Biotechnology and the UN: new challenges, new failures.
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Biomedical subjects
Publications and source records attributed to H I Miller.
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The vascular endothelium serves as a dynamic interface between circulating blood elements and the interstitial tissues. As such, it communicates with cells in the vessel wall as well as with the surrounding tissue, sensing its environment and responding accordingly. The vasculature must maintain a delicate balance when initiating a functional response by producing both pro-inflammatory and anti-inflammatory mediators, vasoconstrictors and vasodilators, growth stimulators and inhibitors, and prothrombotic and anti-thrombogenic factors. Any response to injurious agents could lead to pathologic responses. One response to injury by the endothelium is the new or increased expression of surface receptors for immune elements. In atherosclerosis, the adhesion of monocytes and T cells to the endothelium is a key event triggered by some form of insult. Subsequent events include monocytic infiltration of the vessel wall, alterations in lipid metabolism, and the activation of these cells into foam cells. The presence of large numbers of foam cells in the intima may produce a high concentration of cytokines and growth factors within a localized area, extracellular matrix perturbations, smooth muscle cell proliferation, and ultimately platelet aggregation at the site of stenosis. Endothelial cells will propagate an inflammatory response long after the initial insult to the arterial vessel. Thus, all of the cellular elements of the vessel wall, as well as the atherosclerotic plaque itself, produce adhesive molecules, cytokines and growth factors that amplify and propagate the pathologic process.
The purpose of this work was to examine in vivo the safety of sonication in the coronary arteries in a live animal model. In intact dogs (n = 8), balloon dilatation was performed on the proximal left anterior descending artery (LAD) followed by sonication to the left circumflex artery (LCX) in power levels found to be optimal for thrombus ablation. Post-dilatation and post-ultrasound coronary angiography, echocardiography, histopathology, CK-MB, indices of hemolysis, and coagulation were compared. Sonication did not induce changes in the ECG or blood pressure. Coronary angiography revealed no adverse side effects or change in arterial diameter (2.3 +/- 0.7 vs. 2.4 +/- 0.3 mm). Echocardiography showed transient opacification of the myocardium. Histopathology revealed a comparable minimal degree of endothelial denudation. After sonication there were no changes in the level of CK-MB (312 +/- 168 vs. 283 +/- 207 IU), hemoglobin (11.3 +/- 0.9 vs. 12.7 +/- 1.1 gr%), haptoglobin (479 +/- 136 vs. 451 +/- 121 mg/dL), fibrinogen (142 +/- 18 vs. 165 +/- 28 mg%), partial thromboplastin time (17.3 +/- 3.2 vs. 17.6 +/- 3.4 sec), prothrombin time (13.3 +/- 7.8 vs. 11.5 +/- 2.9 sec), and degree of platelet aggregation (55 +/- 17 vs. 62 +/- 8%). Thus, the data suggest that transluminal coronary sonication exerts no overt adverse effects in vivo.
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Ischemia causes significant damage to the heart as manifested by decreases in ventricular performance. Several different methods have been shown to protect the heart from ischemic injury--one is operative over a short period (an hour) and the other over longer periods (a day). The latter form of protection has been demonstrated in rats after induction of Gram-negative sepsis or administration of endotoxin or cytokines. In the present study we determined whether guinea pigs would also show induction of cardiac protection subsequent to a dose of endotoxin. Male guinea pigs were injected with 1 mg of endotoxin and studied the following day. Hearts were perfused at a constant perfusion pressure and studied in an isovolumic mode. Left ventricular developed pressure was significantly lower in the endotoxin-treated group than in the control group. After 35 min of total ischemia and 25 min of reperfusion, recovery of left ventricular developed pressure was complete in the endotoxin group but significantly decreased in the control group such that after ischemia and reperfusion, there was no significant difference in left ventricular performance between the two groups. Coronary flow was significantly greater in the endotoxin group than in the control group both prior to and after ischemia. Hearts from endotoxin-treated guinea pigs resumed spontaneous contractile activity sooner and released less lactate upon reperfusion than did the control group. Thus prior treatment of guinea pigs with endotoxin resulted in depression of the isolated heart but also resulted in protection of the isolated heart from further damage due to ischemia/reperfusion injury.
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Ultrasound angioplasty is a newly developed technology for percutaneous arterial recanalization. Data suggest that ultrasound is particularly effective in ablating fresh thrombi. Arterial walls were found to be resistant to ultrasound ablation. Thrombi, aortic wall segments, and hydroxyproline gelatin were studied in vitro to determine their respective ablation rates. The elasticity of the samples was determined in a force-mode apparatus. The cavitation threshold was determined in an arterial phantom apparatus. Thrombi displayed ablation rates that were > 20 times higher than those of aortic wall samples (591 +/- 82 vs 25 +/- 14 mg/s, p < 0.001). The differences in ablation rates were accompanied by significantly lower elasticities in the thrombus group compared with those in the aortic wall group (0.16 +/- 0.05 vs 312 +/- 37 g/cm2, p < 0.001). Experiments with hydroxyproline gelatin suggest a negative correlation (r = -0.90) between elasticity and ultrasound ablation. Ultrasound ablation of thrombi was evident only above the cavitation threshold. Thus, ultrasound angioplasty has the potential to induce the selective injury required for successful transluminal intervention in the treatment of thrombus-rich lesions.
