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Objectives: The intention this PEPCAD-DES (Treatment of Drug-eluting Stent [DES] In-Stent Restenosis With SeQuent Please Paclitaxel Eluting Percutaneous Transluminal Coronary Angioplasty [PTCA] Catheter) study update was to demonstrate the safety and efficacy of paclitaxel-coated balloon (PCB) angioplasty in patients with DES-ISR at 3 years., Background: In the PEPCAD-DES trial late lumen loss and the need for repeat target lesion revascularization (TLR) was significantly reduced with PCB angioplasty compared with plain old balloon angioplasty (POBA) in patients with drug-eluting stent in-stent restenosis (DES-ISR) at 6 months. We evaluated whether the clinical benefit of reduced TLR and major adverse cardiac events (MACE) was maintained up to 3 years., Methods: A total of 110 patients with DES-ISR in native coronary arteries with reference diameters ranging from 2.5 mm to 3.5 mm and lesion lengths ≤22 mm were randomized to treatment with either PCB or POBA in a multicenter, randomized, single-blind clinical study. With a 2:1 randomization, 72 patients were randomized to the PCB group and 38 patients to the POBA group. At baseline, there were lesions with at least 2 stent layers in PCB (52.8%, 38 of 72) and POBA (55.3%, 21 of 38) patients., Results: At 36 months, the TLR rates were significantly lower in the PCB group compared with the POBA control group (19.4% vs. 36.8%; p = 0.046). Multiple TLRs in individual patients were more frequent in the POBA group compared with the PCB group (more than 1 TLR: POBA, 13.2%; PCB, 1.4%; p = 0.021). The 36-month MACE rate was significantly reduced in the PCB group compared with the POBA group (20.8% vs. 52.6%, log-rank p = 0.001)., Conclusions: PCB angioplasty was superior to POBA for the treatment of DES-ISR patients in terms of MACE and TLR for up to 36 months. There was no late catch-up phenomenon. (Treatment of Drug-eluting Stent [DES] In-Stent Restenosis With SeQuent® Please Paclitaxel Eluting Percutaneous Transluminal Coronary Angioplasty [PTCA] Catheter [PEPCAD-DES]; NCT00998439)., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Predictors of long-term outcome after ST-elevation myocardial infarction (STEMI) complicated by out-of-hospital cardiac arrest (OHCA) are incompletely understood, including the influence of successful coronary reperfusion., Methods: We analysed clinical and procedural data as well as 1-year outcome of 72 consecutive patients who underwent primary coronary intervention (PCI) after witnessed OHCA and STEMI and compared the results with 695 patients with STEMI and PCI, but without OHCA. Neurological recovery after OHCA was assessed using the Cerebral Performance Category (CPC) scale., Results: PCI was successful in 83.3% after OHCA vs. 84.3% in the non-OHCA group (p=0.87). One-year mortality was 34.7% vs. 9.5% (p<0.001). 58.3% of the OHCA-patients showed complete neurological recovery (CPC 1) or moderate neurological disability (CPC 2). Another 6.9% showed severe cerebral disability (CPC 3) or permanent vegetative status (CPC 4). Delay from collapse until start of Advanced Cardiopulmonary Life Support (ACLS) was shorter for survivors with CPC status ≤2 (median 1 min, range 0-11 min) compared to non-survivors or survivors with CPC status >2 (median 8 min, range 0-13 min), p<0.0001. Age-adjusted multivariate analysis identified 'unsuccessful PCI', 'vasopressors on admission' and 'start of ACLS after >6 min' as independent predictors of negative long-term outcome (death or CPC >2)., Conclusions: Mortality is high in patients with STEMI complicated by OHCA - even though PCI was performed with the same success rate as in patients without OHCA. The majority of survivors had favourable neurological outcomes at 1 year, especially if advanced life support had been started within ≤6 min and PCI was successful., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The purpose of this study was to evaluate the image quality and diagnostic accuracy of very low-dose, dual-source computed tomography (DSCT) angiography for the evaluation of coronary stents., Background: Iterative reconstruction (IR) leads to substantial reduction of image noise and hence permits the use of very low-dose data acquisition protocols in coronary computed tomography angiography., Methods: Fifty symptomatic patients with 87 coronary stents (diameter 3.0 ± 0.4 mm) underwent coronary DSCT angiography (heart rate, 60 ± 6 beats/min; prospectively electrocardiography-triggered axial acquisition; 80 kV, 165 mA, 2 × 128 × 0.6-mm collimation; 60 ml of contrast at 6 ml/s) before invasive coronary angiography. DSCT images were reconstructed using both standard filtered back projection and a raw data-based IR algorithm (SAFIRE, Siemens Healthcare, Forchheim, Germany). Subjective image quality (4-point scale from 0 [nondiagnostic] to 3 [excellent image quality]), image noise, contrast-to-noise ratio as well as the presence of in-stent stenosis >50% were independently determined by 2 observers., Results: The median dose-length product was 23.0 (22.0; 23.0) mGy · cm (median estimated effective dose of 0.32 [0.31; 0.32] mSv). IR led to significantly improved image quality compared with filtered back projection (image quality score, 1.8 ± 0.6 vs. 1.5 ± 0.5, p < 0.05; image noise, 70 Hounsfield units [62; 80 Hounsfield units] vs. 96 Hounsfield units [82; 113 Hounsfield units], p < 0.001; contrast-to-noise ratio, 11.0 [9.6; 12.4] vs. 8.0 [6.2; 9.3], p < 0.001). To detect significant coronary stenosis in filtered back projection reconstructions, the sensitivity, specificity, positive predictive value, and negative predictive value were 97% (32 of 33), 53% (9 of 17), 80% (32 of 40), and 90% (9 of 10) per patient, respectively; 89% (43 of 48), 79% (120 of 152), 57% (42 of 74), and 96% (121 of 126) per vessel, respectively; and 85% (12 of 14), 69% (51 of 73), 32% (11 of 34), and 96% (51 of 53) per stent, respectively. In reconstructions obtained by IR, the corresponding values were 100% (33 of 33), 65% (11 of 17), 85% (33 of 39), and 100% (11 of 11) per patient, respectively; 96% (46 of 48), 84% (129 of 152), 66% (47 of 71), and 98% (127 of 129) per vessel, respectively; and 100% (14 of 14), 75% (55 of 73), 44% (14 of 32), and 100% (55 of 55) per stent, respectively. These differences were not significant., Conclusions: In selected patients, prospectively electrocardiography-triggered image acquisition with 80-kV tube voltage and low current in combination with IR permits the evaluation of patients with implanted coronary artery stents with reasonable diagnostic accuracy at very low radiation exposure., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Effective radiation dose from a single coronary artery calcification CT scan can range from 0.8 to 10.5 mSv, depending on the protocol. Reducing the effective radiation dose to reasonable levels without affecting diagnostic image quality can result in substantial dose reduction in CT., Objectives: We prospectively compared tube voltages of 120 and 100 kV in a low-dose CT acquisition protocol for measuring coronary artery calcified plaque with prospectively electrocardiogram (ECG)-triggered high-pitch spiral acquisition., Methods: In 150 consecutive patients, measurement of coronary artery calcified plaque was performed with prospectively ECG-triggered high-pitch spiral acquisition. Imaging was first done with tube voltage of 120 kV voltage and subsequently repeated with 100 kV and otherwise unchanged parameters. CT was performed with a dual-source CT system with 280 milliseconds of rotation time, 2 × 128 slices, pitch of 3.4, triggered at 60% of the R-R interval. Tube current for both protocols was set at 80 mAs. With the use of a medium sharp reconstruction kernel (Siemens B35f), cross-sectional images were reconstructed with 3.0-mm slice thickness and 1.5-mm increment. Agatston scores were determined per patient for both scan settings by 2 independent readers with the use of a standard threshold of 130 HU for calcium detection. In addition, the Agatston score was calculated with a previously proposed threshold of 147 HU for 100-kV acquisitions., Results: Mean image noise was 20 ± 5 and 27 ± 7 for 120 and 100 kV, respectively (P < 0.0001). Mean dose length product was 24 ± 6 cm · cGy for the 120-kV protocol and 14 ± 4 cm · cGy for the 100-kV protocol, corresponding to average estimated effective doses of 0.3 and 0.2 mSv (P < 0.0001). Five patients were excluded from the analysis. In the remaining 145 patients, using the standard tube voltage of 120 kV, any coronary calcium was detected in 76 identical patients by both observers. In 75 of these patients, calcium was also identified by both observers in 100-kV data sets, whereas 1 patient was scored negative by 1 reader and was assigned an Agatston score of 0.7 (threshold, 130 HU) and 0.2 (threshold, 147 HU) by the other. Interobserver disagreement for assigning a patient a zero Agatston score was the same for both scan settings (each 4 patients). The mean Agatston scores for 120-kV and 100-kV (threshold, 147 HU) scans were 105 ± 245 (range, 0-1865) and 116 ± 261 (range, 0-1917), respectively (P < 0.0001). Bland-Altman analysis indicated a systematic overestimation of the Agatston score with tube voltage of 100 kV and threshold of 147 HU (mean difference, 11; 95% limits of agreement, 62 to -40). Similar results were observed for coronary calcium volume scores., Conclusion: High-pitch spiral acquisition allows coronary calcium scoring with effective doses below 0.5 mSv. The use of 100-kV tube voltage further reduces effective radiation dose compared with the standard of 120 kV; however, it leads to significant overestimation of the Agatston score when the standard threshold of 130 HU is used. Adjusting the threshold to 147 HU leads to a better agreement compared with standard 120 kV protocols yet with a remaining systematic bias toward overestimation of the Agatston score. For high-pitch spiral acquisition mode, effective radiation dose reduction when using a 100-kV setting is minimal compared with the standard 120-kV setting and may be considered nonsignificant in a clinical setting., (Copyright © 2013 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: Coronary computed tomography (CT) angiography can be associated with high radiation exposure. Reduction of tube voltage from 120 kV to 100 kV can reduce the dose by up to 40%, but it also increases image noise., Objective: We aimed to find a patient-specific predictor of image noise to determine the use of reduced tube voltage., Methods: Contrast-enhanced coronary dual-source CT angiography data sets [prospectively electrocardiogram (ECG)-triggered axial and retrospectively ECG-gated spiral acquisition, rotation of 280 milliseconds, 2 × 128 × 0.6 mm collimation, 100 kV, 320 mAs] of 165 patients (age, 54 ± 13 years) for the detection of coronary artery stenoses were analyzed. Image noise was measured in the aortic root. Influence of body weight, height, body mass index, thoracic cross sectional area, as well as the area of the thoracic solid tissue were analyzed., Results: Mean image noise in the aorta was 35.1 ± 8.9 HU. Mean dose length product was 207 ± 184 cm · cGy with an average effective dose of 2.9 ± 2.6 mSv. The patient cohort was divided into tertiles according to image noise. Numerous parameters, including BMI and body weight, were significantly different between the highest and lowest tertiles. In multivariable regression analysis, the area of the thoracic solid tissue was the only independent predictor of image noise (P < 0.0001)., Conclusions: The area of the thoracic solid tissue at the level of the aortic root predicts image noise and may hence be used for the decision to reduce tube voltage from 120 kV to 100 kV., (Copyright © 2013 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: In transcatheter aortic valve implantation (TAVI), optimal selection of fluoroscopic projections that permit orthogonal visualization of the aortic valve plane is important but may be difficult to achieve., Objective: We developed and validated a simple method to predict suitable fluoroscopic projections on the basis of cardiac CT datasets., Methods: In 75 consecutive patients that underwent TAVI, angulations in which a 35-mm thick maximum intensity projection would render all aortic valve calcium into 1 plane were determined by manual interaction with contrast-enhanced dual-source CT datasets. TAVI operators used the predicted angulation for the first aortic angiogram and performed additional aortic angiograms if no satisfactory view of the aortic valve plane was obtained. Predicted angulations were compared with the angulation used for valve implantation. Radiation exposure and contrast use was compared between patients with accurate prediction of fluoroscopic angulations by CT and patients in whom CT failed to predict a suitable view., Results: The mean difference between the predicted angulation according to CT and the angulation used for implantation was 3 ± 6 degrees. CT predicted a suitable angulation (<5-degree deviation) in 63 of 75 cases (84%). The mean number of aortic angiograms acquired in patients with correct prediction (1.02 ± 0.1) was significantly lower than in patients with incorrect prediction of the implantation angle by CT (3.0 ± 1.7; P < 0.001). Contrast agent required for the entire TAVI procedure was lower in patients with correct prediction (72 ± 36 mL vs 106 ± 39 mL; P = 0.001)., Conclusion: CT permits prediction of suitable angulations for TAVI in most cases., (Copyright © 2012 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: Coronary CT angiography allows visualization of the coronary arteries. However, motion artifact can impair delineation of the coronary artery lumen and detection of coronary artery stenoses., Objective: We investigated the influence of heart rate and the segment of the cardiac cycle during which images are reconstructed on the occurrence of motion artifacts., Methods: We evaluated coronary CT angiography datasets obtained by 64-slice dual-source CT in 100 consecutive patients. Data were reconstructed at 13 time instants during the cardiac cycle and evaluated for the presence of motion artifact., Results: Mean heart rate was 66±14 beats/min. Overall, 98 of 100 patients had evaluable datasets. For heart rates ≤60 beats/min, optimal image quality was uniformly found during late diastole (100% of cases with evaluable image quality during a time window between 65% and 75% of the cardiac cycle). With increasing heart rates, images reconstructed during late systole more frequently provided best image quality. However, image reconstruction could not be restricted to a systolic time period. To achieve evaluable image quality in 95% of cases, data acquired between 25% and 75% of the cardiac cycle had to be available for patients with heart rates >60 beats/min., Conclusion: Dual-source CT provides high image quality across a wide range of heart rates. Although data acquisition may be limited to diastole for patients with heart rates ≤60 beats/min, the availability of data acquired both during systole and diastole is necessary for patients with higher heart rates., (Copyright © 2012 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: Because of their similar visual appearance, differentiation of left ventricular thrombotic material and myocardial wall can be difficult in contrast-enhanced coronary computed tomography (CT) angiography., Objective: We identified typical thrombi attenuation of left ventricular thrombi with the use of CT measurement., Methods: Over a time period of 6 years, we retrospectively identified 31 patients who showed a left ventricular thrombus in CT angiography datasets. Patients underwent routine contrast cardiac CT to investigate coronary artery disease. CT attenuation of each thrombus was assessed in the 4-chamber view. CT densities were also determined in the ascending aorta, left ventricle, and myocardial wall both in the mid-septal and mid-lateral segments. The mean CT attenuation of thrombi and the difference between attenuation in thrombi, left ventricular cavity, and myocardial wall were determined. The ratio of attenuation values in thrombus versus aorta and myocardium versus aorta were also