On the influence of respiratory motion in radial tissue phase mapping cardiac MRI.

PURPOSE: To investigate the impact of respiratory motion on radial tissue phase mapping (TPM) measurements, and to improve image quality and scan efficiency without compromising velocity fidelity by increasing the respiratory acceptance window with and without motion correction. MATERIALS AND METHODS: A radial golden angle TPM sequence was measured in 10 healthy volunteers in three short axis slices at 3T. Ungated ( CFREE), self-gated with a single acceptance window ( CREF), motion-corrected averaging using all ( CMCall), or selected ( CMC) data reconstructions were compared by means of various image quality measures and resulting velocities. RESULTS: Using all data ( CFREE) resulted in significantly higher perceived signal-to-noise ratio (SNR) (P < 0.001), but significantly reduced sharpness (P < 0.001) and contrast (P = 0.02), when compared to CREF. Coefficient of variation (CV) and perceived sharpness were not significantly different (P > 0.05). With motion-correction, perceived sharpness could be significantly improved ( CMC: P = 0.002; CMCall: P = 0.002) in comparison to CFREE. Velocity peaks of CFREE were significantly reduced compared to CREF (all peaks: P < 0.001; except the longitudinal "E" peak: P = 0.03). The peak velocities in CMC and CMCall were not significantly different from CREF (all peaks: P > 0.08; except longitudinal "E"/"A" peaks: P > 0.01). CONCLUSION: Free-breathing reconstruction results in good perceived image sharpness and velocity information with slightly, but significantly, reduced peak velocities. For achieving velocities and image quality comparable to data from a single acceptance window, but higher gating efficiency, selected motion-corrected TPM (CMC) can be applied. J. Magn. Reson. Imaging 2016;44:1218-1228.

CMR reveals myocardial damage from cardiotoxic oncologic therapies in breast cancer patients.

BACKGROUND: Breast cancer is a common and increasingly treatable disease. However, survivors have a significantly elevated risk of cardiac events afterwards. This study aimed to characterise cardiac changes during cardiotoxic cancer therapy using cardiovascular magnetic resonance (CMR) imaging. METHODS: This study involved 34 patients with histologically proven breast cancer and planned cardiotoxic therapy. All patients underwent CMR before starting therapy, and 6 and 12 months thereafter. The CMR protocol included volumetric and functional analyses, parametric mapping, and deformation analysis using feature tracking. As the control group, 10 healthy female volunteers were scanned using the same protocol. RESULTS: With therapy, there was a significant reduction of left ventricular and right ventricular ejection fractions (both p < 0.05) without reaching pathologic values. Left ventricular radial (p = 0.008), circumferential (p = 0.010), and longitudinal strain (p = 0.036) were also reduced at follow-up. In the parametric mapping, there was a significant increase in native T1 time (start: 1037 ± 41 ms vs. 6 months: 1068 ± 51 ms vs. 12 months: 1017 ± 57 ms, p < 0.001) and T2 time (start: 55 ± 4 ms vs. 6 months: 59 ± 3 ms vs. 12 months: 57 ± 3 ms, p = 0.001), with unchanged extracellular volume and relative late gadolinium enhancement. Twelve months after cancer diagnosis, the breast cancer patients exhibited significant impairments in left ventricular global radial (p = 0.001), circumferential (p = 0.001), and longitudinal strain (p = 0.002) and T2 time (p = 0.008) compared to the healthy controls. DISCUSSION: Breast cancer patients receiving cardiotoxic chemotherapy show persistent deterioration in left ventricular strain values. This is accompanied by inflammatory changes in non-invasive tissue characterisation. Larger studies with longer follow-up periods are needed to identify patients at risk and establish preventive and therapeutic approaches.

C-peptide promotes lesion development in a mouse model of arteriosclerosis.

