Novel pyrrolo-1,5-benzoxazepine compounds display significant activity against resistant chronic myeloid leukaemia cells in vitro, in ex vivo patient samples and in vivo.

BACKGROUND: Imatinib is a direct and potent inhibitor of the constitutively active tyrosine kinase, breakpoint cluster region-Abelson (Bcr-Abl), which is central to the pathogenesis of chronic myeloid leukaemia (CML) patients. As such, imatinib has become the front-line treatment for CML patients. However, the recent emergence of imatinib resistance, commonly associated with point mutations within the kinase domain, has led to the search for alternative drug treatments and combination therapies for CML. METHODS: In this report, we analyse the effects of representative members of the novel pro-apoptotic microtubule depolymerising pyrrolo-1,5-benzoxazepines or PBOX compounds on chemotherapy-refractory CML cells using a series of Bcr-Abl mutant cell lines, clinical ex vivo patient samples and an in vivo mouse model. RESULTS: The PBOX compounds potently reduce cell viability in cells expressing the E225K and H396P mutants as well as the highly resistant T315I mutant. The PBOX compounds also induce apoptosis in primary CML samples including those resistant to imatinib. We also show for the first time, the in vivo efficacy of the pro-apoptotic PBOX compound, PBOX-6, in a CML mouse model of the T315I Bcr-Abl mutant. CONCLUSION: Results from this study highlight the potential of these novel series of PBOX compounds as an effective therapy against CML.

Ventricular contraction abnormalities in dilated cardiomyopathy: effect of biventricular pacing to correct interventricular dyssynchrony.

OBJECTIVE: To measure ventricular contractile synchrony in patients with dilated cardiomyopathy (DCM) and to evaluate the effects of biventricular pacing on contractile synchrony and ejection fraction. BACKGROUND: Dilated cardiomyopathy is characterized by abnormal ventricular activation and contraction. Biventricular pacing may promote a more coordinated ventricular contraction pattern in these patients. We hypothesized that biventricular pacing would improve synchrony of right ventricular and left ventricular (RV/LV) contraction, resulting in improved ventricular ejection fraction. METHODS: Thirteen patients with DCM and intraventricular conduction delay underwent multiple gated equilibrium blood pool scintigraphy. Phase image analysis was applied to the scintigraphic data and mean phase angles computed for the RV and LV. Phase measures of interventricular (RV/LV) synchrony were computed in sinus rhythm and during atrial sensed biventricular pacing (BiV). RESULTS: The degree of interventricular dyssynchrony present in normal sinus rhythm correlated with LV ejection fraction (r = -0.69, p < 0.01). During BiV, interventricular contractile synchrony improved overall from 27.5 +/- 23.1 degrees to 14.1 +/- 13 degrees (p = 0.01). The degree of interventricular dyssynchrony present in sinus rhythm correlated with the magnitude of improvement in synchrony during BiV (r = 0.83, p < 0.001). Left ventricular ejection fraction increased in all thirteen patients during BiV, from 17.2 +/- 7.9% to 22.5 +/- 8.3% (p < 0.0001) and correlated significantly with improvement in RV/LV synchrony during BiV (r = 0.86, p < 0.001). CONCLUSIONS: Dilated cardiomyopathy with intraventricular conduction delay is associated with significant interventricular dyssynchrony. Improvements in interventricular synchrony during biventricular pacing correlate with acute improvements in LV ejection fraction.

Potential added value of three-dimensional reconstruction and display of single photon emission computed tomographic gated blood pool images.

