Biomedical subjects

A J Sinusas

Publications and source records attributed to A J Sinusas.

At least 19 recordsLinked to original sources

PubMed2005

On the dark rim artifact in dynamic contrast-enhanced MRI myocardial perfusion studies.

A dark band or rim along parts of the subendocardial border of the left ventricle (LV) and the myocardium has been noticed in some dynamic contrast-enhanced MR perfusion studies. The artifact is thought to be due to susceptibility effects from the gadolinium bolus, motion, or resolution, or a combination of these. Here motionless ex vivo hearts in which the cavity was filled with gadolinium are used to show that dark rim artifacts can be consistent with resolution effects alone.

Algorithms↗

PubMed2005

Molecular imaging. A new approach to nuclear cardiology.

Nuclear cardiology has historically played an important role in detection of cardiovascular disease as well as risk stratification. With the growth of molecular biology have come new therapeutic interventions and the requirement for new diagnostic imaging approaches. Noninvasive targeted radiotracer based as well as transporter gene imaging strategies are evolving to meet these new needs, but require the development of an interdisciplinary approach which focuses on molecular processes, as well as the pathogenesis and progression of disease. This progress has been made possible with the availability of transgenic animal models along with many technological advances. Future adaptations of the developing experimental procedures and instrumentation will allow for the smooth translation and application to clinical practice. This review is intended as a brief overview on the subject molecular imaging. Basic concepts and historical perspective of molecular imaging will be reviewed first, followed by description of current technology, and concluding with current applications in cardiology. The emphasis will be on the use of both single photon emission computed tomography (SPECT) and positron emission tomography (PET) radiotracers, although other imaging modalities will be also briefly discussed. The specific approaches presented here will include receptor-based and reporter gene imaging of natural and therapeutic angiogenesis.

Animals↗

PubMed2004

Vascular cell adhesion molecule-1-targeted detection of endothelial activation in human microvasculature.

The hallmark of endothelial activation, an early and critical step in many alloimmune and inflammatory responses, is the transcriptional induction and expression of endothelial adhesion molecules (eg, vascular cell adhesion molecule-1 [VCAM-1]). We assessed the feasibility of VCAM-1-targeted in vivo detection of endothelial activation using I-125-labeled-F(ab')2 fragments of E1/6, a monoclonal antibody against human but not murine VCAM-1. The Kd and Bmax, determined by saturation binding in tumor necrosis factor (TNF)-activated human endothelial cells (ECs), were 3.2 +/- 0.6 nmol/L and 5600 +/- 300 binding sites per EC, respectively. Biodistribution and in vivo binding characteristics of I-125-E1/6 F(ab')2 were assessed in a novel chimeric human/mouse model, in which human skin (as a source of human microvasculature) is grafted onto SCID/beige mice. I-125-E1/6 F(ab')2 localized to TNF-activated human skin grafts as detected by autoradiography and gamma well-counting. Relative uptakes (uptake in human skin graft/uptake in the surrounding mouse skin) were, respectively, 2.6 +/- 0.8 (n = 14) and 1.6 +/- 0.3 (n = 12) for E1/6 and MOPC-21, an isotype-matched control antibody (P < .01). The preferential uptake in human skin graft was not due to differences in tissue vascularity assessed by Tc-99m-labeled murine red blood cells. In conclusion, the chimeric human/mouse model is a novel experimental tool for in vivo evaluation of human endothelial cell-specific radiopharmaceuticals. Although I-125-E1/6 F(ab')2 localized to human skin grafts, the limited number of VCAM-1 molecules/endothelial cell adversely affects its suitability as a target for in vivo imaging of endothelial activation.

Animals↗

PubMed2001

Estimation of 3D left ventricular deformation from echocardiography.

