tissue. We treated surgically exposed rabbit liver with a combination of MEUS and EA. The controls were treated with only MEUS or 0.05 mL EA. MEUS treatment was administered with a high-pressure-amplitude, pulsed therapeutic ultrasound device and intra-venous injection of microbubbles. Therapeutic ultrasound was delivered at an acoustic pressure of 4.3 MPa and a duty cycle of 0.22%. Contrast-enhanced ultrasound was performed to estimate liver blood perfusion. Livers were harvested for necrotic volume measurements 48 h after treatment. Contrast-enhanced ultrasound demonstrated that liver perfusion was temporally arrested, with a significant peak intensity decline from −46.9 ± 3.8 to −64.0 ± 3.3 dB, after MEUS treatment. The mean volume ablated in MEUS + EA-treated livers (3.3 ± 2.3 cm3) was more than 10 times larger than that in livers treated only with EA (0.3 ± 0.2 cm3). The volume of liver ablated by MEUS treatment alone was minor, scattered and immeasurable. These results indicate that MEUS disruption of the liver circulation can greatly promote EA of liver.

Influence of high-dose lipid lowering treatment compared to low-dose lipid lowering treatment on plaque composition assessed by intravascular ultrasound virtual histology in patients with ST-segment elevation acute myocardial infarction: the VIRHISTAMI trial

The aim of this study was to evaluate the effect of low-dose versus high-dose rosuvastatin therapy on the necrotic core (NC) content in coronary plaques of angiographic non-significant lesions as assessed by intravascular ultrasound - virtual histology. Eighty-seven statin-naive patients with ST-segment elevation myocardial infarction (STEMI) were randomised to 5 mg or 40 mg rosuvastatin. The volume of each plaque component (necrotic core, fibrous tissue, fibro-fatty, and dense calcium) was assessed at baseline and after 12 months of follow-up. Baseline low-density lipoprotein (LDL) cholesterol level was reduced by 31.8% in the low-dose group (from 3.1±0.7 mmol/l to 2.0±0.4 mmol/l, p<0.001) vs. 49.0% in the high-dose group (from 3.1±1.0 mmol/l to 1.6±0.7 mmol/l, p<0.001) (p=0.001 between groups). The plaque component necrotic core was reduced by 7.6% in the low-dose group (44.6±38.2 mm3 vs. 41.2±40.3 mm3, p=0.29) compared to 14.2% in the high-dose group (47.4±38.2 mm3 vs. 40.7±34.4 mm3, p=0.003) (p=0.38 between groups). In statin-naive patients with STEMI, rosuvastatin therapy for 12 months resulted in significant reduction in LDL-cholesterol; however, a significant decrease in necrotic core volume was only seen in the high-dose group.

Meta-Analysis of Plaque Composition by Intravascular Ultrasound and Its Relation to Distal Embolization After Percutaneous Coronary Intervention

Controversies exist regarding the association between plaque composition and distal embolization phenomenon after percutaneous coronary intervention (PCI). We evaluated the effect of plaque characteristics on embolization after PCI by grayscale and virtual histology-intravascular ultrasound (IVUS). We searched PubMed, Ovid MEDLINE, and Cochrane databases for IVUS studies evaluating the coronary plaque characteristics in no reflow, distal embolization, and periprocedural myocardial infarction after PCI. Sixteen studies were included, totaling 1,697 patients who underwent PCI (292 patients with embolization and 1,405 patients without embolization). At the minimum lumen sites, the external elastic membrane (weighted mean difference 2.38 mm(2), 95% confidence interval [CI] 1.02 to 3.74) and the plaque and media cross-sectional areas (weighted mean difference 2.44 mm(2), 95% CI 1.44 to 3.45) were significantly greater in the embolization group than in the no embolization group. Pooled analysis showed that the absolute necrotic core volume (standardized mean difference 0.49, 95% CI 0.13 to 0.85), absolute (standardized mean difference 0.73, 95% CI 0.14 to 1.31) and relative (standardized mean difference 1.02, 95% CI 0.72 to 1.31) necrotic core areas at the minimum lumen sites were significantly greater in the embolization group than in the no embolization group, but the other plaque components were similar in the 2 groups. In conclusion, the necrotic core component derived from virtual histology-IVUS and the morphologic characteristics of plaque derived from grayscale IVUS are closely related to the distal embolization phenomenon after PCI.