determined., Results: Mean (±SD) CT attenuation of all left ventricular thrombi in 31 patients was 43.2 ± 15.3 HU (range, 25-80 HU). Mean CT densities of septal and lateral myocardial wall were 102.9 ± 23.1 HU (range, 63-155 HU) and 99.3 ± 28.7 HU (range, 72-191 HU), respectively, and were thus significantly higher than the CT attenuation of thrombi (P < 0.001). A threshold of 65 HU yielded a sensitivity, specificity, and positive and negative predictive values of 94%, 97%, 94%, and 97%, respectively, to differentiate thrombus from the myocardial wall. The mean ratio between CT attenuation of thrombus and CT attenuation within the ascending aorta was 0.11 ± 0.05 (range, 0.04-0.23), which was significantly lower compared with the mean ratio between CT attenuation of the myocardial wall and the CT attenuation within the ascending aorta., Conclusion: CT attenuation within left ventricular thrombi was significantly lower than myocardial attenuation in CT angiography datasets. Assessment of CT attenuation may contribute to the differentiation of thrombi., (Copyright © 2012 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Objectives: Vascular endothelial growth factor receptor 2 (VEGFR2), a tyrosine kinase receptor activated by VEGF and shear stress, is critically involved in endothelial mechanotransduction. We investigated the role of VEGFR2 in non-uniform shear stress-induced endothelial susceptibility to inflammatory stimuli., Methods: Endothelial cells (ECs) were exposed to non-uniform shear stress, followed by stimulation with TNF-α. ECs were transfected with siRNAs against VEGFR2. Alternatively, ECs were treated with blocking antibody against VEGFR2, or with inhibitors of VEGFR2 (ZM 323881), PI3K (LY 294002), or Src-kinase (PP2). THP-1 monocytes were used for dynamic adhesion assays. Endothelial protein expression was determined by immunofluorescence., Results: siRNA against VEGFR2 decreased VEGFR2 protein expression by 40% as determined by Western blotting. In endothelial cells exposed to non-uniform shear stress, VEGFR2 knockdown inhibited TNF-α-induced NF-κB translocation to the nucleus, and the upregulation of VCAM-1 and E-selectin. Consequently, monocytic cell recruitment to endothelium under non-uniform shear stress conditions was reduced. Similar effects were observed by blocking VEGFR2 activity using a specific inhibitor ZM 323881, or an antibody against VEGFR2 before TNF-α stimulation. Inhibition of PI3K with LY 294002 significantly reduced non-uniform shear stress-induced endothelial susceptibility to TNF-α, whereas blocking Src-kinase with PP2 was ineffective., Conclusion: VEGFR2 is critically involved in adhesion molecule induction and monocytic cell recruitment to endothelium in response to non-uniform shear stress and TNF-α. Targeting the mechanosensory cascade can prevent endothelial activation in atherosclerosis-prone regions., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objectives: We sought to evaluate the diagnostic accuracy of a new prospectively electrocardiogram (ECG)-triggered high-pitch scan mode for coronary computed tomography angiography (CTA), which allows an effective dose of less than 1 mSv., Background: Coronary CTA provides increasingly reliable image quality, but the associated radiation exposure can be high., Methods: Seventy-five patients with suspected coronary artery disease and in sinus rhythm were screened for participation. After exclusion of 25 patients for body weight >100 kg or failure to lower heart rate to ≤ 60 beats/min, 50 patients were studied by prospectively ECG-triggered high-pitch spiral computed tomography (CT). Coronary CTA was performed using a dual-source CT system with 2 × 128 × 0.6-mm collimation, 0.28-s rotation time, a pitch of 3.4, 100-kVp tube voltage, and current of 320 mA. Data acquisition was prospectively triggered at 60% of the R-R interval and completed within 1 cardiac cycle. Diagnostic accuracy for detection of coronary artery stenoses ≥ 50% diameter stenosis was determined by comparison to invasive coronary angiography. Per-patient diagnostic performance was the primary form of analysis., Results: In all 50 patients (34 males, 59 ± 12 years of age), imaging was successful. For the detection of 16 patients with at least 1 coronary artery stenosis, CT demonstrated a sensitivity of 100% (95% confidence interval [CI]: 79% to 100%) and specificity of 82% (95% CI: 65% to 93%). The positive predictive value was 72% (95% CI: 49% to 89%) and the negative predictive value was 100% (95% CI: 87% to 100%). Sensitivity was 100% (95% CI: 88% to 100%) and specificity was 94% (95% CI: 89% to 97%) on a per-vessel basis. Per-segment sensitivity was 92% (95% CI: 80% to 97%), and specificity was 98% (95% CI: 96% to 98%). Mean dose-length product for coronary CTA was 54 ± 6 mGy · cm, the effective dose was 0.76 ± 0.08 mSv (0.64 to 0.95 mSv)., Conclusions: In nonobese patients with a low and stable heart rate, prospectively ECG-triggered high-pitch spiral coronary CTA provides high diagnostic accuracy for the detection of coronary artery stenoses., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Coronary atherosclerotic plaque characterisation may contribute to risk stratification for future cardiovascular events. The ability of computed tomography to classify plaques as 'fibrous' or 'lipid-rich' based on their average CT attenuation has been investigated but is fraught with substantial limitations. In this study, we evaluated the potential of analysing the distribution of CT attenuation values measured in Hounsfield Units (HU) within coronary atherosclerotic plaques to classify non-calcified plaques into fibrous and lipid-rich subtypes. Intravascular ultrasound (IVUS) served as the gold standard., Patients and Methods: We evaluated the data sets of 40 patients (30 males, 59±10 years) who had been referred for invasive coronary angiography for clinical reasons and in whom IVUS was performed in at least one coronary vessel. Using dual source CT, coronary CT angiography was performed as a part of a research protocol within 24 h previous to invasive coronary angiography. A contrast-enhanced volume dataset was acquired with retrospective ECG gating (120 kV, 400 mAs/rot, collimation 2 mm×64 mm×0.6 mm, 60-80 ml contrast agent i.v). IVUS was performed using a 40-MHz IVUS catheter (Atlantis, Boston Scientific Corporation, Natick, MA) and motorized pullback at 0.5 mm/s. Fifty five corresponding non-calcified plaques within the coronary artery system were identified in both DSCT and IVUS using bifurcation points as fiducial markers. In DSCT data sets, serial parallel cross-sections (1mm slice thickness) were rendered orthogonally to the centre line of the coronary artery for each of the 55 plaques. For each cross section and each plaque, a histogram of CT attenuation values (increments of 10HU) was determined. The percentage of pixels with a density ≤30 HU was calculated. Using IVUS as the gold standard, plaques were classified as predominantly fibrous (hyperechoic) or predominantly lipid-rich (hypoechoic)., Results: 15 predominantly fibrous plaques vs. 40 predominantly lipid-rich plaques were identified in IVUS. The mean CT attenuation in both plaque types was significantly different (67±31 HU vs. 96±40 HU, p=0.006), yet with a wide overlap. For the 15 fibrous plaques identified in IVUS, the mean percentage of pixels ≤30 HU in CT was 6±10%. For lipid-rich plaques it was 16±10% (p<0.0001). ROC curve analysis revealed that a cut-off of 5.5% pixels with an attenuation ≤30 HU identified lipid rich plaques in CT angiography with a sensitivity of 95% (38/40, 95% CI 83-99) and a specificity of 80% (12/15, 95% CI 52-96) [AUC 0.9, 95% CI 0.7-1.0]. Using this threshold, the negative predictive value was 86% (12/14, 95% CI 57-98) and the positive predictive value was 93% (38/41, 95% CI 80-98)., Conclusion: Lipid-rich coronary atherosclerotic plaques contain a significantly higher percentage of pixels with low CT attenuation as compared to fibrous plaques. Histogram analysis may help to differentiate both plaque types. A cut-off of 5.5% of pixels with an attenuation of ≤30 HU allowed identification of lipid-rich plaques with a sensitivity of 95% and a specificity of 80%., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study assessed the rate of periprocedural embolic ischemic brain injury during transapical aortic valve replacement in 25 consecutive patients., Background: Transcatheter aortic valve implantation is rapidly being established as a new therapeutic approach for aortic valve stenosis. Although initial clinical results are promising, it is unknown whether mobilization and embolization of calcified particles may lead to cerebral ischemia., Methods: Twenty-five consecutive patients (10 men, 15 women, mean age: 81 ± 5 years, mean log EuroSCORE [European System for Cardiac Operative Risk Evaluation]: 32 ± 10%) scheduled for transapical aortic valve implantation were included. All patients received a baseline cerebral magnetic resonance imaging scan. The scan was repeated approximately 6 days after valve implantation. The magnetic resonance imaging studies included axial diffusion-weighted, T(2)-weighted, fluid attenuated inversion recovery-weighted, and T(2) gradient echo sequences. Standardized assessment of the neurologic status was performed before aortic valve replacement and post-operatively., Results: Transapical aortic valve implantation was successfully performed in all patients. In 17 patients (68%), new cerebral lesions could be detected, whereas 8 patients showed no new cerebral insults. The pattern of distribution and morphology were typical of embolic origin. Despite the high incidence of morphologically detectable lesions, only 5 patients showed clinical neurologic alterations. Out of these patients, only 1 suffered from a permanent stroke., Conclusions: New embolic ischemic cerebral insults are detected in 68% of patients after transapical valve implantation. Clinical symptoms are rare and usually transitory. Larger trials will need to establish the clinical significance of asymptomatic ischemic lesions as well as the rate of ischemic events in patients undergoing transfemoral valve replacement., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: We analyzed typical morphological features of coronary atherosclerotic plaques in acute coronary syndromes (ACS) using contrast-enhanced coronary Dual-Source CT angiography (CTA) in comparison to stable coronary lesions., Patients and Methods: Fifty-five patients with ACS and 55 controls with stable angina pectoris (SAP) with similar atherosclerotic risk profile were studied. CT angiography was performed using a Dual-Source CT scanner (330 ms rotation, 2 x 64 x 0.6mm collimation, 60-80 mL contrast agent i.v. at 6 mL/s) before invasive catheterization. We analyzed plaque volume (mm(3)), mean and minimal CT density (HU), remodeling index, plaque type (calcified/non-calcified/mixed) and presence of "spotty" calcifications as well as presence of contrast rims., Results: In patients with ACS and SAP, 28 and 10 lesions showed both calcified and non-calcified components, but in a greater proportion of non-calcified material, 6 and 23 lesions showed a greater proportion of calcified material and 21 and 8 lesions were completely non-calcified, respectively. None of the culprit plaques in ACS and 14 of the lesions in SAP were completely calcified. A "spotty" pattern of calcification within the plaque and a central filling defect surrounded by a rim of contrast were present in 11 and 14 of 55 ACS cases, but never in SAP lesions. For culprit lesions in ACS and for lesions in patients with SAP, mean plaque volumes were 192.8 + or - 114.9 mm(3) and 103.8+/-51.8 mm(3) (p=0.001), mean and minimal CT densities were 85.6 + or - 45.1HU and 47.2 + or - 33.7 HU versus 143.8 + or - 104.1 HU and 95.9 + or - 84.0 HU (p<0.01) and mean remodeling indices were 1.6 + or - 0.4 and 0.97 + or - 0.17 (p<0.001), respectively., Conclusion: Plaques of culprit lesions in ACS show specific morphologic characteristics in non-invasive coronary CT angiography. As compared to stable lesions, culprit lesions in ACS display greater proportion of non-calcified material and presence of "spotty" calcifications/contrast rims as well as larger plaque volumes, lower CT attenuation and higher remodeling indices., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: The computed tomographic (CT) attenuation of coronary atherosclerotic plaque has been proposed as a marker for tissue characterization and may thus potentially contribute to the assessment of plaque instability., Objective: We analyzed the influence of reconstruction parameters on CT attenuation measured within noncalcified coronary atherosclerotic lesions., Methods: Seventy-two patients were studied by contrast-enhanced dual-source CT coronary angiography (330 millisecond rotation time, 2 x 64 x 0.6 mm collimation, 120 kV, 400 mAs, 80 mL contrast agent intravenously at 6 mL/s), and a total of 100 distinct noncalcified coronary atherosclerotic plaques were identified. Image data sets were reconstructed with a soft (B20f), medium soft (B26f), and sharp (B46f) reconstruction kernel. With the medium soft kernel, image data sets were reconstructed with a slice thickness/increment of 0.6/0.3 mm, 0.75/0.4 mm, and 1.0/0.5mm. Within each plaque, CT attenuation was measured., Results: Mean CT attenuation using the medium soft kernel was 109 +/- 58 HU (range, -16 to 168 HU). Using the soft kernel, mean density was 113 +/- 57 HU (range, -13 to 169 HU), and using a sharp kernel, mean density was 97 +/- 49 HU (range, -23 to 131 HU). Similarly, reconstructed slice thickness had a significant influence on the measured CT attenuation (mean values for medium soft kernel: 102 +/- 52 HU versus 109 +/- 58 HU versus 113 +/- 57 HU for 0.6-mm, 0.75-mm, and 1.0-mm slice thickness). The differences between 0.75-mm and 0.6-mm slice thickness (P = 0.05) and between medium sharp and sharp kernels (P = 0.02) were statistically significant., Conclusions: Image reconstruction significantly influences CT attenuation of noncalcified coronary atherosclerotic plaque. With decreasing spatial resolution (softer kernel or thicker slices), CT attenuation increases significantly. Using absolute CT attenuation values for plaque characterization may therefore be problematic., (Copyright 2010 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Objective: Atherosclerotic plaque formation results from a combination of local shear stress patterns and inflammatory processes. This study investigated the endothelial response to shear stress in combination with the inflammatory cytokine TNF-alpha in a simplified model of arterial bifurcation., Methods: Human umbilical vein endothelial cells (ECs) were exposed to laminar or non-uniform shear stress in bifurcating flow-through slides, followed by stimulation with TNF-alpha. To study cell adhesion, ECs were perfused with medium containing THP-1 monocytic cells. Endothelial protein expression was determined by immunofluorescence., Results: Adhesion of monocytic cells to unstimulated ECs was nearly undetectable under laminar shear stress and was slightly increased under non-uniform shear stress. Exposure of ECs to non-uniform shear stress in combination with TNF-alpha induced a 12-fold increase in monocytic cell recruitment and a significant induction of endothelial E-selectin and VCAM-1 expression. Both these effects were prevented in ECs exposed to laminar shear stress. The significant differences in TNF-alpha-induced monocytic cell recruitment and adhesion molecule expression between laminar and non-uniform shear stress regions were abolished in the absence of shear stress preconditioning. Simvastatin (1 micromol/L) suppressed the non-uniform shear stress- and TNF-alpha-induced increase in monocytic cell adhesion by about 30% via inhibition of VCAM-1 expression. Resveratrol, the active component of red wine, inhibited the expression of both VCAM-1 and E-selectin, and reduced monocytic cell recruitment by 50% at 20 micromol/L., Conclusions: Non-uniform shear stress induces endothelial susceptibility to circulating TNF-alpha and adhesion of monocytic cells. Interference with this process may inhibit inflammatory response in atherosclerosis-prone regions.

