Assessment of transmural distribution of myocardial perfusion with contrast echocardiography

BACKGROUND: We hypothesized that by using our newly defined method of destroying microbubbles and measuring their rate of tissue replenishment, we could assess the transmural distribution of myocardial perfusion. METHODS AND RESULTS: We studied 12 dogs before and after creation of left anterior descending coronary artery stenoses both at rest and during hyperemia (n=62 stages). Microbubbles were administered as a constant infusion, and myocardial contrast echocardiography (MCE) was performed with the use of different pulsing intervals. The video intensity versus pulsing interval plots derived from each myocardial pixel were fitted to an exponential function: y=A(1-ebetat), where A reflects microvascular cross-sectional area (or myocardial blood volume), and beta reflects mean myocardial microbubble velocity. The product A . beta represents myocardial blood flow (MBF). Average values for these parameters were derived from the endocardial and epicardial regions of interest placed over the left anterior descending coronary artery bed. Radiolabeled microsphere-derived MBF was also measured from the same regions. There was poor correlation between radiolabeled microsphere-derived MBF and A-endocardial/epicardial ratios (EER) (r=0.46). The correlation with beta-EER was better (r=0. 69, P<0.01). The best correlation with radiolabeled microsphere-derived MBF-EER was noted with A . beta-EER (r=0.88, P<0. 01). CONCLUSIONS: The transmural distribution of myocardial perfusion can be accurately assessed with MCE with the use of our newly described method of tissue replenishment of microbubbles after their ultrasound-induced destruction. In the model studied, an uncoupling of the transmural distribution of MBF and myocardial blood volume was observed during reversal of the MBF-EER.     

What is normal oesophageal motility? An ambulatory study

BACKGROUND: Ultrasound can cause microbubble destruction. If microbubbles are administered as a continuous infusion, then their destruction within the myocardium and measurement of their myocardial reappearance rate at steady state will provide a measure of mean myocardial microbubble velocity. Conversely, measurement of their myocardial concentration at steady state will provide an assessment of microvascular cross-sectional area. Myocardial blood flow (MBF) can then be calculated from the product of the two. METHODS AND RESULTS: Ex vivo and in vitro experiments were performed in which either flow was held constant and pulsing interval (interval between microbubble destruction and replenishment) was altered, or vice versa. In vivo experiments were performed in 21 dogs. In group 1 dogs (n=7), MBF was mechanically altered in a model in which coronary blood volume was constant. In group 2 dogs (n=5), MBF was altered by direct coronary infusions of vasodilators. In group 3 dogs (n=9), non-flow-limiting coronary stenoses were created, and MBF was measured before and after the venous administration of a coronary vasodilator. In all experiments, microbubbles were delivered as a constant infusion, and myocardial contrast echocardiography was performed using different pulsing intervals. The myocardial video intensity versus pulsing interval plots were fitted to an exponential function: y=A(1-e[-betat]), where A is the plateau video intensity reflecting the microvascular cross-sectional area, and beta reflects the rate of rise of video intensity and, hence, microbubble velocity. Excellent correlations were found between flow and beta, as well as flow and the product of A and beta. CONCLUSIONS: MBF can be quantified with myocardial contrast echocardiography during a venous infusion of microbubbles. This novel approach has potential for measuring tissue perfusion in any organ accessible to ultrasound.     

Myocardial contrast echocardiography: reliable, safe, and efficacious myocardial perfusion assessment after intravenous injections of a new echocardiographic contrast agent

Reliable and reproducible myocardial opacification after intravenous administration of echocardiographic contrast agents has remained elusive. This study was performed to determine whether a new agent, FS069, a suspension of perfluoropropane-filled albumin microspheres (3.6 microns average microbubble size, concentration 8 x 8(8)/ml), could achieve safe and successful myocardial opacification in open-chest dogs. Seventeen dogs (group 1, n = 7, group 2, n = 10) underwent two-dimensional echocardiography before, during, and after the administration of intravenous FS069. Safety was evaluated by measuring arterial and pulmonary artery pressures, heart rate, blood gases, systolic function, myocardial blood flow, and postmortem analysis of myocardial viability by triphenyl-tetrazolium chloride staining. Efficacy to detect changes in regional myocardial perfusion was assessed by injecting FS069 at baseline, after sequential coronary occlusions and reperfusion, and during intravenous vasodilators with and without coronary occlusions. Results were compared with radiolabeled microspheres. FS069 was found to be safe and effective. In the absence of coronary occlusions, uniform myocardial opacification was observed in all dogs. A perfusion defect was observed in all dogs during coronary occlusions. Background-subtracted peak contrast intensity in the myocardium correctly identified regional myocardial blood flow changes and showed a significant correlation with radiolabeled microspheres (r = 0.65, p = 0.0001).     

