In vivo effects of contrast media on coronary thrombolysis.

OBJECTIVES: The aim of the present study was to evaluate the influence of radiographic contrast media (CM) on alteplase-induced coronary thrombolysis. BACKGROUND: Contrast media inhibit fibrinolysis in vitro and interact with endothelial cells, platelets and the coagulation system. The in vivo effects of CM on thrombolysis are not known. METHODS: Occlusive coronary artery thrombosis was induced in 4 groups of 10 dogs by the copper coil technique. After 70 min of occlusion the dogs were randomized to intracoronary injection of 2 ml kg(-1) of either saline, a low-osmolar ionic CM (ioxaglate), a low-osmolar nonionic CM (iohexol) or a high-osmolar ionic CM (amidotrizoate). Thrombolysis with alteplase and co-therapy with aspirin and heparin was initiated after 90 min of occlusion. The coronary artery flow was monitored with an electromagnetic flowmeter throughout the experiment. RESULTS: Iohexol and amidotrizoate, but not ioxaglate, were associated with longer reperfusion delays (time to optimal reperfusion: 67+/-48 min and 65+/-49 min, respectively, vs. 21+/-11 min after placebo; p < 0.05) and shorter periods of coronary perfusion (optimal perfusion time: 21+/-26 min and 21+/-28 min, respectively, vs. 58+/-40 min after placebo; p < 0.05). No significant differences were observed between groups with regard to activated partial thromboplastin times, circulating thrombin-antithrombin III complex concentrations and fibrinogen. CONCLUSIONS: In this animal model administration of iohexol and amidotrizoate before thrombolysis significantly delayed reperfusion. This interaction should be considered in the design of clinical trials of thrombolytic therapy that evaluate coronary artery patency and in patients receiving local infusions of fibrinolytic agents.

Intracardiac measurement of pre-ejection myocardial velocities estimates the transmural extent of viable myocardium early after reperfusion in acute myocardial infarction.

OBJECTIVES: We hypothesized that wall motion velocity during pre-ejection is proportional to the regional content of viable myocardium after reperfusion for acute myocardial infarction (AMI). BACKGROUND: Pre-ejection wall motion consists of short and fast inward and outward movement towards and away from the center of the left ventricle (LV) and is altered during regional ischemia. This short-lived event can be accurately quantified by Doppler myocardial imaging (DMI). METHODS: Fourteen open-chest pigs underwent 60 to 120 min of left anterior descending coronary artery occlusion followed by 30 min of reperfusion. The DMI data were collected using a phased-array intracardiac catheter (LV cavity) from ischemic and nonischemic myocardium encompassed within a plane passing through two epicardial bead markers. Peak tissue velocities during isovolumic contraction (IVC) (peak positive and peak negative), ejection (S) and early filling (E) were measured. The cardiac specimen was sliced through the epicardial markers in a plane approximating the ultrasound imaging plane. The transmural extent of necrosis (TEN) (%) was measured by triphenyltetrazolium chloride staining. RESULTS: During ischemia, positive IVC velocity was zero in ischemic walls with TEN >20%. At reperfusion, positive IVC velocity correlated better with TEN (r = -0.94, p < 0.0001) than it did S (r = -0.70, p < 0.01) and E (r = -0.81, p < 0.01). Differential IVC (the difference between peak positive and peak negative velocity) highly correlated with TEN, during ischemia (r = -0.78, p < 0.001) and during reperfusion (r = -0.93, p < 0.0001). CONCLUSIONS: Pre-ejection tissue velocity, as measured by intracardiac ultrasound, allows rapid estimation of the transmural extent of viable myocardium after reperfusion for AMI.

Regional asynchrony during acute myocardial ischemia quantified by ultrasound strain rate imaging.

OBJECTIVES: We propose a new method to easily quantify asynchronous wall motion due to postsystolic shortening (PSS). We also studied the relationship of the spatial and temporal extent of PSS to the extent of myocardium at ischemic risk after variable duration of ischemia. BACKGROUND: Postsystolic shortening is a sensitive marker of asynchrony during ischemia. Current techniques for detection of asynchrony are either subjective, or invasive and time-consuming. Strain rate imaging (SRI) can noninvasively depict PSS as prolonged compression/expansion crossover. METHODS: Nineteen open-chest pigs were scanned from apical views, before and after left anterior descending coronary artery occlusion. Strain rates were derived offline from tissue Doppler velocity cineloops. The time from electrocardiographic R-wave to the occurrence of compression/expansion crossover (TCEC) was calculated. Prolonged TCEC during ischemia was identified using a standardized analysis and both spatial (% of left ventricle) and temporal extent were quantified. The extent of myocardium at risk was measured in seven animals from dye-stained specimens. RESULTS: Prolonged TCEC was found in all ischemic segments. There was a good correlation (r = 0.91; p < 0.001) and good agreement between the spatial distributions of prolonged TCEC and myocardium at risk. The extent of myocardium at risk was better approximated by TCEC measurement (36 +/- 7% vs. 39 +/- 8%, respectively; p = NS) than by wall motion analysis (47 +/- 17%, p < 0.05). The duration of occlusion did not prolong TCEC. CONCLUSIONS: Prolonged TCEC consistently occurs in ischemic myocardium and is apparently not affected by the duration of ischemia. Standardized analysis of TCEC in SRI closely quantifies the extent of ischemic myocardium. This new method may be a useful tool in other cardiac conditions associated with regional diastolic asynchrony.