BACKGROUND: Single photon emission computed tomographic (SPECT) acquisition provides potential advantages for blood pool imaging. However, the method has been little applied. METHODS: An improved method of three-dimensional (3-D) reconstruction and display of SPECT equilibrium blood pool scintigrams and related phase data was developed. Dynamic slices and volume-rendered dynamic 3-D images were displayed. Images were viewed from each of 34 solid angles referenced to a sphere surrounding the reconstruction field. Each image pixel was "painted" with intensity-coded regional amplitude and color-coded for its phase angle. The method was applied to evaluate the cardiac anatomy, regional contraction, and related conduction sequence at rest in 17 patients. Twelve had normal left ventricular function including 7 patients with minimal septal preexcitation. Five patients had abnormal left ventricular function, including 2 with left bundle branch block. RESULTS: Slices contained all of the functional information, but necessary data integration was time-consuming and evaluation of chamber size and anatomy was difficult. Three-dimensional projection images condensed and integrated the data, presenting new vantage points on anatomy, contraction, and conduction not otherwise available in the clinically limited angulations of planar images. This provided excellent visual separation of cardiac chambers with full and increased visualization of right and left ventricular wall motion in all segments compared with the conventional projections acquired clinically (p < 0.05). Atria and great vessels were well separated with evident size and function. Phase-angle progression paralleled the electrocardiogram, permitting bypass pathway localization and the direct noninvasive localization of posteroseptal pathways. CONCLUSIONS: The 3-D method permits greater access to and utilization of SPECT blood pool image data. It suggests specific advantages for clinical use.

Cardiac activation mapping by MRI.

To establish cardiac MRI as a tool for noninvasive evaluation of activation patterns, 10 healthy volunteers were examined by cine segmented turboFLASH imaging sequences. Sequence modifications for low signal blood-pool appearance were applied, i.e., bilateral spatial saturation for segmented turboFLASH imaging. Pixelwise calculation of first-harmonic Fourier phase values (displayed as color-encoded maps) reveal either anterior septal or left ventricular free-wall sites as areas of earliest phase spreading towards posterior paraseptal sites in segmented turboFLASH scans. Phase scatter is lower in unsaturated than spatially presaturated segmented turboFLASH studies. Phase standard deviation in areas of endocardial displacement is higher in basal than apical slice positions in these scans. Early results indicate that first-harmonic Fourier phase analysis of cardiac-segmented turboFLASH MRI cine studies may provide a tool for noninvasive studies of cardiac activation sequence.

Acute and chronic effects of transient myocardial ischemia on sympathetic nerve activity, density, and norepinephrine content.

OBJECTIVES: The sympathetic nervous system has profound influences on myocardial function, particularly during ischemia. There is controversy, however, as to whether myocardial ischemia results in damage to myocardial sympathetic nerves coursing through the ischemic territory. To further evaluate these issues, we assessed the acute and chronic effects of transient myocardial ischemia on sympathetic nerve function and morphology. METHODS: A total of 20 dogs were studied. For acute studies (n = 9), we performed serial dynamic imaging of I-123 metaiodobenzylguanidine (MIBG) washout during coronary occlusion and reperfusion, and assessed residual myocardial perfusion with thallium-201. For chronic studies (n = 11), we assessed sympathetic innervation and perfusion 11 days following a transient intracoronary balloon occlusion. Imaging results were correlated with electrocardiographic responses, histology, and tissue norepinephrine (NE). RESULTS: In the acute studies, regional MIBG washout increased more than 2-fold in the ischemic territory compared to the control region during coronary occlusion (14.2 +/- 2.3 vs. 5.9 +/- 1.2%, P < 0.01). Tissue NE was reduced in the ischemic territory compared to the non-ischemic territory (335 +/- 162 vs. 751 +/- 190 ng/g, P < 0.01). Myocardial perfusion was normal. In the chronic studies, 9/11 dogs showed ischemic ECG changes during balloon occlusion, and developed ventricular arrhythmias. On follow-up imaging, 5/11 dogs showed reduced MIBG uptake relative to thallium, in viable myocardium overlying necrotic subendocardium, reduced NE (226 +/- 77 vs. 733 +/- 82 ng/g in control regions, P < 0.01), decreased nerve density, and a larger extent of denervation than scar (25.5 +/- 3.7 vs. 8.2 +/- 2.7%, P < 0.02). Six of 11 dogs showed normal innervation patterns. CONCLUSIONS: These studies suggest that the sympathetic nerves are acutely affected in regions of myocardial ischemia as detected by enhanced regional washout of MIBG. In addition, chronic sympathetic nerve denervation can occur in the absence of transmural myocardial necrosis; however, the occurrence of transient ischemia does not predict the development of chronic denervation. The severity of ischemia, as evidenced by the extent of the related necrosis, does appear to predict chronic denervation. The severity of ischemia, as evidenced by the extent of the related necrosis, does appear to predict chronic denervation. The mechanisms leading to chronic denervation of sympathetic nerves in the absence of transmural infarction remain to be defined.