Patients with insulin resistance and early type 2 diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. Typically, these patients show elevated serum levels of the proinsulin cleavage product C-peptide and immunohistochemical data from our group revealed C-peptide deposition in early lesions of these individuals. Moreover, in vitro studies suggest that C-peptide could promote atherogenesis. This study examined whether C-peptide promotes vascular inflammation and lesion development in a mouse model of arteriosclerosis. ApoE-deficient mice on a high fat diet were treated with C-peptide or control injections for 12 weeks and the effect on lesion size and plaque composition was analysed. C-peptide treatment significantly increased C-peptide blood levels by 4.8-fold without having an effect on glucose or insulin levels, nor on the lipid profile. In these mice, C-peptide deposition in atherosclerotic plaques was significantly increased compared with controls. Moreover, lesions of C-peptide-treated mice contained significantly more macrophages (1.6 ± 0.3% versus 0.7 ± 0.2% positive area; P < 0.01) and more vascular smooth muscle cells (4.8 ± 0.6% versus 2.4 ± 0.3% positive area; P < 0.01). Finally, lipid deposition measured by Oil-red-O staining in the aortic arch was significantly higher in the C-peptide group compared with controls. Our results demonstrate that elevated C-peptide levels promote inflammatory cell infiltration and lesion development in ApoE-deficient mice without having metabolic effects. These data obtained in a mouse model of arteriosclerosis support the hypothesis that C-peptide may have an active role in atherogenesis in patients with diabetes and insulin resistance.

Glucagon-like peptide-1(1-37) inhibits chemokine-induced migration of human CD4-positive lymphocytes.

The present study examined the effect of GLP-1(1-37) on chemokine-induced CD4-positive lymphocyte migration as an early and critical step in atherogenesis. Pretreatment with GLP-1(1-37) reduced the SDF-induced migration of isolated human CD4-positive lymphocytes in a concentration-dependent manner. Similar effects were seen when RANTES was used as a chemokine. GLP-1(1-37)'s effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity. Downstream, GLP-1(1-37) inhibited SDF-induced phosphorylation of MLC and cofilin and limited f-actin formation as well as ICAM3 translocation. Furthermore, exendin-4 inhibited SDF-induced migration of CD4-positive lymphocytes similarly to GLP-1(1-37), and transfection of these cells with GLP-1 receptor siRNA abolished GLP-1(1-37)'s action on chemokine-induced ICAM3 translocation, suggesting an effect mediated via the GLP-1 receptor. Thus, GLP-1(1-37) inhibits chemokine-induced CD4-positive lymphocyte migration by inhibition of the PI3-kinase pathway and via the GLP-1 receptor. This effect provides a potential novel mechanism for how GLP-1(1-37) may modulate vascular disease.

Direct inhibitory effects of Ganciclovir on ICAM-1 expression and proliferation in human coronary vascular cells (SI/MPL-ratio: >1).

BACKGROUND: Treatment of the human cytomegalovirus (HCMV) infection with ganciclovir has beneficial indirect effects on the complex interactions of HCMV with restenosis, atherosclerosis, and transplant vascular sclerosis. The current study reports on direct effects of ganciclovir on expression of ICAM-1 and cell proliferation, key events of coronary atherosclerosis/restenosis. A potential clinical relevance of the data will be evaluated with the help of SI/MPL-ratio's. MATERIAL/METHODS: Definition of the SI/MPL-ratio: relation between significant inhibitory effects in vitro/ex vivo and the maximal plasma level after systemic administration in vivo (ganciclovir: 9 µg/ml). Part I of the study investigated in cytoflow studies the effect of ganciclovir (0.05-5000 µg/mL) on TNF-a induced expression of intercellular adhesion molecule 1 (ICAM-1) in endothelial cells derived from umbilical veins (HUVEC), human coronary endothelial cells (HCAEC), and human coronary smooth muscle cells (HCMSMC). Part II of the study analysed the effect of ganciclovir (0.05-5000 µg/mL) on cell proliferation (HUVEC, HCAEC, and HCMSMC). In part III cytotoxic effects of ganciclovir (0.05-5000 µg/mL) were studied (HUVEC, HCAEC, and HCMSMC). RESULTS: Ganciclovir caused slight but significant inhibitory effects on expression of ICAM-1 in HUVEC, HCAEC, and HCMSMC. In all three cell types studied strong dose depending significant antiproliferative effects of ganciclovir were detected. Partially, the antiproliferative effects of ganciclovir were caused by cytotoxic effects. CONCLUSIONS: SI/MPL-ratio's >1 in HCAEC and HCMSMC indicate that the inhibitory effects of gancliclovir on ICAM-1-expression and cell proliferation may only be expected in vivo following local high dose administration e.g. in drug eluting stents (DES).

