Clinical performance of Siemens digital breast tomosynthesis versus standard supplementary mammography for the assessment of screen-detected soft-tissue abnormalities: a multi-reader study.

AIM: To compare the diagnostic accuracy of standard screening images plus single-view digital breast tomosynthesis (DBT), using Siemens DBT equipment, with standard screening images plus supplementary mammographic views in non-calcific, screen-detected mammographic abnormalities. MATERIALS AND METHODS: Participants were unselected women aged 50-69 years recalled within a population-based European breast screening programme for assessment of soft-tissue mammographic abnormalities. Supplementary mammographic views (SMVs) and DBT were performed in all cases. A range of equipment was used for screening and supplementary mammography, but all DBT examinations were performed using the Siemens Mammomat Inspiration. A retrospective multi-reader study including 238 cases for whom either histology or at least 2 years' follow-up was available was performed with eight suitably accredited UK breast screening personnel reading all cases under both conditions, with temporal separation. Readers were blinded to case outcomes and findings from other examinations. Diagnostic accuracy using receiver operating characteristic (ROC) analysis was compared between screening plus SMV images and screening plus DBT images. The study was powered to detect a 3% inferiority margin in diagnostic accuracy between methods. RESULTS: The final sample with complete data available for analysis included 195 benign cases (1,560 reads) and 35 malignant cases (280 reads). The DBT method yielded a slightly higher area under the curve (AUC) value than the SMV method (0.870 versus 0.857), but the difference was not statistically significant (p=0.4890), indicating that the methods have equivalent accuracy. CONCLUSION: Siemens DBT demonstrates equivalent diagnostic accuracy according to ROC curve analysis when used in place of SMVs in screen-detected soft-tissue mammographic abnormalities.

Where's the Floor?

Visual and balance cues concerning the relative orientation of ourselves and our environment combine to direct our steps to select a secure footing. How are visual cues used to select the best support surface? Here we show that, when exposed to tilted, rectangular rooms of various aspect ratios, subjects do not necessarily choose the surface with its normal oriented closest to the gravity-defined vertical. Rather their decision is also strongly biased by the visual area subtended by each candidate surface.

Investigation of the radical product channel of the CH(3)OCH(2)O(2) + HO(2) reaction in the gas phase.

The reaction of CH(3)OCH(2)O(2) with HO(2) has been investigated at 296 K and 700 Torr using long path FTIR spectroscopy, during photolysis of Cl(2)/CH(3)OCH(3)/CH(3)OH/air mixtures. The branching ratio for the reaction channel forming CH(3)OCH(2)O, OH, and O(2) has been determined from experiments in which OH radicals were scavenged by addition of benzene to the system, with subsequent formation of phenol used as the primary diagnostic for OH radical formation. The dependence of the phenol yield on the initial peroxy radical precursor reagent concentration ratio, [CH(3)OH](0)/[CH(3)OCH(3)](0), is consistent with prompt OH formation resulting mainly from the reaction of CH(3)OCH(2)O(2) with HO(2), such that the inferred prompt yield of OH is well-correlated with that of CH(3)OCH(2)OOH, a well-established product of the CH(3)OCH(2)O(2) + HO(2) reaction. The system was fully characterized by simulation, using a detailed chemical mechanism which included other established sources of OH in the system. This allowed a branching ratio of k(2c)/k(2) = 0.19 +/- 0.08 to be determined. The results therefore provide strong indirect evidence for the participation of the radical-forming channel of the title reaction.

Detailed chemical analysis of regional-scale air pollution in western Portugal using an adapted version of MCM v3.1.