The quantitative estimation of regional cardiac deformation from 3D image sequences has important clinical implications for the assessment of viability in the heart wall. Such estimates have so far been obtained almost exclusively from Magnetic Resonance (MR) images, specifically MR tagging. In this paper we describe a methodology for estimating cardiac deformations from 3D echocardiography (3DE). The images are segmented interactively and then initial correspondence is established using a shape-tracking approach. A dense motion field is then estimated using a transversely isotropic linear elastic model, which accounts for the fiber directions in the left ventricle. The dense motion field is in turn used to calculate the deformation of the heart wall in terms of strain in cardiac specific directions. The strains obtained using this approach in open-chest dogs before and after coronary occlusion, show good agreement with previously published results in the literature. They also exhibit a high correlation with strains produced in the same animals using implanted sonomicrometers. This proposed method provides quantitative regional 3D estimates of heart deformation from ultrasound images.

Animals↗

PubMed2001

Quantification of 3-D regional myocardial deformation: shape-based analysis of magnetic resonance images.

A comprehensive three-dimensional (3-D) shape-based approach for quantification of regional myocardial deformations was evaluated in a canine model (n = 8 dogs) with the use of cine magnetic resonance imaging. The shape of the endocardial and epicardial surfaces was used to track the 3-D trajectories of a dense field of points over the cardiac cycle. The shape-based surface displacements are integrated with a continuum biomechanics model incorporating myofiber architecture to estimate both cardiac- and fiber-specific endocardial and epicardial strains and shears for 24 left ventricular regions. Whereas radial and circumferential end-systolic strains were fairly uniform, there was a significant apex-to-base gradient in longitudinal strain and radial-longitudinal shear. We also observed transmural epicardial-to-endocardial gradients in both cardiac- and fiber-specific strains. The increase in endocardial strain was accompanied by increases in radial-longitudinal shear and radial-fiber shears in the endocardium, supporting previous theories of regional myocardial deformation that predict considerable sliding between myocardial fibers.

Animals↗

PubMed2001

A new method for quantification of spatial and temporal parameters of endocardial motion: evaluation of experimental infarction using magnetic resonance imaging.

BACKGROUND: With the development of high-resolution myocardial imaging there has evolved a need for automated techniques that can accurately quantify regional function. OBJECTIVE: To develop a new method for quantification of spatial and temporal parameters of endocardial motion. DESIGN: Magnetic resonance images were analyzed using a unique, shape-based approach that tracks endocardial surface motion at defined points through the cardiac cycle by minimizing the bending energy. SETTING: Animal instrumentation was performed in the Nuclear Cardiology Experimental Research Laboratory at Yale University, New Haven, Connecticut. Magnetic resonance imaging was performed at the Yale New Haven Hospital Center. ANIMALS: Eight mongrel canines were used. INTERVENTIONS: Electrocardiograph-gated gradient-echo magnetic resonance images were obtained before and after occlusion of the left anterior descending coronary. Thirty-two points along automatically defined endocardial contours were tracked. Average displacements and cumulative path lengths were computed from end-diastole for each point over the entire cardiac cycle. The average cumulative path length was computed for each of four quarters of systole for the normal, border and infarct zones. Shape-based parameters of systolic motion were compared with the centreline approach. Infarct zone was defined by postmortem histochemical staining. MAIN RESULTS: Displacement and cumulative path length over the cardiac cycle decreased significantly in the infarct and border zones (P<0.05), but did not change in the normal zone (P was not significant). Temporal changes in motion were observed in all zones. Displacement measured using the shape-based algorithm was more consistent than cumulative path length when compared with systolic motion measured using the centreline method. CONCLUSIONS: An automated, shape-based approach permits quantitative evaluation of both spatial and temporal parameters of regional endocardial motion from high-resolution electrocardiograph-gated images. Analysis of endocardial motion and cumulative motion over the entire cardiac cycle discriminated infarcted from normal and border regions.

Animals↗

PubMed2000

Point-tracked quantitative analysis of left ventricular surface motion from 3-D image sequences.

