Quantification of left-to-right shunting in adult congenital heart disease: phase-contrast cine MRI compared with invasive oximetry.

Atrial septum defects (ASDs), ventricular septum defects (VSDs) and patent ductus arteriosus (PDA) are the most common adult congenital heart defects. The degree of left-to-right shunting as assessed by the ratio of flow in the pulmonary (Qp) and systemic circulation (Qs) is crucial in the management of these conditions. This study compared phase-contrast cine magnetic resonance imaging (PC-MRI), a non-invasive imaging technique, with invasive oximetry for the measurement of shunt volumes during cardiac catheterisation in adults with left-to-right shunting. Both invasive oximetry and shunt quantification by PC-MRI (1.5 T scanner; Sonata, Siemens Medical Solutions) were performed on 21 patients with left-to-right shunting (14 ASD, 5 VSD, 2 PDA) and data on Qp/Qs ratios and left-to-right shunt fraction compared. Mean Qp/Qs ratios assessed by PC-MRI and oximetry were 2.10+/-0.76 and 1.96+/-0.77, respectively (p = 0.37). Mean shunt fraction was 46.3+/-19.6% when calculated by PC-MRI and 42.3+/-20.1% when obtained by oximetry (p = 0.12). There was a strong correlation of Qp/Qs ratios and shunt fraction between both methods (r = 0.61, p < 0.01 and r = 0.84, p < 0.0001, respectively). The two methods had a good agreement according to Bland and Altman plots with a small but non-significant overestimation of Qp/Qs-ratios and shunt fraction by PC-MRI. On receiver operating characteristic analysis, the sensitivity and specificity of PC-MRI to detect an oximetry-derived Qp/Qs ratio of > or =1.5:1 were 93% and 100% at a PC-MRI threshold of a Qp/Qs ratio > or =1.75:1 (area under curve (AUC) = 0.99). Quantification of left-to-right shunting can be performed reliably and accurately by PC-MRI and the data obtained by this method correlate closely to those from invasive oximetry.

Unicuspid aortic valve disease: a magnetic resonance imaging study.

PURPOSE: Congenitally malformed aortic valves are a common finding in adults with aortic valve disease. Most of these patients have bicuspid aortic valve disease. Unicuspid aortic valve disease (UAV) is rare. The aim of our study was to describe valve morphology and the dimensions of the proximal aorta in a cohort of 12 patients with UAV in comparison to tricuspid aortic valve disease (TAV) using magnetic resonance imaging (MRI). MATERIALS AND METHODS/RESULTS: MRI studies were performed on a 1.5 T scanner in a total of 288 consecutive patients with aortic valve disease. 12 aortic valves were retrospectively classified as UAV. Annulus areas and dimensions of the thoracic aorta were retrospectively compared to a cohort of 103 patients with TAV. In UAV, valve morphology was unicuspid unicommissural with a posterior commissure in all patients. Mean annulus areas and mean diameters of the ascending aorta were significantly greater in UAV compared to TAV (12.6 +/- 4.7 cm (2) vs. 8.7 +/- 2.3 cm (2), p < 0.01 and 4.6 +/- 0.7 cm vs. 3.6 +/- 0.5 cm, p < 0.0001, respectively), while no differences were observed in the mean diameters of the aortic arch (2.3 +/- 0.6 cm vs. 2.3 +/- 0.4 cm, p = 0.69). The diameters of the descending aorta were slightly smaller in UAV compared to TAV (2.2 +/- 0.5 cm vs. 2.6 +/- 0.3 cm, p < 0.05). CONCLUSION: In UAV, visualization of valve morphology by MRI is possible with good image quality. Valve morphology was classified as unicuspid unicommissural in all UAV patients. Dilatation of the proximal aorta > 4.5 cm is a frequent finding in UAV. Additional assessment of aortic dimensions is therefore recommended in patients with UAV.

Assessment of the anatomic regurgitant orifice in aortic regurgitation: a clinical magnetic resonance imaging study.