Characteristics of culprit atheromatous plaques obtained in vivo by intravascular ultrasound radiofrequency analysis: Results from the CULPLAC study

We used virtual histology-intravascular ultrasound (VH-IVUS) to investigate the characteristics of culprit lesions in acute coronary syndromes (ACS). Autopsy studies of patients who died of ACS have shown that culprit atheromatous plaques almost always contain a large lipid-necrotic core covered by a ruptured thin fibrous cap. There are no studies of sufficient size that have assessed the in vivo characterization of plaques responsible for ACS. Patients undergoing angiography for stable ischemic heart disease and ACS (with and without ST-segment elevation) were enrolled in a prospective study. Lesions in patients with stable angina were classified as stable and those in patients with ACS as culprit or nonculprit. The study included 189 patients: VH-IVUS was used to assess 253 lesions (73 stable, 82 nonculprit, and 98 culprit lesions). The thin-cap fibroatheroma phenotype (VH-TCFA) was more frequent among lesions in patients with ACS (55.1% in culprit lesions, 36.6% in nonculprit lesions and 14.4% in stable lesions; P = .007). The arc of the VH-TCFA exposed to the vessel lumen was significantly greater in culprit lesions than in nonculprit lesions (122.28° ± 58 vs 89.46° ± 52; respectively; P = .007). Multivariate analysis showed that VH-TCFA (OR 2.1; P = .033), calcified nodules (OR 2.1; P = .046), positive remodeling (OR 3.5; P < .001) and necrotic core volume (OR 1.02;P = .009) were independently associated with a clinically identified culprit lesion. Plaque phenotype, rather than the proportion of each tissue, appears to be associated with plaque instability. VH-TCFA, particularly subtype IV, is associated with lesions responsible for ACS.

Rationale of decreasing low-density lipoprotein cholesterol below 70 mg/dL in patients with coronary artery disease: A retrospective virtual histology-intravascular ultrasound study.

The associations between statin and coronary plaque compositional changes were re-ported according to the use of high dose or not. An evaluation of the impact of low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL by using real world dosages of statin on coronary plaque composition was undertaken. The study subjects consisted of 61 patients (mean 59.9 years old, 45 males) who underwent percutaneous coronary intervention, baseline and follow-up (F/U; mean 8.4 months) virtual histology- -intravascular ultrasound (VH-IVUS) examination. Change of plaque composition at peri-stent area, which was selected in order to measure the identical site at F/U study, was compared according to the F/U LDL-C level. Body mass index, prevalence of dyslipidemia, baseline total cholesterol and baseline LDL-C were significantly lower in F/U LDL-C < 70 mg/dL group (14 segments in 10 patients) than F/U LDL-C ≥ 70 mg/dL group (79 segments in 51 patients). F/U high-density lipoprotein cholesterol (HDL-C, OR 1.06, 95% CI 1.00-1.11, p = 0.054) and F/U LDL-C < 70 mg/dL (OR 3.43, 95% CI 0.97-12.17, p = 0.056) showed strong tendency of regression of necrotic core volume (NCV) ≥ 10%. In multivariable logis-tic regression analysis, F/U HDL-C (OR 1.07, 95% CI 1.01-1.14, p = 0.020) and F/U LDL-C < 70 mg/dL (OR 8.02, 95% CI 1.58-40.68, p = 0.012) were the independent factors for regression of NCV ≥ 10%. Follow-up LDL-C level < 70 mg/dL with any types of statins and increase of HDL-C were associated with regression of NCV ≥ 10% in patients with coronary artery disease.

Hypercholesterolemia and in-vivo coronary plaque composition in patients with coronary artery disease: a virtual histology - intravascular ultrasound study.

