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Biomedical subjects

Thomas Walther

Publications and source records attributed to Thomas Walther.

At least 37 records · Page 2Linked to original sources

Bovine jugular vein conduit for right ventricular outflow tract reconstruction: evaluation of risk factors for mid-term outcome.

BACKGROUND: The bovine jugular vein conduit (Contegra [Medtronic, Inc, Minneapolis, MN]) is one option for right ventricular outflow tract reconstruction. We examined the effect of patient age, conduit size, hemodynamics, and cardiac malformation on early and mid-term outcome. METHODS: Seventy-eight bovine jugular vein implantations were performed over 5 years. Follow-up averaged 31 +/- 17 months. Risk factor and adverse event analyses for graft dysfunction were performed by multivariate logistic regression and Kaplan-Meier analysis. RESULTS: There was no early mortality. Two late deaths occurred after 9 and 15 months. Early postoperative echocardiography revealed bovine jugular vein regurgitation greater than 2+ in 10 patients, all of which had conduit dilatation, had received a 12-mm conduit, and had a right-ventricular-to-left ventricular pressure ratio greater than 0.6. Two additional patients had severe conduit incompetence develop at the 2-year follow-up. During follow-up, mean gradients increased from 15 to 23 mm Hg (p = 0.03) and stenosis at the distal anastomosis occurred in 25% of patients. Percutaneous interventions were performed in 19 patients (24.4%). Conduit exchange was required in 10 patients (12.8%) after a mean of 14.9 months for severe graft incompetence (8 patients) and progressive supravalvular stenosis (2 patients). Freedom from reoperation was 77.6% and 59.3% at 1 and 4 years for patients less than 1 year of age compared with 93.5% and 87.4% for patients older than 1 year of age (p < 0.001). Risk factors for reoperation were age less than 1 year, correction of truncus arteriosus, conduit size of 12 mm, and persistently elevated right-ventricular-to-left ventricular pressure ratio greater than 0.6 (p = 0.001 each). CONCLUSIONS: Bovine jugular vein implantation is associated with low reoperation and acceptable reintervention rate in patients older than 1 year of age. In infants with persistently elevated right ventricular pressure, reoperation rate was high and had to be compared with other established surgical options.

Adolescent↗

Minimally invasive surgery for valve disease.

Heart valve surgery evolved since the early 1960s toward routine clinical application with good patient outcome. Different surgical techniques and valve prostheses have been developed. Thus standard procedures were continuously established. The different surgical procedures have now gained widespread clinical acceptance with good patient outcomes. Aortic valve stenosis and mitral valve incompetence are the most frequently acquired heart valve lesions in the western communities. Usually such lesions reach clinical significance in patients during their fifth to eighth decade of life. Standard surgical techniques of aortic valve repair and mitral valve replacement or repair result in persistent cure of the disease. Surgical access was gained using conventional lateral thoracotomies in the early days and later on using median sternotomy. Minimally invasive techniques, mostly by a partial sternotomy for the aortic and a lateral minithoracotomy for the mitral position, have been increasingly applied to improve patient outcome since the mid 1990s. At specialized centers these techniques have evolved as clinical standard allowing all different valve procedures to be safely performed. Patient recovery is fast leading to a significant improvement in the individual's quality of life. Minimally invasive valve surgery can be considered the standard approach and will reach more widespread clinical application.

Aortic Valve Stenosis↗

Modeling of temperature mapping for quantitative dynamic infrared coronary angiography for intraoperative graft patency control.

OBJECTIVES: Intraoperative application of thermal coronary angiography based on dynamic infrared imaging leads to useful qualitative information concerning coronary artery bypass graft flow and anatomy. Additional quantitative flow estimation is desirable to detect graft failures. The aim of this study was to develop a heat-transfer model for quantitative flow estimation in an experimental setup. The first clinical results in coronary artery bypass grafting are reported. METHODS: Dynamic infrared imaging was applied in pig hearts to collect video data of the rewarming process of the left anterior descending artery supplied by antegrade perfusion. For mathematic description, we used the dynamic enthalpy balance for open systems, and a Laplace transformation was carried out. Therefore the time constant tau was calculated by performing a nonlinear fit procedure on the averaged dynamic temperature curves recorded over a left anterior descending artery segment. Subsequently, left internal thoracic artery-left anterior descending artery bypass graft flow was assessed intraoperatively. Effective left anterior descending artery flow was determined by using a transit-time flowmeter. RESULTS: Tau is a system constant and changes depending on the flow and the system capacity. Assuming system capacity to be constant, tau only depends on the flow. It follows from the differential equation that there is a potential relation between tau and the flow. An excellent comparison (R2 = 0.968, P <.005) was demonstrated. By using the algorithms, quantitative flow estimation in pig hearts was possible. For clinical application, the formulas were applied to intraoperatively derived dynamic temperature curves with a good comparison to the actual left internal thoracic artery-left anterior descending artery flow. CONCLUSION: The developed heat-transfer model allows for precise measurement of graft flow by using dynamic infrared imaging and can be applied for noninvasive graft flow estimation in beating-heart surgery.