Objective: Identification of clinically relevant determinants for acute coronary syndromes (ACS) promises reduction of ACS-associated mortality. C-reactive protein (CRP) has proved to be useful identifying people at risk for cardiovascular events. However, it is unknown whether genetic variants at Fcgamma receptor IIa (FcgammaRIIa), the main receptor for CRP, are involved in CRP-related cardiovascular risk. We evaluated the potential impact of FcgammaRIIa through a genetic association study in patients with ACS., Methods and Results: We conducted a genetic association study among 701 consecutive patients with first event of ACS compared to 467 patients with stable angina pectoris. All patients were genotyped for a frequent functional variant at position 131 of the mature FcgammaRIIa, where the arginine (R) allele results in an increased signal transduction upon CRP binding. In our study, the R/R131 genotype was significantly associated with ACS as the first manifestation of coronary artery disease (P=1.2x10(-9), odds ratio 2.86, 95% CI: 2.06-3.99) compared to the non-R/R131 genotype., Conclusions: Our data show a genetic association of the FcgammaRIIa R/R131 genotype with a more frequent occurrence of ACS as the first manifestation of coronary artery disease, probably mediated via its interaction with CRP. Genotyping of this FcgammaRIIa variant could help to improve risk stratification in the course of coronary disease in the future.

Coronary CT angiography allows high-quality imaging of the coronary arteries when state-of-the-art CT systems are used. However, radiation exposure has been a concern. We describe a new scan mode that uses a very high-pitch spiral acquisition, "Flash Spiral," which has been developed specifically for low-dose imaging with dual-source CT. The scan mode uses a pitch of 3.2 to acquire a spiral CT data set, while covering the entire volume of the heart in one cardiac cycle. Data acquisition is prospectively triggered by the electrocardiogram and starts in late systole to be completed within one cardiac cycle. Images are reconstructed with a temporal resolution that corresponds to one-quarter of the gantry rotation time. Throughout the data set, subsequent images are reconstructed at later time instants in the cardiac cycle. In a patient with a heart rate of 49 beats/min, the Flash Spiral scan mode was used with a first-generation dual-source CT system and allowed artifact-free visualization of the coronary arteries with a radiation exposure of 1.7 mSv for a 12-cm scan range at 120 kVp tube voltage.