BACKGROUND: The aim of our study was to determine whether planimetry of the anatomic regurgitant orifice (ARO) in patients with aortic regurgitation (AR) by magnetic resonance imaging (MRI) is feasible and whether ARO by MRI correlates with the severity of AR. METHODS AND RESULTS: Planimetry of ARO by MRI was performed on a clinical magnetic resonance system (1.5 T Sonata, Siemens Medical Solutions) in 45 patients and correlated with the regurgitant fraction (RgF) and regurgitant volume (RgV) determined by MRI phase velocity mapping (PVM; MRI-RgF, MRI-RgV, n = 45) and with invasively quantified AR by supravalvular aortography (n = 32) and RgF upon cardiac catheterisation (CATH-RgF, n = 15). Determination of ARO was possible in 98% (44/45) of the patients with adequate image quality. MRI-RgF and CATH-RgF were modestly correlated (n = 15, r = 0.71, p<0.01). ARO was closely correlated with MRI-RgF (n = 44, r = 0.88, p<0.001) and was modestly correlated with CATH-RgF (n = 14, r = 0.66, p = 0.01). Sensitivity and specificity of ARO to detect moderately severe and severe aortic regurgitation (defined as MRI-RgF > or =40%) were 96% and 95% at a threshold of 0.28 cm2 (AUC = 0.99). Of note, sensitivity and specificity of ARO to detect moderately severe and severe AR at catheterisation (defined as CATH-RgF > or =40% or supravalvular aortography > or =3+) were 90% and 91% at a similar threshold of 0.28 cm2 (AUC = 0.95). Lastly, sensitivity and specificity of ARO to detect severe aortic regurgitation (defined as MRI-RgF > or =50% and/or regurgitant volume > or =60 ml) were 83% and 97% at a threshold of 0.48 cm2 (AUC = 0.97). CONCLUSIONS: Visualisation and planimetry of the ARO in patients with AR are feasible by MRI. There is a strong correlation of ARO with RgV and RgF assessed by PVM and with invasively graded AR at catheterisation. Therefore, determination of ARO by MRI is a new non-invasive measure for assessing the severity of AR.

MRI planimetry for diagnosis and follow-up of valve area in mitral stenosis treated with valvuloplasty.

PURPOSE: We sought to determine whether noninvasive planimetry by magnetic resonance imaging (MRI) is suitably sensitive and reliable for visualizing the mitral valve area (MVA) and for detecting increases in the MVA after percutaneous balloon mitral valvuloplasty (PBMV). MATERIALS AND METHODS: In 8 patients with mitral valve stenosis, planimetry of the MVA was performed before and after PBMV with a 1.5 T MR scanner using a breath-hold balanced gradient echo sequence (True FISP). The data was compared to the echocardiographically determined MVA (ECHO-MVA) as well as to the invasively calculated MVA by the Gorlin formula at catheterization (CATH-MVA). RESULTS: PBMV was associated with an increase of 0.79 +/- 0.30 cm (2) in the MVA (Delta MRI-MVA). The correlation between Delta MRI-MVA and Delta CATH-MVA was 0.92 (p < 0.03) and that between Delta MRI-MVA and Delta ECHO-MVA was 0.90 (p < 0.04). The overall correlation between MRI-MVA and CATH-MVA was 0.95 (p < 0.0001) and that between MRI-MVA and ECHO-MVA was 0.98 (p < 0.0001). MRI-MVA slightly overestimated CATH-MVA by 8.0 % (1.64 +/- 0.45 vs. 1.51 +/- 0.49 cm (2), p < 0.01) and ECHO-MVA by 1.8 % (1.64 +/- 0.45 vs. 1.61 +/- 0.43 cm (2), n. s.). CONCLUSION: Magnetic resonance planimetry of the mitral valve orifice is a sensitive and reliable method for the noninvasive quantification of mitral stenosis and visualization of small relative changes in the MVA. This new method is therefore capable of diagnosing as well as following the course of mitral stenosis. It must be taken into consideration that planimetry by MRI slightly overestimates the MVA as compared to cardiac catheterization.

Delayed hyperenhancement in magnetic resonance imaging of left ventricular hypertrophy caused by aortic stenosis and hypertrophic cardiomyopathy: visualisation of focal fibrosis.

