Does reperfusion induce myocardial necrosis?
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Animals↗
Biomedical subjects
M C Fishbein
Publications and source records attributed to M C Fishbein.
Histopathologic validation of angioscopy and intravascular ultrasound.
BACKGROUND: To establish a histopathologic basis for angioscopic and ultrasound image interpretation we studied 70 postmortem human arterial segments in vitro. METHODS AND RESULTS: We used 7- to 9-French fiber-optic angioscopes and 20- to 30-MHz intravascular ultrasound imaging catheters. Three observers assigned an angioscopic and ultrasound image classification to each vessel segment. The image and histological classification categories were then compared. The sensitivity, specificity, and accuracy of both methods separately or in combination for normal vessels were each greater than or equal to 95%. The predictive value was better for angioscopy than for ultrasound due to incorrect ultrasound interpretations of normal anatomy in the presence of thrombus. For stable atheroma the sensitivity, specificity, and accuracy of the individual methods were each greater than 90%. However, both angioscopy and ultrasound had classification errors in that disrupted atheroma was identified and classified as stable atheroma. Consequently, the predictive value was 74% for angioscopy and 78% for ultrasound. For disrupted atheroma the sensitivities for angioscopy and ultrasound were only moderate (73% and 81%, respectively), whereas the specificity, accuracy, and predictive value were each high (greater than 90%). For thrombus detection, the specificity, accuracy, and predictive value were high (greater than 93%) for each method. The sensitivity of angioscopy was 100%. However, sensitivity was lower for ultrasound (57%) due to false-negative interpretation of laminar clots in normal vessels and an inability to distinguish disrupted or stable atheroma from intraluminal thrombus. CONCLUSIONS: Contingency analyses showed that each imaging method alone or combined had significant agreement with the results obtained from histology (p less than 0.001). When assessing all cases in which angioscopy and ultrasound were concordant, there was a 92% agreement with the histological classification.
Coronary Artery Disease↗
Dissolution of peripheral arterial thrombi by ultrasound.
BACKGROUND: We have previously shown that continuous-wave ultrasound can rapidly dissolve human thrombi in vitro, with 99% of all residual particles measuring less than 10 microns in diameter. To assess the effects of pulsed-wave ultrasound energy on whole blood clots, 1) in vitro studies were preformed to assess precisely the rates of clot disruption and to quantify particulate size, and 2) in vivo studies were performed to assess the efficacy and safety of catheter-delivered ultrasound for intra-arterial thrombus dissolution. METHODS AND RESULTS: In vitro, we studied 50 samples of human whole blood clots and using an 89-cm-long wire probe, applied pulse-wave energies from 8 to 23 W. The corresponding peak-to-peak tip displacement range was 63.5 - 102 microns. We studied arterial thrombosis in vivo in 21 canine superficial femoral arteries. To produce an acute thrombosis, 200 units of thrombin followed by 2 ml of 72-hour-old autologous clot were injected into a 5-7-cm segment of femoral artery and left to coagulate for 2 hours. Ultrasound energy was intermittently applied at a frequency of 20 kHz with a prototype ultrasound wire ensheathed in a catheter and directed to clots by fluoroscopy. In nine cases, angioscopic guidance was used to put the probe into direct contact with the intra-arterial thromboses. In vitro clot dissolution times were inversely related to the ultrasound power output (r = 0.95). All in vivo canine thromboses were disrupted in 4 minutes or less. All successful recanalizations were confirmed by angiography and in nine cases by angioscopy as well. Angioscopy demonstrated that probe activation caused rapid clot disruption. Histological studies of the vessels showed no evidence of thermal or cavitation injury, occlusive distal embolization, or perforation. CONCLUSIONS: Our findings in this experimental canine model suggest that ultrasound clot dissolution has the potential to be an effective and safe alternative to current treatment modalities for peripheral arterial thrombosis.
Animals↗
Detection and localization of tumor necrosis factor in human atheroma.