Correlation between quantitative angiographic lesion severity and myocardial contrast intensity during a continuous infusion of perfluorocarbon-containing microbubbles

The purpose of this study was to determine whether quantitative measurements of myocardial videointensity (MVI) during continuous intravenous infusions of microbubbles could detect differences in coronary artery stenosis severity during dobutamine stress echocardiography. Coronary artery stenoses were created in seven dogs by progressively tightening a snare around the coronary artery. Intravenous infusions of perfluorocarbon microbubbles were given during dobutamine stress. The initial rate of myocardial contrast enhancement (slope), peak myocardial contrast (peak MVI) at the longest pulsing interval, and the product (slope * peak MVI) were compared as ratios in the stenosed versus adjacent normal perfusion beds. Twenty-two coronary stenoses were compared (range 16% to 80% in diameter). There was a strong correlation between both slope ratios and slope * peak MVI ratios and percent stenosis (r = -0.89 for both, p<0.001). The rate of contrast replenishment during a continuous infusion of microbubbles can be used to determine both the presence and severity of coronary stenoses during stress echocardiography.     

Evaluation of myocardial ischemia with echo planar magnetic resonance imaging (EPI): normal and ischemic heart

We investigated the validity of Gradient recalled EPI(GRE-EPI) after bolus injection of contrast agent(Gadolinium 0.1 mmol/kg) to detect the ischemic zone of myocardium. Seven healthy volunteers and fifteen patients with coronary artery disease who had only one vessel disease more than 99% stenosis in AHA/ACC classification were studied. GRE-EPI was performed in a transaxial, long axis or short axis orientation of the left ventricle on a 1.5-T Signa Horizon Scanner. Images were obtained every heartbeat for 200 consecutive heartbeats. Contrast agent was injected into the antecubital vein in a bolus after 10 heartbeats. Signal intensity changes in the left ventricular blood and myocardium were measured during myocardial contrast perfusion study. In all healthy volunteers, signal intensity in myocardium was reduced by contrast agent following signal loss in the left ventricular blood and recovered with wash out of contrast agent. But in patients, reduction and recovery of signal intensity in the ischemic zone by contrast agent were significantly delayed and much less than that in the nonischemic zone. In conclusion, myocardial perfusion imaging with GRE-EPI was useful in evaluation of ischemic heart disease.     

Subendocardial myocardial ischemia as assessed with myocardial contrast echocardiography in patients with ischemic heart diseases

Myocardial contrast echocardiography was used to characterize changes in the regional and transmural myocardial blood flow distribution that were provoked by rapid atrial pacing stress in patients with coronary artery diseases. In patients with coronary organic stenosis, a decrease in the myocardial contrast-enhancement in the subendocardial half after rapid atrial pacing was associated with stress-induced chest pain and electrocardiographic ST-T changes. The decrease in the myocardial contrast-enhancement in the subendocardial half after rapid atrial pacing was not observed in patients without coronary stenosis or after coronary angioplasty. Thus, the finding was considered to reflect myocardial ischemia. Pacing-induced decreases in myocardial contrast-enhancement were observed in some patients with old myocardial infarction and significant resting coronary collaterals. In these patients, myocardial ischemia was considered to have developed at rapid pacing because collateral function was good enough to perfuse the infarct myocardium at rest, but was not good enough to prevent myocardial ischemia at stress. Thus, myocardial contrast echocardiography seems to be particularly useful in assessing myocardial ischemia at stress due to coronary stenosis in patients with angina pectoris and due to poor dynamic collateral function in patients with old myocardial infarction.     