OBJECTIVE: To compare the extent and distribution of focal fibrosis by gadolinium contrast-enhanced magnetic resonance imaging (MRI; delayed hyperenhancement) in severe left ventricular (LV) hypertrophy in patients with pressure overload caused by aortic stenosis (AS) and with genetically determined hypertrophic cardiomyopathy (HCM). METHODS: 44 patients with symptomatic valvular AS (n = 22) and HCM (n = 22) were studied. Cine images were acquired with fast imaging with steady-state precession (trueFISP) on a 1.5 T scanner (Sonata, Siemens Medical Solutions). Gadolinium contrast-enhanced MRI was performed with a segmented inversion-recovery sequence. The location, extent and enhancement pattern of hyperenhanced myocardium was analysed in a 12-segment model. RESULTS: Mean LV mass was 238.6 (SD 75.3) g in AS and 205.4 (SD 80.5) g in HCM (p = 0.17). Hyperenhancement was observed in 27% of patients with AS and in 73% of patients with HCM (p < 0.01). In AS, hyperenhancement was observed in 60% of patients with a maximum diastolic wall thickness >or= 18 mm, whereas no patient with a maximum diastolic wall thickness < 18 mm had hyperenhancement (p < 0.05). Patients with hyperenhancement had more severe AS than patients without hyperenhancement (aortic valve area 0.80 (0.09) cm(2)v 0.99 (0.3) cm(2), p < 0.05; maximum gradient 98 (22) mm Hg v 74 (24) mm Hg, p < 0.05). In HCM, hyperenhancement was predominant in the anteroseptal regions and patients with hyperenhancement had higher end diastolic (125.4 (36.9) ml v 98.8 (16.9) ml, p < 0.05) and end systolic volumes (38.9 (18.2) ml v 25.2 (1.7) ml, p < 0.05). The volume of hyperenhancement (percentage of total LV myocardium), where present, was lower in AS than in HCM (4.3 (1.9)% v 8.6 (7.4)%, p< 0.05). Hyperenhancement was observed in 4.5 (3.1) and 4.6 (2.7) segments in AS and HCM, respectively (p = 0.93), and the enhancement pattern was mostly patchy with multiple foci. CONCLUSIONS: Focal scarring can be observed in severe LV hypertrophy caused by AS and HCM, and correlates with the severity of LV remodelling. However, focal scarring is significantly less prevalent in adaptive LV hypertrophy caused by AS than in genetically determined HCM.

[Evaluation of radiological teaching programs in the Internet]. / Evaluation radiologischer Lernprogramme im Internet.

PURPOSE: Evaluation of web based training programs, which can be contacted from the homepages of radiological departments of German universities. MATERIAL AND METHOD: From June 2000 to January 2002 the 75 web based training programs of 57 providers,which can be contacted from the web pages of the radiological departments of German universities were evaluated in a prospective study. A medical student experienced in using the world wide web examined each training program three times in an interval of six months using the following criteria: availability of the web sites, target group, kind of training program, contents and structure and the technical solution. RESULTS: 51 of the 57 the homepages were fully available at each visit. 64 of the 75 web based training programs which could be connected from these sites were available at all three visits.One program was only partially available at one spot check. 8 of the 75 programs were designed for physicians and medically trained personal, 23 were made for medical students and 44 addressed both target groups (partially more than once mentioned). The number of the presented cases ranged between one single and 3700. In 31 of 75 training programs links to other teaching files were found. A complete presentation of cases was presented by 48 of the 75 web sites.5 of the 75 web sites offered physiological images for comparison. In 20 training programs the pathological changes were optically marked in the x-ray images. A logical and didactical structure was found in 24 teaching files, 14 gave the possibility to check the learning results. No provider made use of the possibility to pass credits to the students or physicians account with regard to official training programs. Multimedia techniques were used in 15 training programs.43 sites used data reduced preview images (thumbnails). The latest update of the site is mentioned in 55 of the 75 web sites. 19 of 57 providers had either no possibility of contact or did not answer to an e-mail. CONCLUSION: From the homepages of the departments of diagnostic radiology of German universities 75 teaching files can be contacted. There is a great variety in quantity and quality. Most sites offer collections of cases. A web based training program which is comparable in quality to a CD-ROM teaching program could not be found. No program used the possibility to give credits to the users with regard to official training programs.

[Contrast-enhanced MR angiography in the routine work-up of the lower extremity arteries]. / Kontrastmittelverstärkte MR-Angiographie der Becken- und Beingefässe in der klinischen Routinediagnostik.