A version of the Master Chemical Mechanism (MCM) v3.1, refined on the basis of recent chamber evaluations, has been incorporated into a Photochemical Trajectory Model (PTM) and applied to the simulation of boundary layer photochemistry in the Portuguese west coast region. Comparison of modelled concentrations of ozone and a number of other species (NO(x) and selected hydrocarbons and organic oxygenates) was carried out, using data from three connected sites on two case study days when well-defined sea breeze conditions were established. The ozone concentrations obtained through the application of the PTM are a good approximation to the measured values, the average difference being ca. 15%, indicating that the model was acceptable for evaluation of the details of the chemical processing. The detailed chemistry is examined, allowing conclusions to be drawn concerning chemical interferences in the measurements of NO(2), and in relation to the sensitivity of ozone formation to changes in ambient temperature. Three important, and comparable, contributions to the temperature sensitivity are identified and quantified, namely (i) an effect of increasing biogenic emissions with temperature; (ii) an effect of increasing ambient water vapour concentration with temperature, and its influence on radical production; and (iii) an increase in VOC oxidation chain lengths resulting from the temperature-dependence of the kinetic parameters, particularly in relation to the stability of PAN and its higher analogues. The sensitivity of the simulations to the refinements implemented into MCM v3.1 are also presented and discussed.

Investigation of the radical product channel of the CH(3)C(O)CH(2)O(2) + HO(2) reaction in the gas phase.

The reaction of CH(3)C(O)CH(2)O(2) with HO(2) has been studied at 296 K and 700 Torr using long path FTIR spectroscopy, during photolysis of Cl(2)/acetone/methanol/air mixtures. The branching ratio for the reaction channel forming CH(3)C(O)CH(2)O, OH and O(2) () was investigated in experiments in which OH radicals were scavenged by addition of benzene to the system, with subsequent formation of phenol used as the primary diagnostic for OH radical formation. The observed prompt formation of phenol under conditions when CH(3)C(O)CH(2)O(2) reacts mainly with HO(2) indicates that this reaction proceeds partially by channel , which forms OH both directly and indirectly, by virtue of secondary generation of CH(3)C(O)O(2) (from CH(3)C(O)CH(2)O) and its reaction with HO(2) (). The secondary generation of OH radicals was confirmed by the observed formation of CH(3)C(O)OOH, a well-established product of the CH(3)C(O)O(2) + HO(2) reaction (via channel ). A number of delayed sources of OH also contribute to the observed phenol formation, such that full characterisation of the system required simulations using a detailed chemical mechanism. The dependence of the phenol and CH(3)C(O)OOH yields on the initial peroxy radical precursor reagent concentration ratio, [methanol](0)/[acetone](0), were well described by the mechanism, consistent with a small but significant fraction of the reaction of CH(3)C(O)CH(2)O(2) with HO(2) proceeding via channel . This allowed a branching ratio of k(3b)/k(3) = 0.15 +/- 0.08 to be determined. The results therefore provide strong indirect evidence for the participation of the radical-forming channel of the title reaction.

Investigation of the radical product channel of the CH3COO2 + HO2 reaction in the gas phase.