Impact of percutaneous device implantation for closure of patent foramen ovale on valve insufficiencies.

BACKGROUND: In patients with percutaneous device implantation for closure of patent foramen ovale (PFO), a 10% incidence of new or worsened aortic regurgitation within 12 months has been reported with echocardiography. Cardiac magnetic resonance imaging is a powerful noninvasive tool to quantify volume and fraction of valve insufficiencies. We studied the acute and long-term impact of percutaneous device implantation for PFO closure on valve insufficiencies in cardiac magnetic resonance imaging. METHODS AND RESULTS: Sequential cardiac magnetic resonance imaging studies were performed in 102 patients with cryptogenic ischemic events. Cardiac magnetic resonance imaging was performed before PFO closure, the day after device implantation, and at 12 months of follow-up. There was no difference in volumetric and hemodynamic parameters before PFO closure compared with 12 months of follow-up. With a cutoff for relevant regurgitation fraction of 5%, there were no statistically significant differences in regurgitation fraction of the semilunar and atrioventricular valves. The median fraction of aortic valve insufficiency was 3.9% (interquartile range [IQR] 2.0% to 5.1%) before PFO closure, 5.4% (IQR 4.1% to 5.9%) after device implantation, and 4.3% (IQR 3.3% to 6.0%) at 12 months of follow-up. The size and type of the occluder had no impact on aortic valve insufficiency. Median regurgitation fraction for the pulmonary valve was 3.6% (IQR 2.4% to 6.7%) before intervention, 7.3% (IQR 5.1% to 8.2%) after occluder implantation and 5.8% (IQR 4.8% to 7.4%) at 12 months of follow-up. Values for the mitral valve were 3.1% (IQR 1.4% to 6.0%), 5.5% (IQR 3.5% to 7.3%), and 3.8% (IQR 1.5% to 7.9%) and for the tricuspid valve were 5.4% (IQR 0.1% to 8.8%), 5.8% (IQR 1.4% to 9.2%), and 6.0% (IQR 1.1% to 8.4%), respectively. CONCLUSIONS: Percutaneous PFO closure with device implantation has no impact on valve insufficiencies as determined by cardiac magnetic resonance imaging.

LXR activation inhibits chemokine-induced CD4-positive lymphocyte migration.

Migration of CD4-positive lymphocytes into the vessel wall is a critical step in atherogenesis. Recent data suggest that CD4-positive lymphocytes express the nuclear transcription factors Liver-X-Receptor (LXR) alpha and beta with an effect of LXR activators on TH1-cytokine release from these cells. However, the role of LXR in lymphocyte migration remains currently unexplored. Therefore, the present study investigated whether LXR activation might modulate chemokine-induced migration of these cells. Stimulation of CD4-positive lymphocytes with SDF-1 leads to a 2.5 +/- 0.8-fold increase in cell migration (P < 0.05; n = 12). Pretreatment of cells with the LXR activator T0901317 reduces this effect in a concentration-dependent manner to a maximal 0.9 +/- 0.4-fold induction at 1 micromol/L T0901317 (P < 0.05 compared to SDF-1-treated cells; n = 12). Similar results were obtained with the LXR activator GW3965. The effect of LXR activators on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity as determined by PI-3 kinase activity assays. Downstream, T0901317 inhibited activation of the small GTPase Rac and phosphorylation of the myosin light chain (MLC). Moreover, LXR activator treatment reduced f-actin formation as well as ICAM3 translocation to the uropod of the cell, thus interfering with two important steps in T cell migration. Transfection of CD4-positive lymphocytes with LXRalpha/beta siRNA abolished T0901317 inhibitory effect on MLC phosphorylation and ICAM3 translocation. LXR activation by T0901317 or GW3965 inhibits chemokine-induced migration of CD4-positive lymphocytes. Given the crucial importance of chemokine-induced T cell migration in early atherogenesis, LXR activators may be promising tools to modulate this effect.