Animals↗

Does the C-type natriuretic peptide have prognostic value in chagas disease and other dilated cardiomyopathies?

Atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP) are powerful neurohormonal indicators of left-ventricular function and prognosis in heart failure (HF). Chagas disease (CD) caused by the protozoan Trypanosoma cruzi remains a major cause of HF in Latin America. We assessed whether the plasma concentration of the third natriuretic peptide, C-type natriuretic peptide (CNP), also has diagnostic and prognostic properties in patients with CD or other dilated cardiomyopathies (DCM). Blood samples were obtained from 66 patients with CD, 50 patients with DCM from other causes, and 30 gender- and age-matched healthy subjects. Patients were subdivided according to the New York Heart Association (NYHA) class. The CNP concentration was determined by radioimmunoassay (Immundiagnostik, Bensheim, Germany). The main duration of follow-up was 31.4 months (range 13 to 54 months); 19 patients had died and 11 patients received a heart transplant. CNP concentrations were only significantly altered in patients with DCM or CD of the NYHA classes III and IV (P < 0.05). The Pearson correlation of echocardiographic data with CNP revealed an association only with the left-ventricular end systolic volume (P = 0.03) in patients with DCM. Furthermore, CNP did not predict mortality or the necessity for heart transplant. Our data are the first to demonstrate the raised levels of the third natriuretic peptide CNP in CD and other DCM. Whereas ANP and BNP have a high predictive value for mortality in both diseases, CNP is without any predictive potency.

Adult↗

A combined technique for predicting pre-eclampsia: concurrent measurement of uterine perfusion and analysis of heart rate and blood pressure variability.

OBJECTIVE: Pre-eclampsia is a serious complication of pregnancy with high morbidity and mortality and an incidence of 3-5% in all pregnancies. Early prediction is still insufficient in clinical practice. Although most pre-eclamptic patients have pathological uterine perfusion in the second trimester, perfusion disturbance has a positive predictive accuracy (PPA) only of approximately 30%. METHODS: Non-invasive continuous blood pressure recordings were taken simultaneously via a finger cuff for 30 min. Time series of systolic as well as diastolic beat-to-beat pressure values were extracted to analyse heart rate and blood pressure variability and baroreflex sensitivity in 102 second-trimester pregnancies, to assess predictability for pre-eclampsia (n = 16). All women underwent Doppler investigations of the uterine arteries. RESULTS: We identified a combination of three variability and baroreflex parameters to best predict pre-eclampsia several weeks before clinical manifestation. The discriminant function of these three parameters classified patients with later pre-eclampsia with a sensitivity of 87.5%, a specificity of 83.7%, and a PPA of 50.0%. Combined with Doppler investigations of uterine arteries, PPA increased to 71.4%. CONCLUSIONS: This technique of incorporating one-stop clinical assessment of uterine perfusion and variability parameters in the second trimester produces the most effective prediction of pre-eclampsia to date.

Adult↗

Carvedilol-induced antagonism of angiotensin II: a matter of alpha1-adrenoceptor blockade.

OBJECTIVE: To investigate whether renin-angiotensin system blockade might underlie the favorable metabolic effects of the nonselective beta + alpha1-adrenoceptor blocker carvedilol as compared with the selective beta1-adrenoceptor blocker metoprolol. METHODS: Human coronary microarteries (HCMAs), obtained from 32 heart valve donors, were mounted in myographs. RESULTS: Angiotensin II and the alpha1-adrenoceptor agonist phenylephrine constricted HCMAs to maximally 63 +/- 10 and 46 +/- 15% of the contraction to 100 mmol/l K. Neither carvedilol, metoprolol, the nonselective beta-adrenoceptor antagonist propranolol, nor the alpha1-adrenoceptor antagonist prazosin affected the constrictor response to angiotensin II. alpha1-adrenoreceptors and beta-adrenoceptors are thus not involved in the direct constrictor effects of angiotensin II. When added to the organ bath at a subthreshold concentration, angiotensin II greatly amplified the response to phenylephrine. Both carvedilol and the angiotensin II type 1 (AT1) receptor antagonist irbesartan inhibited this angiotensin II-induced potentiation. Furthermore, carvedilol blocked the angiotensin II-induced amplification of phenylephrine-induced inositol phosphate accumulation in cardiomyocytes. CONCLUSIONS: AT1-alpha1-receptor crosstalk, involving inositol phosphates, sensitizes HCMAs to alpha1-adrenoceptor agonists. Our results suggest that, in the presence of an increased sympathetic tone, carvedilol provides AT1 receptor blockade via its alpha1-adrenoceptor blocking effects. This could explain the favorable effects of carvedilol versus metoprolol.

