Biomedical subjects
Publications and source records attributed to T R Griggs.
This study shows an increase in von Willebrand factor antigen in blood collected from the coronary sinus shortly after coronary angiography with an ionic contrast agent (diatrizoate), but not a nonionic contrast agent (iohexol). These findings suggest that ionic contrast agents may cause more endothelial injury than nonionic contrast agents.
Small animal models have several advantageous characteristics, but those used in preclinical restenosis research have lacked efficacy in predicting the success of interventions to inhibit restenosis in humans. Large animal models have been more successful than small animal models in predicting efficacy of interventions to inhibit restenosis in humans, but the results of studies carried out with these models have not been uniformly predictive. Confirmation of the results of small animal studies in large animals has not always yielded information predictive of success in humans; however, the absence of such confirmation has had strong negative predictive value. Small animal models used for evaluation of interventions to inhibit luminal narrowing following arterial instrumentation have failed to closely simulate human atherosclerosis and the stenotic lesions subjected to instrumentation in humans. Transgenic, atherosclerotic animals hold promise for the development of more useful small animal models to study mechanisms of the response of diseased arteries to angioplasty and stents. The pig has been the most useful large animal to study stenosis/ restenosis, but more information is needed to overcome the limitations of this model.
PURPOSE: This study determined the relationship between aerobic power (VO2max), physical activity (PA), and cardiovascular disease (CVD) risk factors. The study also determined how increased VO2max and increased PA levels influence CVD risk factors of 576 low-fit adults (VO2max < 30 mL.kg-1.min-1). METHODS: PA (Baeke questionnaire) and VO2max (submaximal cycle test) of 1664 law enforcement trainees were evaluated with respect to the CVD risk factors of total cholesterol, blood pressure (BP) [BP], smoking, and obesity using separate logistic regression, adjusting for age, gender, and the other major CVD risk factors. RESULTS: Compared with the lowest tertile of VO2max, the highest tertile had a reduced relative risk (RR) for elevated cholesterol (RR, 0.56; CI, 0.36-0.43), BP (RR, 0.32; CI, 0.15-0.62) and obesity (RR, 0.09; CI, 0.06-0.12). The middle tertile of VO2max compared with the lowest had reduced RR for elevated diastolic BP (RR, 0.44; CI, 0.23-0.66) and obesity (RR: 0.38; CI 0.28-0.50). High PA tertile, compared with low PA tertile, only had lower RR for high systolic BP (RR, 0.48; CI, 0.23-0.95). Compared with the low PA tertile, moderate or high PA had no reduction in any of the RR (P > 0.05). Participation in a 9-wk exercise program by low-fit individuals resulted in a 9% increase in PA levels (P < 0.02); however, only those subjects who increased VO2max (> 3 mL.kg-1.min-1; N = 345) had a reduction in RR for high cholesterol (RR: 0.62; CI 0.42-0.92) and systolic BP (RR: 0.57; CI 0.40-0.80). No reduction in RR were noted for diastolic BP or obesity. CONCLUSIONS: Aerobic power appears to have more of an influence on CVD risk factors than PA levels. Further, in low-fit persons, it appears that PA resulting in an increased aerobic power is associated with a reduction in CVD risk factors of cholesterol and BP in as little as 9 wk.
The role of von Willebrand factor (vWF) in arterial neointimal formation that develops in arteries with altered shear stress was investigated using normal, heterozygous, and homozygous von Willebrand disease pigs (ie, vWD, or lacking vWF) that were fed normal pig chow. Shear stress was applied to carotid and femoral arteries with a Goldblatt clamp for 14 days, producing a > or = 80% stenosis. Neointimal lesion size was measured by computer-assisted morphometry. Expression of proliferative cell nuclear antigen (PCNA) by neointimial and medial cells was used as a relative index of proliferative activity. For shear-stressed arteries, there was no significant difference in the number of smooth muscle cell layers in the lesion, lesion size, and percent of PCNA-positive neointimal or medial cells among normal, heterozygous, and homozygous vWD pigs (P> or =.1, ANOVA). Lesions in pigs that expressed vWF (normals and heterozygotes) contained large amounts of vWF in the neointima, whereas lesions in vWD pigs had no detectable vWF. Moreover, no foam cells were detected in the lesions. Thus, the absence of vWF apparently does not alter the size of lesions in shear-stressed arteries in vWD pigs or the number of neointimal or medial cells expressing PCNA. Mechanism(s) involved with shear-induced modulation of smooth muscle cell proliferation, then, can operate independently of vWF in normolipemic pigs.