Metaiodobenzylguanidine as an index of atrioventricular nodal adrenergic activity.

UNLABELLED: Despite its importance, little is known about the uptake, storage and release of catecholamines in the atrioventricular (AV) node and His bundle. Previous in vitro studies have been limited by metabolism of norepinephrine. Metaiodobenzylguanidine (MIBG) shares many transport properties with norepinephrine and is considered a functional marker of adrenergic activity. METHODS: We used [125I]MIBG +/- 99mTc-sestamibi (99mTc-MIBI) and [123I]MIBG +/- 201TI] to evaluate regional differences in adrenergic activity between cardiac conductive and contractile elements in rats. Histological localization of the AV node and His bundle was performed using stains for acetylcholinesterase. RESULTS: Densitometric evaluation of autoradiographs, obtained from 20-mu thick sections of hearts from rats injected with either [125I]MIBG +/- 99mTc-MIBI (n = 4) and [123I]MIBG +/- 201TI (n = 6), revealed that there was approximately 30% more MIBG uptake in the AV node and His bundle compared to atrial or ventricular muscle (p < 0.05). Color-coded functional maps, generated by computer to simultaneously display 123I or [125I]MIBG and perfusion markers, revealed that the heterogeneous distribution of MIBG was independent of myocardial blood flow. CONCLUSION: When used as a selective functional marker of adrenergic activity in the cardiac conduction system, 123I- or [125I]MIBG autoradiography demonstrates increased adrenergic activity in the AV node and His bundle compared with the left ventricle. MIBG imaging provides a new research technique to probe in vivo modulation of AV nodal and His bundle sympathetic activity.

Effects of long-term right ventricular apical pacing on left ventricular perfusion, innervation, function and histology.

OBJECTIVES: The purpose of this study was to better understand the effects of long-term right ventricular pacing on left ventricular perfusion, innervation, function and histology. BACKGROUND: Long-term right ventricular apical pacing is associated with increased congestive heart failure and mortality compared with atrial pacing. The exact mechanism for these changes is unknown. In this study, left ventricular perfusion, sympathetic innervation, function and histologic appearance after long-term pacing were studied in dogs in an attempt to see whether basic changes might be present that might ultimately be associated with the adverse clinical outcome. METHODS: A total of 24 dogs were studied. Sixteen underwent radiofrequency ablation of the atrioventricular (AV) junction to produce complete AV block. Seven of these underwent long-term pacing from the right ventricular apex (ventricular paced group), and nine had atrial and right ventricular apical pacing with AV synchrony (dual-chamber paced group). A control group of eight dogs had sham ablations with normal AV conduction. These dogs had atrial pacing only. Regional perfusion and sympathetic innervation were studied in all dogs by imaging with thallium-201 and [I123]metaiodobenzylguanidine, respectively. The degree of innervation was also determined by assay of tissue norepinephrine levels. Left ventricular function was assessed by radionuclide ventriculography. Cardiac histology was studied with both light and electron microscopy. RESULTS: Mismatching of perfusion and innervation in the ventricular paced group was noted, with perfusion abnormalities of both the septum and free wall. Regional [I123]metaiodobenzylguanidine distribution was homogeneous. Tissue norepinephrine levels were elevated in both the ventricular and dual-chamber paced groups compared with the control group. No light or electron microscopic findings were noted in any groups. In the dual-chamber paced group, diastolic dysfunction was noted, with normal systolic function. CONCLUSIONS: Ventricular pacing resulted in regional changes in tissue perfusion and heterogeneity between perfusion and sympathetic innervation. Both ventricular and dual-chamber pacing were associated with an increase in tissue catecholamine activity. The abnormal activation of the ventricles via right ventricular apical pacing may result in multiple abnormalities of cardiac function, which may ultimately affect clinical outcome.

Assessment of perfused left ventricular mass in normal, ischemic, and reperfused myocardium by means of single-photon emission computed tomography of technetium-99m isonitrile.