The reaction of CH(3)C(O)O(2) with HO(2) has been investigated at 296 K and 700 Torr using long path FTIR spectroscopy, during photolysis of Cl(2)/CH(3)CHO/CH(3)OH/air mixtures. The branching ratio for the reaction channel forming CH(3)C(O)O, OH and O(2) (reaction ) has been determined from experiments in which OH radicals were scavenged by addition of benzene to the system, with subsequent formation of phenol used as the primary diagnostic for OH radical formation. The dependence of the phenol yield on benzene concentration was found to be consistent with its formation from the OH-initiated oxidation of benzene, thereby confirming the presence of OH radicals in the system. The dependence of the phenol yield on the initial peroxy radical precursor reagent concentration ratio, [CH(3)OH](0)/[CH(3)CHO](0), is consistent with OH formation resulting mainly from the reaction of CH(3)C(O)O(2) with HO(2) in the early stages of the experiments, such that the limiting yield of phenol at high benzene concentrations is well-correlated with that of CH(3)C(O)OOH, a well-established product of the CH(3)C(O)O(2) + HO(2) reaction (via channel (3a)). However, a delayed source of phenol was also identified, which is attributed mainly to an analogous OH-forming channel of the reaction of HO(2) with HOCH(2)O(2) (reaction ), formed from the reaction of HO(2) with product HCHO. This was investigated in additional series of experiments in which Cl(2)/CH(3)OH/benzene/air and Cl(2)/HCHO/benzene/air mixtures were photolysed. The various reaction systems were fully characterised by simulations using a detailed chemical mechanism. This allowed the following branching ratios to be determined: CH(3)C(O)O(2) + HO(2)--> CH(3)C(O)OOH + O(2), k(3a)/k(3) = 0.38 +/- 0.13; --> CH(3)C(O)OH + O(3), k(3b)/k(3) = 0.12 +/- 0.04; --> CH(3)C(O)O + OH + O(2), k(3c)/k(3) = 0.43 +/- 0.10: HOCH(2)O(2) + HO(2)--> HCOOH + H(2)O + O(2), k(17b)/k(17) = 0.30 +/- 0.06; --> HOCH(2)O + OH + O(2), k(17c)/k(17) = 0.20 +/- 0.05. The results therefore provide strong evidence for significant participation of the radical-forming channels of these reactions, with the branching ratio for the title reaction being in good agreement with the value reported in one previous study. As part of this work, the kinetics of the reaction of Cl atoms with phenol (reaction (14)) have also been investigated. The rate coefficient was determined relative to the rate coefficient for the reaction of Cl with CH(3)OH, during the photolysis of mixtures of Cl(2), phenol and CH(3)OH, in either N(2) or air at 296 K and 760 Torr. A value of k(14) = (1.92 +/- 0.17) x 10(-10) cm(3) molecule(-1) s(-1) was determined from the experiments in N(2), in agreement with the literature. In air, the apparent rate coefficient was about a factor of two lower, which is interpreted in terms of regeneration of phenol from the product phenoxy radical, C(6)H(5)O, possibly via its reaction with HO(2).

Effect of field of view on the levitation illusion.

Supine subjects inside a furnished room in which both they and the room are pitched 90 degrees backwards may experience themselves and the room as upright relative to gravity. This effect is known as the levitation illusion because observers report that their arms feel weightless when extended, and objects hanging in the room seem to "levitate". This illusion is an extreme example of a visually induced illusion of static tilt. Visually induced tilt illusions are commonly experienced in wide-screen movie theatres, flight simulators, and immersive virtual reality systems. For technical reasons an observer's field of view is often constrained in these environments. No studies have documented the effect of field-of-view (FOV) restriction on the incidence of the levitation illusion. Preliminary findings suggest that when concurrently manipulating the FOV and observer position within an environment, the incidence of levitation illusions depends not only on the field of view but also on the visible scene content.

Gravity and perceptual stability during translational head movement on earth and in microgravity.

We measured the amount of visual movement judged consistent with translational head movement under normal and microgravity conditions. Subjects wore a virtual reality helmet in which the ratio of the movement of the world to the movement of the head (visual gain) was variable. Using the method of adjustment under normal gravity 10 subjects adjusted the visual gain until the visual world appeared stable during head movements that were either parallel or orthogonal to gravity. Using the method of constant stimuli under normal gravity, seven subjects moved their heads and judged whether the virtual world appeared to move "with" or "against" their movement for several visual gains. One subject repeated the constant stimuli judgements in microgravity during parabolic flight. The accuracy of judgements appeared unaffected by the direction or absence of gravity. Only the variability appeared affected by the absence of gravity. These results are discussed in relation to discomfort during head movements in microgravity.

Perceiving a stable world during active rotational and translational head movements.

When a person moves through the world, the associated visual displacement of the environment in the opposite direction is not usually seen as external movement but rather as a changing view of a stable world. We measured the amount of visual motion that can be tolerated as compatible with the perception of moving within a stable world during active, sinusoidal, translational and rotational head movement. Head movements were monitored by means of a low-latency, mechanical head tracker and the information was used to update a helmet-mounted visual display. A variable gain was introduced between the head tracker and the display. Ten subjects adjusted this gain until the visual display appeared stable during sinusoidal yaw, pitch and roll head rotations and naso-occipital, inter-aural and dorso-ventral translations at 0.5 Hz. Each head movement was tested with movement either orthogonal to or parallel with gravity. A wide spread of gains was accepted as stable (0.8 to 1.4 for rotation and 1.1 to 1.8 for translation). The gain most likely to be perceived as stable was greater than that required by the geometry (1.2 for rotation; 1.4 for translation). For rotational motion, the mean gains were the same for all axes. For translation there was no effect of whether the movement was inter-aural (mean gain 1.6) or dorso-ventral (mean gain 1.5) and no effect of the relative orientation of the translation direction relative to gravity. However translation in the naso-occipital direction was associated with more closely veridical settings (mean gain 1.1) and narrower standard deviations than in other directions. These findings are discussed in terms of visual and non-visual contributions to the perception of an earth-stable environment during active head movement.