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The effects of plasma lipids on the clinical and angiographic parameters of 134 patients, in whom coronary angioplasty was performed in 157 vessels, were prospectively examined. During a 6-month follow-up, restenosis was detected angiographically in 39 patients (29%; 45 vessels). None of the clinical, biochemical, or angiographic variables examined was predictive of stenosis and the tendency of a vessel to restenose was not patient-dependent but rather lesion-related. However, restenosis developed in 31 of 102 vessels (30%) in patients with high-density lipoprotein (HDL) cholesterol < or = 40 mg/dl, compared with restenosis in 10 of 55 vessels (19%) in patients with HDL cholesterol > 40 mg/dl (p = 0.092). No significant differences were observed when restenosis rates were compared in patients with total cholesterol levels > 250 mg/dl or < 250 mg/dl; no differences were seen in low-density lipoprotein (LDL) cholesterol levels when comparing patients with > 160 mg/dl and < 160 mg/dl. In 117 patients (132 vessels), complete serial blood specimens were obtained until the concluding angiography at 6 months. During follow-up, both groups (those with and without restenosis) had almost similar findings. Triglycerides decreased equally in both groups, and total cholesterol increased mildly in those who had restenosis; HDL and LDL cholesterol levels increased significantly in each group. No significant differences were observed with respect to extent of these changes between the groups. Thus, although lipid levels at the time of angioplasty and at 6 months follow-up were not found to predict the occurrence of restenosis, the association of low high-density lipoprotein levels and the tendency for restenosis should not be overlooked.
An in vitro model was designed to test the hypothesis that thrombi of varying composition have different echogenic patterns. Thrombi were prepared in specially designed tubes, mounted on a holder that allows introduction of an intravascular ultrasound catheter rotated inside a subselective sheath. The thrombi were made by the addition of thrombin to whole blood, platelet-rich plasma, and to mixtures of whole blood and platelet-rich plasma with increasing concentration of whole blood relative to the volume of the mixture in the following ratios: 1:5, 2:5, 3:5 and 4:5. Sixty-six thrombi prepared from 11 blood samples of healthy subjects were studied and compared with control tubes filled with saline solution. Platelet-rich thrombi showed low echogenicity similar to saline solution. Whole blood thrombi appeared uniformly "speckled." Mixtures of whole blood and platelet-rich plasma showed a gradual increase in echogenicity with an increasing amount of whole blood in the mixture. Quantitative videodensitometry compared the gray scale intensity of each image relative to background saline. The mean value of echogenicity of platelet-rich thrombi was 0.9 +/- 1.2, and the mean value of whole blood thrombi was 13 +/- 5.3. Platelet-rich thrombi are echo-lucent, and the main echogenic reflectance of thrombi originates from red blood cells. The ultrasound intensity is in linear relation to the amount of red blood cells in the thrombus.
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Restenosis is a major clinical problem following successful percutaneous transluminal coronary angioplasty. Since magnesium has vasodilator and antithrombotic effects, this study was designed to evaluate its potential to decrease the rate of restenosis. In an open-labelled, randomized controlled study, 148 patients underwent successful coronary angioplasty. Ninety-eight patients were treated with 46-52 mmol/18-20 h intravenous magnesium sulphate (groups M1 and M2), and 49 of them continued with oral supplements of magnesium hydroxide 600 mg.day-1 (group M2). The other 50 patients served as controls (group C). Coronary angiography was performed before, immediately after and at 6 months follow-up or earlier if clinically indicated. Clinical, laboratory, ergometric and radionuclide evaluations were also carried out. One hundred and thirty-nine patients (94%) with 163 dilated segments completed the study. Intravenous magnesium was well tolerated. The cross-sectional area at the site of angioplasty increased by 3.55 +/- 2.01 mm2 in groups M1 and M2 compared with an increase of 2.90 +/- 1.63 mm2 in the control group, (P = 0.03). A trend towards a lower rate of restenosis (> 50% reduction in luminal diameter) was noticed in the magnesium groups (28/110, 25%) compared with the control group (20/53, 38%) P = 0.10. Oral administration of magnesium was well tolerated, did not have an additive effect on restenosis, but an improved clinical course was noted. It is concluded that intravenous administration of magnesium in patients undergoing coronary angioplasty is feasible and safe and that the beneficial trend of magnesium to prevent acute recoil and late (within 6 months) restenosis is encouraging and should promote further investigation in a larger patient population.