Functional myocardial perfusion abnormality induced by left ventricular asynchronous contraction: experimental study using myocardial contrast echocardiography

OBJECTIVES: The aim of this study was to clarify how myocardial perfusion is impaired by asynchronous contraction. BACKGROUND: False septal hypoperfusion is noted in some patients with left bundle branch block. METHODS: Eight dogs were examined with epicardial pacing at the left ventricular posterior wall, the right ventricular anterior wall and, as a control, the right atrial appendage. The pacing rate was 80, 110 and 150 beats/min (bpm). Myocardial perfusion was assessed by contrast echocardiography. RESULTS: Left ventricular pacing at 80 and 110 bpm did not change systolic wall thickening or contrast intensity at the pacing site, although an early excitation notch was noted at the pacing site. However, at 150 bpm, systolic thickening was impaired (23.3 +/- 4.2% vs. 37.0 +/- 2.6% during atrial pacing, p < 0.05), and the peak intensity ratio of the pacing site to the ventricular septum was significantly decreased (24.1 +/- 5.7% vs. 37.0 +/- 2.8% at a pacing rate of 80 bpm, p < 0.01). The peak intensity ratio correlated with systolic wall thickening at the pacing site (y = 0.413 x -0.028, r = 0.81, p < 0.0001). However, right ventricular pacing did not change either systolic thickening or the peak intensity ratio at any pacing rate, although an early excitation notch was noted on the ventricular septum. CONCLUSIONS: Wall motion abnormalities after early excitation vary depending on the pacing mode. When tachycardia induces regional wall motion abnormalities, the ventricular wall of the pacing site is functionally hypoperfused.     

Myocardial perfusion imaging in the setting of coronary artery stenosis and acute myocardial infarction using venous injection of a second-generation echocardiographic contrast agent

BACKGROUND: We hypothesized that by producing excellent myocardial opacification, venous injection of FS-069 coupled with intermittent harmonic imaging (IHI) can be used to determine the presence and severity of coronary stenoses during hyperemia, the size of the risk area during coronary occlusion, and the extent of myocardial salvage after reperfusion. METHODS AND RESULTS: Twelve dogs were imaged both continuously and intermittently (every end systole) in the fundamental (2 MHz) and harmonic (transmit at 2 and receive at 4 MHz) modes. FS-069 (1 mL) was injected intravenously for all stages and modes of imaging. Myocardial video intensity was severalfold (P<.01) higher during IHI than all other modes of imaging. Perfusion defects were difficult to measure during continuous and intermittent fundamental imaging and during continuous harmonic imaging. In comparison, the defects were clearly demarcated during IHI. When this mode was used, the magnitude of perfusion mismatch during hyperemia in the presence of a coronary stenosis correlated closely with the magnitude of flow mismatch when radiolabeled microspheres were used (r=.94). The perfusion defect sizes during coronary occlusion and reperfusion also correlated closely with postmortem risk area (r=.89) and infarct size (r=.96), respectively. CONCLUSIONS: Venous injection of FS-069 coupled with IHI produces excellent myocardial opacification. This approach can be used to determine the severity of coronary stenoses during hyperemia, the size of the risk area during coronary occlusion, and the extent of myocardial salvage after reperfusion. This approach, therefore, holds promise in the clinical setting.     

Myocardial contrast echocardiography in acute myocardial infarction. Pathophysiological background and clinical applications

Myocardial contrast echocardiography is a technique used in experimental and clinical settings in order to visualize the pattern of intramyocardial perfusion. In the acute phase of myocardial infarction, regional absence of flow during myocardial contrast echocardiography delineates the area at risk of necrosis, while the definitive non-perfused area expresses infarct size. Reopening the infarct-related artery, which may be achieved spontaneously by thrombolysis or percutaneous transluminal coronary angioplasty, is not a reliable indicator of intramyocardial reperfusion. If myocardial ischaemia due to coronary occlusion has been sufficiently prolonged and severe, not only myocyte viability, but also microvascular integrity is lost. Myocardial contrast echocardiography, using intracoronary injection of sonicated contrast medium, gives information about microvascular integrity and the effective presence of intramyocardial reflow. Anatomical integrity of microvasculature does not necessarily imply preserved function, and thus the microvessel vasodilating reserve may also be impaired. Myocardial contrast echocardiography has the potential to assess alterations in microvascular function, showing, in the myocardial area with reduced coronary reserve, a relatively reduced increase in echocontrast signal intensity when an intravenous vasodilator agent is administered.     

