Noninvasive characterization of myocardial molecular interventions by integrated positron emission tomography and computed tomography.

OBJECTIVES: We sought to investigate the usefulness of integrated positron emission tomography (PET) and computed tomography (CT) for in vivo characterization of an angiogenesis-directed molecular intervention. BACKGROUND: Controversies about the effectiveness of molecular therapies for cardiovascular disease have prompted the need for more powerful noninvasive imaging techniques. METHODS: In a model of regional adenoviral transfer of the VEGF(121) gene to myocardium of healthy pigs, PET-CT using multiple molecular-directed radiotracers was employed. RESULTS: Two days after gene transfer, successful transgene expression was noninvasively confirmed by a reporter probe targeting co-expressed HSV1-sr39tk reporter gene. The CT-derived ventricular function and morphology remained unaltered (left ventricular ejection fraction 57 +/- 5% in adenovirus-injected animals vs. 53 +/- 5% in controls; p = 0.36). Increased regional perfusion was identified in areas overexpressing VEGF (myocardial blood flow during adenosine-induced vasodilation 1.47 +/- 0.49 vs. 1.14 +/- 0.27 ml/g/min in remote areas; p = 0.01), corroborating in vivo effects on microvascular tone and permeability. Finally, regional angiogenesis-associated alpha(v)beta3 integrin expression was not enhanced, suggesting little contribution to the perfusion increase. Fusion of CT morphology and tracer-derived molecular signals allowed for accurate regional localization of biologic signals. Findings were validated by control vectors, sham-operated animals, and ex vivo tissue analysis. CONCLUSIONS: Integrated PET-CT has the potential to dissect cardiovascular biologic mechanisms from gene expression to physiologic function and morphology. The VEGF overexpression in healthy myocardium increases myocardial perfusion without significant up-regulation of alpha(v)beta3 integrin adhesion molecules early after the intervention.     

(99m)Tc-Annexin-V uptake in a rat model of variable ischemic severity and reperfusion time.

BACKGROUND: To determine whether mild to moderate ischemia that is not severe enough to induce myocardial infarction will cause myocardial cell damage or apoptosis, the (99m)Tc-Annexin-V (Tc-A) uptake was studied in groups of rats with various intervals of coronary occlusion and reperfusion times. METHODS AND RESULTS: After left coronary artery occlusion for 15 min (n=23), 10 min (n=23), or 5 min (n=12), Tc-A (80-150 MBq) was injected at 0.5, 1.5, 6, or 24 h after reperfusion. One hour later, to verify the area at risk, (201)Tl (0.74 MBq) was injected just after left coronary artery re-occlusion and the rats were killed 1 min later. Dual tracer autoradiography was performed to assess Tc-A uptake and area at risk. In all 5-min occlusion and reperfusion models, no significant Tc-A uptake was observed in the area at risk. Tc-A uptake ratios in the 15-min and 10-min ischemia models were 4.46+/-3.16 and 2.02+/-0.47 (p=0.078) at 0.5 h after reperfusion, 3.49+/-1.78 and 1.47+/-0.11 (p<0.05) at 1.5 h after reperfusion, 1.60+/-0.43 and 1.34+/-0.23 (p=0.24) at 6 h after reperfusion, 1.50+/-0.33 and 1.28+/-0.33 (p=0.099) at 24 h after reperfusion, respectively. With 15-min ischemia, in 3 of the 5 rats there were a few micro-foci of myocardial cell degeneration and cell infiltration in less than 1% of the ischemic area at 24 h after reperfusion. No significant histological change was observed in rats with 10-min or 5-min ischemia. CONCLUSION: The data indicate that Tc-A binding depends on the severity of ischemia even without a significant amount of histological change or infarction.     

Myocardial perfusion and viability by positron emission tomography in infants and children with coronary abnormalities: correlation with echocardiography,coronary angiography,and histopathology