Sclerotic calcification of the aortic valve is a common disease in advanced age. However, pathophysiologic processes leading to valve calcifications are poorly understood. Transformation of atherosclerotic triggers to osteogenic differentiation is controversially discussed and is thought as a trigger of bone transformation in end stage disease. This study focuses on the transcriptional gene-profiling of severe calcified stenotic human aortic valves to clarify the molecular basis of the pathophysiological process. We collected severely calcified and stenotic human aortic valves (CSAV) with (CSAV+, n=10) and without (CSAV-, n=10) at least 4 weeks of statin pre-treatment prior to valve replacement and investigated transcriptional steady-state gene-profiling by using micro array technique and GAPDH-adjusted PCR for confirmation. Results were compared with findings in non-sclerotic aortic valves: C (n=6). Various parameters of inflammation were significantly up regulated as compared to C: eotaxin3, monokine induced by gamma-interferon, vascular adhesion protein-1 (VAP-1), peroxisome proliferative activated receptor-alpha or transforming growth factor beta 1 (TGF beta 1). Except for TGF beta 1 and VAP-1, statin pre-treatment neutralized altered gene expression. Genes of osteogenic bone transformation (tenascin C, bone sialoprotein, Cbfa1, Osteocalcin, Beta-catenin, Sox- and Cyclin-genes) were found unaltered in their expression in both, CSAV- or CSAV+ in comparison to C. This study shows continuing atherosclerotic inflammation on CSAV. Additionally, no evidence of initiated osteoblastic differentiation process was found. Pre-treatment of patients with statins partially neutralized the gene pattern of inflammation on the aortic valves. This suggests that there are potent benefits of statins on early development of inflammation on calcified aortic valves.