Three markers of platelet activation (platelet-derived microparticles, fibrinogen binding and expression of P-selectin) were assessed by flow cytometry during diagnostic coronary angiography and therapeutic coronary interventions. In 24 patients undergoing diagnostic angiography, blood was collected to determine if our sampling techniques or coronary angiography caused platelet activation. Changes during diagnostic angiography were used to establish baseline values and interpret changes during coronary interventions. In 21 patients, blood samples were obtained at 5 time points during percutaneous transluminal coronary angioplasty (PTCA) (n = 17) or directional coronary atherectomy (DCA) (n = 4). During coronary interventions, mean values for the percentage of platelets expressing P-selectin or binding fibrinogen increased, but with considerable variation among patients. Individual responses for platelet activation markers in each patient were characterized using a twofold increase to indicate elevation related to the intervention. Patients were classified as having complicated or uncomplicated procedures based on the presence of acute closure, dissection, or thrombus observed by angiography. There were no differences in the percentage of elevated markers between patients with uncomplicated (12.5%) and complicated (19%) PTCA procedures. However, patients treated with DCA had more elevated markers (38%) than those treated with PTCA (15%) (p = 0.04). Our data suggest that the extent of platelet activation in individual patients cannot be predicted by common angiographic findings or complications. More markers of platelet activation were present after DCA and may reflect a greater degree of vascular trauma associated with this procedure.
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The purpose of this quasi-experimental study was to determine the effectiveness of an occupation based health and fitness program. Subjects were 1,504 police trainees (85% male, 15% female) with an ethnic distribution of 82% white, 16% African American, and 2% other. Data were collected at 25 sites across the state of North Carolina. The sites were randomly assigned to either the experimental group (implemented the intervention) or the control group (continued usual training). As compared with controls, subjects at the experimental sites improved significantly in cardiovascular fitness (aerobic power), general muscular strength (number of sit ups per minute), and flexibility, and lowered their body fat. The intervention required minimal equipment and was taught primarily by peers who received a 1 week training program. This occupational approach to improving health could be particularly useful in occupations with many workers who seldom engage in leisure time physical activity.
Currently, therapeutic platelet concentrates can be stored for only 5 days. We have developed a procedure that permits long-term storage of fixed and lyophilized platelets that retain hemostatic properties after rehydration. These rehydrated lyophilized platelets (RL platelets) restore hemostasis in thrombocytopenic rats and become incorporated in the hemostatic plug of bleeding time wounds of normal dogs as well as von Willebrand disease dogs with partially replenished plasma von Willebrand factor. Ultrastructurally, these platelets are well preserved and are comparable to control normal washed platelets. Flow cytometry analysis shows that RL platelets react with antibodies to the major surface receptors, glycoprotein (GP)Ib and GPIIb/IIIa. These receptors are involved in platelet agglutination, aggregation, and adhesion. In vitro functional tests document the ability of RL platelets to adhere to denuded subendothelium and to spread on a foreign surface. Circulating RL platelets participated in carotid arterial thrombus formation induced in normal canine subjects. The participation of RL platelets in these vital hemostatic properties suggests that with further development they could become a stable platelet product for transfusion.
Low levels of high-density lipoproteins (HDLs) may constitute an independent risk factor that may be as important as elevated low-density lipoproteins (LDLs) in coronary artery disease (CAD). Concentrations and distributions of lipids, apolipoprotein (apo) B, and apoA-I in the plasma and lipoprotein subfractions of two groups of swine, one with familial hypercholesterolemia (FHC) and the other with diet-induced hypercholesterolemia (DHC), were examined. Normolipidemic (NL) animals served as controls. All pigs carried the Lpb5 apoB mutation, which is known to influence the formation of atherosclerotic lesions. Mean concentrations of serum total cholesterol in NL, DHC, and FHC were 80.0 +/- 9.3, 774.3 +/- 54.5, and 316.5 +/- 36.1 mg/dL, respectively; HDL cholesterol (HDL-C), 33.5 +/- 1.9, 137.0 +/- 9.9, and 22.3 +/- 2.2 mg/dL; triglycerides, 33.0 +/- 16.3, 40.3 +/- 11.7, and 56.8 +/- 7.2 mg/dL; apoB, 35.7 +/- 3.1, 142.0 +/- 4.8, and 169.3 +/- 13.9 mg/dL; and apoA-I, 62.4 +/- 9.3, 170.9 +/- 6.9, and 42.6 +/- 4.8 mg/dL. The distributions of total cholesterol, apoB, and apoA-I in plasma lipoprotein subfractions were also examined. Compared with NL, FHC had fourfold and 4.7-fold increases in total cholesterol and apoB, respectively, distributed in the lower densities (d < 1.043 g/mL), and low HDL-C and apoA-I levels, resulting in a high total cholesterol/HDL-C ratio (14.4:1) and elevated triglyceride levels. DHC was characterized by 10-fold and fourfold increases in total cholesterol and apoB, respectively, resulting in an LDL particle highly enriched in cholesterol, a fourfold increase of HDL-C, an almost threefold increase in apoA-I, and a normal triglyceride level.(ABSTRACT TRUNCATED AT 250 WORDS)