OBJECTIVES: This study was designed to assess the feasibility and accuracy of positron emission tomography (PET) imaging in infants and children. BACKGROUND: Positron emission tomography is employed in adults for the evaluation of myocardial perfusion and the detection of myocardial viability. METHODS: Perfusion and metabolism findings on PET in infants and children with suspected coronary abnormalities (age 14 days to 12 years old, mean 3.3 +/- 4.0 years) were correlated with findings on coronary angiography, echocardiography, and myocardial histopathology. The segmental myocardial uptake of the flow tracer (13)N-ammonia and of the glucose tracer (18)F-deoxyglucose ((18)FDG) was graded on a five-point scale and compared with the angiographic perfusion score, with regional wall motion, and the presence of fibrosis. RESULTS: There was an agreement of r = 0.72 (p < 0.05) between regional myocardial perfusion and angiography. The correlation of histopathologic changes with normal, moderately, and severely reduced segmental (13)N-ammonia uptake was 87%, 60%, and 75%, respectively. Segmental myocardial (18)FDG uptake and histopathologic findings were concordant in 48 (79%) of 64 segments without fibrosis; absence of viability by perfusion and metabolism imaging correlated with the presence of fibrosis in 21 (84%) of 25 segments. CONCLUSIONS: The observed agreements between the findings on PET perfusion and metabolism imaging with those on coronary angiography, echocardiography, and histopathology support the utility and accuracy of PET for characterizing myocardial perfusion abnormalities and viability in pediatric patients.     

In vivo delineation of myocardial hypoxia during coronary occlusion using fluorine-18 fluoromisonidazole and positron emission tomography: a potential approach for identification of jeopardized myocardium

Previous studies have demonstrated that the positron-emitting fluorine-18 (18F)-labeled fluoromisonidazole is a specific tracer of myocardial hypoxia. Its fractional extraction is enhanced in ischemic or hypoxic myocardium but returns to baseline levels on reperfusion and recovery of normal function. Thus, this agent might be useful in delineating acutely hypoxic but potentially salvageable myocardium. Accordingly, to delineate the relation between the myocardial extraction of 18F-fluoromisonidazole after intravenous administration and the time of antecedent ischemia in vivo, uptake of tracer was measured with positron emission tomography and direct postmortem tissue analysis in 14 dogs in which tracer was administered within 3 h of coronary occlusion (a time associated with marked potential for salvage on reperfusion); in 4 dogs after 6 h of coronary occlusion (a time associated with minimal salvage of myocardium on reperfusion); and in 8 dogs after greater than 24 h of coronary occlusion (to delineate uptake in tissue that is irreversibly damaged). The residual fraction (that is, the amount of tracer extracted and retained in a region) in ischemic myocardium in the dogs in which 18F-fluoromisonidazole was administered within 3 h after occlusion averaged (+/- standard deviation) 23 +/- 18%, which was higher than the residual fraction in myocardium subjected to ischemia for either 6 or greater than 24 h before tracer administration (12 +/- 7% and 5 +/- 2%, respectively, p less than 0.01 for both). Retention of tracer in remote normal myocardium averaged 2 +/- 1%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Expression and cellular distribution of alpha(v)integrins in beta(1)integrin-deficient embryonic stem cell-derived cardiac cells

beta(1)integrin-deficient (beta(1)-/-) ES cells showed increased differentiation of cardiac cells characterized by reduced adhesion and high beating frequency. Whereas in whole embryoid body outgrowths of beta(1)-/- cells maximum levels of alpha(v), beta(3)and beta(5)integrin mRNA were delayed and transiently upregulated, in cardiac clusters isolated from beta(1)-/- cells, only beta(3)integrin mRNA levels were enhanced in comparison to wild-type (wt) cells. To answer the question, whether alpha(v)and beta(3)integrins may compensate, at least partially, the loss of beta(1)integrin function during cardiac differentiation, the distribution of alpha(v)and beta(3)integrins in beta(1)-/- and wt pacemaker-like cardiac cells was analyzed. A different distribution of alpha(v)and beta(3)integrins in beta(1)-/- v wt cardiac cells was found. In wt cardiac cells, beta(1)integrin was localized in specialized subsarcolemmal regions, in particular, at focal contacts and costameres, but alpha(v)integrin was diffusely distributed. In contrast, in beta(1)-/- cardiac cells, alpha(v)integrin was preponderantly localized at cell membranes, focal contacts and costameres. beta(3)integrin displayed a diffuse pattern both in wt and in beta(1)-/- pacemaker-like cells at early differentiation stages, whereas at terminal stages, beta(3)was colocalized with sarcomeres in wt, but not in beta(1)-/- pacemaker-like cells. Quantitative immunofluorescence analysis revealed increased alpha(v)and beta(3)integrin levels in beta(1)-/- pacemaker-like cardiac cells. Our results led us to conclude that altered cellular distribution of alpha(v)integrin and upregulation of beta(3)integrin correlate with growth and survival of beta(1)-/- cardiac pacemaker-like cells at an early developmental state. However, alpha(v)and beta(3)integrins cannot functionally compensate the loss of beta(1)integrin during terminal differentiation of cardiac cells implicating that cardiomyocytes require specific beta(1)integrin functions for cardiac specialization.     