Background and ObjectivesHypercholesterolemia is a key factor in the development of atherosclerosis. We sought to evaluate the relation between hypercholesterolemia and plaque composition in patients with coronary artery disease.Subjects and MethodsStudy subjects consisted of 323 patients (mean 61.5 years, 226 males) who underwent coronary angiography and virtual histology-intravascular ultrasound examination. Patients were divided into two groups according to total cholesterol level: hypercholesterolemic group (≥200 mg/dL, n=114) and normocholesterolemic group (<200 mg/dL, n=209).ResultsHypercholesterolemic patients were younger (59.7±13.3 years vs. 62.6±11.5 years, p=0.036), than normocholesterolemic patients, whereas there were no significant differences in other demographics. Hypercholesterolemic patients had higher corrected necrotic core volume (1.23±0.85 mm3/mm vs. 1.02±0.80 mm3/mm, p=0.029) as well as percent necrotic core volume (20.5±8.5% vs. 18.0±9.2%, p=0.016) than normocholesterolemic patients. At the minimal lumen area site, percent necrotic core area (21.4±10.5% vs. 18.4±11.3%, p=0.019) and necrotic core area (1.63±1.09 mm2 vs. 1.40±1.20 mm2, p=0.088) were also higher than normocholesterolemic patients. Multivariate linear regression analysis showed that total cholesterol level was an independent factor of percent necrotic core volume in the culprit lesion after being adjusted with age, high density lipoprotein-cholesterol , hypertension, diabetes mellitus, smoking and acute coronary syndrome (beta 0.027, 95% confidence interval 0.02-0.053, p=0.037).ConclusionHypercholesterolemia was associated with increased necrotic core volume in coronary artery plaque. This study suggests that hypercholesterolemia plays a role in making plaque more complex, which is characterized by a large necrotic core, in coronary artery disease.

Virtual histology study of atherosclerotic plaque composition in patients with stable angina and acute phase of acute coronary syndromes without ST segment elevation

Rupture of vulnerable atherosclerotic plaques is the cause of most acute coronary syndromes (ACS). Postmortem studies which compared stable coronary lesions and atherosclerotic plaques in patients who have died because of ACS indicated high lipid-core content as one of the major determinants of plaque vulnerability. Our primary goal was to assess the potential relations of plaque composition determined by IVUS-VH (Intravascular Ultrasound -Virtual Histology) in patients with stable angina and subjects in acute phase of ACS without ST segment elevation. The study comprised of 40 patients who underwent preintervention IVUS examination.Tissue maps were reconstructed from radio frequency data using IVUS-VH software. We analyzed 53 lesions in 40 patients. Stable angina was diagnosed in 24 patients (29 lesions), while acute phase of ACS without ST elevation was diagnosed in 16 patients (24 lesions). In the patients in acute phase of ACS without ST segment elevation IVUS-VH examination showed a significantly larger area of the necrotic core at the site of minimal lumen area and a larger mean of the necrotic core volume in the entire lesion comparing to stable angina subjects (1.84+/-0.90 mm2 vs. 0.96+/-0.69 mm2; p<0.001 and 20.94+/-15.79 mm3 vs. 11.54+/-14.15 mm3; p<0.05 respectively). IVUS-VH detected that the necrotic core was significantly larger in atherosclerotic lesions in patients in acute phase of ACS without ST elevation comparing to the stable angina subjects and that it could be considered as a marker of plaque vulnerability.

Impact of Plaque Composition on Long-Term Clinical Outcomes in Patients with Coronary Artery Occlusive Disease

Background and ObjectivesIt is unclear which plaque component is related with long-term clinical outcomes in patients with coronary artery occlusive disease (CAOD). We assessed the relationship between plaque compositions and long-term clinical outcomes in those patients.Subjects and MethodsThe study subjects consisted of 339 consecutive patients (mean 61.7±12.2 years old, 239 males) who underwent coronary angiogram and a virtual histology-intravascular ultrasound examination. Major adverse cardiac and cerebrovascular events (MACCE), including all-cause death, non-fatal myocardial infarction, cerebrovascular events, and target vessel revascularization were evaluated during a mean 28-month follow-up period.ResultsPatients with high fibrofatty volume (FFV, >8.90 mm3, n=169) had a higher incidence of MACCE (25.4% vs. 14.7%, p=0.015), male sex (75.7% vs. 65.3%, p=0.043), acute coronary syndrome (53.3% vs. 35.9%, p=0.002), multivessel disease (62.7% vs. 41.8%, p<0.001) and post-stent slow flow (10.7% vs. 2.4%, p=0.002) than those with low FFV (FFV≤8.90 mm3, n=170). Other plaque composition factors such as fibrous area/volume, dense calcified area/volume, and necrotic core area/volume did not show any impact on MACCE. Cardiogenic shock {hazard ratio (HR)=8.44; 95% confidence interval (CI)=3.00-23.79; p<0.001} and FFV (HR=1.85; 95% CI=1.12-3.07; p=0.016) were the independent predictors of MACCE by Cox regression analysis. Thin-cap fibroatheroma, necrotic core area, and necrotic core volume were not associated with MACCE.ConclusionFFV of a culprit lesion was associated with unfavorable long-term clinical outcomes in patients with CAOD.