Tumor necrosis factor (TNF) is a secretory product of normal macrophages that can cause cell necrosis, new blood vessel formation and thrombosis. These are also 3 characteristic features of the progression of stable atheroma to endothelial disruption. Accordingly, an immunohistochemical method was developed to detect TNF in human tissue. Using this method TNF positivity was demonstrated in 57 of 65 (88%) of tissue sections classified as atherosclerotic and in 5 of 11 (45%) sections classified as minimally atherosclerotic. TNF was absent in 6 sections classified as normal. TNF positivity was found not only in the cytoplasm of macrophages, but also in the cytoplasm and attached to the cell membrane of smooth muscle cells and endothelial cells of the human atheroma. Because TNF is known to cause new vessel formation, hemorrhagic necrosis and increased thrombogenicity, it may play a role in the evolution of uncomplicated to complex atheroma.
Antibodies, Monoclonal↗
Reperfusion injury.
This article reviews the early and late morphologic changes associated with reperfusion of ischemic myocardium. If instituted within minutes of coronary artery occlusion, all reversibly injured myocardium is salvaged. Once some irreversibly injured myocardium is present, the usually bland region of coagulation necrosis is transformed into an edematous, hemorrhagic zone with "contraction-band" necrosis and vascular obstruction (no-reflow phenomenon). Whether or not these changes occur in otherwise salvageable myocardium is controversial. Data from studies with conflicting results are presented. Popular proposed mechanisms of reperfusion injury include the no-reflow phenomenon and free radical-mediated injury. No reflow has been related to direct vascular injury, compression of capillaries by edema fluid, and obstruction of vascular channels by leukocytes. Free radicals, which inactivate enzymes and destroy membranes, are primarily oxygen derived, and produced by neutrophils, endothelial cells, and myocardial cells. Whether or not reperfusion injury exists is still debated; if it does, the mechanism of injury remains to be proven. Ongoing research in this field will augment our knowledge of cell death and interventions to delay or prevent it.
Free Radicals↗
Primary endocardial fibroelastosis associated with hydrops fetalis in a premature infant.
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Endocardial Fibroelastosis↗
Ultrasonic clot disruption: an in vitro study.
We studied in vitro the efficacy of ultrasound in human blood clot disruption, as well as the effects of clot age, wire probe length, and streptokinase on the outcome. The study included sizing the resulting particulate debris. Clot age (1 to 7 days) had no effect on the time required for disruption. Three groups of 1-day-old clots (n = 10 for each) were exposed to the same ultrasonic power source via probes of different lengths. The time required for clot disruption varied approximately as the square of the length for probes of 31, 56, and 105 cm, but was less than 3 minutes even for the longest probe employed. Disrupted whole-blood clot as well as cell-free fibrin clot solutions were analyzed for particulates by the resistive-pulse technique (size range: 2.5 to 80 microns). Debris as large as 80 microns were seen after disruption of whole blood clots, while cell-free fibrin clots contributed little above 40 microns. In all size ranges, whole blood clots produced two orders of magnitude more particulates than cell-free fibrin clots. Addition of streptokinase (7500 U/mL) had little effect on the size distribution of debris, with 99% of all particulates being smaller than 10 microns. D-dimer analysis was performed on the dissolved cell-free fibrin clots with and without streptokinase. While the former had analytically higher D-dimer concentrations than the latter (from eight- to 16-fold), the levels in both cases would be below detectability if measured in vivo. Hence the present study supports the concept that ultrasound can be employed to disrupt human blood clots by mechanisms (mechanical and cavitational) other than fibrinolysis.
Chemical Phenomena↗
Cardiac physiology, biochemistry and morphology in response to excess growth hormone in the rat.