To test the hypothesis that single-photon emission tomography of technetium (Tc) 99m hexakis 2-methoxyisobutyl isonitrile (Tc-MIBI) can accurately measure perfused left ventricular (LV) mass in nonischemic, ischemic, and reperfused myocardium, we acquired Tc-MIBI tomographic images in canines with normally perfused hearts (n = 33) after occlusion of the left anterior descending coronary artery (n = 15), after reperfusion (n = 13), and with subsequent second injection of Tc-MIBI (15 to 18 mCi; n = 12). In all ischemic studies the initial dose of Tc-MIBI (5 to 6 mCi) was injected after coronary artery occlusion but before reflow. Scintigraphic perfused LV mass was calculated from the total voxels demonstrating Tc-MIBI uptake x voxel volume (cm3) x specific gravity of myocardium (1.05 gm/cm3). After being imaged the animals were killed, the left ventricle was weighed, and the risk area was determined by dual perfusion with phthalocyanine blue dye and triphenyltetrazolium chloride (TTC). Perfused LV mass was defined as total LV mass minus the risk area mass. There was good correlation between scintigraphic and morphologic determinations of perfused left ventricular mass in nonischemic hearts (Tc-MIBI left ventricular distribution = 0.84 x left ventricular weight + .20.4, n = 33, r = 0.93, p = 0.0001) and ischemic hearts (Tc-MIBI left ventricular distribution = 0.51 x left ventricular weight + 37.9, n = 15, r = 0.83, p = 0.0001). In animals imaged both before and after reperfusion, scintigraphic determinations of the nonischemic region correlated closely (after-reflow Tc-MIBI distribution = 1.07 x before-reflow Tc-MIBI distribution--8.0, n = 13, r = 0.88, p = 0.0001), indicating that Tc-MIBI does not significantly redistribute into the ischemic zone after reperfusion. After injection of the second dose of Tc-MIBI in acutely reperfused canines, there was good correlation between the distribution mass of Tc-MIBI and the mass of viable myocardium by TTC staining (Tc-MIBI distribution = 0.61 x viable LV mass + 34.2, n = 12, r = 0.77, p = 0.0001). Furthermore, the apparent redistribution of myocardial Tc-MIBI from before and after second injection images correlated with the degree of myocardial salvage by histochemical staining (r = 0.72, p = 0.0082). In conclusion, single-photon emission computed tomography of Tc-MIBI can measure perfused LV mass accurately in both ischemic and nonischemic canine preparations.(ABSTRACT TRUNCATED AT 400 WORDS)

Scintigraphic assessment of MIBG uptake in globally denervated human and canine hearts--implications for clinical studies.

To further characterize the behavior of metaiodobenzylguanidine (MIBG) in the myocardium and to test the hypothesis that the denervated heart would show normal early uptake on MIBG due to non-neuronal localization, we examined the early and late distribution of 123I-labeled MIBG in normal and globally denervated canine and human hearts. Canine hearts were denervated by intravenous injections of 6-hydroxydopamine, while patients were studied a mean of 4.3 mo following cardiac transplantation. Results in denervated hearts were compared to normal controls. Normal hearts showed prominent MIBG uptake on initial 5-min and 3-hr delayed images. Globally denervated canine hearts showed prominent uptake on initial images and absence of localization on delayed images, indicating complete washout of non-neuronally bound radionuclide. The transplanted human hearts showed no localization of MIBG on either early or delayed images. These results suggest that the non-neuronal uptake mechanism (uptake 2) is not significant in human myocardium. This finding has significant implications for interpreting the myocardial behavior of MIBG in various pathologic situations such as dilated cardiomyopathy.

Usefulness of adenosine in augmenting ventricular preexcitation for noninvasive localization of accessory pathways.

Adenosine was administered to test the hypothesis that it would maximize preexcitation and facilitate noninvasive localization of accessory pathways in 22 patients with suspected accessory pathway-mediated tachycardias. Twelve-lead electrocardiograms and 2-dimensional echocardiograms were recorded at baseline and during adenosine-augmented ventricular preexcitation to localize the accessory pathway. Phase analysis was performed on digitized 4-chamber and short-axis views using a first harmonic Fourier transformation. At baseline, 15 patients had manifest preexcitation. In 14 of these patients (93.3%), preexcitation became more prominent after adenosine. Four patients without preexcitation at baseline clearly had it after adenosine. In patients who had preexcitation in response to adenosine, the electrocardiogram correctly identified the accessory pathway locations in 18 of 19 patients at a regional level and was incorrect in 1 of 19 patients. Echocardiographic phase analysis correctly identified the accessory pathway location in all 17 patients, who had technically adequate studies, at a regional level. In conclusion, administration of adenosine accentuates preexcitation, allowing for more accurate electrocardiographic and echocardiographic accessory pathway localization.