Alphavbeta3 integrin signaling pathway is involved in insulin-like growth factor I-stimulated human extravillous trophoblast cell migration

IGF-I and -II provide paracrine and autocrine stimuli, respectively, for extravillous trophoblast (EVT) cell migration. This study examined the role of alpha(v)beta(3) integrin and its signaling pathway in IGF-I-stimulated migration. Migration assays were conducted using cultured EVT cells treated with or without IGF-I in the presence or absence of alphaIR3, Arg-Gly-Asp (RGD) hexapeptide, and antibody against alpha(v)beta(3) integrin. Morphological changes were studied using scanning electron microscopy. Colocalization of alpha(5)beta(1) alpha(v)beta(3) integrins, vinculin, focal adhesion kinase, and paxillin were determined by immuno-cytochemistry and immunoblotting. The results showed that IGF-I could stimulate EVT cell migration in a time- and dose-dependent manner and addition of alphaIR3, Arg-Gly-Asp hexapeptide, and antibody against alpha(v)beta(3) integrin attenuated the IGF-I migratory effect. Scanning electron microscopy images revealed that IGF-I promoted lamellipodia formation. Immunostaining and immunoblotting exhibited the colocalization of alpha(v)beta(3) integrin with phosphorylated focal adhesion kinase, paxillin, and vinculin at focal adhesions after IGF-I treatment. Immunoblotting demonstrated an increase in focal adhesion kinase and paxillin tyrosine phosphorylation followed by tyrosine phosphorylation of IGF-I receptor in a time- and dose-dependent manner. These findings indicated alpha(v)beta(3) integrin localization in the core of focal adhesions of EVT cells and that alpha(v)beta(3) integrin signaling pathways are activated in IGF-I-mediated migration of these cells.     

BMS-747158-02: a novel PET myocardial perfusion imaging agent.

BACKGROUND: BMS-747158-02 is a fluorine 18-labeled pyridaben derivative designed as a new myocardial perfusion imaging agent for use with positron emission tomography (PET). This study evaluated BMS-747158-02 in animal models of cardiac perfusion and compared it with established single photon emission computed tomography agents. METHODS AND RESULTS: In a rat biodistribution study, BMS-747158-02 (15 microCi) had substantially higher myocardial uptake than technetium 99m sestamibi (100 microCi) at 15 minutes (3.5% +/- 0.3% %ID/g vs 1.9% +/- 0.1% %ID/g) and 120 minutes (3.2% +/- 0.4% of injected dose per gram vs 1.8% +/- 0.0% of injected dose per gram) after intravenous administration. Uptake ratios of heart to lung and liver at 60 minutes were also higher for BMS-747158-02 (12.7 +/- 1.4 and 3.7 +/- 0.2, respectively) than Tc-99m sestamibi (5.9 +/- 0.5 and 2.4 +/- 0.4, respectively). In an isolated rabbit heart model at flow rates of 1.66 to 5.06 mL x min(-1).g(-1) wet left ventricular weight, the net BMS-747158-02 heart uptake increased proportionally (0.93 +/- 0.15 to 2.44 +/- 0.40 mL.min(-1) x g(-1)) and to a greater extent than that of thallium 201 (0.76 +/- 0.02 to 1.11 +/- 0.02 mL x min(-1) x g(-1)) or Tc-99m sestamibi (0.49 +/- 0.03 to 0.77 +/- 0.08 mL x min(-1) x g(-1)). PET imaging with BMS-747158-02 showed a clear and sustained cardiac uptake in rats, rabbits, and nonhuman primates with minimal lung interference and rapid liver clearance. Myocardial perfusion deficit zones created by either permanent left coronary ligation or reperfusion after ligation in rats were both clearly identified on PET cardiac images of BMS-747158-02 and had good agreement with in vitro histology. CONCLUSIONS: BMS-747158-02 exhibited high and sustained cardiac uptake that was proportional to blood flow, and it represents a new class of PET myocardial perfusion imaging agent.     

