Establishment of Submillisievert Abdominal CT Protocols With an In Vivo Swine Model and an Anthropomorphic Phantom.

OBJECTIVE. The purpose of this study was to evaluate radiation dose, effective dose, and image quality of different low-dose abdominal CT protocols in a swine model and an anthropomorphic phantom using a third-generation dual-source CT scanner. MATERIALS AND METHODS. Four different abdominal low-dose protocols were established using a swine model and were regarded as diagnostic by two experienced radiologists on the basis of clarity and sharpness of anatomic structures. General image conditions such as noise and spatial resolution as well as diagnostic acceptability and artifacts were evaluated. Objective image quality was determined by measuring signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in different anatomic locations. To evaluate the effective dose, thermoluminescent dosimeter (TLD) measurements were repeated in a phantom. RESULTS. Diagnostic acceptability, spatial resolution, and noise were rated as optimal in all four protocols, which were therefore regarded as diagnostic. We found no statistically significant differences in SNR or CNR for the four low-dose protocols. Effective dose determined from the phantom measurements did not exceed 0.33 mSv for any protocol. Overall evaluation of the 86 TLD measurements for the four low-dose protocols revealed a statistically significant difference in radiation dose (p < 0.0001), showing that the dual-source protocol had the lowest radiation dose. CONCLUSION. Submillisievert abdominal CT is feasible with good image quality and doses even lower than conventional abdominal radiography. Our dual-source protocol achieved the lowest dose, which further shows that dual-source imaging is possible in the submillisievert range without additional dose.

Three-dimensional ultrashort echo time MRI and Short T2 images generated from subtraction for determination of tumor burden in lung cancer: Preclinical investigation in transgenic mice.

PURPOSE: To investigate the potential of 3D ultrashort echo time MRI and short T2 images generated by subtraction for determination of total tumor burden in lung cancer. METHODS: As an animal model of spontaneously developing non-small cell lung cancer, the K-rasLA1 transgenic mouse was used. Three-dimensional MR imaging was performed with radial k-space acquisition and echo times of 20 µs and 1 ms. For investigation of the short T2 component in the recorded signal, subtraction images were generated from these data sets and used for consensus identification of tumors. Next, manual segmentation was performed on all MR images by two independent investigators. MRI data were compared with the results from histologic investigations and among the investigators. RESULTS: Tumor number and total tumor burden from imaging experiments correlated strongly with the results of histologic investigations. Intra- and interuser comparison showed highest correlations between the individual measurements for ultra-short TE MRI. CONCLUSIONS: Three-dimensional MRI protocols facilitate accurate tumor identification in mice harboring lung tumors. Ultrashort TE MRI is the superior imaging strategy when investigating lung tumors of miscellaneous size with 3D MR imaging strategies. Magn Reson Med 79:1052-1060, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Comparison of Metal Artifact Reduction in Dual- and Single-Source CT: A Vertebral Phantom Study.

OBJECTIVE: The objective of this study was to compare the capability of two algorithms for metal artifact reduction and virtual monoenergetic imaging (VME), a metal artifact reduction application for dual-source CT. MATERIALS AND METHODS: A bovine vertebra phantom with 16 artificial osteolyses and two 20 × 4.5 mm stainless steel screws was scanned on two single-source CT scanner and one dual-source CT scanner at a dose identical to the single-source acquisitions. Datasets were reconstructed with a metal artifact reduction algorithm for orthopedic implants (O-MAR, Philips Healthcare), an iterative metal artifact reduction algorithm (iMAR, Siemens Healthineers), and VME. Blinded to the method used for artifact reduction, three independent observers evaluated datasets regarding the extent of metal artifacts using a 4-point scale. Depicted osteolyses were counted and screw diameters measured for each reconstruction. Interobserver variability was evaluated using the Kendall coefficient of concordance for ordinal variables and the intraclass correlation coefficient for continuous data. RESULTS: VME showed the best metal artifact reduction capability among evaluated methods; overall artifacts were rated 1.08 ± 0.29 for VME, 3.33 ± 0.65 for iMAR, and 3.91 ± 0.29 for O-MAR (p < 0.01). VME resulted in better representation of the cortical bone, trabecular structure, and soft tissue compared with the other two algorithms. VME provided the most realistic reconstruction of screw diameter. However, VME missed osteolyses. Good to almost perfect agreement was achieved for nearly all evaluated attributes. CONCLUSION: In our vertebral phantom, VME led to the most detailed representation of the osteosynthesis screw, caused the lowest amount of artifact, and represented the adjacent tissue best. Thus, VME should be considered as an alternative method to evaluate implants when other algorithms fail.