We propose and validate the hypothesis that we can use differential shape properties of the myocardial surfaces to recover dense field motion from standard three-dimensional (3-D) image sequences (MRI and CT). Quantitative measures of left ventricular regional function can be further inferred from the point correspondence maps. The noninvasive, algorithm-derived results are validated on two levels. First, the motion trajectories are compared to those of implanted imaging-opaque markers of a canine model in two imaging modalities, where subpixel accuracy is achieved. Second, the validity of using motion parameters (path length and thickness changes) for detecting myocardial injury area is tested by comparing algorithms derived results to postmortem analysis TTC staining of myocardial tissue, where the achieved Pearson product-moment correlation value is 0.968.

Algorithms↗

PubMed2000

Reproducibility and accuracy of gated SPECT for determination of left ventricular volumes and ejection fraction: experimental validation using MRI.

UNLABELLED: Quantitative gated SPECT (QGS) has been used for computation of left ventricular volumes and ejection fraction. This study evaluated, first, the effect of injected dose, time of imaging, and background activity on the reproducibility of QGS and, second, the accuracy of QGS, compared with cine MRI, for determining left ventricular volumes and ejection fractions in dogs with and without perfusion defects. METHODS: Sixteen dogs were subjected to either chronic occlusion of the circumflex artery (group I, no perfusion defect) or acute occlusion of the anterior descending coronary artery (group II, perfusion defect). Both groups underwent serial MRI and SPECT. RESULTS: ( QGS was very reproducible using the automated program (r = 0.99997). Correlation between left ventricular ejection fraction (LVEF) at 15 and 45 min was poor after the low-dose injection (r = 0.54; SE = 9%) and only fair after the high-dose injection (r = 0.77; SE = 5%). Correlation was poor in the presence of significant background activity (r = 0.36; SE = 12%). Correlation between QGS left ventricular volumes and MRI was good for group I (end-diastolic volume, r = 0.86; end-systolic volume, r = 0.81) and only fair for group II (end-diastolic volume, r = 0.66; end-systolic volume, r = 0.69). The overall LVEF correlation between QGS and MRI was poor (r = 0.51). QGS LVEF (mean +/- SD, 42% +/- 3%) overestimated MRI LVEF (29% +/- 2%). CONCLUSION: QGS provides a highly reproducible estimate of LVEF. However, QGS is affected by changes in background activity, time of imaging, and injected dose. In the presence of perfusion defects, QGS overestimated volume relative to MRI. The correlation between QGS- and MRI-derived LVEF was poor in this canine model.

Animals↗

PubMed1999

Regulation of myocardial glucose uptake and transport during ischemia and energetic stress.

Myocardial glucose utilization increases in response to the energetic stress imposed on the heart by exercise, pressure overload, and myocardial ischemia. Recruitment of glucose transport proteins is the cellular mechanism by which the heart increases glucose transport for subsequent metabolism. Moderate regional ischemia leads to the translocation of both glucose transporters, GLUT4 and GLUT1, to the sarcolemma in vivo. Myocardial ischemia also stimulates 5'-adenosine monophosphate-activated protein kinase, which may be a fuel gauge in the heart and other tissues signaling the need to turn on energy-generating metabolic pathways. Pharmacologic stimulation of this kinase increases cardiac glucose uptake and transporter translocation, suggesting that it may play an important role in augmenting glucose entry in the setting of ischemic or energetic stress. Thus, recent work has provided insight into the cellular and molecular mechanisms responsible for glucose uptake during energetic stress, which may lead to new approaches to the treatment of patients with coronary artery disease.

Adenosine Monophosphate↗

PubMed1999

The potential for myocardial imaging with hypoxia markers.