PURPOSE: Prospective evaluation of the effectiveness of contrast-enhanced moving-table magnetic resonance angiography (CE-MRA) as the sole routine tool for the diagnosis of peripheral arterial occlusive disease and determination whether it can replace catheter arteriography. SUBJECTS AND METHODS: In a time period of 23 weeks, 100 consecutive patients were evaluated. A total of 112 contrast-enhanced moving-table MR angiograms were performed at 1.5 Tesla. A dedicated vascular coil system was used. It was evaluated in which cases MR angiography was sufficient to determine the treatment plan and in which cases limited quality required additional examinations. RESULTS: In 93.75 % (105/112) of all examinations, the treatment plan was determined by MRA as the sole diagnostic tool. Twenty-two patients underwent surgery or percutaneous angioplasty based on MRA findings. Additional examinations due to impaired quality were performed in seven (6.25 %) cases: two MR angiographies of the pelvic arteries, one MR angiography of the calf, and four selective arteriographies because of venous overlay at the calf. CONCLUSION: Contrast-enhanced MR angiography can take the place of catheter angiography in the routine work-up of patients with peripheral arterial occlusive disease. Further assessment might be necessary in five to ten percent of the cases when the diagnostic quality is inadequate, mostly due to venous overlay in the lower leg.

[Treatment of para-ostium renal artery stenoses with a new, solidly premounted balloon expandable stent]. / Behandlung von ostiumnahen Nierenarterienstenosen mit einem neuen, fest vormontierten, ballonexpandierbaren Stent.

PURPOSE: Evaluation of the handling, technical success rate, and six-months patency rate of a new, premounted balloon-expandable stent in ostial renal artery stenoses. MATERIAL AND METHODS: In a prospective study, 27 ostial renal artery stenoses in 20 patients were primarily treated with the new "Renal Bridge Stent" (Medtronic AVE, Düsseldorf). All patients had a history of hypertension and 8 patients had renal dysfunction. The handling and visibility of the stent was scored on a three grade scale by the operators. Follow-up angiography including intra-arterial trans-stenotic pressure measurements was performed in 23 out of 27 stenoses (17 patients). RESULTS: Handling and visibility were scored as good by all operators. 26 of 27 stenoses were treated with technical success by implantation of 28 stents. The mean degree of stenosis was reduced from 74.2% to less than 5%. At 6 months, 8 stents out of 23 (35%) showed a significant in-stent stenosis (stenosis degree > 50% and intra-arterial pressure gradient > 10 mmHg). The stenosis rates were 63% using 5-mm stents, 30% using 6-mm stents, and 0% using 7-mm stents. CONCLUSION: Endovascular treatment of ostial renal artery stenosis with the used stent is safe and effective. The new stent shows a good handling and visibility. The high rate of in-stent stenoses might be explained by the rigid follow-up protocol including angiography, trans-stenotic pressure measurements, and the high number of 5-mm vessels in our study.

[Results after placement of Memotherm stents in iliac and femoral arteries]. / Ergebnisse nach Memotherm-Stent-Implantation in Becken- und Leistenarterien.

PURPOSE: To evaluate the effectivity, safety and midterm patency rates of iliac and femoral stent placement with the Memotherm stent (Bard-Angiomed, Karlsruhe). MATERIAL AND METHODS: In 41 patients (11 female, 30 male, mean age 63.9 years) 49 lesions were treated with 50 stents. Mean lesion length was 4.8 cm for 5 occlusions and 3.1 cm for 44 stenoses. Lesions were located in the common iliac (n = 31), the external iliac (n = 15), and the common femoral artery (n = 3). Patients were followed-up clinically, with ankle-brachial indices (ABI), and angiography. Angiographic patency rates (< or = 50% restenosis) were calculated using the Kaplan-Meier method, ABIs were compared before and after therapy with the Wilcoxon test. RESULTS: An immediate technical success was achieved in 48/49 lesions (98%, intention-to-treat). Visibility of the stent was poor. Four stent placement procedures were complicated by an advancement of the stent, which could not be corrected. A thrombosis of one stent during deployment had to be treated surgically. After a mean of 10.4 months (6-24) 33 lesions were followed-up with angiography. The primary angiographic patency rate was determined to be 89.9% after 9 months. An improvement of at least one Fontaine stage was observed in 85.4%. The mean ABI increased significantly from 0.64 to 0.84 after therapy. CONCLUSIONS: The patency rate of the Memotherm stent is comparable to that of other stent systems. The poor visibility and the advancement of the stent during deployment requires further modifications.