Two-dimensional echocardiographic phase analysis. Its potential for noninvasive localization of accessory pathways in patients with Wolff-Parkinson-White syndrome.

BACKGROUND: In patients with the preexcitation syndrome who are undergoing transcatheter or surgical ablation, accurate localization of accessory pathways is critical. Because preexcitation is known to alter ventricular activation sequence and result in focal areas with presystolic contraction, we investigated whether phase analysis applied to two-dimensional echocardiographic cine loops objectively identifies these focal areas and can be used to localize ventricular insertion sites of accessory pathways. METHODS AND RESULTS: We prospectively obtained phase images in 17 patients (11 males; age range, 11-35 years) during minimal preexcitation in normal sinus rhythm and during maximal preexcitation induced by right atrial pacing. A group of 11 normal subjects (six men; age range, 26-37 years) served as controls. Pathway locations predicted from phase imaging were compared with those predicted from routine 12-lead ECGs, from visual inspection of cine loop images, and from catheter-mounted electrode endocardial mapping. Cross-sectional views in a digital cine loop format were mathematically transformed using a first harmonic Fourier algorithm to obtain the corresponding phase images. Phase angle histograms were derived in eight wall segments. Mean and earliest phase angles were derived by computer analysis to quantitate contraction sequence. We found that during right atrial pacing, phase angles in focal areas markedly deviated from normal--mean phase angles from 33 degrees to 164 degrees, and earliest phase angles from 50 degrees to 180 degrees. Accessory pathways could be precisely localized in 53% of the patients by 12-lead ECG, in 59% by visual inspection of cine loop images, in 82% by phase imaging, and in 94% by a combination of the three methods. CONCLUSIONS: Our results suggest that phase imaging, especially when used in combination with cine loop and 12-lead ECG, can be used to localize ventricular insertion sites of accessory pathways and may be clinically useful as a noninvasive adjunct to endocardial mapping in patients with Wolff-Parkinson-White syndrome.

Scintigraphic assessment of sympathetic innervation after transmural versus nontransmural myocardial infarction.

To evaluate the feasibility of detecting denervated myocardium in the infarcted canine heart, the distribution of sympathetic nerve endings using I-123 metaiodobenzylguanidine (MIBG) was compared with the distribution of perfusion using thallium-201, with the aid of color-coded computer functional map in 16 dogs. Twelve dogs underwent myocardial infarction by injection of vinyl latex into the left anterior descending coronary artery (transmural myocardial infarction, n = 6), or ligation of the left anterior descending coronary artery (nontransmural myocardial infarction, n = 6). Four dogs served as sham-operated controls. Image patterns were compared with tissue norepinephrine content and with histofluorescence microscopic findings in biopsy specimens. Hearts with transmural infarction showed zones of absent MIBG and thallium, indicating scar. Adjacent and distal regions showed reduced MIBG but normal thallium uptake, indicating viable but denervated myocardium. Denervation distal to infarction was confirmed by reduced norepinephrine content and absence of nerve fluorescence. Nontransmural myocardial infarction showed zones of wall thinning with decreased thallium uptake and a greater reduction or absence of MIBG localized to the region of the infarct, with minimal extension of denervation beyond the infarct. Norepinephrine content was significantly reduced in the infarct zone, and nerve fluorescence was absent. These findings suggest that 1) MIBG imaging can detect viable and perfused but denervated myocardium after infarction; and 2) as opposed to the distal denervation produced by transmural infarction, nontransmural infarction may lead to regional ischemic damage of sympathetic nerves, but may spare subepicardial nerve trunks that course through the region of infarction to provide a source of innervation to distal areas of myocardium.

Blood pool scintigraphy.

Scintigraphic techniques offer a variety of computer aided analytic methods for the assessment of ventricular size and function. They are objective, quantitative, and reproducible, and contribute to the clinical evaluation of all forms of cardiac disease. In some cases complementary to other methods, the scintigraphic assessment of ventricular function is often unique in the valuable clinical data which they supply.