Direct "hot spot" imaging of myocardial tissue hypoxia is potentially of great clinical importance because available noninvasive approaches for the detection of myocardial ischemia have generally been based on the detection of flow heterogeneity or identification of regional alterations of myocardial metabolism. These existing approaches provide only an indirect assessment of regional myocardial ischemia, and may be affected by either sympathetic activation or substrate availability. The assessment of tissue oxygenation with hypoxic compounds may be the best indicator of the balance of flow and oxygen consumption. These compounds may provide a means of identifying dysfunctional chronically ischemic but viable "hibernating" myocardium and find a critical place in the assessment of angiogenesis. Nitroimidazole compounds hold promise for positive imaging of hypoxia in the heart. However, refinement of these compounds is needed to improve target specificity. The potential of technetium-99m (Tc99m) complexes derived from removal of the nitroimidazole moiety from a nitroimidazole-containing ligand is interesting and warrants further investigation. Experimental studies support the possibility of identifying myocardial hypoxia with the positron-emitting compound F18-fluoromisonidazole noninvasively. The potential of a Tc99m labeled nitroimidazole for positive imaging of myocardial ischemia is tremendous because single-photon imaging is more widely available. The true clinical potential of these nitroimidazole compounds can only be defined with future experimental and clinical studies. Ideally, these studies should include comparisons of tracer uptake with independent measures of regional ischemia or measures of oxygen tension, potentially using magnetic resonance imaging.

Animals↗

PubMed1998

Additive effects of hyperinsulinemia and ischemia on myocardial GLUT1 and GLUT4 translocation in vivo.

BACKGROUND: Myocardial ischemia increases glucose uptake through the translocation of GLUT1 and GLUT4 from an intracellular compartment to the sarcolemma. The present study was performed to determine whether hyperinsulinemia causes translocation of myocardial GLUT1 as well as GLUT4 in vivo and whether there are additive effects of insulin and ischemia on GLUT1 and GLUT4 translocation. METHODS ADN RESULTS: Myocardial glucose uptake and transporter distribution were assessed by arteriovenous measurements, cell fractionation, and immunofluorescence. In fasted anesthetized dogs, hyperinsulinemia increased myocardial glucose extraction 3-fold (P<0.01) and the sarcolemmal content of GLUT4 by 90% and GLUT1 by 50% (P<0.05 for both) compared with saline infusion. In subsequent experiments, glucose uptake and transporter distribution were determined in ischemic and nonischemic regions of hearts from hyperinsulinemic animals during regional myocardial ischemia. Glucose uptake was 50% greater in the ischemic region (P<0.05). This was associated with a 20% increase in sarcolemmal GLUT1 and a 60% increase in sarcolemmal GLUT4 contents in the ischemic region (P<0.05 for both). CONCLUSIONS: Insulin stimulates myocardial glucose utilization through translocation of GLUT1 as well as GLUT4. Insulin and ischemia have additive effects to increase in vivo glucose utilization and augment glucose transporter translocation. We conclude that recruitment of both GLUT1 and GLUT4 contributes to increased myocardial glucose uptake during moderate reductions in coronary blood flow under insulin-stimulated conditions.

Animals↗

PubMed1998

Limitations of dobutamine for enhancing flow heterogeneity in the presence of single coronary stenosis: implications for technetium-99m-sestamibi imaging.

