Quantification of myocardial perfusion with myocardial contrast echocardiography during left atrial injection of contrast. Implications for venous injection

BACKGROUND: The purpose of this study was to determine whether myocardial perfusion can be quantified with myocardial contrast echocardiography using left atrial (LA) injection of contrast. METHODS AND RESULTS: Based on a series of in vitro and in vivo experiments, the optimal dose of sonicated albumin microbubbles injected into the LA for establishing a linear relation between video intensity and blood volume in the anterior myocardium was determined. In 10 open-chest dogs, myocardial blood flow (MBF) was augmented by increasing myocardial blood volume (MBV) with an intravenous infusion of phenylephrine HCl. In the presence of this drug, left anterior descending artery stenosis was produced, followed by release of stenosis, to change MBF within the anterior myocardium. MBV was calculated by dividing radiolabeled microsphere-derived MBF by microbubble transit rate. There was close coupling between MBF and MBV in the anterior myocardium during LA injection of contrast (y = 1.0x-0.03, SEE = 1.07, r = .92, P < .001). An excellent correlation was also noted between background-subtracted peak video intensity and MBV (y = 0.24x + 0.73, SEE = 0.36, r = .88, P < .001). On multivariate analysis, background-subtracted peak video intensity correlated best with MBV. CONCLUSIONS: Myocardial perfusion can be quantified from time-intensity curves derived from the anterior myocardium after LA injection of contrast. Background-subtracted peak video intensity in this situation correlates closely with MBV. When MBV and MBF are closely coupled, such as during inotropic stimulation of the heart, background-subtracted peak video intensity also correlates closely with MBF. Since there are similarities in the models of LA and venous injections, these data indicate that it may be feasible to quantify myocardial perfusion with myocardial contrast echocardiography after venous injection of contrast.     

Relation between ST-segment changes and myocardial perfusion evaluated by myocardial contrast echocardiography in patients with acute myocardial infarction treated with direct angioplasty

The aim of this study was to evaluate the relation between myocardial perfusion and ST-segment changes in patients with acute myocardial infarction treated with successful direct angioplasty. Thirty-seven patients, successfully treated with direct angioplasty, underwent myocardial contrast echocardiography before and after angioplasty. The sum of ST-segment elevation divided by the number of the leads involved (ST-segment elevation index) was calculated at 1, 5, 10, 20, and 30 minutes after restoration of a Thrombolysis In Myocardial Infarction trial grade 3 flow. After recanalization, myocardial reperfusion within the risk area was observed in 26 patients, whereas a no-reflow phenomenon occurred in 11. In patients with myocardial reperfusion, the ST-segment elevation index progressively declined, whereas in patients with no reflow, no significant change was observed. Reduction of > or = 50% in the ST-segment elevation index occurred in 20 of the 26 patients with reflow and in 1 of the 11 with no reflow (p = 0.0002). An additional increase of > or = 30% in the ST-segment elevation index occurred in 3 patients with reflow and in 7 with no reflow (p = 0.003). Sensitivity, specificity, positive and negative predictive values, and accuracy of the reduction in the ST-segment elevation index for predicting microvascular reflow were 77%, 91%, 95%, 62%, and 81%, respectively. The corresponding values of the increase in ST-segment elevation index for predicting no reflow were 64%, 88%, 70%, 85%, and 81%, respectively. In conclusion, after successful angioplasty, different patterns of myocardial perfusion are associated with different ST-segment changes. Analysis of ST-segment changes predicts the degree of myocardial reperfusion.     

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.     

Assessment of left ventricular volume by contrast echocardiography

Two-dimensional echocardiography for measuring left ventricular volumes usually gives volumes that are smaller than those determined with left ventriculography. This is due to less optimal image quality since manual tracing of endocardial borders requires still frames. Intravenous injection of echocontrast agent (Albunex) improve endocardial border recognition and therefore left ventricular volume measurements become more accurate. It is reported that contrast echocardiography significantly improves the correlation of echocardiographic left ventricular volume measurement with that of left ventriculography. From this points of view, contrast echocardiography is useful for the determination of left ventricular volumes in clinical settings.     

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.     

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).     