We have studied the roles of von Willebrand factor (vWF) and factor VIII in arterial thrombosis in four canine phenotypes: normal (n = 6), hemophilia A (n = 11), von Willebrand disease (vWD) (n = 9), and hemophilia A/vWD (n = 1). vWF activity was determined by botrocetin-induced agglutination of fixed human platelets and vWF antigen (vWF:Ag) by Laurell electroimmunoassay and crossed immunoelectrophoresis. Plasma from normal dogs and those with hemophilia A had vWF activity, vWF:Ag, and a full range of vWF:Ag multimers on gel electrophoresis equivalent to normal canine plasma pool. Platelet cytosol contents were isolated by freezing and thawing, triton X-100 solubilization, or sonication of washed platelets with and without protease inhibitors and inhibitors of platelet activation. Washed platelets were also stimulated with calcium ionophore and MgCl2. There was no measurable vWF activity or vWF:Ag in platelet lysates or releasates in any dog regardless of phenotype. All dogs were studied using a standard arterial stenosis and injury procedure to induce arterial thrombosis. Thromboses were detected by cyclic reductions in Doppler blood flow velocity. Vessels were examined by light and scanning electron microscopy. Thrombosis developed in the arteries of normal (9 of 10) and hemophilia A dogs (16 of 16) but in none of the vWD dogs (0 of 10). Infusion of canine vWF cryoprecipitate into vWD dogs markedly shortened bleeding time but did not support thrombosis as seen in dogs with vWF in the plasma and subendothelium. Thrombosis, then, fails to occur when vWF is absent from the plasma and subendothelial compartments or present only in the plasma compartment. These data are consistent with the hypothesis that vWF in the plasma and subendothelium supports thrombosis. Neither plasma FVIII nor platelet vWF is essential for thrombosis in this model.
Lipoprotein(a) (Lp[a]) is a newly recognized risk factor for the development of coronary heart disease and stroke in human beings; however, the mechanisms by which Lp(a) increases the risk of coronary heart disease remain unclear. The purpose of this study was to examine the effects of Lp(a) on the occurrence of occlusive arterial thrombosis. Occlusive arterial thrombus formation was examined in 18 cynomolgus monkeys with high plasma Lp(a) concentrations (> 35 mg/dL, n = 6), intermediate Lp(a) concentrations (20-25 mg/dL, n = 6), and low Lp(a) concentrations (< 12 mg/dL, n = 6). A Goldblatt clamp was positioned around the left common carotid artery to produce a stenotic segment, and the artery was pinch-injured with needle holders. A 20-MHz Doppler velocity crystal, placed distal to the stenosis/injury site, was used to detect cyclic flow reductions (indicative of transient thrombosis) or permanent cessation of flow velocity (indicative of more stable occlusive thrombosis). All monkeys with high Lp(a) concentrations developed permanent cessation of flow, whereas only one of six arteries from low-Lp(a) monkeys developed permanent cessation of flow (p < 0.05). Arteries from monkeys with intermediate Lp(a) concentrations developed pronounced cyclic reductions of flow but did not progress to permanent cessation of flow. There were no differences in plasma von Willebrand factor activity among the three groups. Immunohistochemical analysis of the damaged arterial segments indicated incorporation of Lp(a) into the adventitia, media, and intima of arteries from monkeys with low and high plasma Lp(a) concentrations, as well as the presence of an occlusive thrombus in arteries that developed permanent cessation of flow.(ABSTRACT TRUNCATED AT 250 WORDS)
The relationship of apolipoprotein-B genotype (Lpb) to diet-induced hypercholesterolemia and atherosclerosis was studied in von Willebrand disease (vWD) and normal pigs. Von Willebrand and normal pigs developed comparable levels of hypercholesterolemia (respectively, 757.9 +/- 49.4 versus 772.8 +/- 47.9 mg/dl, P = 0.95). Pigs with Lpb1/5 and Lpb5/8 genotypes, however, developed significantly higher serum cholesterol levels than those with other Lpb genotypes (866.1 +/- 64.0 mg/dl, P = 0.0343). Coronary and aortic atherosclerosis, measured by computer-assisted automated image analyzer, were not significantly different between vWD and normal pigs. Pigs with an Lpb5 allele developed significantly more atherosclerosis than those with the Lpb3/8 or Lpb8/8 genotypes or the rare Lpb1 allele (r greater than or equal to 0.434, P less than or equal to 0.05). Polymorphism in apolipoprotein B100 genotype, then, significantly influenced the severity of diet-induced hypercholesterolemia and atherosclerotic plaque formation in vWD and normal swine without regard to the vWD genotype.