Local low-dose thrombolysis for safe and effective treatment of venous port-catheter thrombosis.

PURPOSE: Retrospective evaluation of local low-dose thrombolysis for treatment of venous port-catheter thrombosis. METHODS: A total of 1,031 patients with dysfunctional port systems underwent port angiography depicting 181 patients with thrombosis around the port-catheter. A total of 165 patients (male 35, female 130; age 57.3 ± 12.9 [20-83] years) underwent thrombolysis by single injection of 3 mg alteplase into the port system. Patients were followed up by clinical and angiographic/radiological port controls the next day and 12.9 ± 17.9 [1-81] months on the basis of regular oncologic staging examinations. RESULTS: Thrombosis occurred 10.1 ± 19.3 [median 2.9] months after port implantation and was clinically suspected by difficult blood aspiration in 146 of 181 (80.7 %) and high resistance to injection fluids in 75 (41.4 %) patients. A predictor for angiographically confirmed port-catheter thrombosis was a combination of both (73, 40.3 % patients) (Fisher's exact test p < 0.0001; positive predictive value 0.8977), or suboptimal (not cavoatrial) port-catheter position (92, 50.8 % patients) (p = 0.0047; positive predictive value 0.8276). The cumulative success rate of thrombolysis was 92.7 % (153 of 165 patients). Initial thrombolysis was effective in 127 (77.0 %) patients. Repeated (up to 6 times) thrombolysis was effective in 26 of 31 patients after second or third thrombolysis. Extensive central venous thrombosis (9 patients) predicted ineffective thrombolysis (p < 0.0001). Primary patency of successfully treated devices was 92.8 % at 1 month and 84.9 % at 3 months. Rethrombosis occurred in 27 patients after 4.4 ± 6.6 (median 1.8) months. Primary rethrombolysis was effective in 22 (81.5 %) patients. Cumulative patency was 100 % at 3 months. CONCLUSIONS: Difficult aspiration combined with high resistance to injection fluids or suboptimal port-catheter position are strong independent predictors for port-catheter thrombosis. Local low-dose thrombolysis or repeat thrombolysis is safe and effective in the absence of large central venous thrombosis.

Percutaneous Re-positioning of Dislocated Port-Catheters in Patients with Dysfunctional Central-Vein Port-Systems.

PURPOSE: Observational analysis of percutaneous repositioning of displaced port-catheters in patients with dysfunctional central-venous port-systems. METHODS: A total of 1061 patients with dysfunctional venous pectoral port-systems were referred for port-angiography. Dislocated port-catheters were identified in 37 (3.5 %) patients (11 males, mean age 58.1 ± 7.2 [range 48-69] years; 26 females, 57.0 ± 13.5 [range 24-75] years) 3.9 ± 6.6 months (range 1 day-26 months) after port-implantation. Percutaneous repositioning in all patients was performed by transfemoral catheter maneuvers, snaring, or wire-assisted long-loop snaring. Primary endpoint was successful repositioning. Safety endpoints included port-damage or procedure-related complications. Follow-up encompassed routine clinical and radiological controls, including chest X-ray or computed tomography for 12.9 ± 17.9 (range 1-81) months. RESULTS: Clinical signs of port-dysfunction due to dislocation of port-catheters included difficult aspiration in 23 (62.2 %), resistance or inability to inject in 17 (46.0 %), and pain during injection in 2 (5.4 %) patients. Primary technical success for repositioning displaced port-catheters was 97.3 % (36/37 patients). In 1 (2.7 %) patient, repositioning failed due to complete embedding of the port-catheter in an extensive chronic jugular vein thrombosis (Paget-von-Schroetter syndrome) that prevented endovascular access to the port-catheter. Redisplacement occurred after initial successful repositioning: immediately in two patients due to a too short port-catheter (two-tailed Fisher's exact-test, p = 0.0101), and in two patients with appropriate catheter-length after 5, resp. 7 months. No procedure-associated complications, e.g., port-catheter disconnection or disruption, occurred. CONCLUSIONS: Repositioning of dysfunctional displaced central-venous port-catheters with appropriate catheter-length is safe and effective. Even challenging conditions, e.g., wall-adherent port-catheter tip or a thrombosed catheter-bearing vein are feasible. Repositioning of too short port-catheters is ineffective.