Pitfalls in quantitative contrast echocardiography: the steps to quantitation of perfusion

Current methods used clinically to assess myocardial perfusion are invasive and expensive. As the technology of ultrasound imaging improves, CE may provide a relatively inexpensive, noninvasive means of quantitating myocardial perfusion. Issues regarding stability of microbubble contrast agents must be studied more closely under physiologic conditions. As such, encapsulated microbubbles may provide more stability under physiologic pressures than free gas microbubbles. Introducing high concentrations of contrast, either by hyperconcentrating the contrast agent or by increasing the injection rate, may provide greater stability under physiologic conditions. Further, before quantitative statement of tissue perfusion can be made, the relationship between tracer concentration and system response must be established. Further, a "linear" postprocessing ultrasound setting does not eliminate this requirement as data must still undergo nonlinear transformation during log compression and time-gain compensation. Additionally, issues regarding "electronic thresholding" must be explored more extensively in vivo. Commercial ultrasound scanners, in their present form, may not offer adequate sensitivity for absolute quantitative studies. Further development of modified ultrasound systems may provide sufficient sensitivity for quantitative perfusion imaging. CE offers a potentially powerful tool in the clinical management of patients with ischemic heart disease. Conventional coronary angiography provides information on the size of a lesion, but accompanying tissue perfusion distal to the lesion cannot be determined. Doppler ultrasonography determines velocity of blood flow in large vessels but does not offer the potential to quantitate tissue perfusion. Clearly, CE has a place in the future of diagnostic imaging. The recent work of Ito et al. demonstrated the qualitative potential of CE in the identification of "areas at risk" in patients who had undergone thrombolysis or percutaneous transluminal coronary angioplasty after an acute myocardial infarction. With further improvement in the ultrasound imaging techniques and microbubble stability, CE may offer an inexpensive, noninvasive means of assessing myocardial perfusion.     

Potential advantage of flash echocardiography for digital subtraction of B-mode images acquired during myocardial contrast echocardiography

Optimal assessment of myocardial perfusion with contrast echocardiography by using B-mode imaging often requires image alignment and background subtraction, which are time consuming and need extensive expertise. Flash echocardiography is a new technique in which primary images are gated to the electrocardiogram and secondary images are obtained by transmitting ultrasound pulses in rapid succession after each primary image. Myocardial opacification is seen in the primary image and not in the secondary images because of ultrasound-induced bubble destruction. Because the interval between the primary and first few secondary images is very short, cardiac motion between these images should be minimal. Therefore we hypothesized that 1 or more secondary images could be subtracted from the primary image without the need for image alignment. The ability of ultrasound to destroy microbubbles was assessed by varying the sampling rate, line density, and mechanical index in 6 open-chest dogs. The degree of translation between images was quantified in the x and y directions with the use of computer cross-correlation. At sampling rates of 158 Hz or less and a mechanical index of more than 0.6, videointensity rapidly declined to baseline levels by 25 ms. Significant translation between images was noted only at intervals of more than 112 ms. It is concluded that flash echocardiography can be used for digital subtraction of baseline from contrast-enhanced B-mode images without image alignment. Background subtraction is therefore feasible on-line, potentially eliminating the need for off-line image processing in the future.     

Albumin microbubble persistence during myocardial contrast echocardiography is associated with microvascular endothelial glycocalyx damage

BACKGROUND: We hypothesized that the persistence of albumin microbubbles within the myocardium during crystalloid cardioplegia (CP) infusion and ischemia-reperfusion (I-R) occurs because of endothelial injury. METHODS AND RESULTS: The myocardial transit rate of albumin microbubbles was measured in 18 dogs perfused with different CP solutions and in 12 dogs undergoing I-R. Electron microscopy with cationized ferritin labeling of the glycocalyx was performed in 9 additional dogs after CP perfusion and in 3 additional dogs undergoing I-R. Microbubble transit was markedly prolonged during crystalloid CP perfusion. The addition of whole blood to the CP solution accelerated the transit rate in a dose-dependent fashion (P<0.05), which was greater with venous than with arterial blood (P<0.05). The addition of plasma or red blood cells to CP solutions was less effective in improving transit rate than addition of whole blood (P<0.05). Microbubble transit rate was independent of the temperature, K+ content, pH, PO2, osmolality, viscosity, and flow rate of the perfusate. Similarly, a proportion of microbubbles persisted in the myocardium after I-R, which was related to the duration of ischemia (P<0.01) but not of reflow. Crystalloid CP perfusion and I-R resulted in extensive loss of the endothelial glycocalyx without other ultrastructural changes. This effect was partially reversed in the case of crystalloid CP when it was followed by blood CP. CONCLUSIONS: Sonicated albumin microbubbles persist within the myocardium in situations in which the endothelial glycocalyx is damaged. The measurement of the myocardial transit rate of albumin microbubbles may provide an in vivo assessment of endothelial glycocalyx damage.     