Adolescent↗

Comparison of three methods for beat-to-beat-interval extraction from continuous blood pressure and electrocardiogram with respect to heart rate variability analysis.

In recent years the analysis of heart rate variability (HRV) has become a suitable method for characterizing autonomous cardiovascular regulation. The aim of this study was to investigate the differences in HRV estimated from continuous blood pressure (BP) measurement by different methods in comparison to electrocardiogram (ECG) signals. The beat-to-beat intervals (BBI) were simultaneously extracted from the ECG and blood pressure of 9 cardiac patients (10 min, Colin system, 1000-Hz sampling frequency). For both data types, slope, peak, and correlation detection algorithms were applied. The short-term variability was calculated using concurrent 10-min BP and ECG segments. The root mean square errors in comparison to ECG slope detection were: 1.74 ms for ECG correlation detection; 5.42 ms for ECG peak detection; 5.45 ms for BP slope detection; 5.75 ms for BP correlation detection; and 11.96 ms for BP peak detection. Our results show that the variability obtained with ECG is the most reliable. Moreover, slope detection is superior to peak detection and slightly superior to correlation detection. In particular, for ECG signals with higher frequency characteristics, peak detection often exhibits more artificial variability. Besides measurement noise, respiratory modulation and pulse transit time play an important role in determining BBI. The slope detection method applied to ECG should be preferred, because it is more robust as regards morphological changes in the signals, as well as physiological properties. As the ECG is not recorded in most animal studies, distal pulse wave measurement in combination with correlation or slope detection may be considered an acceptable alternative.

Adult↗

Cardiac fibroma as an inherited manifestation of nevoid basal-cell carcinoma syndrome.

We report the case of an 8-month-old male infant presenting with life-threatening ventricular tachycardia. Echocardiography revealed a left ventricular tumor. The tumor was resected through a left ventriculotomy, and the left ventricle was reconstructed after a partial ventriculectomy Histologic investigation showed a completely resected benign fibroma. The 30-year-old mother was known to have nevoid basal-cell carcinoma syndrome, which can be associated with cardiac fibromas. We believe that this is an interesting addition to the medical literature.

Basal Cell Nevus Syndrome↗

Quattro valve trial at mid-term: December 1996 to November 2004.

BACKGROUND AND AIM OF THE STUDY: The Quattro valve is a stentless pericardial mitral bioprosthesis that is treated with a post-tanning aldehyde capping designed to reduce calcification. A prospective trial was started in December 1996; herein are reported the results of the three centers that performed the surgery and followed up patients in the majority of cases. Young patients were deliberately included in the trial. METHODS: Follow up data from 175 patients (mean age 46 years; range: 12-87 years) were collected and analyzed. Among patients, 44% were aged < 40 years. Follow up was 91% complete; mean follow up was 3.4 years (range: 0-7.5 years); total follow up was 465 patient-years (pt-yr). Clinical outcome was assessed according to the AATS/STS guidelines, and results analyzed according to Kaplan-Meier product limit calculation and by FDA Optimal Performance Criteria (OPC). RESULTS: Early mortality was 1.7% (all non-valve related). At 60 months after surgery, mean overall survival was 84.8 +/- 3.6%, mean overall freedom from valve-related death was 99.2 +/- 0.9%, and mean overall freedom from calcification, pannus and tears was 96.1 +/- 2.2%. FDA OPC values (data for mechanical valve, tissue valve, Quattro valve in patients aged < 40 years and of all ages, respectively; expressed as %/pt-yr) were as follows: thromboembolism/stroke 3.0, 2.5, 0, 0.4; thrombosis 0.8, 0.2, 0, 0; major hemorrhage 1.5, 0.9, 0, 0.4; major perivalvular leak 0.6, 0.6, 0.4, 0.6; late endocarditis 1.2, 1.2, 1.8, 1.3; calcification/pannus 0, 0, 0.8, 0.6. Statistical analysis of these data showed there to be no difference between patients aged less or more than 40 years. CONCLUSION: Overall mid-term results with the Quattro valve were acceptable. The lack of early calcification in young patients shows promise. More young patient-years of follow up will be needed to establish a secure indication for use in young, rheumatic patients where anticoagulation control is deficient.