MR imaging-guided stent placement in iliac arterial stenoses: a feasibility study.

PURPOSE: To assess the feasibility of magnetic resonance (MR) imaging-guided stent placement in iliac arterial stenoses. MATERIALS AND METHODS: Thirteen patients with 14 iliac arterial stenoses were examined prospectively. Angioplasty was performed through a femoral sheath by using a conventional 1.5-T MR imaging system. Stents and catheters were visualized on the basis of their artifacts. Nitinol stents were placed with gradient-echo MR imaging guidance. Angioplasty balloons were inflated with gadolinium-based contrast material. Results were evaluated clinically and with both digital subtraction angiography (DSA) and contrast material-enhanced MR angiography. RESULTS: Ten of 13 patients were treated with technical success by using MR imaging-guided intervention alone. Three patients were treated with additional fluoroscopic guidance, because complications (ie, panic attack, subintimal recanalization, and stent misplacement) occurred with MR guidance. The quality of the postinterventional contrast-enhanced MR angiograms of three of 12 lesions with stents was limited owing to stent-induced signal loss of the lumen. The mean stenosis degree after stent placement was significantly higher at contrast-enhanced MR angiography than at DSA (24.6% vs 6.2%). The mean MR imaging-guided procedure time was 74 minutes. CONCLUSION: MR imaging-guided stent placement in iliac arteries is feasible in select patients. The presented technique has limitations-that is, long procedure times, lack of real-time monitoring, and stent artifacts-that necessitate further modifications before it can be recommended for clinical use.

Reduction of motion artifacts in magnetic resonance imaging of the neck and cervical spine by long-term averaging.

RATIONALE AND OBJECTIVES: We performed a prospective comparison of T1-weighted turbo spin-echo (TSE) imaging with standard averaging and with the long-term averaging method (LOTA), comparing the effects on signal-to-artifact noise ratio (S/aN) and motion artifacts. METHODS: In 30 consecutive patients undergoing imaging of the neck or cervical spine, a transverse T1-weighted TSE sequence was applied with and without LOTA by using identical sequence parameters. Quantitative image analysis was done by calculating S/Ns in the phase-encoding direction (S/aN). Visual image analysis was performed by four independent, masked readers using a standardized score sheet for anatomic and pathological findings. RESULTS: The LOTA sequence yielded significantly superior S/aN values compared with the standard averaging sequence. In the subjective evaluation, the LOTA sequence showed significantly fewer motion artifacts and better visualization of normal anatomy of the neck, cervical spine, and spinal cord, as well as of the pathological findings. CONCLUSIONS: LOTA is a valuable method for increasing S/aN in magnetic resonance imaging of the neck and cervical spine. It reduces motion artifacts and increases the conspicuity of pathology without increasing acquisition time. No additional hardware is needed, and this technique can be combined with other artifact-reducing methods.

[Stent angioplasty of pelvic artery stenosis with MRI control: initial clinical results]. / Stentangioplastie von Beckenarterienstenosen unter MRT-Kontrolle: Erste klinische Ergebnisse.

PURPOSE: To investigate the feasibility of MR-guided stent angioplasty of iliac artery stenoses under passive visualization. MATERIAL AND METHODS: Three patients with short, concentric stenoses of the iliac arteries were enrolled. The vascular interventions were performed on a 1.5 T MR scanner (Magnetom Symphony, Siemens, Erlangen, Germany). Stents, guidewires, and balloon catheters were visualized on the basis of susceptibility artifacts. Contrast-enhanced MR angiography (ceMRA) was used to localized the stenosis prior to stent deployment. Nitinol stents were placed under MR-guidance using a fast 2D gradient echo technique. Balloon dilatiation was performed with an angioplasty catheter inflated with diluted gadolinium-DTPA. Postinterventional results were evaluated by ceMRA, DSA, and Doppler indices. RESULTS: Position of the stent, stent deployment, and balloon dilatation were depicted by MR. All stents were correctly placed within the stenosis. Stent positions as monitored by MRI were identical to those seen on DSA images. All patients were treated successfully by the MR-guided intervention. CONCLUSION: An MR-guided stent angioplasty of simple iliac artery stenosis is feasible under passive visualization.