Endothelial cells are maintaining atherosclerotic signaling mediated by Extracellular Regulated Kinases 1 and 2 (ERK). Signaling gets activated upon stimulation of G protein-coupled receptors mediated by G(q) and G(i/o) proteins subjected to regulation by RGS proteins. The goal of the study was to delineate the specificity of RGS proteins modulating induced ERK phosphorylation. We used stimulated HUVEC, silenced specifically RGS proteins and compared assessed ERK 1/2 activation with immunohistochemical stainings on atherosclerotic plaques. Increased ERK phosphorylation was detected upon stimulation with Phenylephrine (2.6+/-0.1 times over basal), Endothelin-1 (1.8+/-0.2), Dopamine (5.1+/-0.2), TNF (9.8+/-0.7) or IL-4 (3.1+/-0.3). RGS silencing increased activation of ERK 1/2: Phen (RGS3, 5), ET-1 (RGS3, 4), Dopa (RGS3), TNF (RGS2, 3, 4) or IL-4 (RGS2, 3, 4). Immunohistochemically, increased ERK activation was detected on atherosclerotic plaques. This data supports the role of RGS proteins on ERK activation in human atherosclerosis which identifies RGS proteins as new therapeutical targets.

Invasive catheterization can lead to mechanically induced spasm of coronary arteries. In this case report, CT angiography allowed us to unmask catheter-induced coronary spasm as the underlying reason for isolated left main coronary artery stenosis seen in invasive angiography.

The ability of contrast-enhanced CT to detect "late enhancement" in a fashion similar to magnetic resonance imaging has been reported previously. Typical myocardial distribution patterns of "late enhancement" have been described for MRI. The same patterns can be observed in CT imaging, albeit at a lower signal to noise ratio. We report a case of cardiac amyloidosis with a typical pattern of subendocardial, circumferential late enhancement in all four cardiac chambers.

The signal transduction activating extracellular-regulated kinases (ERK) is triggered by G protein-coupled receptors (GPCR). In turn, the GPCR are mediated by G(q) and G(i/o) proteins subjected to regulation of regulators of G protein-mediated signaling (RGS) proteins. This network compiles extracellular growth signals to intracellular targets of sclerosis on calcified and stenotic human aortic valves (CSAV). Statins are known as partial inhibitors of atherosclerotic inflammation on CSAV. This study identifies descriptively the role of statins on RGS subjected ERK activation on CSAV. We collected human CSAV with (n=10, CSAV+) or without (n=10, CSAV-) at least 4 weeks of statin pre-treatment and investigated gene-profiling of RGS proteins, intermediaries and ERK using microarray technique, real-time and semi-quantitative PCR. Human non-calcified aortic valves were controls (n=6, C). Immunohistochemical stainings defined activation of expressed ERK 1/2 on CSAV (+/-) or C. As compared to C, in CSAV- several cardiac expressed RGS proteins were translationally upregulated: RGS1 (2.6 compared C), RGS3 (3.1), RGS5 (2.1) and RGS8 (2.5). In CSAV+, statins neutralized observed RGS expression. ERK expression was found unchanged in all valves: CSAV-, CSAV+ or C. In contrast, immunohistochemically we found enhanced activation of phosphorylated ERK in CSAV+ as compared to CSAV- or control. This study shows reduced RGS protein expression through statins leading to increased activation of ERK on human CSAV. In regard to known studies, the partial therapeutical failure of statins on severe end-stage CSAV is due to the induction of ERK activation which offers the need for more investigation.

Cardiac computed tomography (CT) angiography permits detection of myocardial scars through "late enhancement." We report the case of a patient with suspected cardiac sarcoidosis. Because of implanted defibrillator leads, magnetic resonance imaging was not possible. Dual-source CT with intravenous contrast injection was used as an alternative technique to detect late myocardial enhancement. A typical pattern of myocardial scarring allowed us to establish the diagnosis of cardiac sarcoidosis. CT imaging may be an alternative diagnostic tool to visualize late enhancement in patients with contraindications to magnetic resonance imaging.

Unlabelled: Multi-detector CT (MDCT) permits non-invasive visualization of the coronary arteries. Coronary plaque can be visualized, and earlier studies have indicated that the CT attenuation measured in atherosclerotic plaques is influenced by plaque composition. Also, MDCT has been shown to permit assessment of remodeling of coronary atherosclerotic lesions. It is assumed that both lipid-rich plaques and those that display positive remodeling are more prone to rupture and erosion. We thus evaluated the relationship between remodeling and CT attenuation of coronary atherosclerotic plaque by MDCT., Methods: Seventy-six patients were investigated by contrast-enhanced 64-slice CT. One-hundred twelve atherosclerotic lesions without substantial calcification and visualized with high image quality were selected. Multiplanar reconstructions orthogonal to the coronary artery were rendered at the lesion and the proximal reference site. Cross-sectional vessel areas were measured to determine the remodeling index (RI: lesion vessel area/reference vessel area) and the CT attenuation of plaque was measured by fitting a region of interest to the plaque area. CT attenuation of plaque was correlated to the presence of positive remodeling index (RI>1.05)., Results: The mean cross-sectional vessel area in the lesion was 0.25+/-0.08 cm(2), the mean reference vessel area was 0.22+/-0.09 cm(2). The mean CT attenuation of the atherosclerotic plaque in the lesions was 71+/-26 HU. CT attenuation of plaque was significantly lower in 72 lesions that displayed positive remodeling (59+/-22 HU) than in 40 lesions with no or with negative remodeling (91+/-20 HU, p<0.001)., Conclusions: Positive remodeling of coronary atherosclerotic lesions correlates to lower CT attenuation of plaque, which has been demonstrated to be associated with lipid-rich plaque. Both characteristics indicate increased risk for plaque rupture and subsequent events and could thus prove useful when the use of CT imaging for the detection of "vulnerable plaque" is considered.