Myocardial contrast echocardiography versus dobutamine echocardiography for predicting functional recovery after acute myocardial infarction treated with primary coronary angioplasty

OBJECTIVES: We sought to compare myocardial contrast echocardiography with low dose dobutamine echocardiography for predicting 1-month recovery of ventricular function in acute myocardial infarction treated with primary coronary angioplasty. BACKGROUND: The relation between myocardial perfusion and contractile reserve in patients with acute myocardial infarction, in whom anterograde flow is fully restored without significant residual stenosis, is still unclear. METHODS: Thirty patients with acute myocardial infarction treated successfully with primary coronary angioplasty underwent intracoronary contrast echocardiography before and after angioplasty and dobutamine echocardiography 3 days after the index infarction. One month later, two-dimensional echocardiography and coronary angiography were repeated in all patients and contrast echocardiography in 18 patients. RESULTS: After coronary recanalization, 26 patients showed myocardial reperfusion within the risk area, although 4 did not. At 1-month follow-up, all patients had a patient infarct-related artery without significant restenosis. Both left ventricular ejection fraction and wall motion score index within the risk area significantly improved in the patients with reperfusion ([mean +/- SD] 38 +/- 8% vs. 48 +/- 12%, p < 0.005; and 2.35 +/- 0.5 vs. 2 +/- 0.6, p < 0.001, respectively), but not in those with no reflow. Of the 72 nonperfused segments before angioplasty, 27 showed functional improvement at follow-up. Myocardial contrast echocardiography had a sensitivity and a negative predictive value similar to dobutamine echocardiography in predicting late functional recovery (96% vs. 89% and 89% vs. 93%, respectively), but a lower specificity (18% vs. 91%, p < 0.001), positive predictive value (41% vs. 86%, p < 0.001) and overall accuracy (47% vs. 90%, p < 0.001). CONCLUSIONS: Microvascular integrity is a prerequisite for myocardial viability after acute myocardial infarction. However, contrast enhancement shortly after recanalization does not necessarily imply a late functional improvement. Thus, contractile reserve elicited by low dose dobutamine is a more accurate predictor of regional functional recovery after reperfused acute myocardial infarction than microvascular integrity.     

Visualization and quantification of myocardial mass at risk using three-dimensional contrast echocardiography

To investigate possible biochemical mechanisms underlying the "toxic gain of function" associated with polyglutamine expansions, the ability of guinea pig liver tissue transglutaminase to catalyze covalent attachments of various polyamines to polyglutamine peptides was examined. Of the polyamines tested, spermine is the most active substrate, followed by spermidine and putrescine. Formation of covalent cross links between polyglutamine peptides and polyamines yields high-M(r) aggregates--a process that is favored with longer polyglutamines. In the presence of tissue transglutaminase, purified glyceraldehyde-3-phosphate dehydrogenase (a key glycolytic enzyme that binds tightly to the polyglutamine domains of both huntingtin and dentatorubral-pallidoluysian atrophy proteins) is covalently attached to polyglutamine peptides in vitro, resulting in the formation of high-M(r) aggregates. In addition, endogenous glyceraldehyde-3-phosphate dehydrogenase of a Balb-c 3T3 fibroblast cell line overexpressing human tissue transglutaminase forms cross-links with a Q60 polypeptide added to the cell homogenate. Possibly, expansion of polyglutamine domains (thus far known to occur in the gene products associated with at least seven neurodegenerative diseases) leads to increased/aberrant tissue transglutaminase-catalyzed cross-linking reactions with both polyamines and susceptible proteins, such as glyceraldehyde-3-phosphate dehydrogenase. Formation of cross-linked heteropolymers may lead to deposition of high-M(r) protein aggregates, thereby contributing to cell death.     

Myocardial contrast echocardiography

MCE has evolved from a laboratory tool to a clinical procedure. It would be wrong to consider it merely another tool for imaging of myocardial perfusion. As discussed, it allows physicians to bring physiology and pathophysiology to the bedside, providing a better understanding of the underlying mechanisms of abnormal findings in individual patients. MCE can provide quantitative measurements that can be repeated as often as necessary in a patient. Because of its complexity, large clinical studies are necessary to define the role of MCE in the general clinical milieu. Advances in MCE continue at a very rapid pace, and its potential for the study of endothelial function, site-specific targeting, and local delivery of drugs appears promising. Its role will continue to evolve into the early part of the next century. What we learn of the myocardium can be easily applied to other organ systems accessible to ultrasound. The future of MCE appears very exciting.     