UNLABELLED: Dobutamine is used as an alternative to exercise in conjunction with 99mTc-sestamibi SPECT perfusion imaging for detection of coronary artery disease. However, the use of quantitative dobutamine 99mTc-sestamibi SPECT imaging for enhanced detection of coronary stenosis has not been established. The goal of this study is to examine the effects of dobutamine stress on regional myocardial blood flow and relative myocardial 99mTc-sestamibi activity in the presence of a single-vessel stenosis. METHODS: In six open-chest dogs with left circumflex artery stenosis, radiolabeled microspheres were injected during baseline, severe stenosis and peak dobutamine stress (10 microg/kg/min). Technetium-99m-sestamibi was injected intravenously at peak dobutamine. Hearts were excised 20 min after 99mTc-sestamibi injection for SPECT imaging and post-mortem gamma-well counting. RESULTS: Dobutamine significantly increased heart rate, rate-pressure product and the first derivative of left ventricular pressure. Ischemic zone (left circumflex) myocardial blood flows (in ml/min/g) were: baseline, 0.92 +/- 0.15; stenosis, 0.65 +/- 0.16; and dobutamine, 1.19 +/- 0.38. Nonischemic zone myocardial blood flows were: baseline, 0.99 +/- 0.18; stenosis, 1.01 +/- 0.12; and dobutamine, 1.94 +/- 0.32 (p < 0.01 versus stenosis). Ischemic flows, expressed as percentages of nonischemic flows, were: baseline, 94% +/- 2%; stenosis, 63% +/- 11% (p < 0.05 versus baseline) and dobutamine, 60% +/- 12% (p was not significant versus stenosis). Technetium-99m-sestamibi activity in the ischemic zone (75% +/- 6% nonischemic) underestimated the relative flow deficit produced during dobutamine stress (p = 0.056). Myocardial 99mTc-sestamibi activity correlated with flow when flow was less than 1.0 ml/min/g. At higher flow ranges (1.0 ml/min/g-3.5 ml/min/g), 99mTc-sestamibi did not track flow. CONCLUSION: In a canine model of flow-limiting, single-vessel stenosis, dobutamine (10 microg/kg/min) did not augment flow heterogeneity. In addition, relative myocardial 99mTc-sestamibi activity underestimated microsphere flow at higher flows induced by dobutamine, leading to underestimation of ischemia. These findings suggest that dobutamine stress 99mTc-sestamibi scintigraphy may underestimate the relative flow deficit.

Animals↗

PubMed1997

Low-flow ischemia leads to translocation of canine heart GLUT-4 and GLUT-1 glucose transporters to the sarcolemma in vivo.

BACKGROUND: Myocardial ischemia increases heart glucose utilization in vivo. However, whether low-flow ischemia leads to the translocation of glucose transporter (GLUT)-4 and/or GLUT-1 to the sarcolemma in vivo is unknown. METHODS AND RESULTS: In a canine model, we evaluated myocardial glucose metabolism in vivo and the distribution of GLUT-4 and GLUT-1 by use of immunoblotting of sarcolemma and intracellular membranes and immunofluorescence localization with confocal microscopy. In vivo glucose extraction increased fivefold (P < .001) and was associated with net lactate release in the ischemic region. Ischemia led to an increase in the sarcolemma content of both GLUT-4 (15 +/- 2% to 30 +/- 3%, P < .02) and GLUT-1 (41 +/- 4% to 58 +/- 3%, P < .03) compared with the nonischemic region and to a parallel decrease in their intracellular contents. Immunofluorescence demonstrated the presence of both GLUT-4 and GLUT-1 on cardiac myocytes. GLUT-1 had a more prominent cell surface pattern than GLUT-4, which was primarily intracellular in the nonischemic region. However, significant GLUT-4 surface labeling was found in the ischemic region. CONCLUSIONS: Translocation of the insulin-responsive GLUT-4 transporter from an intracellular storage pool to the sarcolemma occurs in vivo during acute low-flow ischemia. GLUT-1 is also present in an intracellular storage pool from which it undergoes translocation to the sarcolemma in response to ischemia. These results indicate that both GLUT-1 and GLUT-4 are important in ischemia-mediated myocardial glucose uptake in vivo.

Animals↗

PubMed1997

Long QTc and torsades de pointes in human immunodeficiency virus disease.