Significant reduced loss of bone mineral density after four vs. six cycles of R-CHOP: an analysis of the FLYER-trial.

Patients with diffuse large B-cell lymphoma (DLBCL) treated with the R-CHOP regime receive a high cumulative dose of prednisone. We used computer tomography-ascertained Hounsfield units (HU) as a surrogate parameter for bone mineral density (BMD) in three different locations of the L3 vertebral body at baseline and post-treatment. HU were measured in 50 patients with DLBCL of the previously published FLYER-trial which compared four cycles of R-CHOP + 2 × rituximab infusion to six cycles of R-CHOP in young, favorable DLBCL patients. In total, median loss was 26.8 HU in all patients over time. The median HU loss was significantly lower in the four cycles arm (21.3 HU vs. 41.3 HU, p = 0.023). In conclusion, young patients with DLBCL receiving R-CHOP have significant HU/BMD loss under treatment with R-CHOP. Patients receiving four cycles of R-CHOP had less HU/BMD loss than patients receiving six cycles.

Diffusion-weighted MRI improves response assessment after definitive radiotherapy in patients with NSCLC.

BACKGROUND: Computed tomography (CT) is the standard procedure for follow-up of non-small-cell lung cancer (NSCLC) after radiochemotherapy. CT has difficulties differentiating between tumor, atelectasis and radiation induced lung toxicity (RILT). Diffusion-weighted imaging (DWI) may enable a more accurate detection of vital tumor tissue. The aim of this study was to determine the diagnostic value of MRI versus CT in the follow-up of NSCLC. METHODS: Twelve patients with NSCLC stages I-III scheduled for radiochemotherapy were enrolled in this prospective study. CT with i.v. contrast agent and non enhanced MRI were performed before and 3, 6 and 12 months after treatment. Standardized ROIs were used to determine the apparent diffusion weighted coefficient (ADC) within the tumor. Tumor size was assessed by the longest longitudinal diameter (LD) and tumor volume on DWI and CT. RILT was assessed on a 4-point-score in breath-triggered T2-TSE and CT. RESULTS: There was no significant difference regarding LD and tumor volume between MRI and CT (p ≥ 0.6221, respectively p ≥ 0.25). Evaluation of RILT showed a very high correlation between MRI and CT at 3 (r = 0.8750) and 12 months (r = 0.903). Assessment of the ADC values suggested that patients with a good tumor response have higher ADC values than non-responders. CONCLUSIONS: DWI is equivalent to CT for tumor volume determination in patients with NSCLC during follow up. The extent of RILT can be reliably determined by MRI. DWI could become a beneficial method to assess tumor response more accurately. ADC values may be useful as a prognostic marker.

Beyond the d-dimer - Machine-learning assisted pre-test probability evaluation in patients with suspected pulmonary embolism and elevated d-dimers.

INTRODUCTION: Acute pulmonary embolism (PE) is a leading cardiovascular cause of death, resembling a common indication for emergency computed tomography (CT). Nonetheless, in clinical routine most CTs performed for suspicion of PE excluded the suspected diagnosis. As patients with low to intermediate risk for PE are triaged according to the d-dimer, its relatively low specifity and widespread elevation among elderly might be an underlying issue. Aim of this study was to find potential predictors based on initial emergency blood tests in patients with elevated d-dimers and suspected PE to further increase pre-test probability. METHODS: In this retrospective study all patients at the local university hospital's emergency room from 2009 to 2019 with suspected PE, emergency blood testing and CT were included. Cluster analysis was performed to separate groups with distinct laboratory parameter profiles and PE frequencies were compared. Machine learning algorithms were trained on the groups to predict individual PE probability based on emergency laboratory parameters. RESULTS: Overall, PE frequency among the 2045 analyzed patients was 41%. Three clusters with significant differences (p ≤ 0.05) in PE frequency were identified: C1 showed a PE frequency of 43%, C2 40% and C3 33%. Laboratory parameter profiles (e.g. creatinine) differed significantly between clusters (p ≤ 0.0001). Both logistic regression and support-vector machines were able to predict clusters with an accuracy of over 90%. DISCUSSION: Initial blood parameters seem to enable further differentiation of patients with suspected PE and elevated d-dimers to raise pre-test probability of PE. Machine-learning-based prediction models might help to further narrow down CT indications in the future.