Comparison of a synthetic antithrombin III-binding pentasaccharide and standard heparin as an adjunct to coronary thrombolysis.

The effects on alteplase-induced thrombolysis of the synthetic ATIII-binding pentasaccharide SR90107A/ORG 31540 (synthetic pentasaccharide, SP) and of standard heparin (SH) were compared in a copper coil model of coronary artery thrombosis in 6 groups of 10 dogs. After 1 h of occlusion, all animals received intravenously alteplase and aspirin, and were randomly assigned to a 2 h infusion of either saline, or one of two doses of SH (100 IU/kg bolus plus 50 IU/kg/h infusion, or 200 IU/kg bolus plus 100 IU/kg/h infusion), or one of three doses of SP (100 nmol/kg bolus plus 50 nmol/kg/h infusion, 200 nmol/kg bolus plus 100 nmol/kg/h infusion, or 400 nmol/kg bolus plus 200 nmol/kg/h infusion). Coronary angiography was performed every 10 min for 4 h. Appropriate doses of SP and SH enhanced alteplase-induced thrombolysis to a similar extent. In contrast, SP was devoid of any anti-IIa activity or aPTT prolongation.

Real-time strain rate echocardiographic imaging: temporal and spatial analysis of postsystolic compression in acutely ischemic myocardium.

Postsystolic compression (PSC) is a sensitive indicator of regional left ventricular ischemic diastolic dysfunction. Quantitative assessment of compression patterns by strain rate imaging could determine the presence and spatial extent of PSC for the detection and analysis of acute ischemic diastolic dysfunction. With the use of a segmental left ventricular model, we evaluated time to compression/expansion crossover (T-CEC) in standard apical views. Data at baseline and after acute left anterior descending coronary artery occlusion were collected from 18 open-chest pigs. We found significant mean prolongation of T-CEC, ranging from 43.9 +/- 48.6 ms to 110.8 +/- 73.8 ms, in all apical segments and in 2 midventricular (anterior and anteroseptal) segments. Analysis of variance demonstrated that the prolonged T-CEC is spatially consistent with perfusion defect. The temporal and spatial analysis of T-CEC with the use of strain rate imaging is a new noninvasive technique for identification and topographic quantitation of ischemic diastolic dysfunction expressed by PSC.

Are changes in myocardial integrated backscatter restricted to the ischemic zone in acute induced ischemia? An in vivo animal study.

Integrated backscatter (IB) from a myocardial region, calculated from radiofrequency echocardiographic data, has been proposed as a useful parameter for investigating changes in myocardial tissue induced by ischemia. In 10 closed-chest dogs, 5 minutes of myocardial ischemia was induced by either a proximal occlusion of the circumflex coronary artery (CX) (5 dogs), resulting in extensive ischemia in the posterior wall, or by occluding the distal CX vessel (5 dogs) to produce a small localized ischemic zone in the posterior wall. High-resolution digital radiofrequency data from the whole left ventricular myocardium, in the imaging plane during one complete heart cycle, were acquired with a whole-image real-time acquisition approach. Regions in the septum and posterior wall (both ischemic tissue and, in the case of distal occlusions, tissue surrounding the ischemic zone) were chosen for analysis, and IB and cyclic variation (CV) of IB were calculated. Post occlusion, an increase in mean IB values was found in the ischemic segment. However, an increase in CV was also observed in the peri-ischemic zone for the distal CX occlusion and in the septum after proximal CX occlusion. These findings show that changes in CV are not restricted to the ischemic zone but may also occur in distal myocardium. This may be explained by changes in the regional contractile state and loading conditions of the "normal" myocardium, which are altered in response to the distal ischemia.

Segmenting high-frequency intracardiac ultrasound images of myocardium into infarcted, ischemic, and normal regions.