Three patients with human immunodeficiency virus (HIV) infection presented with QT, prolongation (> 440 ms) and torsades de pointes. We sought to evaluate the etiology of the long QT syndrome in these patients without previously identified causes for QT, prolongation, and determine the prevalence among patients with HIV infection. The three index patients underwent: (1) left stellate ganglion block; (2) beta-blocker challenge; and (3) electrocardiographic stress testing. QTc interval was measured before and after intervention. We undertook a retrospective analysis of prevalence of QTC prolongation among all patients with computerized ECGs over a 6-month period at one institution and compared it to the prevalence in hospitalized patients with HIV disease. Thirty-four thousand one hundred eighty-one patients with computerized ECGs were screened for QTc prolongation. Forty-two hospitalized patients with HI disease had computerized ECG during the same 6-month period. In the three index patients, the QTc failed to shorten with left stellate ganglion blockade, beta-blocker challenge, or stress testing, suggesting an acquired form of the long QT syndrome in these patients with HIV disease. None had previously recognized acquired causes of QT, prolongation. Mexiletine hydrochloride was useful in preventing recurrences of torsades de pointes. We observed a 7.0% prevalence of QT, prolongation among all patients screened. Hospitalized patients with HIV disease (n = 42) during this same period, demonstrated an increased prevalence of QT, prolongation (28.6%, P = 0.002). Patients with HIV disease have a significantly higher prevalence of QTc prolongation than a general hospital-based population, may have an unrecognized acquired form of the long QT syndrome, and are at risk for torsades de pointes.

Adult↗

PubMed1997

Extracardiac activity complicates quantitative cardiac SPECT imaging using a simultaneous transmission-emission approach.

UNLABELLED: Increased extracardiac activity confounds conventional cardiac SPECT image reconstruction using a filtered backprojection method. Others have proposed that simultaneously acquired transmission-emission (STE) images that are reconstructed with a maximum likelihood (ML) method incorporating a nonuniform attenuation correction would less likely be affected by the presence of extracardiac activity. However, this approach corrects only for decreased myocardial counts from attenuation and not for increased myocardial counts from extracardiac activity. Therefore, STE with nonuniform attenuation correction may also result in reconstruction artifacts when extracardiac activity is present. METHODS: Acquisitions of phantoms with nonuniform and uniform attenuation were performed using STE and conventional approaches, in the absence and presence of extracardiac activity. All acquisitions used a triple-headed SPECT camera. STE acquisitions used fanbeam collimation and a 153Gd transmission source. STE images were reconstructed using ML, with and without nonuniform attenuation correction. Reconstructed short-axis images were quantitated, and percentage variability for each count profile was calculated. RESULTS: In a nonuniform phantom configuration, STE reconstruction with nonuniform attenuation correction significantly improved image uniformity. This improvement in image uniformity was diminished with the addition of increasing extracardiac activity. In a uniform phantom, STE reconstruction with nonuniform attenuation correction significantly improved uniformity only in the presence of extracardiac activity. CONCLUSION: The addition of attenuation correction in the presence of extracardiac activity can have complex effects on ML reconstruction with nonuniform attenuation correction, which depends on the amount of extracardiac activity and pattern of attenuation.

Artifacts↗

PubMed1996

Glucose metabolism distal to a critical coronary stenosis in a canine model of low-flow myocardial ischemia.

Myocardial regions perfused through a coronary stenosis may cease contracting, but remain viable. Clinical observations suggest that increased glucose utilization may be an adaptive mechanism in such "hibernating" regions. In this study, we used a combination of 13C-NMR spectroscopy, GC-MS analysis, and tissue biochemical measurements to track glucose through intracellular metabolism in intact dogs infused with [1-13C]glucose during a 3-4-h period of acute ischemic hibernation. During low-flow ischemia [3-13C]alanine enrichment was higher, relative to plasma [1-13C]glucose enrichment, in ischemic than in nonischemic regions of the heart, suggesting a greater contribution of exogenous glucose to glycolytic flux in the ischemic region (approximately 72 vs. approximately 28%, P < 0.01). Both the fraction of glycogen synthase present in the physiologically active glucose-6-phosphate-independent form (46 +/- 10 vs. 9 +/- 6%, P < 0.01) and the rate of incorporation of circulating glucose into glycogen (94 +/- 25 vs. 20 +/- 15 nmol/gram/min, P < 0.01) were also greater in ischemic regions. Measurement of steady state [4-13C)glutamate/[3-13C]alanine enrichment ratios demonstrated that glucose-derived pyruvate supported 26-36% of total tricarboxylic acid cycle flux in all regions, however, indicating no preference for glucose over fat as an oxidative substrate in the ischemic myocardium. Thus during sustained regional low-flow ischemia in vivo, the ischemic myocardium increases its utilization of exogenous glucose as a substrate. Upregulation is restricted to cytosolic utilization pathways, however (glycolysis and glycogen synthesis), and fat continues to be the major source of mitochondrial oxidative substrate.