The scintigraphic characteristics of ventricular pre-excitation through Mahaim fibers with the use of phase analysis.

The phase image pattern of blood pool scintigrams was blindly assessed in 11 patients exhibiting conduction through Mahaim pathways, including 6 nodoventricular and 5 fasciculoventricular. These patterns were compared with the phase image findings in normal subjects, patients with left and right bundle branch block in the absence of pre-excitation and patients with pre-excitation through atrioventricular (AV) connections. In all patients with a Mahaim pathway, the site of earliest phase angle was septal or paraseptal. Phase progression was asymmetric and the pre-excited ventricle demonstrated the earliest mean ventricular phase angle in 10 of 11 patients. This pattern, and the associated ventricular phase difference, appeared to vary from that in normal subjects and in those with a septal AV connection, in whom phase progression is generally symmetric. Scintigraphic phase analysis provided localizing information and presented patterns consistent with Mahaim pathways. Although not able to differentiate among Mahaim pathway subtypes, these phase patterns differed from those in normal subjects, those with right and left lateral free wall pathways and most patients with a septal AV pathway. However, the phase pattern of patients with a Mahaim pathway may not differ from that of patients with a septal AV connection displaying an asymmetric pattern of phase progression, or those with left and right bundle branch block in the absence of pre-excitation. Objective, yet imperfect phase measurements supported these differences. Such image findings may complement the often complex electrophysiologic evaluation of patients presenting with pre-excitation.

Scintigraphic assessment of regional cardiac adrenergic innervation.

To assess the feasibility of noninvasively imaging the regional distribution of myocardial sympathetic innervation, we evaluated the distribution of sympathetic nerve endings, using 123I metaiodobenzylguanidine (MIBG), and compared this with the distribution of myocardial perfusion, using 201Tl. Twenty dogs were studied: 11 after regional denervation, and nine as controls. Regional denervation was done by left stellate ganglion removal, right stellate ganglion removal, and application of phenol to the epicardial surface. Computer-processed functional maps displayed the relative distribution of MIBG and thallium in multiple projections in vivo and excised heart slices in all animals. In six animals, dual isotope emission computed tomograms were acquired in vivo. Tissue samples taken from innervated and denervated regions of the MIBG images were analyzed for norepinephrine content to validate image findings. Normal controls showed homogeneous and parallel distributions of MIBG and thallium in the major left ventricular mass. In the left stellectomized hearts, MIBG was reduced relative to thallium in the posterior left ventricle; whereas in right stellectomized hearts, reduced MIBG was in the anterior left ventricle. Phenol-painted hearts showed a broad area of decreased MIBG extending beyond the area of phenol application. In both stellectomized and phenol-painted hearts, thallium distribution remained homogeneous and normal. Norepinephrine content was greater in regions showing normal MIBG (550 +/- 223 ng/g) compared with regions showing reduced MIBG (39 +/- 44 ng/g) (p less than 0.001), confirming regional denervation. Combined MIBG-thallium functional maps display the regional distribution of sympathetic innervation. This new ability to noninvasively map the distribution of sympathetic nerves with simultaneous comparison to regional perfusion may provide important new insights into mechanisms, whereby an imbalance in sympathetic activity may relate to clinical disorders.

Improved immune-specificity in monoclonal radioimmunoimaging using dual radionuclide color functional maps.

Diagnostic radioimmunoimaging is potentially limited by tissue localization of radiolabeled antibody products through mechanisms other than antigen binding. Comparing the distributions of reactive and nonreactive products can distinguish tracer in targeted and nontargeted tissues. To achieve this in a single imaging procedure, dual photopeak scintigraphy was performed using 111In and 67Ga products. Melanoma-bearing athymic mice were coadministered intravenously subtype-matched 111In melanoma-reactive and 67Ga melanoma-nonreactive murine monoclonal antibodies. Paired images from 245 and 93 keV windows were processed with a unique dual parameter color display program. The display algorithm expresses pixel counts from paired photo-peak images in polar coordinates and color-encodes angle as hue and magnitude as intensity. The color functional maps permitted ready distinction of immune from nonimmune uptake. Compared with single tracer imaging methods, this technique better depicts antigen distribution.

The effects of coronary angioplasty and reperfusion on distribution of myocardial flow.