Segmenting abnormal from normal myocardium using high-frequency intracardiac echocardiography (ICE) images presents new challenges for image processing. Gray-level intensity and texture features of ICE images of myocardium with the same structural/perfusion properties differ. This significant limitation conflicts with the fundamental assumption on which existing segmentation techniques are based. This paper describes a new seeded region growing method to overcome the limitations of the existing segmentation techniques. Three criteria are used for region growing control: 1) Each pixel is merged into the globally closest region in the multifeature space. 2) "Geographic similarity" is introduced to overcome the problem that myocardial tissue, despite having the same property (i.e., perfusion status), may be segmented into several different regions using existing segmentation methods. 3) "Equal opportunity competence" criterion is employed making results independent of processing order. This novel segmentation method is applied to in vivo intracardiac ultrasound images using pathology as the reference method for the ground truth. The corresponding results demonstrate that this method is reliable and effective.

Is there a change in myocardial nonlinearity during the cardiac cycle?

The distortion of a sound wave during propagation results in progressive transfer of the energy from fundamental to higher harmonics, and is dependent on the nonlinearity of the medium. We studied if relative changes in acoustical nonlinearity occur in healthy myocardium during the cardiac cycle. Radiofrequency data were acquired from transthoracic echocardiography (2.5 and 3.5 MHz), parasternal long axis view, from five dogs and nine healthy volunteers. Integrated backscatter was calculated after filtering for fundamental (FIB) and second harmonic frequencies (SHIB), from a region in the posterior myocardial wall. The results suggest that there is little difference between the SHIB and FIB, although there were large variations between individuals. The maximal changes in nonlinearity, as estimated by SHIB/FIB ratio, mostly occurred during systole. SHIB presented similar cyclic variation with FIB (p = NS). Further studies are necessary to separate the role of myocardial nonlinearity, attenuation, propagating distance, or acoustical properties of the blood. The results are important in further tissue characterization studies employing second harmonic data.

Infarct size, myocardial hemorrhage, and recovery of function after mechanical versus pharmacological reperfusion: effects of lytic state and occlusion time.

BACKGROUND: Whether myocardial reperfusion obtained with thrombolysis or primary angioplasty is associated with a similar recovery of function and with the same risk of hemorrhagic infarction is unknown. We evaluated the effects of mechanical and pharmacological reperfusion (with or without a plasma lytic state) on infarct size, myocardial hemorrhage, and left ventricular (LV) function in a canine model. METHODS AND RESULTS: Six groups of six dogs were subjected to balloon occlusion of the left anterior descending coronary artery (LAD) followed by 2 hours of reperfusion. The study had a two-by-three factorial design with two occlusion periods (90 and 240 minutes) and three different reperfusion strategies (placebo, 0.4 mg/kg recombinant tissue plasminogen activator, and 40 microg/kg recombinant staphylokinase). In a seventh control group, LAD occlusion was maintained without reperfusion. All dogs received aspirin and heparin. A systemic lytic state was present in staphylokinase-treated dogs. Planimetry of LV slices showed larger infarcts (percent of area at risk) and more hemorrhage (percent of IA) after 240 minutes of occlusion than after 90 minutes of occlusion (54+/-17% versus 37+/-18% and 52+/-27% versus 29+/-27%, respectively; P<.01 for both comparisons), with no significant difference among treatments. Hemorrhage was not observed in the control group without reperfusion. LV angiography showed no differences in global and regional LV function between mechanical and pharmacological reperfusion. CONCLUSIONS: In this experimental model, hemorrhagic infarctions of similar extent were observed after both pharmacological and mechanical reperfusion. The extent of hemorrhage was increased by the delay in reperfusion but not by the presence of a lytic state.

Noninvasive measurements of infarct size after thrombolysis with a necrosis-avid MRI contrast agent.