Apical filling abnormality in patients with heart failure assessed with contrast echocardiography using venous injection of Albunex

Contrast echocardiography by venous injection of Albunex was used to visualize apical filling abnormality in patients with heart failure. 1. Contrast echocardiography was serially performed in 24 patients with acute anterior myocardial infarction. Wall motion of the infarct region was better at any stage in patients without apical filling abnormality than in patients with that. Improvement of filling abnormality was observed prior to that of wall motion abnormality. 2. Influence of tachycardia was assessed on apical filling in 20 patients with old myocardial infarction during rapid atrial pacing. Stress contrast echocardiography evidenced that tachycardia deteriorates apical filling abnormality in patients with chronic heart failure. 3. The effect of amrinone on apical filling was assessed in 60 patients with chronic anterior myocardial infarction. Apical filling abnormality improved in 46% of patients after amrinone infusion. The improvement of apical filling abnormality was closely related to the reduction of preload and improvement of asynergy in the infarct area after amrinone. Both adjunctive therapy and anticoagulant therapy should be considered if apical filling abnormalities are observed by contrast echocardiography.     

Physiologic and clinical significance of myocardial blood flow quantitation: what is expected from these measurements in the clinical ward and in the physiology laboratory?

In this essay we review data on absolute quantitation of myocardial blood flow (MBF) in humans. Earlier work established that coronary heart disease (CAD) can be detected by coronary angiography and that this disease has characteristic features at rest and during stress, which indicate the linkage between regional metabolic needs and myocardial perfusion. In the 1970s myocardial perfusion was mapped in patients with radioxenon, but this method had significant technical limitations. About the same time, radioactive microspheres were introduced for cardiovascular research and investigations; these particles provided insights on MBF in acute infarction and ischemia, myocardial reperfusion, collateral circulation, myocardial blood flow during exercise, coronary flow reserve (CFR), and layer-to-layer distribution of MBF. Studies with microspheres also permitted investigators to establish the presence in the heart of MBF heterogeneity. Currently, there are several techniques that aim at extending these concepts into clinical investigation. Two of these techniques, i.e. Doppler coronary flow velocity and fast magnetic resonance imaging assess epicardial flow dynamics and CFR. Contrast myocardial echocardiography is another novel technique which has been useful in mapping the area at risk, reperfusion, myocardial viability and collateral circulation. This essay also considers the emerging technique of intracoronary ultrasound which has shown evidence of disease underestimation by conventional contrast angiography. Positron emission tomography (PET) is a noninvasive technique that uniquely and quantitatively maps myocardial perfusion and CFR. The latter can be computed before and after angioplasty. PET studies have further demonstrated that chronic myocardial ischemia does not exist as a distinct state in patients with CAD. From the above investigations the concept has arisen that not only is CAD an entity involving epicardial vessels but also, in a significant portion of patients, an abnormal microcirculation plays an important role in the pathogenesis of ischemic syndromes. PET studies have relatively low spatial resolution since they cannot resolve layer-to-layer absolute MBF.     

99mTc-HL91. Effects of low flow and hypoxia on a new ischemia-avid myocardial imaging agent

OBJECTIVES: The aim of this study was to determine whether three-dimensional (3D) myocardial contrast echocardiography (MCE) could provide an accurate in vivo assessment of risk and infarct volumes. BACKGROUND: MCE has been shown to accurately define risk area and infarct size in single tomographic slices. The ability of this technique to measure risk and infarct volumes by using three-dimensional echocardiography (3DE) has not been determined. METHODS: Fifteen open chest dogs underwent variable durations of coronary artery occlusion followed by reperfusion. At each stage, MCE was performed by using left atrial injection of AIP201, a deposit microbubble with a mean diameter of 10 +/- 4 microm and a mean concentration of 1.5 x 10(7) x ml(-1). Images were obtained over a 180 degree arc with use of an automated rotational device and were stored in computer as a 3D data set. Postmortem risk area and infarct size were measured in six to eight left ventricular short-axis slices of equal thickness using technetium-99m autoradiography and tissue staining, respectively. MCE images corresponding to these planes were reconstructed off-line. RESULTS: A close linear relation was noted between the volume of myocardium not showing contrast enhancement on 3D MCE during coronary occlusion and postmortem risk volume (y = 1.2x - 3.0, r = 0.83, SEE = 5.1, n = 15). The volume of myocardium not showing contrast enhancement on 3D MCE after reperfusion also closely correlated with postmortem infarct volume (y = 1.1x - 3.9, r = 0.88, SEE = 4.8, n = 11). No changes in systemic hemodynamic variables were noted with injections of AIP201. CONCLUSIONS: When combined with AIP201, a deposit microbubble, 3D MCE can be used to accurately determine both risk and infarct volumes in vivo. This method could be used to assess the effects of interventions that attempt to alter the infarct/risk volume ratio.     