Interferon beta-1b therapy in chronic viral dilated cardiomyopathy--is there a role for specific therapy?

BACKGROUND: Myocardial biopsy can be used for the detection of viral genome in dilated cardiomyopathy (DCM). Pilot studies have previously reported beneficial effects on clinical outcome and safety of an antiviral therapy using interferon beta-1b in chronic viral DCM. METHODS AND RESULTS: Myocardial biopsies were taken from patients with DCM. Using polymerase chain reaction and Southern Blot analysis, viral genome could be detected in 49% of patients. In 42 patients with viral infection, off-label use with interferon beta-1b was initiated. A further 68 patients formed the control group. The outcome was evaluated after follow-up with echocardiography, exercise electrocardiogram, and New York Heart Association class. A total of 81 men and 29 women with a median left ventricular ejection fraction of 34% were included. The follow-up period was 36 months. In 33 (79%) patients with interferon beta-1b treatment, minor adverse reactions occurred, but no major adverse events were reported. No significant benefit for interferon beta-1b treatment on clinical outcome could be detected during follow-up. CONCLUSIONS: Off-label use with interferon beta-1b in patients with viral DCM is feasible and safe under routine clinical practice. Concerning the herein evaluated clinical outcome parameters, promising results from pilot studies could not be confirmed. High prevalence of parvovirus B19 (92%) might influence the results.

Pulsed perfusion in a venous human organ culture model with a Windkessel function (pulsed perfusion venous HOC-model).

BACKGROUND: The effectiveness of human saphenous vein grafting is limited by hyperplasia of the vessel wall. The current paper reports on a pulsed perfused venous human organ culture model (pp-venous HOC-model) with a Windkessel function. MATERIAL/METHODS: Saphenous vein grafts from 21 patients undergoing coronary bypass grafting were cultured either in venous or arterial hemodynamic conditions. Up to four vein segments were fixed in parallel connection and attached to a closed loop pulsed perfusion system consisting of large and small elastic tubes, mimicking the Windkessel function. RESULTS: First, after exposure to arterial blood pressure first signs of reactive cell proliferation (n.s.) were detected at day 4. Second, media thickness of the venous segments in the pulsed pressure group was decreased at day 4 (n.s.) and day 7 (n.s.). Third, staining against smooth muscle alpha actin and v. Willebrand factor was always positive at day 1, 4, and 7. CONCLUSIONS: Pulsed perfusion in a human venous organ culture model with a Windkessel function is an approach to better understand the events taking place during early arterial-vein grafting. First signs of reactive cell proliferation were detected at day four. A period of seven days as described in the current model is probably too short to detect reactive cell proliferation and medial thickening. If the device might be activated for a longer period of time, it should be a suitable model to characterize the effects of intra- and extravascular drug administration as treatment strategies of vein graft disease.

Electrocardiographic and cardiac magnetic resonance imaging parameters as predictors of a worse outcome in patients with idiopathic dilated cardiomyopathy.