A Bacterial RTX Toxin Causes Programmed Necrotic Cell Death Through Calcium-Mediated Mitochondrial Dysfunction

Vibrio vulnificus, a halophilic estuarine bacterium causing fatal septicemia and necrotic wound infection, is highly cytotoxic to eukaryotic cells. We have reported that RtxA1 toxin kills host cells only after they come into contact with bacteria and plays an essential role in the pathogenesis of V. vulnificus. This study was performed to elucidate the mechanism by which the RtxA1 toxin mediates the death of HeLa cells. By using confocal microscopy and immunoblot analysis, we show that the 501-kDa RtxA1 toxin is processed into 2 fragments after its secretion into host cells. The largerN-terminal fragment (RtxA1-N; approximately 370 kDa) remained at the host cell membrane, whereas the smaller C-terminal fragment (RtxA1-C; approximately 130 kDa) was internalized into the host cell cytoplasm. RtxA1-N is believed to polymerize and form pores at the host cell membrane and to induce an increase in necrotic volume related to calcium. The RtxA1 toxin caused an increase in the intracellular Ca(2+) concentration and the subsequent activation of JNK. The cell death mechanism occurred via calcium-dependent mitochondrial pathways, which caused calcium sequestration in the mitochondria, accompanied by irreversible mitochondrial membrane dysfunction and adenosine triphosphate depletion, and was later accompanied by the disruption of the integrity of the plasma membrane.

Abstract 19081: 5-lipoxygenase Inhibitor Via-2291 (atreleuton) Reduces Inflammation and Coronary Necrotic Core Plaque and Improves Left Ventricular Function in Patients After an Acute Coronary Syndrome

Background: The 5-lipoxygenase inhibitor VIA-2291 effectively lowers production of leukotriene metabolites. This study investigates the relations between inflammation, coronary plaque characteristics and left ventricular function in response to treatment with VIA-2291 (Atreleuton) in patients after an acute coronary syndrome (ACS). Methods: Fifty six post-ACS patients who participated in a randomized trial evaluating the effects of VIA-2291 vs. placebo and underwent cardiac computed tomography angiography were studied. Leukotriene E4 (LTE4), high-sensitivity C-reactive protein (hs-CRP), coronary plaque volume (PV) with vulnerable characteristics (Necrotic Core) and left ventricular ejection fraction (LVEF) were measured at baseline and at 6-month follow-up. The relation of changes in LTE4, hs-CRP, PV and LVEF in response to VIA-2291 was analyzed using conditional logistic regression analyses. Results: From baseline to 6 months, after adjustment for risk factors, significant reductions in LTE4, hs-CRP and VP, and an increase in LVEF with VIA-2991 as compared to placebo were noted (p&lt;0.05, Table).After adjustment for risk factors, there were strong associations between the decrease in LTE4, the decrease in necrotic core PV and the increase in LVEF (Table); 71% and 79% of the variance in PV and LVEF was explained by the decrease in LTE4 in response to VIA-2991 (p&lt;0.05). The maximum improvement in LVEF was noted with maximum decrease in LTE4 and PV. Conclusion: This study documented a strong relation between decreases in LTE4, decreases in necrotic core coronary plaque volume and improved LV function in response to VIA-2291.

Application of CT and MRI in volumetric measurement of necrotic lesion in patient with avascular necrosis of the femoral head