To assess the effects of angioplasty (PTCA) and intracoronary streptokinase (ICSK) on relative myocardial perfusion, we administered 99mTc-macroaggregated albumin (MAA) to the uninvolved coronary artery before successful PTCA in 33 patients and before successful infusion of ICSK in eight patients and of 111In-MAA into the same vessel after the intervention. In 10 patients who underwent PTCA, MAA was injected into the involved, instrumented coronary artery. Computer-processed images were acquired in registry and compared. Similar scintigraphic studies were performed in six control patients and in 11 in whom planned interventions were not performed or were unsuccessful. Distribution of MAA was also compared with angiographic results and with the distribution of 201Tl on images obtained in patients at rest or on redistribution images obtained before and soon after intervention in 22 patients. In control patients and those studied after aborted or unsuccessful intervention, scintigraphic results showed excellent correlation with the angiographic anatomy and were without serial change. When MAA was injected into the uninvolved vessel, the scintigram revealed evidence of collateral perfusion with retraction of the perfusion zone from that of the involved coronary in 19 of 33 patients undergoing PTCA and in three of eight of those receiving ICSK. When MAA was injected into the involved artery, a relative increase in perfusion was seen in eight of 10 patients after PTCA. Although 30 patients demonstrated scintigraphic evidence of collateral vessels, only 10 patients had angiographic evidence of collateral circulation before intervention. The distribution of 201Tl demonstrated little change in its global pattern and regions previously supplied by collaterals were generally well perfused after intervention. Coronary collateral perfusion may be inapparent angiographically and regress rapidly after angioplasty or reperfusion. Native perfusion is generally and quickly restored after successful PTCA or ICSK infusion, which obviates the need for collaterals. After intervention, the distribution of total perfusion may not change, but its regional source may demonstrate beneficial alterations, shifting from collateral to native circulation.

An accurate means of detecting and characterizing abnormal patterns of ventricular activation by phase image analysis.

The ability of scintigraphic phase image analysis to characterize patterns of abnormal ventricular activation was investigated. The pattern of phase distribution and sequential phase changes over both right and left ventricular regions of interest were evaluated in 16 patients with normal electrical activation and wall motion and compared with those in 8 patients with an artificial pacemaker and 4 patients with sinus rhythm with the Wolff-Parkinson-White syndrome and delta waves. Normally, the site of earliest phase angle was seen at the base of the interventricular septum, with sequential change affecting the body of the septum and the cardiac apex and then spreading laterally to involve the body of both ventricles. The site of earliest phase angle was located at the apex of the right ventricle in seven patients with a right ventricular endocardial pacemaker and on the lateral left ventricular wall in one patient with a left ventricular epicardial pacemaker. In each case the site corresponded exactly to the position of the pacing electrode as seen on posteroanterior and left lateral chest X-ray films, and sequential phase changes spread from the initial focus to affect both ventricles. In each of the patients with the Wolff-Parkinson-White syndrome, the site of earliest ventricular phase angle was located, and it corresponded exactly to the site of the bypass tract as determined by endocardial mapping. In this way, four bypass pathways, two posterior left paraseptal, one left lateral and one right lateral, were correctly localized scintigraphically. On the basis of the sequence of mechanical contraction, phase image analysis provides an accurate noninvasive method of detecting abnormal foci of ventricular activation.

Sex bias in graduate admissions: data from berkeley.

Examination of aggregate data on graduate admissions to the University of California, Berkeley, for fall 1973 shows a clear but misleading pattern of bias against female applicants. Examination of the disaggregated data reveals few decision-making units that show statistically significant departures from expected frequencies of female admissions, and about as many units appear to favor women as to favor men. If the data are properly pooled, taking into account the autonomy of departmental decision making, thus correcting for the tendency of women to apply to graduate departments that are more difficult for applicants of either sex to enter, there is a small but statistically significant bias in favor of women. The graduate departments that are easier to enter tend to be those that require more mathematics in the undergraduate preparatory curriculum. The bias in the aggregated data stems not from any pattern of discrimination on the part of admissions committees, which seem quite fair on the whole, but apparently from prior screening at earlier levels of the educational system. Women are shunted by their socialization and education toward fields of graduate study that are generally more crowded, less productive of completed degrees, and less well funded, and that frequently offer poorer professional employment prospects.