Objectives: The purpose of this study was to analyze the influence of a systematic approach to lower heart rate for coronary computed tomography (CT) angiography on diagnostic accuracy of 64-slice single- and dual-source CT., Background: Coronary CT angiography is often impaired by motion artifacts, so that routine lowering of heart rate is usually recommended. This is often conceived as a major limitation of the technique. It is expected that higher temporal resolution, such as with dual-source 64-slice CT, would allow diagnostic imaging even without systematic pre-treatment for lowering the heart rate., Methods: Two hundred patients with suspected coronary artery disease were first randomized to either 64-slice single-source CT (n = 100) or dual-source CT (n = 100) for contrast-enhanced coronary artery evaluation. In each group, patients were further randomized to either receive systematic heart rate control (oral and intravenous beta-blockade for a target heart rate < or =60 beats/min) or receive no premedication. Evaluability of datasets and diagnostic accuracy were compared between groups against the results obtained from invasive angiography., Results: Systematic pre-treatment lowered heart rate during CT coronary angiography by 10 beats/min. Heart rate control significantly improved evaluability in single-source CT (93% vs. 69% on a per-patient basis, p = 0.005), whereas it did not in dual-source CT (96% vs. 98%). In evaluable patients, sensitivity to detect the presence of at least 1 coronary stenosis by single-source CT was 86% and 79%, respectively, with and without heart rate control (p = NS). For dual-source CT, it was 100% and 95%, respectively (p = NS). The rate of correctly classified patients, defined as evaluable and correct classification as to the presence or absence of at least 1 coronary artery stenosis, was significantly improved by heart rate control in single-source CT (78% vs. 57%, p = 0.04), whereas there was no such influence in dual-source CT (87% vs. 93%)., Conclusions: Systematic heart rate control significantly improves image quality for coronary visualization by 64-slice single-source CT, whereas image quality and diagnostic accuracy remain unaffected in dual-source CT angiography. Improved temporal resolution obviates the need for heart rate control.

Shear stress changes play an important role in atheroma formation. This study focussed on atherogenic protein expression under non-uniform shear stress and the pharmacological modulation of shear-related endothelial dysfunction. Bifurcating flow-through cell culture slides were used to expose HUVECs to steady laminar or non-uniform shear stress for 18 h at 10 dyn/cm(2). Protein expression was determined by immunofluorescence, and quantified using MetaVue software. Laminar shear stress resulted in cell alignment, reduced F-actin fibers, and significant induction of endothelial nitric oxide synthase expression. Under non-uniform shear stress at bifurcations, minor upregulation of adhesion molecules was observed. Connective tissue growth factor (CTGF) was significantly downregulated by laminar shear stress and induced in cells exposed to non-uniform shear stress. CTGF upregulation by non-uniform shear stress was RhoA-dependent, because it was almost completely inhibited in cells transfected with dominant negative RhoA-N19, and when cells were treated with 1 micromol/L simvastatin during flow. Pre-incubation of HUVECs with inhibitors of Rho-associated kinase before exposure to flow significantly suppressed the CTGF induction in regions of non-uniform shear stress. In conclusion, non-uniform shear stress-dependent CTGF expression requires active RhoA and can be prevented pharmacologically. Interference with shear stress-induced protein expression may inhibit endothelial dysfunction in atheroprone vessel regions.

Sclerotic calcification of the aortic valve is a common disease in advanced age. Its pathophysiology is unclear. However, pathobiological similarities to atherosclerosis have been shown in several studies. The current study assesses gene profiling of severe calcified stenotic human aortic valves identifying transforming growth factor (TGF)-beta, Eotaxin3, vascular adhesion protein-1 (VAP-1) and monokine induced by interferon-gamma (MIG) as potential atherosclerotic target genes in severe calcified and stenotic aortic valves, and analyzes the effects of statins on their expression as part of an anti-inflammatory treatment strategy. We collected human severe calcified and stenotic aortic valves with (CSAV+) or without (CSAV-) statin pre-treatment prior to valve replacement and investigated gene profiling by using micro-array technique and real-time PCR for the TGF-beta, Eotaxin3, VAP-1 and MIG expression. In comparison to atherosclerotic plaques of carotid arteries, immunohistochemical staining was investigated. Results were contrasted to human normal non-calcified aortic valves as controls (C). As compared to C, TGF-beta, Eotaxin3, MIG or VAP-1 was significantly upregulated in CSAV-. In CSAV+ no significant change in gene expression was found for Eotaxin3 and MIG. In contrast, VAP-1 and TGF-beta were still upregulated. Corresponding gene expression was confirmed on atherosclerotic plaque formations of carotid arteries. Monocyte/Macrophage infiltration (presence of CD68) on aortic valves (CSAV+, CSAV-, or C) confirmed inflammatory nature of the disease. Our data support further evidence for atherosclerotic inflammation as a trigger for sclerosis in end-stage calcified stenotic aortic valves by showing upregulation of gene expression for TGF-beta, VAP-1, MIG and Eotaxin3, which is only partially inhibited by previous statin therapy. Potent benefits of statin treatment on early stages of valve disease are still propagated.

Emerging evidence implicating the participation of dendritic cells (DCs) and T cells in various vascular inflammatory diseases such as giant cell arteritis, Takayasu's arteritis, and atherosclerosis led us to hypothesize that they might also participate in the pathogenesis of coronary arteritis in Kawasaki disease (KD). Coronary artery specimens from 4 patients with KD and 6 control patients were obtained. Immunohistochemical and computer-assisted histomorphometric analyses were performed to detect all myeloid DCs (S-100(+), fascin(+)), all plasmacytoid DCs (CD123(+)) as well as specific DC subsets (mature myeloid DCs [CD83(+)], myeloid [BDCA-1(+)] and plasmacytoid DC precursors [BDCA-2(+)]), T cells (CD3(+)), and all antigen-presenting cells (HLA-DR(+)). Co-localization of DCs with T cells was assessed using double immunostaining. Significantly more myeloid DCs at a precursor, immature or mature stage were found in coronary lesions of KD patients than in controls. Myeloid DC precursors were distributed equally in the intima and adventitia. Mature myeloid DCs were particularly abundant in the adventitia. There was a significant correlation between mature DCs and HLA-DR expression. Double immunostaining demonstrated frequent contacts between myeloid DCs and T cells in the outer media and adventitia. Plasmacytoid DC precursors were rarely found in the adventitia. In conclusion, coronary artery lesions of KD patients contain increased numbers of mature myeloid DCs with high HLA-DR expression and frequent T cell contacts detected immunohistochemically. This suggests that mature arterial myeloid DCs might be activating T cells in situ and may be a significant factor in the pathogenesis of coronary arteritis in KD.

The presence of immune cells is important for plaque destabilization. Disturbed flow conditions were shown to enhance the recruitment of circulating immune cells. Thus, we analyzed in 54 atherosclerotic carotid plaques the frequency of different immune cells, HLA-DR, chemokines, and chemokine receptors, comparing the upstream with the downstream plaque shoulder. The presence of neovascularization and intraplaque hemorrhages was investigated by CD34 immunostaining and Mallory's iron stain. Immunohistochemical analyses were performed to detect smooth muscle cells (SMC: actin), macrophages (CD68), T cells (CD3), dendritic cells (DC: fascin), mature DC (CD83), and the expression of HLA-DR, chemokine receptors (CCR-2, CCR-6), and chemokines (MCP-1, MIP-3alpha). Significantly more SMC were detected downstream than upstream (p<0.001). In contrast, significantly more macrophages (p=0.01), DC (p=0.03), mature DC (p=0.007), and a higher expression of HLA-DR (p=0.004), CCR-2 (p=0.002), CCR-6 (p<0.001), MCP-1 (p=0.04), and MIP-3alpha (p=NS) were observed upstream than downstream. Immune cells were strongly associated with neovascularization. The abundance of SMC downstream provides an explanation for distal plaque growth. Enhanced recruitment of immune cells through neovessels into the upstream shoulder might be contributing to plaque destabilization.