The relative role of visual and non-visual cues in determining the perceived direction of "up": experiments in parabolic flight.

In order to measure the perceived direction of "up", subjects judged the three-dimensional shape of disks shaded to be compatible with illumination from particular directions. By finding which shaded disk appeared most convex, we were able to infer the perceived direction of illumination. This provides an indirect measure of the subject's perception of the direction of "up". The different cues contributing to this percept were separated by varying the orientation of the subject and the orientation of the visual background relative to gravity. We also measured the effect of decreasing or increasing gravity by making these shape judgements throughout all the phases of parabolic flight (0 g, 2 g and 1 g during level flight). The perceived up direction was modeled by a simple vector sum of "up" defined by vision, the body and gravity. In this model, the weighting of the visual cue became negligible under microgravity and hypergravity conditions.

A kinetics and mechanistic study of the OH and NO2 initiated oxidation of cyclohexa-1,3-diene in the gas phase.

The kinetics and products of the OH and NO2-initiated oxidation of cyclohexa-1,3-diene have been investigated at 296 K and 700 Torr using long path FTIR spectroscopy. Relative rate methods were employed using the photolysis of cyclohexa-1,3-diene/CH3ONO/NO/air mixtures to measure kappa(OH + cyclohexa-1,3-diene) = (1.68 +/- 0.43) x 10(-10) cm3 molecule(-1) s(-1). From the pseudo-first order decay of cyclohexa-1,3-diene in the presence of excess NO2, a value of kappa(NO2 + cyclohexa-1,3-diene) = (1.75 +/- 0.15) x 10(-18) cm3 molecule)-1) s(-1) was derived. An upper limit of kappa < or = 7 x 10(-21) cm3 molecule(-1) s(-1) was established for the reaction of NO with cyclohexa-1,3-diene. Benzene was observed as a product of both the OH and NO2 initiated oxidation, providing evidence of H atom abstraction in both reactions. Assuming the reaction of cyclohexadienyl radicals (C6H7) with O2 produces benzene as the sole organic product, the results are consistent with abstraction channel branching ratios of (8.1 +/- 0.2)% and (1.5 +/- 0.4)%, respectively. The results also indicate that C6H7 reacts with NO2, with a relative rate coefficient kappa(C6H7 + NO2)/kappa(C6H7 +O2) = (1.8 +/- 0.5) x 10(5), and that this partially forms benzene, with a branching ratio of (27 +/- 7)%. The stoichiometry and products of the NO2 reaction were investigated in the absence of O2, in the presence of O2, and in the presence of O2 and NO. Reaction mechanisms consistent with the observations are presented. In the presence of NO and O2, the NO2-initiated chemistry leads to NO-to-NO2 conversion, and the formation of HOx radicals in significant yield, (0.79 +/- 0.05), such that cyclohexa-1,3-diene removal occurs by reaction with both NO2 and OH. HCOOH was detected as a product in this system, providing evidence for significant formation of stabilised C6 alpha-hydroxyperoxy radicals from the OH-initiated chemistry, and their subsequent reaction with NO. An estimate of ca. 500-1000 s(-1) is made for their decomposition rate, based on the [NO]-dependence of the HCOOH yields. The implications of the results are discussed within the context of the atmospheric chemistry of conjugated dienes.

Perceptual stability during active head movements orthogonal and parallel to gravity.

