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Biomedical subjects

G V Born

Publications and source records attributed to G V Born.

At least 37 records · Page 2Linked to original sources
PubMed1992

Collagen types I and III, collagen content, GAGs and mechanical strength of human atherosclerotic plaque caps: span-wise variations.

Measurements of total collagen, of the ratio of collagen types III/(I+III) and of sulphated glycosaminoglycans (GAGs) were compared with mechanical strength for individual ulcerated and non-ulcerated human aortic plaque caps and with intima adjacent to the plaques. The distributions of the collagen type ratio were similar for both ulcerated and non-ulcerated plaque caps but different from that of the adjacent intima. The proportions of different collagen types were not related to fracture stress and are thus unlikely to affect the potential to ulcerate. The distributions of the sulphated GAGs showed lower amounts for the plaque caps compared with the nearby intima, with the centres of ulcerated plaque caps having the lowest values. Total collagen had higher values in the peripheries of plaque caps compared with the nearby intima, but was distinctly lower in the centres of ulcerated plaque caps. Plaque caps appeared to require a higher collagen content than adjacent intima to support a given level of mechanical strength, suggesting that while collagen production had occurred in the plaque caps it was not as efficiently organized to resist fracture as a similar amount of collagen in the adjacent intima. Ulcerated plaque caps are notable for much larger transverse (centre vs. periphery) gradients of connective tissue constituents than for non-ulcerated plaque caps. The development of these transverse gradients may be a critical aspect in determining the propensity of a plaque to ulcerate.

Aortic Diseases↗
PubMed1992

Adrenaline increases the uptake of low-density lipoproteins in carotid arteries of rabbits.

The uptake of low-density lipoprotein was compared in carotid arteries of anaesthetized male New Zealand rabbits after infusing alternate carotids with adrenaline, or with saline as a control. The infusions were at approximately 2% of the carotid blood flow, the adrenaline being at approximately 10 nM in the carotid blood. Human low density lipoprotein, methylated to prevent recognition by the high affinity receptor (m-LDL), was labelled with 125I and injected intravenously. Adrenaline infusions for 2 or 4 h significantly increased m-LDL radioactivity in the carotid walls. The radioactivity of reinjected red cells labelled with 51Cr was the same in the walls of both carotids. This excluded the possibility that the excess LDL radioactivity in adrenaline infused carotids was accounted for by increased amounts of blood in the arterial wall. It also made it improbable that the excess LDL resulted from decreased elimination through a vasoconstriction effect of adrenaline on the vasa vasorum, which should have decreased the amount of radioactivity due to red cells. The results, therefore, suggest that adrenaline at its pathophysiological blood concentrations accelerates the uptake of LDL by large arteries in rabbits.

Animals↗
PubMed1992

Plaque fissure: the link between atherosclerosis and thrombosis.

The immediate cause of arterial, predominantly coronary thrombosis is almost always cracking or fissuring of the cap of an atheromatous plaque. This exposes collagen and lipids to the flowing blood and thereby initiates thrombotic platelet aggregation, almost immediately followed by coagulation. The thrombi tend to extend into the arterial lumen, causing obstruction to blood flow and clinical symptoms and signs. Evidence for this sequence of events comes, inter alia, from angiograms of patients with unstable angina and developing myocardial infarction. Direct angioscopy in life is also visualising mural thrombi over fissured plaques in atheromatous coronary arteries. We are investigating the initial development of atheromatous plaques liable to fissuring. The cap over such plaques covers a "lipid pool". We have discovered that one factor promoting the uptake of lipid, in the form of plasma low-density lipoprotein, is the concentration of circulating catecholamines (Cardona-Sanclemente LE, Gorog P, Born GVR (1992) J Physiol London, in press). We are also investigating the immediate cause(s) of plaque fissure. We have evidence for a complex interaction of different determinants, including the concentration of macrophages, presumably as foam cells, in the plaque caps (Lendon CL, Davies MJ, Born BVR, Richardson PD (1991) Atherosclerosis 87: 87).

Angina, Unstable↗
PubMed1991

Atherosclerotic plaque caps are locally weakened when macrophages density is increased.

The density of macrophages, identified by the antibody EBMII, in human aortic plaque caps was counted. A contiguous strip of cap tissue was tested mechanically. Aortic plaque caps which had undergone rupture (ulceration) at one end (n = 18) were compared with caps of intact plaques (n = 22). The caps of ruptured plaques showed a significant increase in macrophage density, an increased extensibility and decreased maximum stress (force per unit area) at fracture when compared with caps from intact plaques.