Artifacts in Contrast-Enhanced Ultrasound during Follow-up after Endovascular Aortic Repair: Impact on Endoleak Detection in Comparison with Computed Tomography Angiography.

The study described here systematically analyzed how specific artifacts in contrast-enhanced ultrasound (CEUS) can affect the detection of endoleaks during follow-up after endovascular aortic repair (EVAR). Patients undergoing EVAR of atherosclerotic or mycotic abdominal aortic aneurysms using various standard and branched stent-graft material for visceral and iliac preservation were enrolled over 5 y and followed up with computed tomography angiography (CTA) and CEUS simultaneously. CEUS artifacts were frequently identified after EVAR procedures (59% of examinations) and were caused mainly by contrast agent, different prosthesis or embolization material and postinterventional changes in the aneurysm sac. This article describes how to identify important artifacts and how to avoid false-negative or false-positive interpretations of endoleaks. Despite artifacts, CEUS had higher sensitivity for endoleak detection after EVAR than CTA. CEUS was superior to CTA in the identification of late endoleaks type II and in follow-up examinations after embolization procedures, where beam-hardening artifacts limited CTA.

Abdominal imaging dose in radiology and radiotherapy - Phantom point dose measurements, effective dose and secondary cancer risk.

PURPOSE: To compare abdominal imaging dose from 3D imaging in radiology (standard/low-dose/dual-energy CT) and radiotherapy (planning CT, kV cone-beam CT (CBCT)). METHODS: Dose was measured by thermoluminescent dosimeters (TLD's) placed at 86 positions in an anthropomorphic phantom. Point, organ and effective dose were assessed, and secondary cancer risk from imaging was estimated. RESULTS: Overall dose and mean organ dose comparisons yield significantly lower dose for the optimized radiology protocols (dual-source and care kV), with an average dose of 0.34±0.01 mGy and 0.54±0.01 mGy (average ±â€¯standard deviation), respectively. Standard abdominal CT and planning CT involve considerably higher dose (13.58 ±â€¯0.18 mGy and 18.78±0.27 mGy, respectively). The CBCT dose show a dose fall-off near the field edges. On average, dose is reduced as compared with the planning or standard CT (3.79 ±â€¯0.21 mGy for 220° rotation and 7.76 ±â€¯0.37 mGy for 360°), unless the high-quality setting is chosen (20.30 ±â€¯0.96 mGy). The mean organ doses show a similar behavior, which translates to the estimated secondary cancer risk. The modelled risk is in the range between 0.4 cases per million patient years (PY) for the radiological scans dual-energy and care kV, and 300 cases per million PY for the high-quality CBCT setting. CONCLUSIONS: Modern radiotherapy imaging techniques (while much lower in dose than radiotherapy), involve considerably more dose to the patient than modern radiology techniques. Given the frequency of radiotherapy imaging, a further reduction in radiotherapy imaging dose appears to be both desirable and technically feasible.

The Impact of Diffusion-Weighted MRI on the Definition of Gross Tumor Volume in Radiotherapy of Non-Small-Cell Lung Cancer.

OBJECTIVE: The study was designed to evaluate diffusion-weighted magnetic resonance imaging (DWI) vs. PET-CT of the thorax in the determination of gross tumor volume (GTV) in radiotherapy planning of non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Eligible patients with NSCLC who were supposed to receive definitive radio(chemo)therapy were prospectively recruited. For MRI, a respiratory gated T2-weighted sequence in axial orientation and non-gated DWI (b = 0, 800, 1,400 and apparent diffusion coefficient map [ADC]) were acquired on a 1.5 Tesla scanner. Primary tumors were delineated on FDG-PET/CT (stGTV) and DWI images (dwGTV). The definition of stGTV was based on the CT and visually adapted to the FDG-PET component if indicated (e.g., in atelectasis). For DWI, dwGTV was visually determined and adjusted for anatomical plausibility on T2w sequences. Beside a statistical comparison of stGTV and dwGTB, spatial agreement was determined with the "Hausdorff-Distance" (HD) and the "Dice Similarity Coefficient" (DSC). RESULTS: Fifteen patients (one patient with two synchronous NSCLC) were evaluated. For 16 primary tumors with UICC stages I (n = 4), II (n = 3), IIIA (n = 2) and IIIB (n = 7) mean values for dwGTV were significantly larger than those of stGTV (76.6 ± 84.5 ml vs. 66.6 ± 75.2 ml, p<0.01). The correlation of stGTV and dwGTV was highly significant (r = 0.995, p<0.001). Yet, some considerable volume deviations between these two methods were observed (median 27.5%, range 0.4-52.1%). An acceptable agreement between dwGTV and stGTV regarding the spatial extent of primary tumors was found (average HD: 2.25 ± 0.7 mm; DC 0.68 ± 0.09). CONCLUSION: The overall level of agreement between PET-CT and MRI based GTV definition is acceptable. Tumor volumes may differ considerably in single cases. DWI-derived GTVs are significantly, yet modestly, larger than their PET-CT based counterparts. Prospective studies to assess the safety and efficacy of DWI-based radiotherapy planning in NSCLC are warranted.