AIMS: Clinical parameters are weak predictors of outcome in patients with idiopathic dilated cardiomyopathy (IDC). We assessed the prognostic value of cardiac magnetic resonance (CMR) parameters in addition to conventional clinical and electrocardiographic characteristics. METHODS AND RESULTS: One hundred and forty-one IDC patients were studied. QRS and QTc intervals were measured in 12-lead surface electrocardiogram. Patients were followed for median 1339 days, including 483 patient-years. The primary endpoint-cardiac death or sudden death-occurred in 25 (18%) patients, including 16 patients with cardiac death, 3 patients with sudden cardiac death (SCD), and 6 patients with ICD shock. Late gadolinium enhancement (LGE) was detected in 36 patients (26%). Kaplan-Meier survival analysis displayed QRS >110 ms (P = 0.010), the presence of LGE (P = 0.037), and diabetes mellitus (P < 0.001) as significant parameters for a worse outcome. Multivariable analysis revealed cardiac index (P < 0.001), right ventricular end-diastolic volume index (RVEDVI) (P = 0.006) derived from CMR imaging, the presence of diabetes mellitus (P = 0.006), and QRS >110 ms (P = 0.045) as significant predictors for the primary endpoint. CONCLUSION: Cardiac index and RVEDVI derived from CMR imaging in addition to QRS duration >110 ms from conventional surface ECG and diabetes mellitus provide prognostic impact for cardiac death and SCD in patients with IDC.

Myocardial inflammation and non-ischaemic heart failure: is there a role for C-reactive protein?

Whereas C-reactive protein (CRP) is acknowledged as a cardiovascular risk marker, there is ongoing discussion about its role as a risk factor. Previous studies focused on the effects of CRP on ischaemic heart failure and atherosclerosis. In this study we investigated distribution of CRP, the Terminal Complement Complex (C5b-9) and macrophages (CD68) in the myocardium of patients suffering from non-ischaemic heart failure and their implication on clinical parameters. Endomyocardial biopsies were taken from 66 patients suffering from dilated cardiomyopathy (DCM). Biopsies were analysed by immunohistochemical and immunofluorescent staining for CRP, C5b-9 and CD68. Viral DNA/RNA for adenovirus, enterovirus, parvovirus B19 and human herpes virus 6 was detected by PCR and Southern blot analysis. Myocardial biopsy findings were correlated with plasma level of hsCRP and NT-proBNP as well as echocardiography, exercise test and NYHA class. In 18 (27%) patients, a positive staining for CRP and in 57 (86%) patients a positive staining for C5b-9 was detected. All patients showed myocardial infiltration with macrophages with an average of 39 cells/mm(2). CRP, C5b-9 and CD68 co-localised within the myocardium. No correlation was observed for inflammatory proteins and plasma level of hsCRP, NT-proBNP and clinical parameters. CRP is frequently present in the myocardium of patients suffering from DCM and co-localises with C5b-9 and macrophages. CRP may contribute to myocardial damage in DCM via activation of the complement system and chemotaxis of macrophages.

Detection of bone metastases in patients with lung cancer: 99mTc-MDP planar bone scintigraphy, 18F-fluoride PET or 18F-FDG PET/CT.

PURPOSE: The aim of the study was to compare the diagnostic accuracy of (18)F-fluorodeoxyglucose (FDG) PET/CT versus standard planar bone scintigraphy (BS) and (18)F-labelled NaF ((18)F) PET for the detection of bone metastases (BM) in non-small cell lung cancer (NSCLC). METHODS: (18)F-FDG PET/CT was performed in 126 patients with NSCLC. Within 7 days BS (n = 58) or (18)F PET (n = 68) was performed. (18)F-FDG PET/CT, BS and (18)F PET were evaluated by two experienced readers. Lesions were graded on a scale from 1 (definite BM) to 5 (degenerative lesion), and equivocal lesions were determined as indifferent (grade 3). RESULTS: A total of 92 patients showed degenerative lesions (grade 4/5) on PET/CT, BS or (18)F PET. In 34 patients (27%) BM lesions were diagnosed (grades 1 and 2). In 13 of 18 patients BM were concordantly diagnosed with PET/CT and (18)F PET. PET/CT showed more BM compared to (18)F PET (53 vs 40). In one patient one osteolytic BM was false-negative on (18)F PET. However, (18)F PET identified four patients with BM compared to negative findings on PET/CT. Of 16 patients, 11 had concordant findings of BM on PET/CT and BS. In three patients BS was false-negative and in two patients BM were diagnosed as indifferent. CONCLUSION: Integrated (18)F-FDG PET/CT is superior to BS in the detection of osteolytic BM in NSCLC. Thus, PET/CT may obviate the need to perform additional BS or (18)F PET in the staging of NSCLC, which significantly reduces costs.