BACKGROUND: Gadophrin-2 is a new MRI contrast agent with high affinity for necrotic myocardium. The aim of the study was to evaluate whether noninvasive measurements of infarct size after thrombolysis are possible with gadophrin-2-enhanced MRI. METHODS AND RESULTS: Coronary artery thrombosis was induced in 3 groups of dogs by the copper-coil technique. Thrombolytic therapy together with aspirin and heparin was initiated after 90 minutes of occlusion. One day (group A), 2 days (group B), or 6 days (group C) after infarction, gadophrin-2 was injected intravenously (50 micromol. kg-1). In vivo T1-weighted segmented turbo-FLASH, in vivo T2-weighted segmented half-Fourier turbo spin echo (HASTE), and T1- and T2-weighted spin-echo MRI of the excised heart were performed 24 hours after gadophrin-2 injection. Regions of strong enhancement were observed on T1-weighted images. Planimetry of short-axis MR images and of corresponding triphenyltetrazolium chloride (TTC)-stained left ventricular (LV) slices showed a close correlation between the enhanced areas and TTC-negative areas for both in vivo (r2=0.98, P<0.0001; mean difference, 0.9+/-2.0% [SD] of the LV volume [LVV]) and postmortem (r2=0.99, P<0.0001; mean difference, 0.9+/-1.4% of LVV) measurements. T2-weighted images overestimated the infarct size by 8.1+/-5.4% of LVV. The mean infarct size was 10.8+/-11.6% of LVV (group A), 22.4+/-11.7% (group B), and 5.1+/-9.3% (group C). CONCLUSIONS: In this animal model, in vivo gadophrin-2-enhanced MRI could precisely determine infarct size after thrombolytic therapy. This technique may be very useful for the noninvasive evaluation of infarct size after reperfusion for AMI.

High frame rate myocardial integrated backscatter. Does this change our understanding of this acoustic parameter?

AIMS: Integrated backscatter (IB) and its cyclic variation (CV) derived from radio-frequency (RF) data have been used as parameters to attempt myocardial tissue characterization. Prior imaging systems used to measure IB and its CV typically acquired data at frame rates of 20-30 Hz and at a resolution of 6-8 bits. If changes in IB levels are in part related to specific short-lived events, occurring within the cardiac cycle, this frame rate and resolution could have been too low to resolve adequately what might be a more complex data set. METHODS AND RESULTS: To investigate this possibility, we acquired real time two-dimensional (2D) myocardial IQ data (the 'in-phase quadrature' sampled RF data) at high frame rate (> 100 Hz), high dynamic resolution (theoretical 19-bit) and a sector angle of 20 degrees. Several consecutive heart cycles of myocardial data were acquired from individual cardiac walls in five closed chest dogs and 10 healthy, young volunteers at normal heart rates. On the reconstructed RF data regions of interest were indicated, and IB and its CV were calculated. The extracted high frame rate curves showed that the CV of IB is not a smooth sinusoidal-like curve, but is made up of multiple reproducible peaks and troughs with local minima and maxima which are temporally related to active or passive mechanical events, i.e. systolic contraction, early ventricular relaxation and ventricular filling due to atrial contraction. CONCLUSIONS: This study shows that increasing the rate of real-time RF data acquisition results in a more complex, reproducible IB curve. The resolved maxima and minima in IB levels are related to specific phases of the myocardial contraction. Furthermore, spectral analysis showed that IB curves acquired at normal heart rates contain information up to 40 Hz. Hence, cardiac imaging data sets used to analyse regional myocardial function obtained at frequencies lower than 80 frames per second can contain aliased information.

Intracoronary delivery of Gd-DTPA and Gadophrin-2 for determination of myocardial viability with MR imaging.

The aim of this study was to compare intracoronary (i.c.) administration of Gadophrin-2, a necrosis-avid contrast agent (NACA), and nonspecific agent Gd-DTPA for determination of myocardial viability (MV) in acute myocardial infarction (AMI) with MRI. Reperfused AMI was induced in 12 dogs by transcatheter balloon occlusion of coronary artery. In 6 dogs each, Gd-DTPA at 0.1 mmol/kg or Gadophrin-2 at 0.005 mmol/kg was administered into coronary artery by fast bolus (n = 3) or slow infusion (n = 3). Serial ECG-triggered cardiac MRI of T1-weighted segmented turbo fast low-angle shot (FLASH) sequence was conducted and compared with triphenyltetrazolium chloride (TTC) histochemical staining. The contrast ratio and infarct size were quantified and analysed statistically. No cardiovascular side effects were found with local delivery of both agents. After i.c. administration, Gadophrin-2 induced a strong (CR > or = 1.78) and persistent (> or = 10 h) contrast enhancement of infarcted region. The infarct size defined with Gadophrin-2 was almost identical to that with TTC staining throughout the postcontrast period. With a dose 20 times higher, Gd-DTPA also strongly enhanced infarct-to-normal contrast; however, the enhancement diminished with time, i.e. from early strong to later faint enhancement and eventual loss of contrast. The delineated infarct size was also unstable, i.e. from early overestimation to later underestimation and eventual disappearance of the enhanced infarct. In combination with PTCA procedure, i.c. administration of MRI contrast agents may prove useful for post-procedure verification of diagnosis. The NACA-enhanced MRI may serve as an in vivo surrogate of postmortem histochemical staining for determination of MV. Although applicable in clinical setting, cardiac MRI with nonspecific Gd-DTPA is less reliable and should be performed within less than 1 h after contrast.