The cardiac effects of excess growth hormone (GH) were studied in the intact adult rat and in tissues prepared from the rat. Female Wistar-Furth rats were inoculated with a clonal cell line of pituitary cells which secrete GH. Five weeks later, heart weight had increased 37% compared to control (P less than 0.01) due to concomitant increases in left and right ventricular weight. Hemodynamic measurements in the anesthetized rat showed that GH stimulated rats had a decrease in blood pressure and heart rate and a small increase of left ventricular end-diastolic pressure (P less than 0.05). Measurement of left ventricular contractility and relaxation, and response to beta-adrenergic stimulation were decreased in GH compared to control (P less than 0.05). Contractile protein biochemistry showed an 18% reduction in Ca2(+)-myosin ATPase activity of the left ventricle (P less than 0.05) and non-denaturing pyrophosphate gels of purified myosin demonstrated a significant shift of isoforms from the exclusive V1 pattern to both V1 and V3 isomyosins in both ventricles (P less than 0.05). In contrast to the physiological and protein biochemistry adaptations, left ventricular morphology by light microscopy and ultrastructure by electron microscopy were normal in the GH stimulated heart. There were no significant changes in myofibril fraction, in the myofibril to mitochondria ratio or in the capillary numerical density of the hypertrophied left ventricle (P = N.S.). This study demonstrates that under prolonged and extreme stimulation by GH, the heart undergoes considerable growth/hypertrophy. Although cardiac morphology remains normal during this growth, there are alterations of the isomyosins such that ATPase activity is diminished and ventricular function is decreased.
Animals↗
Photodynamic therapy of choriocarcinoma transplanted to the hamster cheek pouch. I. Intraperitoneal photosensitization.
Human choriocarcinoma (JEG-3) cells were transplanted into the cheek pouch of hamsters and treated with photodynamic therapy. Twenty-four hours after intraperitoneal injection of the photosensitizer dihematoporphyrin ether (DHE), 20 tumors were illuminated with 100 J/cm2 of 630-nm light from an argon pumped dye laser. Contralateral tumors served as controls. Dihematoporphyrin ether alone had no effect on tumor growth, while laser light in the absence of DHE resulted in complete regression in 3 tumors (17%), and partial regression in 4 of 18 tumors (22%), possibly due to hyperthermia, P greater than 0.10. Using the combination of DHE plus light (photodynamic therapy) complete tumor regression was noted after a single treatment in 11 of 20 tumors (55%, mean tumor volume 279 mm3) and in 7 of 7 tumors (100%) after a second treatment. Two of 20 tumors were not retreated. Therefore, 18 of 20 tumors (90%) were grossly destroyed by one or two photodynamic treatments. Contralateral control tumors continued to grow to a median volume of 990 mm3 (chi 2 = 26.30, P less than 0.0001). Choriocarcinoma transplanted into the hamster cheek pouch is highly responsive to photodynamic therapy.
Animals↗
Coronary artery plaque morphology after balloon angioplasty.
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Angioplasty, Balloon, Coronary↗
In vivo ultrasound arterial recanalization of atherosclerotic total occlusions.
The purpose of this study was to assess the potential of intraarterial ultrasound for in vivo recanalization of atherosclerotic total occlusions. Ultrasound energy at a frequency of 20 kHz was applied with a prototype solid wire probe to 12 surgically implanted occluded human atherosclerotic arterial xenografts, 9 of which were calcified, as well as to the intimal surface of 12 normal canine arteries. In both the normal canine arteries and the atherosclerotic occluded xenografts, there was no angiographic evidence of vasospasm, thrombosis or arterial dissection. Eleven of the 12 atherosclerotic complete arterial occlusions were resistant to passage of a conventional guide wire or probe without ultrasound energy. However, the occlusions were recanalized after administration of 15 s to 4 min (mean 1.5 +/- 1.3 min) of intermittent ultrasound energy. After ultrasound, 8 of the 12 vessels underwent balloon angioplasty. Angiographic residual stenosis after ultrasound alone was 62 +/- 24% and after combined ultrasound and balloon angioplasty, 29 +/- 13%. Although routine angiography did not reveal arterial emboli, high resolution cut films did demonstrate a few distal nonocclusive thrombi of a size similar to that reported with other recanalization methods. Histologic studies demonstrated changes similar to those after balloon angioplasty, with focal cracking of the fibrotic and calcified plaque. The findings demonstrate that ultrasound energy applied through a catheter delivery system can be used in vivo to open completely obstructed atherosclerotic vessels. These studies suggest that it might be clinically feasible to use the ultrasound probe to create a lumen, allowing subsequent balloon dilation.