Adolescent↗

Reverse remodeling of cardiac collagen protein expression after surgical therapy for experimental aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: Reversal of myocardial collagen gene expression was examined in parallel to left ventricular reverse remodeling after surgical correction of experimental aortic stenosis. METHODS: A standard growing sheep model (age at baseline 6-8 months) was used. Measurements were performed at baseline (point A) when inducing left ventricular hypertrophy (LVH) through supracoronary banding, at 8.3 +/- 1.0 months later at surgical correction (point B), and after another 10.1 +/- 2.0 months during final examinations (point C). Gene expression for collagen I and III was also studied. RESULTS: Left ventricular function was stable throughout the study. The left ventricular mass index (LVMI) was 82 +/- 21 g/m2 at point A, 150 +/- 33 g/m2 at B, and 78 +/- 18 g/m2 at C (p <0.01). Myocardial fiber diameter was 11.3 +/- 0.8, 15.9 +/- 1.2 and 11.4 +/- 1 microm at points A, B and C, respectively (p <0.01). Protein expression for collagen I was 0.71 +/- 0.2 (at A), 1.13 +/- 0.3 (at B) and 0.85 +/- 0.4 (at C) (p <0.01), while that for collagen III was 0.72 +/- 0.4 (at A), 1.26 +/- 0.8 (at B) and 0.83 +/- 0.3 (at C) (p <0.01). There was a significant correlation between changes in LVMI and myocardial collagen expression. CONCLUSION: Complete reverse remodeling with regression of LVH and myocardial collagen protein expression can be anticipated after surgical correction of experimental aortic stenosis.

Animals↗

Angiotensin II type 1 receptor agonistic antibodies reflect fundamental alterations in the uteroplacental vasculature.

Abnormal uterine perfusion detected by Doppler sonography reflects impaired trophoblast invasion, a factor involved in the pathogenesis of pregnancy complications such as preeclampsia or intrauterine growth retardation. Recent studies have demonstrated an autoantibody against the angiotensin type 1 (AT1) receptor in pregnant women with preeclampsia. Our aim was to determine whether the AT1 autoantibody precedes the clinical symptoms and is thus predictive of preeclampsia. We therefore detected this antibody in serum from second trimester pregnancies with abnormal uterine perfusion because these women show an indirect sign of inadequate trophoblast invasion. Then the AT1 autoantibody distribution/concentration was compared with that of women at term with or without pregnancy pathology. The AT1 autoantibody was already detectable in second trimester pregnant women with abnormal uterine perfusion before the clinical manifestation of preeclampsia (80%). However, it was also found in second trimester pregnant women with abnormal uterine perfusion who later developed intrauterine growth retardation (60%) or even had a normal course of pregnancy (62%). In the third trimester, the AT1 autoantibody was demonstrated in 89% of patients with manifest preeclampsia, 86% of those with manifest intrauterine growth retardation, and even in healthy pregnant women at term with a history of abnormal uterine perfusion in the second trimester. We conclude that the AT1 autoantibody is an early but nonspecific marker for preeclampsia. The generation of this antibody seems to be associated with distinct types of pregnancy disorders resulting from impaired placental development. The AT1 autoantibody may thus be causative for pathological uteroplacental perfusion.

Adult↗

Fusion of bone marrow-derived stem cells with cardiomyocytes in a heterologous in vitro model.