Unlabelled: Multi-detector row Computed Tomography (MDCT) permits non-invasive visualization of the coronary arteries. The ability to visualize and, with limitations, to characterize non-calcified coronary atherosclerotic plaque has been described. We investigated the CT attenuation of non-calcified plaques as determined by 16-slice MDCT in comparison to intravascular ultrasound (IVUS)., Methods and Results: Thirty-two patients were investigated by contrast-enhanced 16-slice CT. In addition, IVUS of one coronary artery (motorized pullback) was performed (LM+LAD: 22, LM+LCX: 4, RCA: 6). At 252 sites within the coronary system, in which non-calcified atherosclerotic plaque could be identified both in MDCT and IVUS, the CT attenuation within the plaque was measured using a centrally placed region of interest and correlated to the appearance of the plaque in IVUS at the corresponding location. The mean CT attenuation within plaque that corresponded to hyper-echogenic appearance in IVUS was 121+/-34HU (n=76). The mean CT attenuation within plaque that corresponded to hypo-echogenic appearance was 58+/-43HU (n=176, p<0.001). However, there was substantial overlap of the density values measured by MDCT in the two groups., Conclusions: A significant difference of the mean CT attenuation within atherosclerotic lesions of hypo-echogenic and hyper-echogenic appearance in IVUS could be observed. However, we observed substantial overlap of attenuation values between plaque types so that the differentiation of "vulnerable" and "stable" plaques based on their CT attenuation is doubtful.

Background: We investigated the potential of 16-slice multi-detector row spiral CT (MDCT) with retrospective ECG-gating for evaluation of coronary artery anomalies., Methods: A total of 35 patients (23 men, 12 women, 19-81 years) in whom anomalous coronary arteries had been detected by invasive coronary angiography underwent MDCT (Sensation 16, Siemens, Germany). During one breathhold, a contrast-enhanced (90 ml, 5 ml/s) volume data set of the heart was acquired (16x0.75mm collimation, gantry rotation 375 ms). Images were reconstructed with a slice thickness of 1.0 mm in 0.5-mm intervals using retrospective ECG-gated reconstruction. The 35 data sets and 80 data sets of patients with angiographically normal coronary anatomy were analysed in random order concerning the origin and course of the coronary arteries. The results were compared to invasive coronary angiography., Results: All patients with coronary artery anomalies and all controls with normal coronary anatomy were identified by MDCT. In addition, the origins and course concerning their anatomical relationship to adjacent cardiac structures were visualized in all patients, including right-sided origin of the left main (n=10), left anterior descending coronary artery (n=4) or left circumflex coronary artery (n=10); left-sided origin of the right coronary artery (n=6); four coronary fistula to the pulmonary artery (two from the left anterior descending, one from the right coronary artery, one from the left main), and one fistula from the circumflex coronary artery to the left atrium, Conclusions: The study demonstrates that MDCT is a reliable noninvasive technique to identify and define anomalous coronary arteries and their course.

Unlabelled: We compared the extent of coronary calcifications as quantified by electron beam tomography (EBT) to the predicted 10-year cardiovascular event risk based on Framingham and PROCAM algorithms in patients with a first myocardial infarction (MI)., Methods: In 156 patients (56.7 +/- 22 years), EBT was performed <4 weeks after MI. Coronary calcifications were quantified using the "Agatston Score" and age-related calcium percentiles were determined. The predicted 10-year event risk was determined using Framingham and PROCAM algorithms., Results: Coronary calcifications were present in 148 patients with a mean "Agatston Score" of 589.2 +/- 976. The "Agatston Score" was >400 in 44% and >90th percentile in 42% of the patients. Framingham risk was >20% in 32% and PROCAM risk was >20% in 28%., Conclusion: Coronary calcifications were detected in the vast majority of patients with a first MI, independent from the patient's age. The determination of age-related percentiles was superior to the Framingham or PROCAM algorithm.

Biological effects on endothelium induced by contrast ultrasound (US) may be relevant for transferring drugs into the tissue. An in vitro tissue-mimicking phantom was developed to simulate clinical precordial echocardiography of three modalities (two-dimensional (2DE), pulsed wave (PW), and Power Doppler echocardiography) with gradual increases of acoustic output (mechanical index (MI) 0.0-1.6 and thermal index soft tissue (TIS) 0.0-1.3, respectively; transmit-frequency 1.8 MHz in second harmonic mode (SHI) by 2DE, 1.8 MHz for PW-Doppler, and 3.2 MHz for Power Doppler) as well as contrast agent (CA) concentrations (0.002-4 mg/mL Levovist). Disintegration of the endothelial monolayer was quantitatively analyzed by counting intercellular gaps in light microscopy. No gaps were observed in CA application without sonication. Only few gaps appeared at sonication without CA application in 2DE at MI=1.6 and in PW- and Power Doppler at TIS > or =0.4 and MI > or =0.4. The number of gaps increased significantly with the gradual increase of US output and to a comparably lesser but also significant extent with CA concentrations. Diagnostic contrast echocardiography may induce endothelial disintegrations dependent on US output as well as on CA concentrations. This aspect might be helpful in further in vivo series on local drug delivery.

Objectives: Macrophage migration inhibitory factor 1alpha (MIF), a cytokine with immunoregulatory functions has been suggested to be involved in atherosclerotic plaque development. However, little is known about MIF-inducing conditions in the atherosclerotic process and the association of MIF with plaque instability., Methods and Results: Forty-two carotid endatherectomy samples from 36 patients and 4 aortic samples from young accident victims (as healthy controls) were analyzed for MIF staining. MIF expressing tissues in the atherosclerotic plaques are mainly mononuclear cells (MNCs), but also endothelial cells of intimal microvessels (MVECs). The magnitude and the intensity of their MIF expression was associated with the progression of plaques from early lesions (Stary I-III) to complicated plaque stages (Stary IV-VIII). In highly inflammatory and neovascularized regions of the plaques the colocalization of MIF expressing MNCs with CD40-L+ and angiotensin II (Ang II)-producing MNCs could be established. This finding supports the notion that CD40-L fusion protein and Ang II are able to induce MIF production in the monocytic cell line THP-1. Furthermore hypoxia (< or =1% O2) as a further proinflammatory and especially proangiogenetic factor was able to stimulate MIF secretion by THP-1, human monocytes and HUVECs. Hyperglycemia and insulin remained without effect., Conclusion: MIF is expressed in advanced atherosclerotic lesions in close correlation with signs of instability, such as mononuclear cell inflammation and neointimal microvessel formation. Furthermore, the colocalization of MIF with Ang II-producing MNCs and CD40-L+ cells in these plaques and the finding that proathero- and -angiogenic mediators such as CD40-L, Ang II and hypoxia are able to stimulate MIF expression in vitro suggest an important role of MIF in the modulation of atherosclerotic plaque stability.