Animals↗
Intravascular ultrasound cross-sectional arterial imaging.
In this paper we review the current status of intravascular ultrasound. Data from qualitative and quantitative studies is presented. Our experimental findings and those of other investigators are reviewed. Intravascular ultrasound has been shown to delineate normal and abnormal arterial morphology as well as to identify and differentiate fibrous, lipid-rich, calcified plaques and complicated plaques. Quantitative studies show strong correlations between ultrasound and histology for lumen area, wall thickness, and plaque area. In vivo studies from our experimental work and clinical laboratory as well as the work of other researchers is presented. This data supports the potential of ultrasound imaging for guidance of intravascular intervention. The potential advantages and limitations of this new technology are discussed. This methodology shows promise for the assessment of the extent and severity of atherosclerosis, monitoring its progression and regression and guiding intravascular plaque ablation technologies.
Animals↗
Comparative studies of angioscopy and ultrasound for the evaluation of arterial disease.
In this in vitro investigation, we studied the histopathological basis for intravascular ultrasound image interpretation and how this technique compares with fiberoptic angioscopy in assessing atherosclerosis. This article presents the sensitivity and specificity of these techniques in the recognition of arterial abnormalities. The relevance of these data in interventional therapeutic procedures and the clinical implications of intravascular imaging methods are also discussed.
Animals↗
Does reperfusion extend necrosis? A study in a single territory of myocardial ischemia--half reperfused and half not reperfused.
The purpose of this study was to confirm or disprove the existence of reperfusion-induced extension of necrosis. To avoid the effect of the variability of collateral circulation when groups of dogs are compared, we compared the effect of reperfusion and nonreperfusion on myocardial necrosis in a single ischemic territory, half of which was reperfused and half of which was not. The left anterior descending coronary artery (LAD) territory between its last diagonal branch and the apex was studied because it was found to have uniform collateral blood flow. In 20 dogs, the LAD was occluded for 90-240 minutes to produce necrosis of different degrees of transmurality. Before release of this occlusion, the LAD was occluded distally halfway to the apex to keep the distal half nonreperfused. After 5 minutes of proximal reperfusion. Monastral blue dye was injected into the left atrium for demarcation of the reperfused region, and the heart was arrested, excised, cut parallel to the LAD, and placed into triphenyl tetrazolium chloride (TTC) solution for delineation of the region of necrosis. The validity of TTC staining under the conditions of this study was confirmed by light and electron microscopy. The transmurality of necrosis, measured within 1 or 0.5 cm on either side of the boundary, ranged from 30% to 88% of wall thickness and was not different in the reperfused compared with the nonreperfused region (paired t test). Reperfusion did not advance the epicardial edge of necrosis compared with the nonreperfused region. In conclusion, at 5 minutes after reperfusion, comparison of necrosis in the reperfused and nonreperfused halves of a single ischemic territory could not demonstrate an extension of necrosis by reperfusion.
Animals↗
Induction of insulin-like growth factor I messenger RNA in rat aorta after balloon denudation.
Insulin-like growth factor I (IGF-I) is a widely distributed mitogen that mediates the growth-promoting effects of platelet-derived growth factor in mesenchymal cells. We show that rat aortic IGF-I messenger RNA (mRNA) is induced 24 hours after deendothelialization, at a time when smooth muscle cell proliferation within the intima is still not apparent. After 7 days, IGF-I mRNA induction peaks at about ninefold control levels and then falls to about threefold 14 days after denudation when smooth muscle cell proliferation is at its peak. We also show that, of the 5' untranslated IGF-I mRNA transcripts, only the class C transcript is expressed and regulated in aortic tissue. In contrast, treatment of rats with supraphysiological doses of growth hormone, the major endocrine regulator of IGF-I gene expression, elicited only twofold induction of aortic IGF-I mRNA. Our findings suggest that IGF-I may be an important autocrine or paracrine regulator of smooth muscle cell proliferation and that it may be significant in determining the cellular response to arterial wall injury.