Aorta↗
PubMed1991

In vivo and in vitro effects of low molecular weight heparan sulphate on the human fibrinolytic enzyme system.

The aim of this study was to evaluate the effects of a preparation of low molecular weight heparan sulphate (LMW-HS) on the fibrinolytic system. Twenty-five healthy volunteers received LMW-HS by mouth in three separate experiments. In the first experiment, 10 volunteers received either 80 mg LMW-HS or placebo in a single-blind cross-over study; blood samples were taken before and 1, 2, 3 and 6 h after treatment. LMW-HS caused an increase in global fibrinolysis, the effect being greatest after 2-3 h and disappearing by 6 h. However, neither plasminogen activator activity nor tissue-type plasminogen activator (tPA) antigen levels were changed. In the second experiment, daily doses of 80 mg LMW-HS were administered to 10 volunteers for 7 days; this regimen did not produce a statistically significant increase in fibrinolytic activity for the whole group although some individuals did respond markedly. In the third experiment, 160 mg LMW-HS administered to five volunteers did not affect ADP- and collagen-induced platelet aggregation. In vitro, LMW-HS added to plasma at concentrations of 20 and 30 micrograms/ml, brought about a significant increase in apparent plasminogen activator activity. These results suggest that the increased fibrinolytic activity seen after LMW-HS is due to the recruitment of additional amounts of tPA in the ex vivo test system. LMW-HS had no effect on plasminogen activator inhibitor.

Adenosine Diphosphate↗
PubMed1991

Recent evidence for the involvement of catecholamines and of macrophages in atherosclerotic processes.

The atherogenetic uptake of low density lipoprotein (LDL) is accelerated by the catecholamines adrenaline and noradrenaline at their pathophysical blood concentrations in rabbits and rats. A similar effect in man could account for the coronary risk factor status of cigarette smoking, hypertension, stress, etc. when associated with elevated circulating catecholamines. In human atheromatous lesions, the concentration of macrophages is greater in plaques which have fissured or ulcerated than in those which have not. This is compatible with the proposition that macrophages contribute to plaque fissure, the commonest immediate cause of coronary thrombosis.

Animals↗
PubMed1990

Dissociation of platelet activation and spontaneous myocardial ischemia in unstable angina.

A dynamic thrombotic process, coronary spasm or both can be responsible for recurrent episodes of transient reduction of coronary blood flow in unstable angina. We have investigated the temporal relationship between episodic platelet activation, as detected by increased urinary excretion of 11-dehydro-TXB2, and spontaneous myocardial ischemia, assessed by continuous electrocardiographic monitoring and recording in 21 patients with unstable angina pectoris. In order to validate measurements of metabolite excretion as a reflection of intracoronary platelet activation, we have also performed repeated urine sampling from 8 patients undergoing PTCA and from 6 patients with peripheral vascular disease. The latter showed a 16% coefficient of variation in 3 consecutive 8-h urine samples. 11-dehydro-TXB2 increased significantly, by up to 15-fold, in the 2.5- to 5.0-h urine collection encompassing PTCA and decreased by greater than 50% during the following 2-h period. Patients with unstable angina were characterized by episodic increases (greater than 2 SD of controls) in metabolite excretion, in successive 6-8 h specimens. Paired measurements of 11-dehydro-TXB2 and 2,3-dinor-TXB2 in 15 urine samples did not reveal evidence of altered metabolic disposition of endogenously released TXB2. A total of 125 ECG ischemic episodes were recorded, of which 64% asymptomatic. We have compared these biochemical and ECG changes in patients randomized to i.v. low-dose aspirin or i.v. isosorbide dinitrate and oral diltiazem. Twenty-five of 56 (i.e. 45%) urine samples obtained in aspirin-free periods showed increased metabolite excretion as compared to 15 of 88 (i.e. 17%) samples collected during aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Coronary thrombosis: pathogenesis and prevention.

Acute myocardial infarction is most commonly initiated by fissuring of an atheromatous plaque. Through such fissures the blood is exposed to thrombogenic constituents of the intima, causing thrombotic obstruction of the coronary artery. Why plaque fissuring occurs is not known. Our investigation is to establish which types of plaque undergo fissuring by relating their mechanical with their cellular and biochemical properties; and to quantify the distribution of fissures. Results so far indicate that fissures occur predominantly in plaques with lipid pools in one segment of intima, and that the commonest single site of fissuring is that of maximal stress concentration as predicted by computer modelling. The results also suggest that arterial spasm at the immediate site of fissuring is not involved, as more than half the fissures occur at sites where there is no residual medial smooth muscle. Obstructive coronary thrombosis is initiated in most cases by plaque fissure with local haemorrhage which induces intravascular platelet aggregation. Recent observations with novel techniques have provided evidence that platelet aggregation in vivo is initiated by ADP and potentiated by thromboxane A2 and thrombin, with actual contribution of exposed collagen still undetermined. These observations provide an explanation for the limited effectiveness of any simple platelet-inhibiting drug, including Aspirin, by itself whenever arterial, eg. coronary or cerebral thrombosis is initiated by haemorrhages into atheromatous plaques. On the other hand, Aspirin is significantly effective when myocardial infarction follows unstable angina and when strokes follow transient episodes of cerebral ischaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin↗
PubMed1990