[Therapy of iliac artery lesions with a new premounted balloon-expandable stent ("Flexible Iliac Bridge Stent")]. / Therapie von Beckenarterienläsionen mit einem neuen vormontierten ballonexpandierbaren Stent ("Flexible Iliac Bridge Stent").

PURPOSE: Evaluation of the handling, technical success rate and six month patency rate of a new, premounted balloon-expandable stent in iliac artery lesions. MATERIALS AND METHODS: In a prospective study 26 stenoses and 3 occlusions of the iliac arteries were primary treated in 24 patients (Fontaine IIa-III, mean age 60.4 year) with the "Flexible Iliac Bridge Stent" (Medtronic AVE, Düsseldorf). Five patients had bilateral stenoses. The ankle-brachial index (ABI) in rest and after exercise was determined before the intervention as well as 1-3 days, 1 and 6 months after the Intervention. The handling and visibility of the stent was scored on a three grade scale by the operators. Follow-up angiography including intraarterial pressure measurement was performed in 17 out of 24 patients (21 out of 29 lesions) after 6 months. RESULTS: All 29 lesions were treated with technical success by implantation of 36 stents. The mean degree of the stenoses before intervention was 72.7 +/- 13.8% (+/- 1 standard deviation) and less than 5% in all cases postinterventionally. The mean pressure gradient before and after stent placement was 21 +/- 13.1 mm Hg and 0.8 +/- 2.3 mm Hg, respectively. The Fontaine stage improved by at least one in all patients. The mean ABI at rest improved from 0.63 +/- 0.15 to 0.89 +/- 0.16, and after exercise from 0.46 +/- 0.17 to 0.8 +/- 0.2, respectively. At 6 months 2 lesions out of 21 (9.5%) showed a restenosis of 55% and 70% with an intraarterial pressure gradient of 16 mm Hg and 27 mm Hg, respectively. After 6 months the mean ABI at rest decreased to 0.83 +/- 0.13, and to 0.72 +/- 0.14 after exercise. Handling and visibility was scored as good by all operators. CONCLUSION: Endoluminal therapy of iliac artery lesions with the used stent is safe and effective. The six month patency rate is comparable to the published data of other stents.

[Contrast medium-enhanced MR angiography of the pelvic and leg vessels with an automated table-feed technique]. / Kontrastmittelverstärkte MR-Angiographie der Becken- und Beingefässe mit automatisierter Tischverschiebetechnik.

PURPOSE: To evaluate contrast enhanced magnetic resonance angiography (ceMRA) with an automated table-feed technique in patients with arterio-occlusive disease for imaging of the pelvic and peripheral arteries. METHODS: Twenty-two patients underwent three-dimensional gadolinium-enhanced MR angiography in a three-step automatic table-feed technique on a Magnetom Symphony operating at 1.5 Tesla. Maximum intensity projection images (MIP) were generated from the subtracted and original studies. Image quality and venous contrast were evaluated by two groups of observers. 304 vessels (17 patients) were compared with DSA as the standard of reference. RESULTS: All examinations were performed without any technical problems. Diagnostic quality of the MIP of subtracted data sets was superior to that of the unsubtracted images. Venous overlay was 61% in the lower leg. In a total of 599 observations, a sensitivity of 96% (95%, 82%) and a specificity of 87% (88%, 99%) were high compared to DSA in the detection of significant stenoses > or = 50% (> or = 75%, occlusions). Interobserver correlation was good (linear correlation 0.9). CONCLUSION: Stepping-table digital subtraction contrast enhanced MRA is a promising technique in the diagnosis of peripheral arterio-occlusive disease.

Angiotensin II receptor blockade in TGR(mREN2)27: effects of renin-angiotensin-system gene expression and cardiovascular functions.