Responses of blood flow, oxygen consumption, and contractile function to inotropic stimulation in stunned canine myocardium

To examine the effects of inotropic stimulation on regional myocardial blood flow (MBF), oxidative metabolism, and contractile function in stunned myocardium, nine closed-chest dogs were studied 2 hours postreperfusion after a 25 minute occlusion of the left anterior descending coronary artery (LAD). MBF was determined with microspheres, and regional myocardial oxygen consumption (MVO2) was estimated from the rate constant k1 of the rapid clearance phase of [1-11C] acetate time activity curves, recorded with dynamic positron emission tomography. Myocardium at risk was determined from [13N] ammonia images obtained during occlusion. Wall motion, assessed by two-dimensional echocardiography, was impaired in postischemic myocardium in all dogs 2 hours after reperfusion. Dobutamine infusion increased the rate pressure product by 70% +/- 31% and significantly improved contractile function in the postischemic region in all dogs. In remote myocardium, MVO2 increased from 5.7 +/- 1.2 to 8.6 +/- 1.6 mumol/gm/min, and blood flow from 0.87 +/- 0.16 to 1.52 +/- 0.42 ml/gm/min in response to dobutamine. In reperfused myocardium, MVO2 increased from 3.1 +/- 0.7 to 7.4 +/- 1.5 mumol/gm/min, and blood flow from 0.51 +/- 0.12 to 1.2 +/- 0.4 ml/gm/min. Oxygen extraction increased significantly in reperfused myocardium relative to remote myocardium consistent with a flow-limited response to dobutamine stimulation. The improvement in contractile function failed to correlate significantly with relative increases in MBF or MVO2, suggesting that mechanical function is not as tightly coupled as MBF and MVO2 in postischemic myocardium during inotropic stimulation.     

Ultrasonic tissue characterization in predicting residual ischemia and myocardial viability for patients with acute myocardial infarction

The identification of viable myocardium and residual ischemia in patients with acute myocardial infarction has important prognostic implications. The ultrasonic tissue characterization with integrated backscatter and dobutamine-atropine stress echocardiography were performed 8.3+/-3 days after AMI in 30 patients. After coronary angioplasty for the residual stenosis of infarct-related artery, both modalities were repeated. The parameter obtained from ultrasonic tissue characterization, phase-weighted variation, could differentiate the myocardium with residual coronary stenosis or nonviable myocardium from the viable myocardium without residual coronary stenosis (p < 0.001). Using the cutoff value of 5.8 dB, the sensitivity, specificity and accuracy for detecting viable myocardium without residual coronary stenosis were 75%, 100% and 90.2%, respectively. The phase-weighted variation of the viable infarction zone restored after the coronary stenosis was relieved. In contrast, the nonviable myocardium had a small phase-weighted variation that was irrelevant to the patency of the infarct-related artery. The ultrasonic tissue characterization may be used in identifying patients with acute myocardial infarction whose infarction zones are viable without residual ischemia.     

Adenosine technetium-99m sestamibi single-photon emission tomography for the assessment of jeopardized myocardium early after acute myocardial infarction. Paradoxical scintigraphic underestimation of jeopardized myocardium in patients with a severe infarct-related stenosis