Use of animal models of von Willebrand factor (vWF) deficiency, both inherited and induced, continues to advance the knowledge of vWF-related diseases. Three examples are reviewed in this article--von Willebrand's disease (vWD), thrombotic thrombocytopenic purpura, and coronary artery thrombosis. The success of gene transfer by liver and bone marrow transplantation in porcine vWD and canine hemophilia A, with a change in phenotype that establishes improved hemostasis, portends imminent testing of gene therapy in these models. With use of recombinant technology, the phenotype of hemophilia B fibroblasts has been transformed to normal, as evidenced by secretion of the normal hemostatically active protein. This result is a prelude to implantation in hemophilic animals. Thrombotic thrombocytopenic purpura is characterized by qualitative and quantitative alterations in vWF. A new animal model induced by the venom factor botrocetin, a cofactor of vWF, closely mimics the human syndrome. A proposed pathophysiologic mechanism for thrombotic thrombocytopenic purpura is outlined. The third contribution is recognition that occlusive coronary thrombosis is a vWF-dependent condition. Without vWF, as in porcine vWD or normal pigs treated with a monoclonal anti-vWF antibody, occlusive thrombi do not develop, even with luminal stenosis. The thrombogenicity of coronary atheromas, including those with fissures of the fibrous cap, is also vWF-dependent.
With normal and von Willebrand disease (vWD) pigs, we studied the role of von Willebrand factor (vWF) in platelet-vessel wall interactions and occlusive arterial thrombosis. Two methods of arterial injury have been used to determine the thrombotic response of flowing blood in vivo. The first involves balloon catheter injury. After superficial denudation of endothelium from coronary intima, platelets adhere to the subendothelium in a monolayer. Similar numbers of adherent platelets are found in both phenotypes, but platelets in vWD pigs have impaired pseudopod formation and are less well spread morphological indexes of limited platelet activation. Deeper injury, which involves the media, produces nonocclusive platelet-fibrin microthrombi. The second injury method involves pinching the artery at a site of superimposed stenosis, a procedure that almost always exposes media. This procedure induces platelet-fibrin microthrombi in normal and vWD pigs, but only normal pigs develop occlusive thrombosis. Both methods of arterial injury have also been performed in normal and vWD pigs with diet-induced hypercholesterolemia and atherosclerosis. Atherosclerosis promotes platelet spread in vWD pigs but does not abolish the protection from stenosis and injury-induced occlusive thrombosis. In addition, neutralization of vWF activity in normal pigs by a monoclonal antibody prevents the induction of occlusive thrombosis by the stenosis and pinch-injury procedure. This monoclonal antibody also causes performed platelet aggregates to break up. These experimental models of inducing arterial thrombosis have been used in normal and vWD pigs to demonstrate interactions between normal and atherosclerotic vessel wall constituents, circulating platelets and vWF that are fundamental in the process of arterial thrombosis.
The purpose of this investigation was to determine the effectiveness of a fitness program designed as an alternative to the standard weight-training and running program and using limited resources and facilities. Forty-three men from the North Carolina Justice Academy, randomly assigned into two groups, completed 12 weeks of physical training. The WT group used a standard weight training and running, whereas the REC group ran and completed a resistive exercise circuit. The REC circuit consisted of nine exercises designed to improve muscular strength and endurance separated by 30 seconds of aerobic exercise. The exercises used chairs, tables, sawhorses, and body weight to provide the resistance. The results indicated that the REC program improved muscular strength and aerobic capacity as well as the WT program. Furthermore, the REC group lost more weight, reduced body fat, and improved their lipid profiles significantly more than the WT group. Thus, the REC program is a viable alternative for the training of public safety officers when only limited resources are available.