OBJECTIVE: Recent studies have demonstrated that transplanted bone marrow-derived stem cells (BMCs) possess a broad differentiation potential and are able to form new cardiomyocytes. However, the identity of BMCs as true cardiomyocytes is still ambiguous. Therefore, we investigated the fate of transplanted fluorescence labeled BMCs and cardiomyocytes in co-culture. METHODS: For cell tracking we used two different fluorescent probes, Vybrant/DiO and Vybrant/DiI. BMCs were taken from human sternal marrow, purified using a Ficoll-gradient-centrifugation, treated with 5-azacytidine and stained with Vybrant/DiO. Furthermore, isolated spontaneous beating cardiomyocytes of neonatal rats (CM) were labeled with Vybrant/DiI. Thereafter, the BMCs were transplanted into CM-cultures and investigated on day 1, 4, 7, 14 and 28 using two-color fluorescence phenotyping by laser-scanning-cytometry (LSC). Two-color positive cells were harvested by patch-clamp technique and beta-MHC mRNA expression was analyzed by single-cell PCR. RESULTS: Two different morphological phenotypes were observed by LSC. First, isolated DiO labeled BMCs without contact or with direct cell contact to DiI labeled CMs. Second, some BMCs and CMs were double positive for DiO/DiI spontaneously forming hybrids. This population increased by 18% from day 1 to 4 and decreased only slightly until day 28. Additionally, few two-color positive cell formations expressed both human and rat specific beta-MHC mRNA as well as only human beta-MHC mRNA indicating that cell-fusion and transdifferentiation has occurred. CONCLUSION: These observations provide in vitro evidence for spontaneous cell fusion and transdifferentiation of BMCs in co-culture, raising the possibility that the observed phenomenons may contribute to development or maintenance of these cell types.

Animals↗

Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction and oxidative stress in experimental diabetic cardiomyopathy.

The mechanisms contributing to diabetic cardiomyopathy, as well as the protective pathways of the kallikrein-kinin-system (KKS), are incompletely understood. In a kallikrein-overexpressing rat model of streptozotocin (STZ)-induced diabetic cardiomyopathy, we investigated the involvement of inflammatory pathways, endothelial dysfunction, and oxidative stress. Six weeks after STZ injection, impairment of left ventricular (LV) function parameters measured by a Millar-tip catheter (peak LV systolic pressure; dP/dtmax; dP/dtmin) was accompanied by a significant increment of ICAM-1 and VCAM-1 (CAMs) expression, as well as of beta2-leukocyte-integrins+ (CD18+, CD11a+, CD11b+) and cytokine (TNF-alpha and IL-1beta)-expressing infiltrates in male Sprague-Dawley (SD-STZ) rats compared with normoglycemic littermates. Furthermore, SD-STZ rats demonstrated a significant impairment of endothelium-dependent relaxation evoked by acetylcholine and significantly increased plasma TBARS (plasma thiobarbituric acid reactive substances) levels as a measure of oxidative stress. These diabetic cardiomyopathy-associated alterations were significantly attenuated (P<0.05) in diabetic transgenic rats expressing the human kallikrein 1 (hKLK1) gene with STZ-induced diabetes. CAMs expression, beta2-leukocyte-integrins+, and cytokine-expressing infiltrates correlated significantly with all evaluated LV function parameters. The multiple protective effects of the KKS in experimental diabetic cardiomyopathy comprise the inhibition of intramyocardial inflammation (CAMs expression, beta2-leukocyte-integrins+ infiltration and cytokine expression), an improvement of endothelium-dependent relaxation and the attenuation of oxidative stress. These insights might have therapeutic implications also for human diabetic cardiomyopathy.

Acetylcholine↗

Photofragmentation of phase-transferred gold nanoparticles by intense pulsed laser light.

Gold nanoparticles with an average diameter of approximately 20 nm were prepared in an aqueous solution by a wet chemistry method. The parent gold nanoparticles were then capped with a 4-aminothiophenol protecting layer and transferred into toluene by tuning the surface charge of the modified nanoparticles. Gold nanoparticles before and after phase transfer were subjected to photofragmentation by a pulsed 532 nm laser. The effects of solvent properties and surface chemistry on the photofragmentation of the gold nanoparticles have been investigated. Fast photofragmentation has been observed in the organic solvent in which the dielectric constant, heat capacity, and thermal conductivity are lower. The results suggest new approaches for the preparation of very small gold clusters from gold nanoparticles.

Journal Article↗

Influence of intense pulsed laser irradiation on optical and morphological properties of gold nanoparticle aggregates produced by surface acid-base reactions.

Gold nanoparticles were surface modified with an ionizable and pH-sensitive monolayer of thiobarbituric acid (TBA). By variation of the pH value of the solution, nanoparticle aggregates can be produced in a controlled way. The aggregates thus prepared were irradiated with an intense pulsed laser at 532 nm. The products in solution were examined by transmission electron microscopy (TEM) and optical absorption spectroscopy. The TEM images of the products revealed that the nanoparticle aggregates dissociate upon laser irradiation and form much smaller gold nanoparticles. The optical absorption spectra measured simultaneously show the gradual disappearance of the absorbance band of the aggregates at around 680 nm. Additionally, a blue shift (from 534 to 524 nm) of the resonance absorbance corresponding to isolated nanoparticles has been observed. All the observations suggest that the colloidal solution becomes more stable after laser irradiation. Both the reduced nanoparticle size and the stabilizing TBA ligands present on the particle surface contribute to the acquired stability of the colloidal solutions.