Volume-targeted and whole-heart coronary magnetic resonance angiography using an intravascular contrast agent.

PURPOSE: To compare volume-targeted and whole-heart coronary magnetic resonance angiography (MRA) after the administration of an intravascular contrast agent. MATERIALS AND METHODS: Six healthy adult subjects underwent a navigator-gated and -corrected (NAV) free breathing volume-targeted cardiac-triggered inversion recovery (IR) 3D steady-state free precession (SSFP) coronary MRA sequence (t-CMRA) (spatial resolution = 1 x 1 x 3 mm(3)) and high spatial resolution IR 3D SSFP whole-heart coronary MRA (WH-CMRA) (spatial resolution = 1 x 1 x 2 mm(3)) after the administration of an intravascular contrast agent B-22956. Subjective and objective image quality parameters including maximal visible vessel length, vessel sharpness, and visibility of coronary side branches were evaluated for both t-CMRA and WH-CMRA. RESULTS: No significant differences (P = NS) in image quality were observed between contrast-enhanced t-CMRA and WH-CMRA. However, using an intravascular contrast agent, significantly longer vessel segments were measured on WH-CMRA vs. t-CMRA (right coronary artery [RCA] 13.5 +/- 0.7 cm vs. 12.5 +/- 0.2 cm; P < 0.05; and left circumflex coronary artery [LCX] 11.9 +/- 2.2 cm vs. 6.9 +/- 2.4 cm; P < 0.05). Significantly more side branches (13.3 +/- 1.2 vs. 8.7 +/- 1.2; P < 0.05) were visible for the left anterior descending coronary artery (LAD) on WH-CMRA vs. t-CMRA. Scanning time and navigator efficiency were similar for both techniques (t-CMRA: 6.05 min; 49% vs. WH-CMRA: 5.51 min; 54%, both P = NS). CONCLUSION: Both WH-CMRA and t-CMRA using SSFP are useful techniques for coronary MRA after the injection of an intravascular blood-pool agent. However, the vessel conspicuity for high spatial resolution WH-CMRA is not inferior to t-CMRA, while visible vessel length and the number of visible smaller-diameter vessels and side-branches are improved.

T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance.

BACKGROUND: Adipose tissue inflammation may play a critical role in the pathogenesis of insulin resistance (IR). The present study examined the role of lymphocytes in adipose tissue inflammation and IR. METHODS AND RESULTS: In a mouse model of obesity-mediated IR, high-fat diet (HFD) induced IR already after 5 weeks, which was associated with a marked T-lymphocyte infiltration in visceral adipose tissue. In contrast, recruitment of macrophages was delayed with an increase of MAC3-positive staining and F4/80 mRNA expression after 10 weeks of HFD, suggesting a dissociation of macrophage invasion into adipose tissue and IR initiation. In patients with type 2 diabetes, lymphocyte content in adipose tissue biopsies significantly correlated with waist circumference, a marker of IR. Immunohistochemical staining of human adipose tissue revealed the presence of mainly CD4-positive lymphocytes as well as macrophage infiltration. Most macrophages were HLA-DR-positive, reflecting activation through IFNgamma, a cytokine released from CD4-positive lymphocytes. CONCLUSIONS: Proinflammatory T-lymphocytes are present in visceral adipose tissue and may contribute to local inflammatory cell activation before the appearance of macrophages, suggesting that these cells could play an important role in the initiation and perpetuation of adipose tissue inflammation as well as the development of IR.

Dual stack black blood carotid artery CMR at 3T: application to wall thickness visualization.