This study investigated the value of technetium-99m sestamibi scintigraphy in identifying patients at risk for post-infarct ischaemia (=jeopardized myocardium), especially within the reperfused infarct region. In 51 patients with a recent (<1 month) myocardial infarction, adenosine 99mTc-sestamibi single-photon emission tomography (SPET) and dobutamine stress echocardiography (DSE) were performed and correlated with the presence of significant coronary artery stenosis [% diameter stenosis (DS) >50%] on quantitative coronary angiography. Regional perfusion activity was analysed semi-quantitatively (score 0-4) on a 13-segment left ventricular model. DSE was used for the estimation of the infarct size (low-dose DSE) and for concomitant evaluation of ischaemia (high-dose DSE). A reversible perfusion defect within the infarct region was observed in 20 of the 37 patients with a significant infarct-related lesion (sensitivity of 54%) and only in one patient without a significant infarct-related lesion (specificity of 93%). Further analysis revealed that the scintigraphic assessment of jeopardized myocardium was fairly good in patients with a moderate (DS 51%-64%) infarct-related stenosis but was inadequate in patients with a severe (DS>/=65%) infarct-related stenosis (sensitivity of 80% vs 36%, P<0.01), while the echocardiographic detection of ischaemia was not influenced by stenosis severity (sensitivity of 73% in both subgroups). This scintigraphic underestimation of jeopardized myocardium was mainly related to a severely impaired myocardial perfusion under baseline conditions, as was evidenced by a significantly more severe rest perfusion score in the infarct region in patients with a severe stenosis as compared to those with a moderate stenosis (average score: 1.5+/-0.7 vs 2.1+/-0.6, P<0.01), while infarct size on echocardiography was similar for both subgroups. It may be concluded that early after an acute myocardial infarction, adenosine 99mTc-sestamibi SPET may underestimate reperfused but still jeopardized myocardium, particularly in patients with a severe infarct-related stenosis. In these patients the evaluation of the ischaemic burden on rest-stress scintigraphy is hampered by the presence of a severely impaired myocardial perfusion in resting conditions.     

Myocardial contrast echocardiography demonstrates that collateral flow can preserve myocardial function beyond a chronically occluded coronary artery

Myocardial contrast echocardiography, unlike coronary angiography, can define collateral perfusion. This study shows that collateral blood flow can preserve myocardial function beyond a chronically occluded coronary artery.     

Assessment of myocardial viability with 99mTc-sestamibi tomography before coronary bypass graft surgery: correlation with histopathology and postoperative improvement in cardiac function

BACKGROUND: Assessment of myocardial viability by 99mTc-sestamibi remains controversial. Accordingly, we investigated the use of sestamibi as a marker of myocardial viability, defined by histopathology, and for predicting improvement of myocardial function after coronary artery bypass graft surgery (CABG). METHODS AND RESULTS: 99mTc-sestamibi perfusion tomography and radionuclide angiography were performed within 2 days before CABG in 21 patients with > or = 75% stenosis of the left anterior descending coronary artery and resting anterior wall dyssynergy. During CABG, transmural myocardial biopsies were obtained from the dyssynergic anterior wall and from normal myocardial segments to determine the extent of viable myocardium by histopathology. Improvement of regional left ventricular function was evaluated by radionuclide angiography at 6 to 8 weeks after CABG. There was a good correlation (r=.85, P<.001) between the quantified sestamibi activity and the extent of viable myocardium determined morphometrically. Among 21 biopsied dyssynergic myocardial segments, 11 improved their function after CABG and 10 failed to improve. Biopsied segments with improved postoperative function had significantly higher sestamibi activity (81+/-5% versus 49+/-16%, P<.0001) and significantly lower extent of interstitial fibrosis (7+/-4% versus 31+/-21%, P=.0002) than segments that failed to improve. A 55% threshold of 99mTc-sestamibi activity had positive and negative predictive values of 79% and 100%, respectively, for recovery of function after CABG in the biopsied segments. CONCLUSIONS: Myocardial 99mTc-sestamibi activity correlates well with the extent of viable myocardium and predicts improvement in regional function after CABG. This lends support to the use of sestamibi as a myocardial viability agent.     

Dynamics of myocardial contrast enhancement: an in vivo computed-tomographic study

Enhancement of normal functioning myocardium was quantitated in 15 dogs by serial computed transmission tomographic (CT) images during the bolus (10 ml/sec.) or slow (1 ml/sec.) intravenous injection of diatrizoate contrast media (1 ml/kg body weight) in concentrations of 37, 18.5, or 9.25 g iodine (I)/dl. Homogenous images of myocardial enhancement were obtained. However, major streak artifacts were observed frequently when contrast material was injected as a bolus, and myocardial edges were not defined clearly when contrast material with a concentration of 9.25 g I/dl was injected slowly. Time-attenuation curves of normal myocardial enhancement constructed from serial CT images demonstrated a peak in contrast enhancement (delta Hounsfield units, 22-45) followed by a period of deterioration that lasted two to three minutes. These results can be applied to make optimal use of both single (static) and serial (dynamic) myocardial CT images.     