Letter↗

Pacemaker dependent patients with device infection--a modified approach.

A modified surgical concept for temporary cardiac pacing in pacemaker dependent patients requiring total removal of infected devices is presented. Proximal to the infected pocket a permanent bipolar pacing lead is placed transcutaneously into the ipsilateral subclavian or jugular vein. The lead is placed in the right ventricle and fixed into the skin using the suture sleeve. Pacing is established by connecting an external pacing generator. Subsequently the infected device can be removed completely. After wound dressing the externalized lead is connected to a permanent VVI-pacemaker allowing for prolonged temporary pacing.

Aged↗

On-pump beating heart versus off-pump coronary artery bypass surgery-evidence of pump-induced myocardial injury.

OBJECTIVE: By maintaining native coronary blood flow in on-pump beating heart surgery (OnP-BH) and comparing with OPCAB strategy pump-related effects on myocardial injury and cardiac dysfunction could be specifically differentiated from ischemia/reperfusion-related consequences of surgical coronary revascularization. METHODS: In a randomized-prospective design, 40 elective patients with normal EF and three vessels coronary artery disease (left main disease excluded) were assigned to OPCAB or OnP-BH surgery. Before coronary occlusion and 1, 30, 60, and 90 min after reperfusion with the LIMA graft, coronary sinus (CS) blood was sampled to determine intraoperative myocardial ischemia (pH, lactate, pO2) and oxidative stress (malondialdehyde, MDA). Additionally to CS blood arterial blood was analyzed 4, 12, and 24 h postoperatively to determine myocardial necrosis (CK-MB, cardiac troponin I), myocardial dysfunction (NT-proBNP) and inflammation (C-reactive protein). RESULTS: Groups were identical with regards to age and gender (OPCAB 63.0+/-6.0 versus OnP-BH 65.3+/-3.9 y, 20% female patients). Number of grafts were 3.0+/-0.5 in OPCAB versus 2.9+/-0.3 in OnP-BH (n.s.) with 44 versus 34% bilateral IMAs and 56 versus 50% complete arterial revascularization. Regarding ischemia, intraoperatively only lactate values increased significantly in the OnP-BH group. Significantly higher CK-MB and troponin I levels were found from LIMA-LAD flow release onwards to 4 h postoperatively in the OnP-BH group. NT-proBNP levels were significantly higher in the OnP-BH group during the entire study period. CRP levels were higher in the OnP-BH group 12 and 24 h postoperatively. CONCLUSIONS: In this randomized study on routine coronary patients with normal ventricular function, OPCAB revealed less myocardial injury than OnP-BH. These findings implicate that CPB slightly affects the myocardium.

Aged↗

G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor.

BACKGROUND: We previously identified the G-protein-coupled receptor Mas, encoded by the Mas proto-oncogene, as an endogenous receptor for the heptapeptide angiotensin-(1-7); however, the receptor is also suggested to be involved in actions of angiotensin II. We therefore tested whether this could be mediated indirectly through an interaction with the angiotensin II type 1 receptor, AT1. METHODS AND RESULTS: In transfected mammalian cells, Mas was not activated by angiotensin II; however, AT1 receptor-mediated, angiotensin II-induced production of inositol phosphates and mobilization of intracellular Ca2+ was diminished by 50% after coexpression of Mas, despite a concomitant increase in angiotensin II binding capacity. Mas and the AT1 receptor formed a constitutive hetero-oligomeric complex that was unaffected by the presence of agonists or antagonists of the 2 receptors. In vivo, Mas acts as an antagonist of the AT1 receptor; mice lacking the Mas gene show enhanced angiotensin II-mediated vasoconstriction in mesenteric microvessels. CONCLUSIONS: These results demonstrate that Mas can hetero-oligomerize with the AT1 receptor and by so doing inhibit the actions of angiotensin II. This is a novel demonstration that a G-protein-coupled receptor acts as a physiological antagonist of a previously characterized receptor. Consequently, the AT1-Mas complex could be of great importance as a target for pharmacological intervention in cardiovascular diseases.

Angiotensin II↗