Coronary artery reperfusion in acute myocardial infarction: assessment by pre- and postintervention thallium-201 myocardial perfusion imaging

In a randomized trial of intracoronary streptokinase (STK) therapy in acute myocardial infarction, 44 patients (21 control subjects and 23 patients treated with STK) underwent sequential thallium-201 planar imaging before angiography and after 4 hours (redistribution), 4 days and 6 weeks. Patients were classified according to the presence or absence of angiographic reperfusion of the infarct-related artery. The semiquantitative score of myocardial thallium uptake was expressed as percent of maximal defect score. Both in control and in STK-treated groups, thallium defect scores decreased over time, but this decrease was smaller in the control group (before angiography, 33 +/- 4%; redistribution, 29 +/- 4%; 4 days, 25 +/- 4%; and 6 weeks, 22 +/- 4%) than in the STK group (44 +/- 4%, 38 +/- 4%, 26 +/- 4% and 21 +/- 3%, respectively). In patients in whom reperfusion was achieved (20 STK-treated, 6 control subjects), a marked decrease in thallium score was observed (before angiography, 40 +/- 4%; redistribution, 32 +/- 4%; 4 days, 20 +/- 5%; and 6 weeks, 14 +/- 22%) compared with patients in whom reperfusion was not achieved (37 +/- 4%, 36 +/- 5%, 33 +/- 5% and 33 +/- 4%, respectively). These results indicate that serial thallium imaging is an accurate method of assessing changes in myocardial perfusion after acute myocardial infarction. Restoration of thallium uptake was observed after reperfusion of the infarct-related artery whether this recanalization was seen spontaneously or after successful thrombolysis.     

Use of positron emission tomography with methyl-11C-choline and 2-18F-fluoro-2-deoxy-D-glucose in comparison with magnetic resonance imaging for the assessment of inflammatory proliferation of synovium

OBJECTIVE: To compare positron emission tomography (PET) and magnetic resonance imaging (MRI) in the evaluation of inflammatory proliferation of synovium. METHODS: Ten patients (mean +/- SD age 36 +/- 13 years) with inflammatory joint disease and with clinical signs of inflammation of the joint were studied. A new tracer for cellular proliferation, methyl-(11)C-choline ((11)C-choline), and a widely used tracer for the detection of inflammation and cancer, 2-(18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG), were applied for PET imaging, and the results were compared with the findings from gadolinium diethylenetriaminepentaacetic acid-enhanced MR images. The uptake of (11)C-choline and (18)F-FDG in the inflamed synovium was measured and expressed as the standardized uptake value (SUV) and the kinetic influx constant (K(i)) obtained from graphic analysis, and these values were compared with quantitative values on MRI. Synovial volumes were measured on the coronal contrast-enhanced T1-weighted MR images using the standard software of the MR imager. RESULTS: All patients showed high accumulation of both (11)C-choline and (18)F-FDG at the site of arthritic changes, where quantification of the tracer uptake was performed. The SUV of (11)C-choline was 1.5 +/- 0.9 gm/ml (mean +/- SD; n = 10) and the SUV of (18)F-FDG was 1.9 +/- 0.9 gm/ml (n = 10) (P = 0.017). The K(i) of (11)C-choline (mean +/- SD 0.048 +/- 0.042 minute(-1)) was 8-fold higher than the K(i) of (18)F-FDG (0.006 +/- 0.003 minute(-1)) (P = 0.009). Both the uptake of (11)C-choline and the uptake of (18)F-FDG correlated highly with the volume of synovium; the highest correlation was observed with the K(i) of (11)C-choline (r = 0.954, P < 0.0001). CONCLUSION: In the use of PET scans,(11)C-choline can be regarded as a promising tracer for quantitative imaging of proliferative arthritis changes. Nevertheless, subsequent prospective studies with larger numbers of patients are necessary to further characterize the relationship between the findings on PET imaging and the clinical and functional measures of inflammation.     

Smooth muscle cell matrix metalloproteinase production is stimulated via alpha(v)beta(3) integrin

This study tests the hypothesis that alpha(v)beta(3) integrin receptors play a critical role in smooth muscle cell (SMC) migration after arterial injury and facilitate migration through the upregulation of matrix metalloproteinase (MMP) activity. We showed that beta(3) integrin mRNA was upregulated by SMCs in the balloon-injured rat carotid artery in coincidence with MMP-1 expression and early SMC migration. Treatment with the beta(3) integrin-blocking antibody F11 significantly decreased SMC migration into the intima at 4 days after injury, from 110.8+/-30.8 cells/mm(2) in control rats to 10.29+/-7.03 cells/mm(2) in F11-treated rats (P=0.008). By contrast, there was no effect on medial SMC proliferation or on medial SMC number in the carotid artery at 4 days. In vitro, we found that human newborn SMCs produced MMP-1 but that adult SMCs did not. This was possibly due to the fact that newborn SMCs expressed alpha(v)beta(3) integrin receptors, whereas adult SMCs did not. Stimulation of newborn (alpha(v)beta(3)+) SMCs with osteopontin, a matrix ligand for alpha(v)beta(3), increased MMP-1 production from 114.4+/-35.8 ng/mL at 0 nmol/L osteopontin to 232.5+/-57.5 ng/mL at 100 nmol/L osteopontin. Finally, we showed that stimulation of newborn SMCs with platelet-derived growth factor-BB and osteopontin together increased the SMC production of MMP-9. Thus, our results support the hypothesis that SMC alpha(v)beta(3) integrin receptors play an important role in regulating migration by stimulating SMC MMP production.     