Flow versus uptake comparisons of thallium-201 with technetium-99m perfusion tracers in a canine model of myocardial ischemia

We investigated the myocardial flow kinetics of six putative radioperfusion agents (99mTc-Q3, 99mTc-Q4, 99mTc-Q12, 99mTc-sestamibi, 99mTc-tetrofosmin and 99mTcN-NOET) and 201Tl in a canine model of myocardial ischemia with pharmacologic coronary artery vasodilation. METHODS: In 31 open-chest dogs with acute coronary occlusion, dipyridamole (approximately 0.56 mg/kg) was infused intravenously, followed by a perfusion tracer injection and radioactive microspheres for myocardial blood flow (MBF) measurement. The paired data were normalized using three techniques; average, normal or maximum myocardial tracer activity and MBF. RESULTS: The upper limit of MBF obtained for the group of tracers ranged from 4.2 ml/min/g to 8.2 ml/min/g. There was a statistically significant (p < 0.0001) linear correlation (r = 0.87-0.98) between the normalized myocardial activity and the normalized MBF values of each of the tracers. The slope of the curve normalized by average for 201Tl (0.83) was greater than those for the 99mTc tracers, and the intercept (0.07) was lower than those for the 99mTc tracers. Slopes and intercepts for the 99mTc agents were as follows: 99mTc-Q3, 0.81 and 0.18; 99mTc-Q4, 0.61 and 0.41; 99mTc-Q12, 0.63 and 0.39; 99mTc-sestamibi, 0.62 and 0.34; 99mTc-tetrofosmin, 0.68 and 0.32; and 99mTcN-NOET, 0.71 and 0.29, respectively. CONCLUSION: In an anesthetized open-chest canine model of regional myocardial ischemia with dipyridamole induced hyperemia, 201Tl shows a more ideal relationship between tracer uptake and MBF than do the 99mTc-based agents. Of the various 99mTc-based imaging agents studied, the myocardial flow kinetics of 99mTc-Q3 appear to be closest to ideal. This relationship is maintained regardless of the normalization technique used. This may, in theory, imply a higher sensitivity in discerning ischemic from normal myocardium and a role in diagnostic nuclear imaging for 99mTc-Q3.     

Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia

BACKGROUND: We initiated a phase 1 clinical study to determine the safety and bioactivity of direct myocardial gene transfer of vascular endothelial growth factor (VEGF) as sole therapy for patients with symptomatic myocardial ischemia. METHODS AND RESULTS: VEGF gene transfer (GTx) was performed in 5 patients (all male, ages 53 to 71) who had failed conventional therapy; these men had angina (determined by angiographically documented coronary artery disease). Naked plasmid DNA encoding VEGF (phVEGF165) was injected directly into the ischemic myocardium via a mini left anterior thoracotomy. Injections caused no changes in heart rate (pre-GTx=75+/-15/min versus post-GTx=80+/-16/min, P=NS), systolic BP (114+/-7 versus 118+/-7 mm Hg, P=NS), or diastolic BP (57+/-2 versus 59+/-2 mm Hg, P=NS). Ventricular arrhythmias were limited to single unifocal premature beats at the moment of injection. Serial ECGs showed no evidence of new myocardial infarction in any patient. Intraoperative blood loss was 0 to 50 cm3, and total chest tube drainage was 110 to 395 cm3. Postoperative cardiac output fell transiently but increased within 24 hours (preanesthesia=4.8+/-0.4 versus postanesthesia=4.1+/-0.3 versus 24 hours postoperative=6. 3+/-0.8, P=0.02). Time to extubation after closure was 18.4+/-1.4 minutes; average postoperative hospital stay was 3.8 days. All patients had significant reduction in angina (nitroglycerin [NTG] use=53.9+/-10.0/wk pre-GTx versus 9.8+/-6.9/wk post-GTx, P<0.03). Postoperative left ventricular ejection fraction (LVEF) was either unchanged (n=3) or improved (n=2, mean increase in LVEF=5%). Objective evidence of reduced ischemia was documented using dobutamine single photon emission computed tomography (SPECT)-sestamibi imaging in all patients. Coronary angiography showed improved Rentrop score in 5 of 5 patients. CONCLUSIONS: This initial experience with naked gene transfer as sole therapy for myocardial ischemia suggests that direct myocardial injection of naked plasmid DNA, via a minimally invasive chest wall incision, is safe and may lead to reduced symptoms and improved myocardial perfusion in selected patients with chronic myocardial ischemia.