A murine monoclonal antibody (mAb) against porcine von Willebrand factor (vWF) induced an antithrombotic state in normal pigs. Thrombosis was induced by a standard procedure of stenosis and mechanical injury of the artery. The mAb was an IgG1 kappa that inhibited vWF-induced platelet aggregation at a titer of 1:6250 and bound to immobilized vWF at a maximal dilution of 1:512,000. The antibody did not affect two other vWF functions, platelet adhesion and binding of coagulant factor VIII (factor VIII:C). The antithrombotic state was characterized by a prolonged bleeding time and lack of plasma vWF activity, but with near-normal levels of factor VIII:C and von Willebrand antigen. The circulating Ag.mAb complex demonstrated a multimeric distribution comparable to that of native plasma vWF. Three groups of pigs were studied: group A consisted of nine untreated animals, eight of which developed occlusive coronary thrombosis; group B, four treated animals with a long bleeding time, none of which developed occlusive thrombosis; and group C, two animals with preexisting thrombosis treated with mAb, in which stable blood flow was reestablished. Morphologically, the group B animals showed adherent platelets covering the injured intima but no thrombosis. This mAb is an antithrombotic agent that prevents platelet thrombosis without affecting intrinsic platelet function.
We studied the role of von Willebrand factor in coronary thrombosis in normal, heterozygous, and homozygous von Willebrand's disease pigs by producing coronary stenosis with a Goldblatt clamp positioned around the left anterior descending coronary artery. Flow velocity was assessed by a 20-MHz Doppler velocity probe distal to the Goldblatt clamp. Myocardial extracellular potassium levels were measured by potassium-sensitive electrodes in myocardium supplied by the left anterior descending artery. Whereas stenosis sufficient to block reactive hyperemia to a 20-second occlusion produced an elevation of myocardial extracellular potassium, it produced neither spontaneous cyclic flow reductions nor permanent cessation of coronary blood flow velocity. Injury of the coronary artery at the stenosis site with spring-loaded forceps produced cyclic flow reductions or permanent cessation of flow in eight of nine phenotypically normal pigs. On the other hand, flow variations occurred in none of the 10 von Willebrand's disease pigs, including four given purified von Willebrand factor at a dose that failed to correct the bleeding time (p less than 0.001, chi 2 test). Permanent cessation of flow was caused by an occlusive platelet-fibrin-red-blood-cell thrombus. Scanning electron micrographs from pigs with cyclic flow variations and from von Willebrand's disease pigs showed injured endothelium covered by adherent platelets, red and white blood cells, and fibrin. These data suggest an important role of native von Willebrand factor in sudden occlusive arterial thrombosis following stenosis and intimal injury.
A role of von Willebrand factor-mediated platelet function in porcine atherogenesis is strongly suggested by these studies. This influence of platelet function is probably most important in experimental systems that involve long-term observation and low or moderately elevated levels of serum cholesterol. On the other hand, effects of platelet function on development of atherosclerosis in animals with extremely high serum cholesterol levels are difficult to demonstrate and may be of relatively less importance. These observations are consistent with the results of numbers of recent studies describing the relationship of vascular injury to intimal smooth muscle cell proliferation. There is considerable evidence that lipid-rich intimal lesions occur in hypercholesterolemic animals with no antecedent denudation of endothelium or platelet adherence. It is difficult to ascribe intimal proliferation to platelet effects in this setting. On the other hand, endothelial cells, smooth muscle cells, and monocytes, which are all known to be involved in the atherosclerotic process, can produce mitogenic and chemotactic proteins, including platelet-derived growth factor. Therefore, metabolic aberrations of various kinds, including those initiated by mechanical injury or hypercholesterolemia, may promote proliferation in the vascular wall and resultant lesion development. Data from studies of pigs with vWD suggest a contribution of platelets to this process, but the effects of this contribution are modulated by numbers of variables, most of which are yet to be identified. The control of these multiple variables will be necessary before a clear understanding of the magnitude of the platelet-mediated effects can be gained. This will require carefully defined conditions of hypercholesterolemia, special attention to the immunologic variables and study of properly selected vascular segments under known conditions of flow. This later element will be especially important in the study of vWF-mediated platelet function, since shear forces are a critical determinant of vWF function. Systems that model flow conditions in various segments of the aorta, carotid, and coronary arteries are presently under development for this purpose. Finally, studies examining the molecular basis of vWF-mediated and other platelet functions will probably guide the most productive use of these models. Platelet membrane glycoprotein (GP) receptor Ib and the complex GP IIb and IIIa have been shown in ex vivo studies to be binding sites for vWF molecules.(ABSTRACT TRUNCATED AT 400 WORDS)