Doughnut pattern of technetium-99m pyrophosphate myocardial uptake in patients with acute myocardial infarction: a sign of poor long-term prognosis.

Thirty survivors of acute myocardial infarction with 3+ or 4+ positive technetium-99m pyrophosphate myocardial scintigrams were followed up for 28 +/- 3.1 months (mean +/- standard deviation). Three patient groups were identified from the pattern of radioactive uptake in the scintigram: Group I, 16 patients with focal uptake (anterior in 7, lateral in 2, posterior in 3 and inferior in 4); Group II, 6 patients with anterior myocardial infarction and a doughnut pattern of uptake; Group III, 8 patients with nontransmural myocardial infarction and a diffuse pattern of uptake. Late complications developed in all patients with the doughnut pattern of uptake compared with 43 percent of patients with the focal pattern and 12 percent of patients with the diffuse pattern. After discharge from the hospital, five of six patients with a doughnut pattern of uptake died (mean survival time 9.8 months after the initial myocardial infarction). This mortality rate (83 percent) was significantly greater than that of patients with a focal (mortality rate 6 percent) or diffuse (no mortality) pattern of uptake. The doughnut pattern of technetium-99m pyrophosphate myocardial uptake in patients with acute myocardial infarction appears to identify a subgroup of patients with a very poor long-term prognosis.     

Simultaneous integrin alphavbeta3 and glycoprotein IIb/IIIa inhibition causes reduction in infarct size in a model of acute coronary thrombosis and primary angioplasty

OBJECTIVE: We tested the hypothesis that simultaneous inhibition of the endothelial integrin alpha(v)beta(3) and the platelet glycoprotein IIb/IIIa receptor will substantially reduce infarct size in a model of acute coronary thrombosis and primary angioplasty. METHODS: Dogs were subjected to thrombus formation in the left anterior descending coronary artery followed by primary angioplasty. Prior to angioplasty, they were randomized into 3 treatment groups. Group 1 (n=7) received saline; Group 2 (n=9) received MK-383 that inhibits only IIb/IIIa; and Group 3 (n=9) received CP-4715, that inhibits both IIb/IIIa and alpha(v)beta(3). RESULTS: There was a 59% reduction in infarct size in dogs receiving CP-4715 compared to controls (p=0.002) and a 37% reduction compared to the dogs receiving MK-383 (p=0.04). Myocardium microthrombi were seen to be reduced similarly with both drugs on post-mortem (99m)Tc-DMP444 autoradiography that reflects in vivo IIb/IIIa receptor activity. In vivo imaging using echistatin-conjugated and leukocyte-targeted microbubbles revealed significant alpha(v)beta(3) inhibition and reduction in active leukocyte recruitment only in Group 3 dogs. Myocardial blood flow and regional function after reperfusion were also significantly better in this group. CONCLUSION: Simultaneous inhibition of IIb/IIIa and alpha(v)beta(3) causes a marked reduction in infarct size in a model of acute coronary thrombosis and primary PTCA that is associated with reduced myocardial microthrombi and inflammation, as well as improved myocardial blood flow and regional function. These results may have important implications in the treatment of acute coronary syndromes.     