OBJECTIVE: To study the effect of angiotensin II receptor AT1 blockade on blood pressure, gene expression and pathomorphology of transgenic rats harbouring the mouse Ren-2 gene [TGR(mREN2)27], that develop fulminant hypertension while exhibiting suppressed components of the circulating renin-angiotensin system. DESIGN: TGR(mREN2)27 were treated orally with the newly developed AT1-specific angiotensin receptor antagonist Telmisartan, 4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl) methyl]-[1,1'-biphenyl]-2-carboxylic acid, in three doses (0.1, 1 and 3 mg/kg body weight) for 9 weeks. METHODS: The concentrations of the renin-angiotensin system components were analysed in plasma and tissues by radioimmunoassay. Messenger RNA levels for the angiotensinogen and renin genes were quantified by RNAase protection assay in several tissues. Heart hypertrophy and kidney morphology and function were monitored at the end of the treatment. RESULTS: In contrast to 0.1 mg/kg, 1 and 3 mg/kg Telmisartan normalized tail blood pressure measured once a week. Plasma renin and angiotensin II concentration increases were dose-dependent. The renin-angiotensin system genes in various cardiovascular organs were differentially regulated by angiotensin II receptor blockade. Treatment with Telmisartan stimulated angiotensinogen gene expression in the liver, kidney and heart, whereas it remained unchanged in the hypothalamus, thymus and adrenal gland. In the kidney, the expression of the endogenous, but not of the mouse Ren-2 gene, was increased in parallel to the renin concentration. Telmisartan reduced the severe glomerulosclerosis and proteinuria as well as cardiac hypertrophy observed in untreated TGR(mREN2)27 even with the lowest dose of 0.1 mg/kg, at which the blood pressure of the rats still exceeded 225 mmHg and the plasma renin-angiotensin system parameters were unchanged. CONCLUSION: From these experiments using a specific antagonist we can conclude that high blood pressure in TGR(mREN2)27 is angiotensin II-dependent. Furthermore, the expression of the renin-angiotensin system genes seems to be regulated not only by blood pressure and the plasma renin-angiotensin system but also by other, tissue-specific mechanisms. Pathomorphological changes in the kidney and in the heart do not seem to be caused by the systemic hypertension exclusively, but are also influenced by angiotensin II directly.

Chronic dexamethasone treatment suppresses hypertension development in the transgenic rat TGR(mREN2)27.

INTRODUCTION: The transgenic rat TGR(mREN2)27 is a monogenetic rat model in hypertension research. Integration of mouse Ren-2 gene into the rat genome led to fulminant hypertension despite suppressed plasma and kidney renin concentrations. Renin is highly expressed in extrarenal tissues, especially throughout the adrenal cortex. AIMS AND METHODS: Because plasma and urinary corticosteroid concentrations are elevated during the development of hypertension in these rats, we investigated the effect of dexamethasone on blood pressure, adrenal renin and steroid metabolism. RESULTS: A daily injection of 100 micrograms/kg dexamethasone for 8 weeks was capable of suppressing the development of hypertension in the transgenic rats. The same regimen did not alter blood pressure in Sprague-Dawley control rats. Plasma concentrations of adrenocorticotrophic hormone (ACTH)-dependent steroids (corticosterone and 18-hydroxydeoxycorticosterone) decreased markedly in both strains treated with dexamethasone, but more pronouncedly in transgenic rats. Surprisingly, plasma aldosterone concentrations increased exclusively in the transgenic rats, and not in control rats, treated with dexamethasone. The decrease in corticosterone and 18-hydroxydeoxycorticosterone production was accompanied by a decrease in the abundance of the messenger RNA (mRNA) encoding the rate-limiting enzyme in steroidogenesis (P450scc cholesterol side-chain cleavage) and a decrease in the mRNA encoding P450c11 beta (11 beta-hydroxylase). The increase in aldosterone was accompanied by a massive increase in the abundance of the mRNA encoding zona glomerulosa-specific P450c11AS (aldosterone synthase), which was not increased in control rats. CONCLUSION: We conclude that ACTH-dependent steroids other than the mineralocorticoid aldosterone are responsible for the development of hypertension in the transgenic rat.

Rodent models for studying steroids and hypertension: from fetal development to cells in culture.