Objective To investigate the feasibility and accuracy of volumetric measurement of necrotic lesion using CT and MRI,and to assess the value of necrotic lesion volume in predicting collapse of the femoral head in patients with avascular necrosis of the femoral head(ANFH). Methods Comparison among CT,MRI and gross section was performed in 25 femoral heads of 18 patients who underwent total hip replacement for established ANFH.The volume of necrotic lesion was measured using fluid displacement.CT and MRI data were transferred to a computer to calculate the volume of necrotic lesion using software.One way ANOVA was used to compare the volumes of necrotic lesion measured by CT,MRI and gross section.A total of 62 patients (92 hips) who were diagnosed with ANFH but without collapse by CT were followed up 24 months.Student t-test was used to compare the ratio of the volumes of the necrotic lesion and entire femoral head in the hips with and without collapse and ROC curve analysis was carried out.Results CT and MRI coincided with gross section in the necrotic area,proliferative area and extralesional area.The volumes of the necrotic lesion measured by CT,MRI and gross section were ( 20.5 ± 5.2 ),( 21.4 ± 4.8 ),( 20.9 ± 5.2 ) cm3,respectively.There was no significant difference among the necrotic volumes measured by the three methods(F =0.185,P =0.831 ).In fifty-seven out of 92 hips,collapse of the femoral head occurred during the follow-up.The ratio of the volumes of the necrotic lesion and entire femoral head was higher in hips with collapse than in hips without collapse[ (34.5 ±9.3)％ vs.(23.4 ±8.4)％ ;t =5.749,P=0.000].The area under the ROC curve was 0.808. Conclusions The volume of the necrotic lesion plays an important role in the collapse of femoral head in patients with ANFH.Both CT and MRI can identify the shape and location of the necrotic lesion intuitively and stereospecifically and can determine the volume of the necrotic lesion accurately. Key words: Osteonecrosis; Femur head; Magnetic resonance imaging; Tomography,X-ray computed

Effect of statin therapy on the progression of coronary atherosclerosis

BackgroundAn increasing number of authors employing intravascular ultrasound (IVUS) and virtual histology (VH-IVUS) have investigated the effect of statin use on plaque volume (PV) and plaque composition. However, inconsistent results have been reported. Therefore, we conducted a meta-analysis to determine the appropriate regimen of statins to effectively stabilize vulnerable coronary plaques.MethodsOnline electronic databases were carefully searched for all relevant studies. We compared mean values of PV and plaque composition between baseline and follow-up in patients receiving statin therapy. We pooled treatment effects and calculated mean differences (MD) with the 95% confidence interval (CI) using a random-effects model. By stratified analyses, we explored the influence of clinical presentation, dose and duration of statin treatment, and low-density lipoprotein-cholesterol (LDL-C) levels on the effects of statins.ResultsSeventeen studies involving 2,171 patients were analyzed. Statin therapy significantly decreased PV (−5.3 mm3; 95% CI: –3.3 mm3 to −7.2 mm3; P < 0.001), without heterogeneity. When considering the dose and duration of statins used, only subgroups employing a high dose and long duration demonstrated a significant reduction in PV (p < 0.001). A significant decrease in PV was noted if achieved LDL-C levels were <100 mg/dL (p < 0.001). Statin treatment could induce a twofold decrease in PV in patients with acute coronary syndrome (ACS) compared with that observed in patients with stable angina pectoris (SAP). A regressive trend was seen for necrotic core volume (MD: –2.1 mm3; 95% CI: –4.7 mm3 to 0.5 mm3, P = 0.11). However, statin use did not induce a significant change for fibrotic, fibro-fatty, or dense calcium compositions.ConclusionsOur meta-analysis demonstrated that statin therapy (especially that involving a high dose and long duration and achieving <100 mg/dL LDL-C levels) can significantly decrease PV in patients with SAP or ACS. These data suggested that statins can be used to reduce the atheroma burden for secondary prevention by appropriately selecting the statin regimen. No significant change in plaque composition was seen after statin therapy.

Effect of pitavastatin treatment on changes of plaque volume and composition according to the reduction of high-sensitivity C-reactive protein levels

BackgroundThere are few data regarding the effect of statins on regression and compositional changes of plaque according to the reduction in high-sensitivity C-reactive protein (hs-CRP) levels in acute myocardial infarction (AMI) patients. MethodsWe used serial virtual histology-intravascular ultrasound to assess the efficacy of pitavastatin (dosage: 2mg/day) on plaque regression and compositional changes according to the degree of reduction in hs-CRP levels from baseline to follow-up [≥1mg/dl (n=62) vs. <1mg/dl (n=32)] in non-intervened non-infarct related artery in AMI patients who were enrolled in the Livalo in acute myocardial infarction study (LAMIS). ResultsTotal atheroma and percent atheroma volumes decreased more significantly in patients with reduction in hs-CRP ≥1mg/dl compared with those with reduction in hs-CRP <1mg/dl (−1.7±12.4mm3 vs. +2.7±7.8mm3, p<0.015, and −0.4±3.4% vs. +0.4±4.8%, p<0.001, respectively). Absolute and %necrotic core volumes decreased more significantly in patients with reduction in hs-CRP ≥1mg/dl compared with those with reduction in hs-CRP <1mg/dl (−0.4±3.5mm3 vs. +1.9±3.4mm3, p=0.038, and −1.1±4.9% vs. +2.7±4.7%, p=0.016, respectively). Reduction in hs-CRP ≥1mg/dl at follow-up was the independent predictor of reduction of percent atheroma volume and %necrotic core volume at follow-up [odds ratio (OR), 2.228; 95% confidence interval (CI), 1.390–2.977, p=0.016, and OR, 2.204; 95% CI, 1.512–2.916, p=0.020, respectively]. ConclusionsReduction in hs-CRP levels in AMI patients plays an important role in the beneficial effects of statins on the regression and compositional change of coronary plaque.