Animals↗
Tumor necrosis factor gene expression in human vascular intimal smooth muscle cells detected by in situ hybridization.
We used immunohistochemistry to detect tumor necrosis factor (TNF) and in situ hybridization to detect TNF messenger RNA (mRNA) in the intimal mesenchymal-appearing cells and in the medial smooth muscle cells of human atherosclerotic arteries. Medial smooth muscle cells showed localization of immunoreactive TNF on the cell surface and did not express TNF mRNA. Conversely, in intimal mesenchymal-appearing cells, TNF was localized in the cytoplasm and TNF mRNA was expressed by in situ hybridization. Thus 89% of intimal cells were immunohistochemically positive for TNF, 96% of them were positive by in situ hybridization, and 76% were positive for the smooth muscle cell marker, HHF35. Our results suggest that intimal mesenchymal-appearing cells are mostly, but not exclusively, derived from smooth muscle cells. These cells express TNF, whereas the medial smooth muscle cells in the atherosclerotic human arteries do not. The expression of TNF by these mesenchymal-appearing cells may have implications regarding the evolution of the atherosclerotic plaque.
Arteries↗
Overestimation of myocardial infarct size by histologic measurement in a model of occlusion followed by reperfusion.
We studied 32 transverse left ventricular slices of myocardium from 16 pigs after 45 to 100 minutes of coronary artery occlusion followed by 180 minutes of reperfusion. Infarct area for each slice was determined as follows: (1) grossly, by triphenyl tetrazolium chloride staining of each slice, and (2) microscopically, by complete histologic sectioning of the triphenyl tetrazolium chloride-stained surface of each slice. Planimetry of necrotic and nonnecrotic areas was performed from tracings and photographs of triphenyl tetrazolium chloride-stained slices and from actual histologic sections. When triphenyl tetrazolium chloride and histologic measurements were compared, necrotic tissue area had decreased 11.4% +/- 15.0% (2.59 +/- 1.04 vs 2.09 +/- 0.86 cm2). Nonnecrotic tissue area decreased 20.6% +/- 24.0% (8.31 +/- 3.79 vs 5.16 +/- 2.73 cm2). In this model of ischemia followed by reperfusion, with fixation and processing, viable tissue shrank almost twice as much as necrotic tissue. This differential shrinkage introduces an error resulting in overestimation of infarct size by histologic quantitation.
Animals↗
Effect of chemical sympathectomy on cardiac hypertrophy and hemodynamics following myocardial infarction in the rat.
The effects of sympathectomy on cardiac structure and function were studied in an animal model of myocardial infarction. Ninety-six rats were double randomized to control or infarction disease state and to placebo or chemical sympathectomy (guanethidine, 30 mg/kg daily, intraperitoneal). Five weeks after anterior infarction, there was hypertrophy in placebo-treated animals in myocardial fibers remote from the infarct (9.8 +/- 1.8 microns in infarction vs 8.1 +/- 1.0 microns in control, p less than 0.05). However, myocardial hypertrophy was not present in guanethidine-treated animals (8.6 + 1.6 microns in infarction vs 8.0 + 0.6 microns in control, p = N.S.). Guanethidine treatment caused significant reductions in systolic arterial blood pressure and indices of left ventricular contractility and relaxation (p less than 0.05), but these effects were not different between infarct and control treatments (p = N.S.). Although both effects of guanethidine treatment (sympathectomy and hemodynamic) were correlated with myocardial fiber diameter by univariate analysis, only sympathectomy was significant by stepwise regression analysis (p less than 0.05). Therefore, the cardiac sympathetic nerves have important effects on the development of hypertrophy after myocardial infarction, and sympathectomy alters this process in the rat model.
Analysis of Variance↗