Ramipril and telmisartan exhibit differential effects in cardiac pressure overload-induced hypertrophy without an additional benefit of the combination of both drugs.

OBJECTIVES: We aimed to characterize different cellular effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin 1 (AT1) receptor blockers (ARBs) as mono- or combination therapy in cardiac pressure overload. Methods and RESULTS: C57B1/6 mice received either the ACEI ramipril (2.5 mg/kg body weight), the ARB telmisartan (20 mg/kg body weight), or the combination. In all groups, pressure overload was induced by transverse aortic constriction (TAC). Cardiac hypertrophy (heart weight/tibia length) induced by TAC was reduced in all 3 treatment groups, with the most pronounced effect in the telmisartan group. The cardiomyocyte short-axis diameter and cardiac fibrosis were increased by TAC and similarly reduced by ACEI, ARB, and the combination therapy. The TAC-induced increase in the number of proliferating Ki67(pos) cardiomyocytes and noncardiomyocytes was reduced more potently by ACEI than by ARB. Four days of drug treatment induced a significant increase in Scal(pos)/VEGFR1(pos) endothelial progenitor cells (EPCs) in all animals in the treated SHAM groups. After 1 day of aortic constriction, only ramipril increased EPC numbers; after 5 weeks, telmisartan monotherapy did not change the EPC levels compared to vehicle or the combination therapy but raised it compared to ramipril. Neither TAC nor one of the therapies changed the number of cardiac capillaries per cardiomyocytes. CONCLUSIONS: ACE inhibition and AT1 receptor blockade have beneficial effects in remodeling processes during cardiac pressure overload. There are small differences between the 2 therapeutical approaches, but the combination therapy has no additional benefit.

Inhibition of endothelial nitric oxide synthase induces and enhances myocardial fibrosis.

AIMS: The endothelial nitric oxide synthase (eNOS) contributes to cardiac remodelling. We studied the role of eNOS in the development of myocardial fibrosis during cardiac overload. METHODS AND RESULTS: Ten-week-old male C57/Bl6 wildtype (WT) and eNOS mice (eNOS(-/-)) were subjected to transverse aortic constriction (TAC, 360 µm) and WT were treated with L-N(G)-nitroarginine methyl ester (L-NAME, 100 mg/kg/day) for 35 days. Inhibition of eNOS by L-NAME induced interstitial fibrosis, augmented replacement fibrosis, and induced apoptosis of cardiac fibroblasts and cardiomyocytes. L-NAME and eNOS(-/-) markedly increased the fibrosis induced by TAC and enhanced the myocardial prevalence of CXCR4(pos) fibroblasts. Myocardial stromal-derived factor-1 (SDF-1) expression was up-regulated by l-NAME and down-regulated after TAC. Blood pressure lowering by co-treatment with hydralazine (250 mg/L/day) did not reverse the L-NAME effects. In mice transplanted with green fluorescent protein (GFP)(pos) bone marrow, L-NAME increased the percentage of GFP(pos) fibroblasts in the myocardium to 45-70%. Strain-mismatched BMT of eNOS(-/-)-BM increased and of WT-BM decreased the percentage of CXCR4(pos) fibroblasts in all groups. The number of fibrocytes (CD45(pos) collagen I(pos) cells) in the peripheral blood and in the bone marrow was increased both by TAC and L-NAME. L-NAME but not the inhibitor of inducible NOS 1400 W and of neuronal NOS 7-nitroindazole increased hydroxyproline and collagen Iα1. L-NAME up-regulated SDF-1 mRNA in cultured neonatal rat cardiac fibroblasts as well as their migratory capacity. CONCLUSION: eNOS inhibition induces and enhances cardiac fibrosis independently of blood pressure by activating SDF-1/CXCR4, extracellular matrix production in cardiac fibroblasts and by increasing recruitment of fibrocytes from the bone marrow.