Relation Between Angiographic Lesion Severity, Vulnerable Plaque Morphology and Future Adverse Cardiac Events (from the Providing Regional Observations to Study Predictors of Events in the Coronary Tree Study)

Previous angiographic studies have suggested that the future risk for major adverse cardiovascular events (MACEs) is related to coronary stenosis severity. The aim of this study was to use the grayscale and virtual histology (VH)-intravascular ultrasound (IVUS) data from the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study to identify underlying lesion morphologic characteristics that might explain these findings. In PROSPECT, patients presenting with acute coronary syndromes in whom percutaneous coronary intervention was successful underwent 3-vessel grayscale and VH-IVUS and were followed for a median of 3.4 years for the incidence of MACEs. Overall, 3,115 nonculprit lesions detected by IVUS were divided into quartiles according to baseline angiographic diameter stenosis. From the first to fourth quartiles, there were increases in the prevalence of lesions with IVUS minimum luminal areas ≤ 4 mm(2), IVUS plaque burden ≥ 70%, and VH-IVUS thin-cap fibroatheroma (13.4%, 22.0%, 24.2%, and 30.3%, respectively, p <0.001), along with an increased frequency of plaque ruptures and greater necrotic core volumes. The incidence of lesions with plaque burden ≥ 70%, minimum luminal area ≤ 4 mm(2), and VH thin-cap fibroatheroma was highest in the fourth quartile (0%, 0.4%, 0.4%, and 2.8% in the first through fourth quartiles, respectively, p <0.001). Three-year MACE rates were also highest in the fourth quartile (0.3%, 0.7%, 1.3%, and 5.1%, respectively, p <0.001). In conclusion, increasing angiographic diameter stenosis was associated with an increased frequency of grayscale and VH-IVUS lesion morphologic features that have been associated with adverse events and that may, in part, explain why future MACEs were related to baseline lesion severity.

Core decompression combined with implantation of a demineralised bone matrix for non-traumatic osteonecrosis of the femoral head

Core decompression is the standard surgical procedure in the treatment of early stage non-traumatic osteonecrosis of the femoral head (ONFH). However, there is still a debate whether decompression in combination with supplementary augmentation by bone grafts, growth factors, or cell implementation is superior to conventional decompression alone. This study evaluated patients after core decompression combined with an augmentation by a demineralised bone matrix, and particularly aimed to report long-term conversion rates to total hip replacement (THR). 14 patients with 18 hips suffering from ONFH (Ficat stage I-IIB) underwent this surgical procedure. All patients underwent radiographic and MRI investigations at baseline and at follow-up periods of 12 and 24months. The clinical follow-up was done using the Merle d'Aubigné-score for an average period of 9years after surgery. 14 of the 18 subjects (77%) achieved at least a good clinical result after 2years. The Merle d'Aubigné-score improved significantly after 12 (p=0.0001) and 24months (p=0.0002). However, the MRI volumetric analysis showed an increased necrotic bone volume from 3.16±0.54 to 3.88±0.62cm(3) (p=0.04). Within 9years, 13 out of 18 cases (72%) required further surgery by THR. Only 7 out of 18 subjects (39%) reported an ongoing postoperative clinical benefit, and would retrospectively redo the same surgical approach again. The five patients that did not require THR were still satisfied after 9years. In patients with early- stage femoral head osteonecrosis core decompression combined with the implantation of a demineralised bone matrix leads to a limited, temporary pain relief as seen in core decompression alone. However, long-term results were not encouraging with a high rate of conversion to arthroplasty. Therefore, core decompression with implantation of a demineralised bone matrix may be not appropriate to avoid THR in the long term.