Anti-thrombotic drugs in the treatment of coronary heart disease: the present situation with aspirin.

The most important clinical studies of acetylsalicylic acid in coronary heart disease are compiled. In early 1970 trials unnecessarily high doses have been used. Since 1980 acetylsalicylic acid was given in a dose of about 1000 mg/day. Trials covering 10,000 patients were performed. Significantly decreased cardiovascular morbidity and mortality in patients with previous myocardial infarction was observed. Side effects were significant, haematemesis occurred in 0.1 per cent of patients per year. In secondary-prevention trials to treat unstable angina, which were performed in USA and Canada, the number of non-fatal myocardial infarctions was reduced by about 50 per cent. The dose applied was once 325 mg/day or four times the same dose. In patients after coronary artery by-pass graft acetylsalicylic acid in a dose of 100 mg/day was clinically effective. The effectiveness of acetylsalicylic acid in secondary prevention is strongly supported by the ISIS-2 (Second international Study of Infarct Survival) trial reported in 1988. 17,000 patients were admitted to the trial. With respect to acetylsalicylic acid they received 160 mg/daily for 4 weeks. In addition the effect of streptokinase 1.5 mega-units i.v. was investigated in a cross over design against placebo. Acetylsalicylic acid in the low dose applied, significantly reduced non-fatal reinfarction. The effect of a combination with streptokinase was additive. Primary prevention trials: British and an American trial among volunteer doctors are not comparable because of differences in design and execution. No decrease in overall mortality rate was observed. Acetylsalicylic acid showed some effectiveness but the results are not conclusive.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina, Unstable↗
PubMed1990

Determinants of the atherogenic flux of low-density lipoprotein into arteries.

Evidence is provided that in anaesthetized rabbits the atherogenic uptake of low-density lipoprotein (LDL) by arterial walls is accelerated by norepinephrine at its physiological concentrations in rabbit and human blood. The principle of the experiments was to compare the uptake of intravenously injected, radioactively labelled LDL, methylated to prevent removal by high-affinity receptors, in the two carotid arteries of anaesthetized rabbits after infusing low concentrations of norepinephrine noradrenaline into one carotid and saline as control into the other, the volume rates of infusion being about 1% of the carotid blood flows. The results thus obtained may contribute towards an explanation for the accelerated atherosclerosis and the increased incidence of its clinical manifestation in conditions associated with elevated blood norepinephrine concentrations, including the episodic increases associated with stress and cigarette smoking as well as the more persistent increases caused by phaeochromocytoma.

Arteries↗
PubMed1989

Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques.

To find out the types of atherosclerotic plaques that fissure and where they fissure, plaques from 85 patients who had died from coronary thrombosis were examined histologically. 67 of the plaques contained an eccentric pool of extracellular lipid in the intima; 42 (63%) of these plaques had fissured at the junction of the plaque cap with the more normal intima, and the other 25 (37%) had torn through the centre of the cap. Computer modelling of different forms of plaque showed that at systole eccentric pools of lipid concentrated stress on the plaque cap, especially near the edge of the plaque. When the lipid pool occupied less than 15% of the vessel circumference, and when the plaque cap was less stiff than the adjacent normal intima, the point of maximum stress was over the centre of the plaque. Computer modelling also showed that the distribution of circumferential tensile stress across the intima was radically altered by atherosclerotic plaques. Regions of high circumferential stress correlated well with the site of intimal tears found at necropsy. The histological findings showed that site of tearing was influenced by variation in the mechanical strength of cap tissue due to focal accumulation of foam cells. Focal weak points in the cap would explain tears which were not at the point of maximum stress.

Arteriosclerosis↗
PubMed1989

Increased uptake of methylated low-density lipoprotein induced by noradrenaline in carotid arteries of anaesthetized rabbits.