The noninvasive assessment of myocardial viability

The major objective of noninvasive imaging for detection of myocardial viability is to assist in the improved selection of patients with coronary artery disease and severe left ventricular dysfunction who would benefit most from revascularization. The techniques most commonly used to identify viable myocardium are thallium-201 (TI) scintigraphy, positron emission tomography (PET) using a flow tracer in combination with a metabolic tracer, technetium-99m (Tc) sestamibi imaging, and dobutamine echocardiography. On stress TI scintigraphy, asynergic regions showing normal thallium uptake, an initial defect with delayed redistribution at 3–4 h, late redistribution at 24 h, or defect reversibility after reinjection of a second dose of TI at rest all suggest preserved viability. The greater the final uptake of TI in areas of regional myocardial dysfunction preoperatively, the greater the improvement in ejection fraction after coronary revascularization. Demonstration of uptake of fluoro-18 deoxyglucose (FDG) in regions of diminished blood flow on PET imaging also correlates well with improved systolic function after revascularization. Tc sestamibi may also be useful for assessment of myocardial viability, particularly after thrombolytic therapy for acute myocardial infarction. Dobutamine echocardiography has good positive predictive value for viability determination, but absence of systolic thickening in an akinetic zone in response to intravenous infusion of the drug may still be associated with viable myocardium in 25–50% of segments. Of all the techniques cited above, quantitative resting TI scintigraphy may be the best approach for distinguishing between viable and irreversibly injured myocardium.     

Localization of beta 1, beta 3, alpha 5, alpha v, and alpha IIb subunits of the integrin family in spreading human erythroleukemia cells.

The localization of five integrin subunit proteins was studied in human erythroleukemia (HEL) cells spreading on various culture substrata in the presence of 12-O-tetradecanoylphorbol-13-acetate (TPA) and the absence of serum. The cells readily adhered on fibronectin, but TPA was needed for adherence on vitronectin and for the spreading of the cells on both substrata. Indirect immunofluorescence microscopy showed that in the spread cells cultured on vitronectin or fibronectin for 2 hours, beta 1, beta 3, alpha 5, and alpha IIb integrin subunits were localized at focal adhesions as identified by talin-immunoreactivity. The alpha v integrin immunoreactivity was initially found at the focal adhesions when the cells were cultured on vitronectin, but was also found later in cells cultured on fibronectin. The alpha IIb integrin immunoreactivity disappeared from focal adhesions within 24 hours. The alpha 5 and beta 1 integrin immunoreactivities disappeared from the focal adhesions in cells cultured on vitronectin, but not in cells cultured on fibronectin. When the cells were plated on glass substratum in the presence of TPA, they spread much slower than on vitronectin or fibronectin, but some cells showed focal adhesions after only 8 hours in culture. In this case, the alpha v and beta 3 integrin subunits were found at focal adhesions. After TPA treatment, HEL cells deposited thrombospondin-immunoreactive material onto their culture substratum, but synthesis of fibronectin, vitronectin, fibrinogen, or von Willebrand factor was not detected. Thus, the results suggest that TPA would activate several integrin receptors in HEL cells and also stimulate the secretion of thrombospondin, which might be used as an adhesion ligand for the integrin vitronectin receptor alpha v/beta 3 complex.     

Early estimation of acute myocardial infarct size soon after coronary reperfusion using emission computed tomography with technetium-99m pyrophosphate

Early appearance of positive findings on a technetium-99m pyrophosphate scan has been shown to be associated with the presence of a reperfused acute myocardial infarction (AMI). Early technetium-99m pyrophosphate imaging was performed by emission computed tomography to evaluate reperfusion and to test the feasibility of estimating infarct size soon after coronary reperfusion based on acute positive tomographic findings. Twenty-seven patients with transmural AMI who were treated with intracoronary urokinase infusion followed by percutaneous transluminal coronary angioplasty underwent pyrophosphate imaging 8.7 +/- 2.1 hours after the onset of AMI. None of the 8 patients in whom reperfusion was unsuccessful had acute positive findings. Of 19 patients in whom reperfusion was successful, 17 had acute positive findings (p less than 0.001). In these 17, tomographic infarct volumes were determined from reconstructed transaxial images. The threshold for areas of increased pyrophosphate uptake within the infarct was set at 60% of peak activity by the computerized edge-detection algorithm. The total number of pixels in all transaxial sections showing increased tracer uptake were added and multiplied by a size factor and 1.05 g/cm3 muscle to determine infarct volume. The correlations of tomographic infarct volumes with peak serum creatine kinase (CK) levels (r = 0.82) and with cumulative release of CK-MB isoenzyme (r = 0.89) were good. Moreover, the time to positive imaging was significantly shorter than that to peak CK level (8.5 +/- 2.3 vs 10.4 +/- 2.2 hours, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of myocardial perfusion by myocardial contrast echocardiography using harmonic power and the transvenous contrast agent SHU 563A in acute coronary occlusion and after reperfusion