We measured how much the visual world could be moved during various head rotations and translations and still be perceived as visually stable. Using this as a monitor of how well subjects know about their own movement, we compared performance in different directions relative to gravity. For head rotations, we compared the range of visual motion judged compatible with a stable environment while rotating around an axis orthogonal to gravity (where rotation created a rotating gravity vector across the otolith macula), with judgements made when rotation was around an earth-vertical axis. For translations, we compared the corresponding range of visual motion when translation was parallel to gravity (when imposed accelerations added to or subtracted from gravity), with translations orthogonal to gravity. Ten subjects wore a head-mounted display and made active head movements at 0.5 Hz that were monitored by a low-latency mechanical tracker. Subjects adjusted the ratio between head and image motion until the display appeared perceptually stable. For neither rotation nor translation were there any differences in judgements of perceptual stability that depended on the direction of the movement with respect to the direction of gravity.

Relative role of visual and non-visual cues in determining the direction of "up": experiments in the York tilted room facility.

Perceiving a direction as "up" is fundamental to human performance and perception. Astronauts in microgravity frequently experience reorientation illusions in which they, or their world, appear to flip and 'up' becomes arbitrarily redefined. This paper assesses the relative importance of visual cues in determining the perceived up direction. In the absence of information about the origin of illumination, people interpret surface structure by assuming that the direction of illumination is from above. Here we exploit this phenomenon to measure the influence of head and body orientation, gravity and visual cues on the perceived up direction. Fifteen subjects judged the shape of shaded circles presented in various orientations. The circles were shaded in such a way that when the shading was compatible with light coming from above, the circle appeared as a convex hemisphere. Therefore, by finding which shaded circle appeared most convex, we can deduce the direction regarded as "up". The different cues contributing to this percept were separated by varying both the orientation of the subject and the surrounding room relative to gravity. The relative significance of each cue may be of use in spacecraft interior design to help reduce the incidence of visual reorientation illusions.

Ambient concentrations of 1,3-butadiene in the UK.

This paper assesses the current knowledge of 1,3-butadiene as an atmospheric pollutant, considers measurement techniques and reviews available data on 1,3-butadiene monitoring and emissions estimates. Atmospheric chemistry, sources of emission, current legislation, measurement techniques and monitoring programmes for 1,3-butadiene are reviewed. There have been comparatively few studies of the products of oxidation of 1,3-butadiene in the atmosphere. However, on the basis of the available information, and by analogy with the oxidation mechanism for the widely-studied and structurally similar natural hydrocarbon isoprene (2-methyl-1,3-butadiene), it is possible to define some features of the likely oxidation pathways for 1,3-butadiene. The total UK 1,3-butadiene emission to the atmosphere for 1996 has been estimated at 10.60 kTonnes. 1,3-Butadiene is a product of petrol and diesel combustion; consequently this total is dominated by road transport exhaust emissions (accounting for some 68% of the total). Off-road vehicles and machinery are responsible for 14% of the total UK emission. 1,3-Butadiene is used in the manufacture of numerous rubber compounds, and consequently emissions arise from both the manufacture and use of 1,3-butadiene in industrial processes. Emissions from the chemical industry account for 18% of the UK total emission- 8% from 1,3-butadiene manufacture and 10% from 1,3-butadiene use. The United Kingdom Expert Panel on Air Quality Standards (EPAQS) has published a report on 1,3-butadiene, and recommended a national air quality standard of 1.0 ppb (expressed as an annual rolling mean). This was adopted by the Government as part of the National Air Quality Strategy (NAQS) in 1997, and a target of compliance by 2005 was set. Work conducted for the review of the NAQS (1999) indicated that it was likely that all locations would be compliant with the national standard by the end of 2003. As a result, the review updated the air quality objective for 1,3-butadiene, with the deadline for compliance being brought forward to 31/12/2003. The UK Hydrocarbon Monitoring Network provides continuous hourly measurements of 1,3-butadiene at 13 sites, and has been operational since 1993. The dataset that is available allows spatial and temporal trends to be evaluated, and has proved to be invaluable in characterising the current ambient levels of 1,3-butadiene in the UK. Hourly maximum concentrations of 1,3-butadiene of up to 10 ppb (1 ppb=1 ppb, i.e. 1 vol. of 1,3-butadiene in 1,000,000,000 vol. of air. 1 ppb of 1,3-butadiene is ca. equal to 2.25 microg m(-3) at 20 degrees C) may be measured for several hours at the sites. Monthly mean concentrations are typically 0.1-0.4 ppbv. At most sites, these levels are driven by emissions from motor vehicles. Occasionally emissions of 1,3-butadiene from industrial sources may elevate 1,3-butadiene concentrations to several tens of ppb. Trend analysis of the data suggests that ambient concentrations of 1,3-butadiene in the UK are declining at about 10% per year.