Atherosclerosis is accelerated in hyperlipidaemias but, apart from the concentration of low-density lipoprotein (LDL) in the blood, very little is known about other influences on the disease process. We now provide evidence that in anaesthetized rabbits the atherogenic uptake of LDL by arterial walls is accelerated by noradrenaline at its physiological concentrations in rabbit and human blood. The principle of the experiments was to compare the uptake of intravenously injected, radioactively labelled LDL, methylated to prevent removal by high-affinity receptors, in the two carotid arteries of anaesthetized rabbits after infusing low concentrations of noradrenaline into one carotid and saline as control into the other, the volume rates of infusion being about 1% of the carotid blood flows. Human LDL, which behaves sufficiently like rabbit LDL for these purposes, was prepared, methylated and radio-iodinated by standard methods. At the end of the infusions, the arteries were excised and their radioactivities determined. Noradrenaline infused for 2 h to produce local blood concentrations of nominally 1, 10, 50 and 100 nM significantly increased the LDL radioactivities of the walls of the noradrenaline-infused carotids. Concentrations of nominally 100 nM also increased the LDL radioactivities of the walls of the saline-infused carotids; this was associated with significant increases in their blood noradrenaline concentrations. These results may contribute towards an explanation for the accelerated atherosclerosis and the increased incidence of its clinical manifestations in conditions associated with elevated blood noradrenaline concentrations, including the episodic increases associated with stress and cigarette smoking as well as the more persistent increases caused by phaeochromocytoma.

Animals↗
PubMed1989

Polypharmacologic interactions in the management of thrombosis.

Pathologic evidence indicates that thrombosis in coronary arteries is most frequently initiated by fissures in atheromatous plaques and that the associated hemorrhage induces platelet aggregation. Less frequently, thrombosis may be initiated by arterial spasm or by pathologic abnormalities affecting the platelets or the mechanisms of plasma coagulation. For the rational development of antithrombotic drugs on the basis of aggregation inhibitors, the cause (or causes) of plaque fissure and of the ensuing platelet aggregation need therefore to be elucidated. Our current research is based on the working hypothesis that fissuring occurs when plaques have acquired a particular composition that can be disrupted by the cumulative effect of continuously varying hemodynamic forces (reminiscent of fatigue failure in artificial materials), and that fissure-associated hemorrhage, like hemorrhage anywhere else, initiates platelet aggregation via a concurrence of hemodynamic and biochemical mechanisms. Detailed studies are currently being directed toward establishing the sequence of events that determine the contributions of adenosine diphosphate, thromboxane A2, and other endogenous agents in promoting hemostatic platelet aggregation in real life and, by implication, arterial thrombosis. Important recent evidence has demonstrated repeated thrombosis in unstable angina patients. In such patients, aspirin diminishes by about half the incidence of myocardial infarction and death. Presumably, it prevents the formation of platelet thrombi, which would tend to be produced in the turbulent blood flowing through arterial segments severely narrowed by hemorrhage plaques or in spasm. Several other platelet-active drugs are also under investigation.

Animals↗
PubMed1989

Increased microvascular resistance to blood flow in the rat hindlimb after perfusion with neuraminidase.

1. The ability of blood to flow through capillaries with diameters smaller than that of erythrocytes and leucocytes has been explained hypothetically on the basis of electrostatic repulsion between vessel walls and circulating cells, but in the absence of in vivo evidence. Following our discovery of extraordinarily high densities of sialic acids on endothelial surfaces, we have now devised experiments to determine to what extent microcirculatory blood flow might depend on these negative charges. 2. Hindlimbs of rats anaesthetized with ether and pentobarbitone were perfused through the femoral artery at constant volume with continuous recording of inflow resistance: first with carotid arterial blood containing continually infused acetylcholine at concentrations which minimized peripheral resistance without affecting heart rate; then for 5 min with buffered saline containing acetylcholine at the same concentration plus neuraminidase (from Vibrio cholerae, at 0.1 mg/ml) to remove endothelial sialic acids (for control experiments without neuraminidase); and then again with acetylcholine-infused carotid blood. 3. As a consequence of the saline perfusion, there was a rapid initial rise and fall of inflow resistance. The subsequent changes in resistance were calculated as the difference between its lowest value in the first 10 min and the value after 60 min. Controls and neuraminidase-perfused groups were compared using the t test for unpaired measurements. 4. In four control experiments inflow resistance decreased by 10-40% (14 +/- 10%, mean +/- S.E.M.). In three experiments with neuraminidase, inflow resistance increased by 24-38% (29 +/- 4%, mean +/- S.E.M.). The difference between the saline and the neuraminidase-perfused groups was significant (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