We have used several different approaches to study the role of steroids in hypertension, including rodent in vivo models, transgenic animals, and cell culture systems. Using the developing rodent fetus as a model for the ontogeny of regulation of glucocorticoid and mineralocorticoid synthesis, we found that in the developing rodent fetus, expression of both P450scc (cholesterol side chain cleavage) and P450c11 beta (11 beta-hydroxylase) mRNAs occur early, before there is complete organization of the fetal adrenal. Even after the zones of the adrenal are evident, the fetal adrenal still does not express the glomerulosa-specific P450c11AS (aldosterone synthase) mRNA. Stimulating maternal adrenal mineralocorticoid or glucocorticoid synthesis does not affect accumulation of fetal adrenal steroidogenic mRNAs, suggesting that the rodent fetal adrenal may be somewhat transcriptionally quiescent in vivo. We also used two different transgenic rodent systems to study the roles of steroids in hypertension. Using promoter-directed tumorigenesis in transgenic mice, we created transgenic mice that expressed SV40 T antigen under control of the P450scc promoter. Massive adrenal tumors, but not gonadal tumors, developed in all transgenic mice, and cells from these tumors were easily cultured. Using a novel selection tactic, we obtained several adrenocortical cell lines which have distinct characteristics, suggesting they were locked into various stages of differentiation; both expression of steroidogenic mRNAs and the steroids synthesized differ among the lines. Regulation of steroid synthesis and mRNA abundance also varies among cell lines. Several cell lines also express mouse renin, and its synthesis, secretion, and mRNA abundance is also hormonally regulated.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of the adrenal gland in hypertensive transgenic rat TGR(mREN2)27.

The TGR(mREN2)27 is a new monogenetic rat model in hypertension research. As the mouse Ren-2d renin gene is integrated into their genome, they develop fulminant hypertension between 5 and 15 weeks of age, with blood pressure maxima of 300 mm Hg. Their plasma renin-angiotensin system (RAS) is suppressed, but the transgene is highly expressed in the adrenal gland, so we investigated its possible role in steroid metabolism and the pathogenesis of hypertension. During the phase of hypertension development (between 6-18 weeks), the urinary excretion of deoxycorticosterone (DOC), corticosterone (B), 18-hydroxycorticosterone, and aldosterone is 1.5- to 2.5-fold elevated compared with that in Sprague-Dawley (SD) rats (P less than 0.0005) despite the suppressed plasma RAS. Moreover, the adrenal gland in TGR(mREN2)27 shows an increased maximal response to ACTH stimulation in regard to urinary excretion of DOC (after ACTH, 244 +/- 42 ng/24 h in TGR; 62 +/- 10 ng/24 h in SD; P less than 0.0005) and B (after ACTH, 5144 +/- 346 ng/24 h in TGR; 2607 +/- 324 ng/24 h in SD; P less than 0.0005). Additionally, plasma prorenin in TGR was stimulated more than 10-fold, indicating transgene regulation by ACTH. Since spironolactone treatment did not lower the blood pressure in TGR, hypertension solely due to hypermineralocorticoism is unlikely. Our results indicate that the adrenal steroid metabolism is markedly stimulated in young TGR, and the absolute increase in urinary DOC and B after ACTH injections is enhanced, possibly due to a stimulated local intraadrenal RAS.

Role of tissue renin in the pathophysiology of hypertension in TGR(mREN2)27 rats.

A transgenic rat line, TGR(mREN2)27, was established by introducing the murine Ren-2 gene into the genome of rats by microinjection techniques. These rats exhibit severe hypertension, making them an interesting model in which to study the role of renin in the pathophysiology of hypertension. However, although the additional renin gene is the only genetic difference compared with control rats, the exact mechanism of hypertension in TGR(mREN2)27 rats is still unclear. It cannot be attributed to a stimulation of the endocrine renin-angiotensin system or to an overexpression of renin in the kidney, since plasma and kidney renin and renin gene expression in the kidney are low in these animals. Here we describe recent progress made toward elucidating mechanisms of hypertension in TGR(mREN2)27 rats. 1) TGR(mREN2)27 rats were bred to homozygosity. The development of high blood pressure in homozygous rats is accelerated compared with that of heterozygous rats. This is paralleled by a higher mortality rate in homozygous TGR(mREN2)27 rats. Blood pressure and mortality rate of homozygous transgenic rats were effectively reduced by 10 mg captopril per kilogram body weight. 2) Treatment of 8-week-old heterozygous TGR(mREN2)27 rats with 10 mg/kg body wt per day of the angiotensin II receptor antagonist DuP 753 for 4.5 weeks normalized blood pressure. After withdrawal of the drug, blood pressure increased rapidly, reaching control levels after 3 weeks. In another group of TGR(mREN2)27 rats treated with 0.5 mg/kg per day, there was no change in blood pressure. Plasma renin and plasma angiotensin II were significantly higher in the high-dose group compared with the low-dose group.(ABSTRACT TRUNCATED AT 250 WORDS)