Alanine↗

PubMed1995

Kinetic analysis of technetium-99m-labeled nitroimidazole (BMS-181321) as a tracer of myocardial hypoxia.

BACKGROUND: Experimental data have indicated that [99mTc]-nitroimidazole (BMS-181321) is preferentially taken up in hypoxic tissue; its kinetics, however, has not been fully investigated. The purpose of this study was to address the relation between perfusate oxygen level and myocardial retention of [99mTc]nitroimidazole. METHODS AND RESULTS: Bolus injection and constant infusion experiments were performed in Langendorff buffer-perfused rat hearts in normoxic and hypoxic conditions. Data were acquired with a pair of NaI detectors. The initial clearance rate of [99mTc]nitroimidazole was approximately 20 seconds and independent of perfusate oxygen level. The slow clearance rate was greater than 3 hours in all perfusion conditions. The tissue retention of [99mTc]nitroimidazole varied from 0.61 +/- 0.14% in normoxic conditions to 5.94 +/- 1.16% in the most severe hypoxic conditions. In addition, tissue retention was inversely proportional to perfusate oxygen level in a sigmoidal manner. The constant infusion experiments established that the binding rate at 25% oxygen level (1.94 +/- 0.38 mL of perfusate/min-g dry wt) was twofold of that at 40% and sevenfold at 100%. The binding rate of [99mTc]nitroimidazole was independent of the perfusion sequence, suggesting irreversible binding. CONCLUSIONS: These data indicate that [99mTc]nitroimidazole may be a useful tracer for the identification of myocardial hypoxia. A sigmoidal relation was demonstrated for the uptake of the tracer, which suggests that a threshold level of hypoxia is necessary for the uptake of the tracer.

Animals↗

PubMed1995

Technetium-99m-nitroimidazole (BMS181321): a positive imaging agent for detecting myocardial ischemia.

UNLABELLED: A new technetium-99m-labeled nitroimidazole (BMS181321) has been proposed for positive imaging of myocardial ischemia. METHODS: An in vivo open-chest canine model of partial coronary occlusion and pacing-induced demand ischemia was used to correlate myocardial retention of BMS181321, following an intravenous injection at peak stress, with regional microsphere blood flow. Postmortem measurements of myocardial BMS181321 activity and flow were correlated with in vivo planar and ex vivo SPECT images. Myocardial and hepatic clearance of BMS181321 was derived from ROI analysis of serial planar images. RESULTS: Anaerobic metabolism was documented in the ischemic region by selective venous and arterial sampling for lactate and oxygen consumption. Normalized myocardial BMS181321 activity (165% +/- 42% nonischemic) in the central ischemic region (flow < 0.3 ml/min/gm) was significantly greater than activity in normal regions (p < 0.05). Quantitative circumferential analysis of SPECT images revealed a comparable increase in myocardial BMS181321 activity in the ischemic region. Sixty minutes after injection of BMS181321, liver activity was 423% of ischemic myocardial activity. CONCLUSION: BMS181321 was preferentially retained in ischemic but viable canine myocardium and was inversely related to regional myocardial blood flow. Although enhanced retention of BMS181321 was detectable by ex vivo SPECT imaging, an unfavorable heart-to-liver ratio was observed with in vivo planar imaging which may limit its use in clinical myocardial imaging.

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