BACKGROUND: The increasing understanding of atherosclerosis as an important risk factor for the development of acute ischemic events like ischemic stroke has stimulated increasing interest in non-invasive assessment of the structure, composition and burden of plaque depositions in the carotid artery wall. Vessel wall imaging by means of cardiovascular magnetic resonance (CMR) is conventionally done by 2D dual inversion recovery (DIR) techniques, which often fail in covering large volumes of interest as required in plaque burden assessment. Although the technique has been extended to 2D multislice imaging, its straight extension to 3D protocols is still limited by the prolonged acquisition times and incomplete blood suppression. A novel approach for rapid overview imaging of large sections of the carotid artery wall at isotropic spatial resolutions is presented, which omits excitation of the epiglottis. By the interleaved acquisition of two 3D stacks with the proposed motion sensitized segmented steady-state black-blood gradient echo technique (MSDS) the coverage of the carotid artery trees on both sides in reasonable scan times is enabled. RESULTS: 10 patients were investigated with the proposed technique and compared to conventional transversal DIR turbo spin and gradient echo approaches centered at the height of the carotid bifurcation. In all MSDS experiments sufficient black-blood contrast could be obtained over the entire covered volumes. The contrast to noise ratio between vessel and suppressed blood was improved by 73% applying the motion sensitizing technique. In all patients the suspicious areas of vessel wall thickening could be clearly identified and validated by the conventional local imaging approach. The average assessable vessel wall segment length was evaluated to be 18 cm. While in 50% of the cases motion artifacts could be appreciated in the conventional images, none were detected for the MSDS technique. CONCLUSION: The proposed technique enables the time efficient coverage of large areas of the carotid arteries without compromising wall-lumen CNR to get an overview about detrimental alterations of the vessel wall. Thickening of the vessel wall can be identified and the suspicious segments can be targeted for subsequent high-resolution CMR. The exclusion of the epiglottis may further facilitate reduction of swallowing induced motion artifacts.

Current variables, definitions and endpoints of the European cardiovascular magnetic resonance registry.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly used in daily clinical practice. However, little is known about its clinical utility such as image quality, safety and impact on patient management. In addition, there is limited information about the potential of CMR to acquire prognostic information. METHODS: The European Cardiovascular Magnetic Resonance Registry (EuroCMR Registry) will consist of two parts: 1) Multicenter registry with consecutive enrolment of patients scanned in all participating European CMR centres using web based online case record forms. 2) Prospective clinical follow up of patients with suspected coronary artery disease (CAD) and hypertrophic cardiomyopathy (HCM) every 12 months after enrolment to assess prognostic data. CONCLUSION: The EuroCMR Registry offers an opportunity to provide information about the clinical utility of routine CMR in a large number of cases and a diverse population. Furthermore it has the potential to gather information about the prognostic value of CMR in specific patient populations.

Interleukin-1beta stimulates acute phase response and C-reactive protein synthesis by inducing an NFkappaB- and C/EBPbeta-dependent autocrine interleukin-6 loop.

Cytokines interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) are involved in acute phase response (APR). C-reactive protein (CRP), the prototype acute phase protein, may represent an important component in the pathogenesis of arteriosclerosis and may also be a target for drug development. Inhibition of CRP synthesis is one potential strategy. Understanding CRP synthesis, however, is a prerequirement for the development of CRP-inhibitors. From studies in hepatoma cell lines, IL-1beta and IL-6 were considered as equal inductors of APR and CRP. We investigated IL-1beta- and IL-6-effects on primary human hepatocytes (PHH) and Hep3B-cells. Kupffer cell contamination in PHH preparations was <3%. In PHH, several APP like CRP, haptoglobin (HP), lipopolysaccharide-binding protein (LBP) or hepcidin (HAMP) were regulated similarly by IL-1beta and IL-6, though signal transduction pathways of these cytokines are different. In Hep3B-cells, APP were regulated exclusively by IL-6. IL-1beta induced IL-6-synthesis in PHH but not in Hep3B-cells. C/EBPbeta-overexpression in Hep3B-cells reconstituted IL-1beta-mediated IL-6/CRP inducibility. In PHH and in C/EBPbeta-overexpressing Hep3B-cells, neutralizing anti-IL-6-antibodies blocked IL-1beta-mediated APR. Inhibition of protein synthesis and NFkappaB-signalling blocked IL-1beta- but not IL-6-mediated CRP-expression in PHH, whereas Janus-Kinase-1-inhibition blocked IL-1beta- and IL-6-mediated APR. IL-1beta induces APR in PHH via an NFkappaB- and C/EBPbeta-dependent autocrine IL-6-loop. These findings partly reconcile the understanding of APR and may help to design a transcriptional suppressor of CRP for the treatment of cardiovascular disease.