Characterization of the reactivities of volatile organic compounds using a master chemical mechanism.

A comprehensive description of the ozone-forming potentials of 101 organic compounds has been constructed under North American urban "averaged conditions" using a detailed master chemical mechanism and a simple air parcel trajectory model. This chemical mechanism describes the reactions of 3603 chemical species taking part in more than 10,500 chemical reactions. An index value has been calculated for each organic compound, which describes the increment in ozone concentrations found downwind of an urban area following the emission of a fixed increment in the mass emission of each organic compound. These indices, termed photochemical ozone creation potentials (POCPs), have been expressed on a scale relative to ethylene (ethene) = 100, and, a reactivity scale has been generated for alkanes, alkenes, and oxygenated and halogenated organic compounds. A high degree of correlation (R2 = 0.9) was found between these POCP values and the most widely accepted urban reactivity scale. While the reactivities of most of the 86 organic compounds compared fell within a consistent range, significant discrepancies were found for only 5 compounds. Single-day or multiday conditions appear to be important in establishing quantitative reactivity scales for the less reactive organic compounds.

Humans can use optic flow to estimate distance of travel.

We demonstrate that humans can use optic flow to estimate distance travelled when appropriate scaling information is provided. Eleven subjects were presented with visual targets in a virtual corridor. They were then provided with optic flow compatible with movement along the corridor and asked to indicate when they had reached the previously presented target position. Performance depended on the movement profile: for accelerations above 0.1 m/s2 performance was accurate. Slower optic-flow acceleration resulted in an overestimation of motion which was most pronounced for constant velocity motion when the overestimation reached 170%. The results are discussed in terms of the usual synergy between multiple sensory cues to motion and the factors that might contribute to such a pronounced miscalibration between optic flow and the resulting perception of motion.

Visual and non-visual cues in the perception of linear self-motion.

Surprisingly little is known of the perceptual consequences of visual or vestibular stimulation in updating our perceived position in space as we move around. We assessed the roles of visual and vestibular cues in determining the perceived distance of passive, linear self motion. Subjects were given cues to constant-acceleration motion: either optic flow presented in a virtual reality display, physical motion in the dark or combinations of visual and physical motions. Subjects indicated when they perceived they had traversed a distance that had been previously given to them either visually or physically. The perceived distance of motion evoked by optic flow was accurate relative to a previously presented visual target but was perceptually equivalent to about half the physical motion. The perceived distance of physical motion in the dark was accurate relative to a previously presented physical motion but was perceptually equivalent to a much longer visually presented distance. The perceived distance of self motion when both visual and physical cues were present was more closely perceptually equivalent to the physical motion experienced rather than the simultaneous visual motion, even when the target was presented visually. We discuss this dominance of the physical cues in determining the perceived distance of self motion in terms of capture by non-visual cues. These findings are related to emerging studies that show the importance of vestibular input to neural mechanisms that process self motion.

Vestibular capture of the perceived distance of passive linear self motion.

The relative role of visual and vestibular cues in determining the perceived distance of passive, linear self motion were assessed. Seventeen subjects were given cues to constant acceleration motion: either optic flow, physical motion in the dark or combinations of visual and physical motion. Subjects indicated when they perceived they had traversed a distance that had been previously indicated either visually or physically. The perceived distance of motion evoked by optic flow was accurate relative to a visual target but was perceptually equivalent to a shorter physical motion. The perceived distance of physical motion in the dark was accurate relative to a previously presented physical motion but was perceptually equivalent to a much longer visually presented distance. The perceived distance of self-motion when both visual and physical cues were present was perceptually equivalent to the physical motion experienced and not the simultaneous visual motion even when the target was presented visually. We describe this dominance of the physical cues in determining the perceived distance of self motion as "vestibular capture".