BACKGROUND: Harmonic power Doppler imaging is a novel technique for the assessment of myocardial perfusion by contrast echocardiography. In this study, we examined whether myocardial contrast echocardiography using harmonic power Doppler and the new transvenous contrast agent SHU 563A can identify myocardial perfusion defects during coronary occlusion and reperfusion. METHODS: To assess the potential of this technique, we occluded either the left anterior descending coronary artery or the circumflex coronary artery for 2 to 3 h followed by 1 h reperfusion in 10 dogs in an open chest model. After transvenous administration of SHU 563A, an air-filled, polymeric contrast agent, myocardial contrast echocardiography was performed in short and long axis views with triggered harmonic power Doppler imaging after coronary occlusion and reperfusion. Post-mortem triphenyl tetrazolium chloride staining was performed to verify infarction. Harmonic power Doppler and anatomic data were analyzed by independent observers. RESULTS: During coronary occlusion, harmonic power Doppler showed perfusion defects in all 10 dogs. The defect size in the short axis view at papillary muscle level ranged 4-51% (14+/-13%) and 3-43% (16+/-10%) in the long axis view (% total LV slice area). After reperfusion (1 h) and infusion of dipyridamole (0.56 mg/kg), power Doppler demonstrated perfusion defects in seven dogs: 0-20% (9+/-8%) (short axis view) and 0-48% (13+/-14%) (long axis view). Five dogs showed anatomic infarction. The anatomic infarct area was 0-18% (6+/-8%) (slices corresponding to the echocardiographic short axis images). Perfusion defect size by harmonic power Doppler correlated well with residual infarct size (r=0.82, P<0.01). CONCLUSIONS: Myocardial contrast echocardiography using harmonic power Doppler and the new contrast agent SHU 563A accurately displays perfusion defects during acute coronary occlusion and after reperfusion. The site and size of residual myocardial infarction is reliably identified on line, in color. This approach has excellent potential for clinical application.     

Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomography

The noninvasive functional characterization of the cardiac sympathetic nervous system by imaging techniques may provide important pathophysiological information in various cardiac disease states. Hydroxyephedrine labeled with carbon 11 has been developed as a new catecholamine analogue to be used in the in vivo evaluation of presynaptic adrenergic nerve terminals by positron emission tomography (PET). To determine the feasibility of this imaging approach in the human heart, six normal volunteers and five patients with recent cardiac transplants underwent dynamic PET imaging after intravenous injection of 20 mCi [11C]hydroxyephedrine. Blood and myocardial tracer kinetics were assessed using a regions-of-interest approach. In normal volunteers, blood 11C activity cleared rapidly, whereas myocardium retained 11C activity with a long tissue half-life. Relative tracer retention in the myocardium averaged 79 +/- 31% of peak activity at 60 minutes after tracer injection. The heart-to-blood 11C activity ratio exceeded 6:1 as soon as 30 minutes after tracer injection, yielding excellent image quality. Little regional variation of tracer retention was observed, indicating homogeneous sympathetic innervation throughout the left ventricle. In the transplant recipients, myocardial [11C]hydroxyephedrine retention at 60 minutes was significantly less (-82%) than that of normal volunteers, indicating only little non-neuronal binding of the tracer in the denervated human heart. Thus, [11C]hydroxyephedrine, in combination with dynamic PET imaging, allows the noninvasive delineation of myocardial adrenergic nerve terminals. Tracer kinetic modeling may permit quantitative assessment of myocardial catecholamine uptake, which will in turn provide insights into the effects of various disease processes on the neuronal integrity of the heart.     

Role of alpha4 integrin and VCAM-1 in CD18-independent neutrophil migration across mouse cardiac endothelium

Myocardial damage due to reperfusion of ischemic tissue is caused primarily by infiltrating neutrophils. Although leukocyte beta2 integrins (CD18) play a critical role, significant neutrophil emigration persists when CD18 is neutralized or absent. This study examined the role of leukocyte beta1 integrin (alpha4) and its endothelial ligand VCAM-1 in CD18-independent neutrophil migration across cardiac endothelium. In a mouse model of myocardial ischemia and reperfusion, we show that compared with wild-type mice, neutrophil infiltration efficiency was reduced by 50% in CD18-null mice; in both types of mice, myocardial VCAM-1 staining increased after reperfusion. In wild-type mice, antibodies against CD18, ICAM-1 (an endothelial ligand for CD18), or VCAM-1 given 30 minutes before ischemia did not block neutrophil emigration at 3 hours reperfusion. Although anti-VCAM-1 attenuated neutrophil emigration by 90% in CD18-null mice, it did not diminish myocardial injury. To determine if CD18-independent neutrophil emigration was a tissue-specific response, we used isolated peripheral blood neutrophils from wild-type or CD18-null mice and showed neutrophil migration across lipopolysaccharide-activated cultured cardiac endothelium is CD18-independent, whereas migration across endothelium obtained from inferior vena cava is CD18-dependent. Consistent with our in vivo findings, migration of CD18-deficient neutrophils on cardiac endothelial monolayers is blocked by antibodies against alpha4 integrin or VCAM-1. We conclude tissue-specific differences in endothelial cells account, at least partially, for CD18-independent neutrophil infiltration in the heart.     