Abstract 4546: Variability analysis of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) of hepatocellular carcinoma (HCC)

Abstract INTRODUCTION: HCC is a highly vascular, rapidly fatal cancer and antiangiogenic drugs have shown clinical benefit despite lack of radiographic tumor shrinkage. We standardized imaging methods to assess HCC in the woodchuck animal model (Marmota monax). This is a large unique animal model of spontaneous HCC with several similarities to human Hepatitis b(HBV) related HCC and such studies would allow utilization of this model to assess the functional changes with currently used targeted therapies. METHODS: Fourteen woodchucks infected at birth with known titers of sera from a chronic infectious pool of chronic woodchuck hepatitis virus (WHV), which is similar in structure and replicative function to HBV. Serial measurement of WHV antigen titers was conducted. Chronic WHV infection occurred in greater than 60% of woodchucks by 12 months. The WHV carrier woodchucks were screened with serial ultrasound and ten animals which developed HCC at a median age of 24- 36 months were included. Mediports were placed in the femoral vein under aseptic precautions for intravenous (IV) contrast administration. DCE-MRI methods for assessment of woodchuck HCC blood flow and size were optimized in a 1.5T magnet human head coil and IV gadolinium injected at 5cc per second using a rapid injector. Four variables - the median Ktrans, median AUCBN90, necrotic volume (NV) and total volume (TV) were analyzed by Virtualscopics using published methods. A total of 44 images were obtained, 32 were included in the study. Death due to disease progression or missing paired data resulted in exclusion of 12 images. Statistical analysis: We performed a variability analysis by calculating the concordance correlation coefficient (CCC). This coefficient was calculated for all four variables and compared at different time points. RESULTS: The CCC calculated for images obtained on day 1 and day 8 images was 0.85 for Ktrans, 0.59 for AUCBN90, 0.93 for NV and 0.99 for TV. Strong concordance was seen in 3 of the 4 DCE-MRI variables recorded a week apart. This lack of change over an 8-day period is expected with this cancer. We also compared CCC for day 8 and day 14 with Ktrans 0.76, AUCBN 0.6, NV 0.76, TV 0.89 showing less agreement than day 1 and 8. When compared to day 14 and day 30 CCC for different variables were Ktrans 0.59, AUCBN90 0.38, NV 0.82, TV 0.85, suggesting a downward trend with increasing time. Our data using this technique is able to identify clinically relevant changes in tumor size with little variability in short interval scanning. CONCLUSION: This is the first study validating the accuracy of DCE-MRI in a translational animal model for HCC and has potential to aid development of newer antiangiogenic therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4546. doi:1538-7445.AM2012-4546

Gender and the Extent of Coronary Atherosclerosis, Plaque Composition, and Clinical Outcomes in Acute Coronary Syndromes

This study sought to assess the extent and composition of atherosclerosis contributing to acute coronary syndrome events in women compared with men. Pathological studies suggest that plaque composition and burden may differ by sex. It is unclear whether sex impacts the extent, characteristics, and potential vulnerability of coronary plaques. A total of 697 patients (24% women) with acute coronary syndromes were enrolled in the prospective, multicenter PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study. Three-vessel multimodality intracoronary imaging (quantitative coronary angiography, grayscale, and radiofrequency intravascular ultrasound [IVUS]) was performed after treatment of the culprit lesion(s). Events during a median 3.4-year follow-up were ascribed to recurrent culprit versus untreated nonculprit lesions. The authors performed a post hoc, sex-based subgroup analysis. Women were older and had more comorbid disease than men. By angiography, women had a similar number of angiographic culprit (p = 0.53) but fewer nonculprit (p = 0.05) lesions, and fewer vessels with nonculprit lesions (p = 0.048) compared with men even after multivariable adjustment (p = 0.002). By IVUS, women had fewer nonculprit lesions (p = 0.002), but similar plaque burden (PB) per lesion (55.6% vs. 55.3%; p = 0.35), and female sex was not predictive of severe (> 70%) PB (p = 0.052). Plaque rupture was less common in women (6.6% vs. 16.3%; p = 0.002) even after adjusting for comorbidities (p = 0.004), as was the total necrotic core volume (p < 0.0001). The frequency of other plaque phenotypes was similar for men and women including pathological intimal thickening, thin-cap fibroatheromas (TCFA), and thick-cap fibroatheromas. Rates of major adverse cardiovascular events attributed to culprit and nonculprit lesions at 1-, 2-, and 3-year follow-up were not significantly different between men and women, although women were rehospitalized more frequently due to culprit lesion-related angina. For men, nonculprit lesion minimal lumen area ≤ 4.0 mm(2), PB ≥70%, and TCFA predicted nonculprit MACE at 3 years, whereas for women, only TCFA and PB were predictive. The PROSPECT study validates that despite having more comorbid risk factors than men, women have less extensive coronary artery disease by both angiographic and IVUS measures, and that lesions in women compared with men have less plaque rupture, less necrotic core and calcium, similar plaque burden, and smaller lumens. TCFA may also be a stronger marker of plaque vulnerability in women than men.