Differential regulation of cardiac angiotensin converting enzyme binding sites and AT1 receptor density in the failing human heart.

BACKGROUND: The regulation and interaction of ACE and the angiotensin II (Ang II) type I (AT1) receptor in the failing human heart are not understood. METHODS AND RESULTS: Radioligand binding with 3H-ramiprilat was used to measure ACE protein in membrane preparations of hearts obtained from 36 subjects with idiopathic dilated cardiomyopathy (IDC), 8 subjects with primary pulmonary hypertension (PPH), and 32 organ donors with normal cardiac function (NF hearts). 125I-Ang II formation was measured in a subset of hearts. Saralasin (125I-(Sar1,Ile8)-Ang II) was used to measure total Ang II receptor density. AT1 and AT2 receptor binding were determined with the AT1 receptor antagonist losartan. Maximal ACE binding (Bmax) was 578+/-47 fmol/mg in IDC left ventricle (LV), 713+/-97 fmol/mg in PPH LV, and 325+/-27 fmol/mg in NF LV (P<0.001, IDC or PPH versus NF). In IDC, PPH, and NF right ventricles (RV), ACE Bmax was 737+/-78, 638+/-137, and 422+/-49 fmol/mg, respectively (P=0.02, IDC versus NF; P=0.08, PPH versus NF). 125I-Ang II formation correlated with ACE binding sites (r=0.60, P=0.00005). There was selective downregulation of the AT1 receptor subtype in failing PPH ventricles: 6.41+/-1.23 fmol/mg in PPH LV, 2.37+/-0.50 fmol/mg in PPH RV, 5.38+/-0.53 fmol/mg in NF LV, and 7.30+/-1.10 fmol/mg in NF RV (P=0.01, PPH RV versus PPH LV; P=0.0006, PPH RV versus NF RV). CONCLUSIONS: ACE binding sites are increased in both failing IDC and nonfailing PPH ventricles. In PPH hearts, the AT1 receptor is downregulated only in the failing RV.

Selective downregulation of the angiotensin II AT1-receptor subtype in failing human ventricular myocardium.

BACKGROUND: The regulation of angiotensin II receptors and the two major subtypes (AT1 and AT2) in chronically failing human ventricular myocardium has not been previously examined. METHODS AND RESULTS: Angiotensin II receptors were measured by saturation binding of 125I-[Sar1,Ile8]angiotensin II in crude membranes from nonfailing (n = 19) and failing human left ventricles with idiopathic dilated cardiomyopathy (IDC; n = 31) or ischemic cardiomyopathy (ISC; n = 21) and membranes from a limited number of right ventricles in each category. The AT1 and AT2 fractions were determined by use of an AT1-selective antagonist, losartan. beta-Adrenergic receptors were also measured by binding of 125I-iodocyanopindolol with the beta 1 and beta 2 fractions determined by use of a beta 1-selective antagonist, CGP20712A, AT1 but not AT2 density was significantly decreased in the combined (IDC + ISC) failing left ventricles (nonfailing: AT1 4.66 +/- 0.48, AT2 2.73 +/- 0.39; failing: AT1 3.20 +/- 0.29, AT2 2.70 +/- 0.33 fmol/mg protein; mean +/- SE). The decrease in AT1 density was greater in the IDC than in the ISC left ventricles (IDC: 2.73 +/- 0.40, P < .01; ISC: 3.89 +/- 0.39 fmol/mg protein, P = NS versus nonfailing). beta 1 but not beta 2 density was decreased in the failing left ventricles. AT1 density was correlated with beta 1 density in all left ventricles (r = .43). AT1 density was also decreased in IDC right ventricles. In situ reverse transcription-polymerase chain reaction in sections of nonfailing and failing ventricles indicated that AT1 mRNA was present in both myocytes and nonmyocytes. CONCLUSIONS: AT1 receptors are selectively downregulated in failing human ventricles, similar to the selective downregulation of beta 1 receptors. The relative lack of AT1 downregulation in ISC hearts may be related to differences in the degree of ventricular dysfunction.