Planar myocardial scintigraphy with 99mTc sestamibi for the evaluation of the infarct area and the efficacy of the thrombolytic therapy]

BACKGROUND: Nuclear cardiology permits the estimation of myocardial infarction size and the result of the thrombolytic therapy. The aim of the study was to demonstrate the feasibility of the planar myocardial scintigraphy with tecnetium-99m-sestamibi in the coronary intensive care unit for the early identification of the infarct size and the results of the thrombolytic therapy. MATERIAL AND METHODS: We studied 15 patients affected by a first acute myocardial infarction (AMI), 10 anterior and 5 inferior wall, treated with thrombolysis (APSAC 30U i.v.) within and interval of 3 hours from the symptoms onset, tecnetium-99m-sestamibi was injected before thrombolysis and after 3 +/- 1 hours the planar imaging was registered with a mobile gamma-camera. Scintigraphic evaluation was repeated after 24 hours and before patient discharge. Within 48 hours from the thrombolytic therapy the coronary angiography was performed for the demonstration of patency of the infarct-related artery. The left ventricle myocardial perfusion was divided in the 3 planar projections into 13 segments. The perfusion in each segment was evaluated with a perfusion score: 0 = normal, 1 = moderately reduced, 2 = severely reduced, 3 = absent. The sum of the hypoperfused segments represented the infarct size. A perfusion score improvement greater than 40% was considered a marker of reperfusion. RESULTS: The infarct size involved 4.2 +/- 1.5 segments in the anterior and 2 +/- 0.8 segments in the inferior wall infarctions (p < 0.05). The scintigraphic imaging made 24 hours after AMI allowed the diagnosis of coronary reperfusion in 10 patients. The coronarography demonstrated the infarct related artery patency in 14 patients. The nuclear imaging at patient discharge provided the diagnosis or reperfusion in 11 cases and demonstrated an improvement of the myocardial perfusion score in 8 cases. CONCLUSIONS: In patients with AMI treated with thrombolysis the scintigraphic imaging with tecnetium-99m-sestamibi is feasible with a mobile gamma-camera in the intensive coronary care unit. The quality of planar imaging is good and allows the evaluation of myocardial infarct size and the efficiency of thrombolytic therapy. An earlier scintigraphic imaging should be taken into consideration for a more timely non-invasive evaluation of patients who need coronary angiography and, if necessary, a rescue-PTCA.     

Transient increase in ST-segment elevation immediately after reperfusion in acute myocardial infarction]

The significance of transient increase in ST-segment elevation immediately after reperfusion in acute myocardial infarction (AMI) was assessed by 12-lead electrocardiography. The study population consisted of 18 patients with initial anterior AMI, whose totally-occluded left anterior descending arteries were reperfused within 6 hours after the onset of symptoms. The ST-segment elevation was defined as that of more than 0.2 mV in the V3 lead immediately after reperfusion. Collateral circulation, timing of reperfusion, CPK release, left ventricular ejection fraction and mean % 201Tl uptake in the infarct regions were compared between patients with and without ST elevation. Eleven patients (61%) had ST-segment elevation (0.61 +/- 0.29 mV). Well-developed collaterals were observed in 43% of patients without ST-segment elevation (p < 0.05) but not in those with ST elevation. ST-segment elevations were accompanied by delays in timing of reperfusion (3.7 +/- 1.2 hrs vs 2.5 +/- 0.9 hrs, p < 0.05), higher peak CPK values (6,190 +/- 3,156 IU/l vs 3,222 +/- 2,053 IU/l, p < 0.05) and lower mean % 201Tl uptake (54.2 +/- 11.4% vs 73.9 +/- 11.3%, p < 0.01). We concluded that transient increase in ST-segment elevation immediately after reperfusion may relate to poorly-developed collaterals and prolongation of ischemia; i.e., severe ischemia before reperfusion, and therefore may reflect myocardial reperfusion injuries.