Efficacy and safety of combination chemotherapy with mitomycin and vinorelbine for the treatment of advanced non-small cell lung cancer.

BACKGROUND: Aim of this study was to evaluate efficacy, toxicity and tolerability of chemotherapy with a combination of mitomycin and vinorelbine (M/V) in patients with advanced non-small cell lung cancer (NSCLC). METHODS: We enrolled 110 patients (median age 67 years) with locally advanced or metastatic NSCLC, who had no prior chemotherapy or progressive disease after at least one prior chemotherapy regimen. 45 patients (41%) were > or =70 years old. All patients received vinorelbine 25mg/m(2) (d1,8) and mitomycin 8mg/m(2) (d1) every 3-4 weeks. Restaging was performed by CT-scan after every two courses M/V according to RECIST criteria. RESULTS: M/V was well tolerated, even in patients with a poor performance status or > or =70 years Median progression free survival was 4.4 months. Median overall survival was 9.0 months with a 1-year survival rate of 39%. Partial response was observed in 15% and stable disease in 51% of patients. Both hematological and non-hematological toxicities were generally mild. CTC grade 3 toxicities observed included neutropenia in 3%, anemia in 3%, thrombocytopenia in 1% and suspected pneumonitis in 2% of patients. Except neutropenia in 2% and acute dyspnea in 1%, there were no other grade 4 toxicities and no treatment associated casualties. There was no relevant difference in outcome or toxicity between patients > or =70 and <70 years. CONCLUSIONS: M/V seems to be a well-tolerated and effective chemotherapy regimen with low toxicity in patients with advanced NSCLC. It seems to be an interesting option even for patients > or =70 years or with a reduced performance status.

C-Peptide induces vascular smooth muscle cell proliferation: involvement of SRC-kinase, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinase 1/2.

Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest a potential causal role of C-peptide in atherogenesis by promoting monocyte and T-lymphocyte recruitment into the vessel wall. The present study examined the effect of C-peptide on vascular smooth muscle cells (VSMCs) proliferation and evaluated intracellular signaling pathways involved. In early arteriosclerotic lesions of diabetic subjects, C-peptide colocalized with VSMCs in the media. In vitro, stimulation of human or rat VSMCs with C-peptide induced cell proliferation in a concentration-dependent manner with a maximal 2.6+/-0.8-fold induction at 10 nmol/L human C-peptide (P<0.05 compared with unstimulated cells; n=9) and a 1.8+/-0.2-fold induction at 0.5 nmol/L rat C-peptide (P<0.05 compared with unstimulated cells; n=7), respectively, as shown by [H3]-thymidin incorporation. The proliferative effect of C-peptide on VSMCs was inhibited by Src short interference RNA transfection, PP2, an inhibitor of Src-kinase, LY294002, an inhibitor of PI-3 kinase, and the ERK1/2 inhibitor PD98059. Moreover, C-peptide induced phosphorylation of Src, as well as activation of PI-3 kinase and ERK1/2, suggesting that these signaling molecules are involved in C-peptide-induced VSMC proliferation. Finally, C-peptide induced cyclin D1 expression as well as phosphorylation of Rb in VSMCs. Our results demonstrate that C-peptide induces VSMC proliferation through activation of Src- and PI-3 kinase as well as ERK1/2. These data suggest a novel mechanism how C-peptide may contribute to plaque development and restenosis formation in patients with insulin resistance and early type 2 diabetes mellitus.

Statins stimulate RGS-regulated ERK 1/2 activation in human calcified and stenotic aortic valves.

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.