Endothelial nitric oxide synthase of the bone marrow regulates myocardial hypertrophy, fibrosis, and angiogenesis.

AIMS: The endothelial nitric oxide synthase (eNOS) regulates the mobilization and function of endothelial progenitor cells (EPC). We hypothesized that eNOS of the bone marrow (BM) affects cardiac remodelling during myocardial hypertrophy via the regulation of BM-derived vascular progenitor cells. METHODS AND RESULTS: Ten-week-old male C57/Bl6 wild-type (WT) and eNOS mice (eNOS(-/-)) were subjected to transverse aortic constriction (TAC, 360 µm, 35 days) or sham operation inducing cardiac hypertrophy and increasing the numbers of Ki67+ cardiomyocytes in both strains. Myocardial fibrosis was more pronounced in eNOS(-/-) TAC (3.4 ± 0.4 vs. 2.1 ± 0.2% in WT-TAC, P < 0.05). TAC up-regulated the number of EPCs in the peripheral blood and in the BM in WT but not in eNOS(-/-). Baseline migratory capacity of EPCs was lower in eNOS(-/-) and was not raised by TAC in either strain. To test the role of eNOS in the BM during pressure overload, strain-mismatched (WT/eNOS(-/-); eNOS(-/-)/WT) and strain-matched (WT/WT; eNOS(-/-)/eNOS(-/-)) BM transplantations (BMTs) were performed. Cardiac hypertrophy was most pronounced in WT/eNOS(-/-) TAC. Strain-mismatched BMT of eNOS(-/-) BM deteriorated and of WT BM ameliorated cardiac fibrosis, capillary density, the numbers of EPCs in the peripheral blood and in the BM, and their migratory capacity in pressure overload. Following transplantation of green fluorescent protein (GFP)-positive BM, TAC increased the number of BM-derived podocalyxin(pos)GFP(pos) endothelial cells in both strains. CONCLUSION: eNOS of the BM plays a key role for amelioration of cardiac hypertrophy, capillary density, and fibrosis during increased afterload.

ACE inhibition promotes upregulation of endothelial progenitor cells and neoangiogenesis in cardiac pressure overload.

AIMS: Inhibition of the angiotensin-converting enzyme (ACE) prevents maladaptive cardiac remodelling. Endothelial progenitor cells (EPC) from the bone marrow contribute to endothelial repair and neovascularization, effects that are potentially important during cardiac remodelling. We hypothesized that ACE inhibitors may exert beneficial effects during pressure-induced myocardial hypertrophy by regulating progenitor cell function. METHODS AND RESULTS: In C57/Bl6 mice, development of cardiac hypertrophy induced by transaortic constriction (TAC) for 5 weeks was reduced by ramipril, 5 mg/kg p.o., independent of blood pressure lowering. Ramipril prevented TAC-induced apoptosis of cardiac myocytes and endothelial cells. On day 1 after TAC, upregulation of Sca-1(pos)/KDR(pos) EPC was observed, which was further increased by ramipril. EPC were persistently elevated in the TAC mice receiving vehicle treatment but not in the ramipril group after 5 weeks. These effects were independent of hypoxia-inducible factor-1alpha mRNA and protein expression. The ACE inhibitor but not TAC improved the migratory capacity of DiLDL(pos) EPC. Increased cardiac afterload induced upregulation of extracardiac neoangiogenesis. This effect was enhanced by ACE inhibition. Ramipril but not TAC markedly increased cardiac capillary density determined by the ratio of CD31(pos) cells to cardiomyocytes. Bone marrow transplantation studies revealed that TAC increased the percentage of bone marrow-derived GFP(pos) endothelial cells in the myocardium, and ramipril made this effect more pronounced. CONCLUSIONS: ACE inhibition prevents pressure-induced maladaptive cardiac hypertrophy and increases intra- and extracardiac neoangiogenesis associated with the upregulation of EPC and amelioration of EPC migration. The regulation of progenitor cells from the bone marrow identifies a novel effect of ACE inhibitors during cardiac remodelling.