Validating the woodchuck model for studying antiangiogenic therapies for human hepatocellular carcinoma (HCC).

239 Background: Anti-angiogenic agents have become the backbone of advanced HCC treatment and provide clinical benefit despite infrequent radiographic response. Animal models that mimic human HCC and treatment response are greatly needed. The laboratory woodchuck (Maramota monax) is a unique animal model that replicates the complex human liver milieu of HCC in the context of chronic hepatitis B viral infection and was selected for this translational study. Methods: Humans: Patients with inoperable HCC were consented and prospectively treated with sunitinib 37.5mg PO qd for one week prior to liver directed therapy(chemoembolization). Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) was done pre-sunitinib and after one week as part of the trial. Woodchucks: Laboratory bred eastern woodchucks were inoculated at birth with known titers of sera from a chronic infectious pool of chronic woodchuck hepatitis virus (WHV), confirmed by ultrasound exam at 12-18 months to have developed HCC. Methods for assessment of woodchuck HCC blood flow using DCE-MRI were optimized. Woodchucks received sunitinib 12mg/kg/day poQD and identical image acquisition and analysis techniques were used for both species and identical parameter sets were obtained for cross comparison done by Dr. Ashton in a blinded fashion. Results: A total of seven patients and eight woodchucks with HCC were included (2 scans per patient/woodchuck, pre and post sunitinib). The “Exact Wilcoxon rank-sum test” was used for statistical analysis. Comparison between median Ktrans, AUCBN(90), necrotic and total volumes of the tumors in both groups revealed all parameters to be similar and only total tumor volume reached statistical significance (P=0.002). Conclusions: Our data indicate similarities between human and woodchucks in the tumor histology, blood flow and baseline and post antiangiogenic therapy functional imaging assessment by DCE-MRI. The current sample size of n=7+8 can detect large differences of roughly 1.5 standard deviation units between humans and woodchucks for our measures at alpha=0.05 and power=0.80. Further studies that explore the translational potential of this unique animal model are warranted.

Molecular imaging of inflammation for detection of vulnerable atheromatous plaques

This editorial refers to ‘Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed tomography’, by O. Gaemperli et al. , doi:10.1093/eurheartj/ehr367 Inflammation plays a major pathogenic role in the development of atheromatous plaques and the progression of atherosclerosis. Disruption of the fibrous cap of atheromatous lesions has been shown to lead to acute cardiovascular events. Atheromatous plaque disruption is the mechanism most commonly associated with the occurrence of acute coronary syndrome, i.e unstable angina and acute myocardial infarction.1 Plaque disruption is directly linked to inflammation, particularly to macrophage activation,1,2 which results in the release of proinflammatory cytokines and metalloproteases that contribute to the destruction of the fibrous cap of the atheroma thus weakening its structure and leading to the development of fissures that allow a direct contact between the prothrombotic atheromatous core and the circulating blood in the affected vessel. This process can result in the development of acute thrombosis and serious clinical events.3 The early identification—in a given individual—of plaques prone to disruption (‘vulnerable plaques’) is desirable, as this may allow the implementation of preventative strategies and, possibly, effective therapeutic intervention. Vulnerable plaques often show large necrotic core volumes, positive vascular remodelling, and attenuation of fibrous plaque caps ( Figure 1 ). Figure 1 The use of combined markers of risk, i.e. imaging and circulating biomarkers, may allow the early identification of vulnerable plaques and thus help clinicians to devise more rational preventative and therapeutic strategies. Multimodal imaging of atheromatous structures with PET and CTA, as in the study of Gaemperli et al. ,15 and other diagnostic modalities combining anatomical and functional measurements are likely to allow an effective, integrated assessment of atheromatous plaques. Current evidence that molecular imaging is suited for the identification of monocyte–macrophage infiltration in the setting of acute vascular events in …