Objective: Angiotensin converting enzyme (ACE) inhibitors significantly improve survival in patients with atherosclerosis. Although ACE inhibitors reduce local angiotensin II (AngII) formation, serine proteases form AngII to an enormous amount independently from ACE. Therefore, our study concentrates on the effect of the ACE-inhibitor ramiprilat on chemokine release, AngII receptor (ATR) expression, and NF-kappaB activity in monocytes stimulated with AngII., Methods and Results: AngII-induced upregulation of IL-8 and MCP-1 protein and RNA in monocytes was inhibited by the AT1R-blocker losartan, but not by the AT2R-blocker PD 123.319. Ramiprilat dose-dependently suppressed AngII-induced upregulation of IL-8 and MCP-1. The suppressive effect of ramiprilat on AngII-induced chemokine production and release was in part caused by downregulation of NF-kappaB, but more by a selective and highly significant reduced expression of AT1 receptors as shown in monocytes and endothelial cells., Conclusion: In our study we demonstrated for the first time that ramiprilat reduced expression of AT1R in monocytes and endothelial cells. In addition, ramiprilat downregulated NF-kappaB activity and thereby reduced the AngII-induced release of IL-8 and MCP-1 in monocytes. This antiinflammatory effect, at least in part, may contribute to the clinical benefit of the ACE inhibitor in the treatment of coronary artery disease.

Tissue transglutaminase (tTgase) contributes to the organisation of the basement membrane and is therefore thought to be important for the integrity and stability of the vessel wall. In the present study, we hypothesised that the HMG-CoA reductase inhibitor atorvastatin may up-regulate the tTgase expression in endothelial cells and thereby exert beneficial effects on endothelial function. Treatment of human umbilical vein endothelial cells (HUVEC) with atorvastatin (1-10 microM) caused a clear increased expression of tTgase in both permeabilised and non-permeabilised HUVEC. In contrast, stimulation of HUVEC with TNFalpha had no substantial effect on tTgase expression or localisation but inhibited the atorvastatin-induced up-regulation and externalisation of tTgase. Propidium iodide staining revealed that statin-induced apoptosis is not responsible for the enhanced expression. By inducing the expression of tTgase, statins may promote tTgase-mediated stabilisation of the basement membrane. This effect of atorvastatin may contribute to the beneficial role of statins on endothelial function.

Dendritic cells (DC), which are critically involved in various immunological disorders, were detected in atherosclerotic plaques in 1995. Since DC might be related to the immunological processes in atherosclerosis (AS), we analyzed the emergence of DC and other inflammatory cells in different stages of AS. Serial cross-sections of 44 carotid specimens were immunohistochemically analyzed for the presence of DC, T cells, macrophages, and HLA-DR. Atherosclerotic specimens were histologically defined as initial lesions, advanced stable, or vulnerable plaques. In initial lesions significantly lower DC numbers were detected than in advanced plaques (P < 0.001). For advanced plaques, DC numbers were significantly higher in vulnerable than in stable plaques (P = 0.005). In contrast to initial lesions, approximately 70% of DC in advanced plaques exhibited a mature phenotype (CD83+, DC-LAMP+), indicating a functional activity of DC. In plaques of patients with acute ischemic symptoms DC numbers were markedly elevated (P = 0.03), whereas significantly lower DC numbers and more often a stable plaque morphology were detected in statin-treated patients (P = 0.02). DC clusters with a strong HLA-DR expression and frequent DC-T cell contacts were located particularly in the rupture-prone plaque regions and at complications. The results of the present study indicate that DC might contribute to plaque destabilization through an activation of T cells.

We present the case of a 36-year-old woman with Noonan syndrome and congenital heart disease in whom extragenital endometriosis caused an extraordinarily large jelly-like paracardiac and abdominal mass. Protrusion through an intercostal space caused a pulsating subcutaneous tumor on the left lateral thoracic wall. The patient never complained of menstruation-related pain. Histology obtained during several prior surgical interventions had been inconclusive. Thus definitive diagnosis was delayed for years. A literature review revealed no known association between Noonan syndrome and endometriosis.

The beneficial effects of statins in atherosclerosis have been partly attributed to their immunomodulating functions. Dendritic cells (DC), which are "professional" antigen-presenting cells, were recently detected in atherosclerotic plaques. It is assumed that DC play a critical role in the immunological processes related to atherosclerosis. Thus, we investigated the effects of statins on maturation and antigen-presenting function of DC. Human monocyte-derived DC were incubated with simvastatin or atorvastatin (1-10microM) for different periods (1-48h), and were subsequently stimulated with a cytokine cocktail (1.25ng/ml TNF-alpha, 1ng/ml Il-1beta, and 0.5microg/ml prostaglandin E(2)) to induce maturation. In contrast to untreated DC, statin-preincubated DC exhibited an immature phenotype and a significantly lower expression of the maturation-associated markers CD83, CD40, CD86, HLA-DR, and CCR7. The inhibitory statin effect was completely reversed by mevalonate or geranylgeranyl pyrophosphate. In addition, preincubation with statins significantly reduced the ability of cytokine-stimulated DC to induce T cell proliferation. In the present study, we have shown that statins inhibit the maturation and antigen-presenting function of human myeloid dendritic cells, thus maybe contributing to their beneficial effects in atherosclerosis. Therefore, the use of statins as immunomodulators might also provide a new therapeutic approach to other immunological disorders.

Background: The use of internal thoracic arteries is an established method for treating coronary artery disease because of their excellent long-term patency rates. However, these results mainly referred to the left internal thoracic artery (LITA) grafted to the left anterior descending coronary artery (LAD). The aim of this study was to compare the patency rate of the LITA after its placement to the diagonal branch., Methods: A total of 302 patients (median age 65 years) with previous arterial revascularization were retrospectively enrolled in the study. We compared LITA grafts to the LAD with those to the diagonal branch and with sequential LITA grafts to both vessels with respect to the patency rate over a median follow-up of 39 months after prior operation. Angiography was performed for recurrent angina., Results: The average occlusion/stenosis rate of saphenous vein and LITA grafts were 43.1% and 14.1%, respectively (p < 0.0001). Of the 302 patients, 248 had received a single LITA graft to the LAD; 21 patients, a single LITA graft to the diagonal branch; and 33 patients, a sequential LITA graft to both vessels. Thirty-three LITA grafts to the LAD (13.3%), three LITA grafts to the diagonal branch (14.3%), and six sequential LITA grafts to the LAD and the diagonal branch (18.2%) were occluded or stenosed more than 50%, respectively (p = 0.68). Seventy-nine percent of LITA graft stenoses were located at the peripheral anastomosis., Conclusions: Patency of single LITA grafts to the diagonal branch or sequential LITA grafts to the LAD and diagonal branch were comparable to single LITA grafts to the LAD. Most stenoses of LITA grafts were located at peripheral anastomoses.

Objectives: The hypothesis was tested that CD40-CD154 interaction is involved in the induction of cyclooxygenase-2 and the release of prostanoids in human endothelial cells., Methods and Results: In a coculture model of human endothelial cells and a transfected CD154 positive cell line, engagement of CD40 on endothelial cells dramatically increased the synthesis of prostacyclin, prostaglandin E(2) and thromboxane A(2). This upregulation was mediated through an induction of cyclooxygenase-2 (Cox-2), as it was blocked by Cox-2-selective inhibitors. Western blot analysis demonstrated that Cox-2 protein was markedly increased in endothelial cells following CD40 engagement, an effect that was inhibited by pretreatment of cells with an anti-CD154 antibody., Conclusion: The data indicate that signaling via CD40 constitutes a major pathway in human endothelial cells for the induction of Cox-2 and release of prostanoids. The CD40-Cox-2 axis thus may represent an important pathway for initiating or maintaining an inflammatory process at the vessel wall.

Aortic dissection is a life-threatening cardiovascular emergency requiring immediate diagnosis and treatment. It is mainly associated with hypertension and the Marfan syndrome. Diagnosis has been revolutionized by the use of transesophageal echocardiography (TEE), which allows for rapid and safe assessment of this condition. Echocardiographic hallmarks of aortic dissection ar the presence of a dissection membrane separating a true from a false lumen, rupture sites in the membrane with to-and-from flow, aortic regurgitation, and pericardial effusion. Dissection of the ascending aorta, which has an extremely high mortality and necessitates emergency surgery, is diagnosed quickly and accurately by TEE.