Contrast echocardiography and myocardial perfusion: what is the current status?

Progress in the field of echocardiographic contrast agent combined with progress in imaging techniques (second harmonic imaging, intermittent imaging, Doppler Energy) should allow a real revolution in the field of noninvasive cardiac imaging, and one of the main advantages will probably be myocardial perfusion imaging in ischaemic heart disease.     

Improved quantification of myocardial mass by three-dimensional echocardiography using a deposit contrast agent

Adhesion-dependent cell signaling is known to be important in carcinogenesis. It is postulated that several types of adhesion molecules act as tumor suppressor genes by enforcing cell-substrate and cell-cell adhesion thereby preventing the migration of cells and their invasion into surrounding tissues. Recent evidence, however, suggests that disruption of adhesion systems can both initiate neoplastic transformation and contribute a rate-limiting step to progression. Adhesion may modulate neoplastic processes by altering pathways that control genomic stability. Analysis of the adhesion-controlled inactivation of the p53 protein and the concomitant relaxation of cell cycle checkpoint control could identify the critical contributions of adhesion-mediated influences to carcinogenesis.     

Assessment of myocardial perfusion hemodynamics using echo planar MR imaging

It was possible to obtain images for individual heart beats using single-shot Echo Planar Imaging(EPI), and changes of myocardial signal intensity could be assessed visually after GD-DTPA administration. Measurement of the same site in the myocardium on myocardial perfusion images for individual heart beats was facilitated by imaging during breath-holding, and accurate evaluation was possible. In patients with coronary artery disease, the site of myocardial infarction tended to show less increase in signal intensity than the normal myocardium, and could easily be distinguished from normal myocardium according to the change in signal intensity. In patients with atrial fibrillation, the signal intensity of the myocardium varied with each heart beat, and it was difficult to assess perfusion hemodynamics. Myocardial perfusion studies using EPI still present problems with respect to spatial resolution, but the myocardial perfusion hemodynamics for individual heart beats can be determined by preparing time/intensity curves. It is also possible to obtain information on cardiac morphology, wall motion, and myocardial metabolism in addition to perfusion data by combining myocardial perfusion studies with methods such as high speed cine MRI, tagging, or myocardial MRS. It is possible that this method will also be useful in studying myocardial viability.     

Prolonged contrast infusion echocardiography with hydrogen peroxide

A new method of prolonged C-echo-CG with HP implies intravenous administration of 0.3% HP solution for continuous contrasting of right heart chambers for 5-20 minutes. A new technique of C-echo-CG was introduced in 277 patients with innocent cardiac murmur (93), interventricular septal defects (19), interatrial septal defects (26), open oval foramen (42), tricuspid regurgitation (56), pulmonary artery regurgitation (41). Prolonged C-echo-CG with HP was combined with respiratory stress tests. The technique is simple, more effective than short-term C-echo-CG, free of severe side effects and complications.     

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.     

Evaluation of contrast echocardiography and lung perfusion scan in detecting intrapulmonary vascular dilatation in normoxemic patients with early liver cirrhosis

BACKGROUND/AIMS: Intrapulmonary vascular dilatations (IPVD) are extrahepatic complications occurring in liver transplant candidates, that can result in severe hypoxemia. The aim of this study was to compare the use of two diagnostic modalities, contrast echocardiography and lung perfusion scan, in detecting IPVD in normoxemic patients with early liver cirrhosis. METHODOLOGY: Fifty-six consecutive outpatients with biopsy-proven cirrhosis had contrast-echocardiography, a lung perfusion scan, pulmonary function tests, and arterial blood gas estimations. All patients were grade A or B according to the Child-Pugh classification. Patients with chronic intrinsic lung disease, heart failure or malignancy were excluded from the study. RESULTS: All patients had normal arterial blood-gas analyses. Eight out of 56 patients (14.3%) had a positive contrast echocardiogram, all with a decreased diffusion capacity (DLCO < 75% of the predicted value). An isolated DLCO impairment was observed in 40% of the patients with normal spirometry. None of the patients with echocardiography-proven IPVD had a positive lung perfusion scan (p<0.005). CONCLUSIONS: In normoxemic cirrhotic patients, subclinical pulmonary vasodilatation and gas-exchange abnormalities can occur. Contrast-enhanced echocardiography is the most valuable screening test in detecting IPVD in the early stages of hepatic insufficiency.