J. O'Grady

Autologous low-density lipoprotein labelling allows characterization of human atherosclerotic lesions in vivo as to presence of foam cells and endothelial coverage

The monitoring of local vascular kinetics after injection of autologous radiolabelled low-density lipoprotein (LDL) allows characterization of human atherosclerotic lesions as to the presence of foam cells and the quality of endothelial coverage. The following evidence exists: (1) dynamic imaging reveals two types of visual LDL accumulation in the vascular bed, one increasing, becoming visible sometimes only as late as after 24 h, and the other one appearing very early on, but decreasing with time; (2) the accumulation of iodine-123 LDL or iodine-131 LDL in the vascular bed shows three major types of local kinetic curves, which correlate with scintigraphic findings; (3) the accumulation of radiolabelled LDL in the vascular bed of humans in vivo is similar to its uptake in de- and re-endothelialized vessels of experimental animals using 125I-LDL; (4) morphological control in endarteriectomy samples confirms the hypothesis that this promising new approach may for the first time allow the in vivo monitoring of preclinical lesions in humans.

Isradipine: A potent calcium blocker with beneficial effects on platelet function and vascular prostacyclin production

Calcium blockers inhibit platelet aggregation induced in vitro by various stimuli, such as ADP and collagen. In this study the in vitro effects of isradipine, a new dihydropyridine-derivative, and of nifedipine on platelet aggregation and malondialdehyde-production were tested. The lowest concentrations affecting ADP-induced platelet aggregation were 1.0 micrograms/ml isradipine and 12.5 micrograms/ml nifedipine. Both drugs exhibited an inhibitory action on malondialdehyde-production in concentrations 2 to 3 times lower than those affecting platelet aggregation. In vitro, PGI2-formation by rat aortic rings incubated with calcium blockers was increased in a dose-dependent manner. The lowest concentration of isradipine which increased PGI2-generation amounted 0.5 micrograms/ml. The corresponding value for nifedipine was 10 micrograms/ml. The findings demonstrate isradipine to be more potent than nifedipine in affecting in vitro platelet aggregation and enhancing PGI2-formation.

Ex-vivo and in-vivo platelet function in patients with severe hypercholesterolemia undergoing LDL-apheresis

Patients with severe familial hypercholesterolemia (HC) show abnormal platelet function and shortened platelet survival. Atherosclerosis is associated with platelet hyperactivity. Low-density lipoporotein (LDL)-apheresis eliminates the most atherogenic lipid fraction and inhibits the progression of atherosclerosis inducing even regression. In order to assess the influence of LDL-apheresis on platelet function ex-vivo and in-vivo, 6 patients with severe heterozygous HC, all of them being pharmacologically treated with HMG-CoA reductase inhibitors and anion exchange resins were investigated. Ex-vivo platelet function was assessed by the aggregation response to ADP before starting apheresis treatment, as well as after 2 and 24 weeks, respectively. In-vivo platelet function was determined by measuring platelet survival after radiolabeling with 111In-oxine before starting LDL-apheresis and after 24 weeks of twice monthly treatment. LDL-apheresis therapy induced a significant (p < 0.01) drop in cholesterol by 64%, LDL-cholesterol by 77% and in triglycerides by 46% over a period of 24 weeks. ADP-induced platelet aggregation revealed a decreased aggregability of platelets with a decline in the maximal amplitude and the slope of the response curve. Changes in platelet sensitivity to prostaglandins (PG) were significantly for PGI2, but did not reach statistical significance for PGE1. The results revealed a significant (p < 0.001) increase in platelet survival of 111In-oxine-radiolabeled autologous platelets from a mean of 106.50 hours before to 137.50 hours (p < 0.01) after treatment, being accompanied by an increase in labeling efficiency (p < 0.001) and recovery (p < 0.001). These data provide evidence for improved hemostatic regulation in vivo as a result of maintainance of lipid-lowering achieved with LDL-apheresis.

Comparable effect of prostaglandin E1 in decreasing in vivo platelet deposition on human lesion sites after intravenous and intraarterial application

It had been claimed that prostaglandin E1 is degraded during first lung passage to a major extent. Clinical results, however, as well as various platelet function tests and coagulation parameters revealed no apparent difference after i.v. and i.a. infusion. Thus, we examined the question what the quantitative difference between i.v. and i.a. PGE1-application would be upon in-vivo platelet function assessed by platelet uptake over active lesion sites as well as platelet half-life monitoring after autologous 111-In-oxine platelet labelling. In patients suffering from peripheral vascular disease stage II according to Fontaine PGE1 was able to decrease platelet uptake after i.v. and i.a. therapy to a comparable extent; similarily, a significant prolongation in platelet half-life was noted, again revealing no difference. As the decrease in platelet uptake is assumed to be predominantly a vascular effect, it is hypothetized that more stable derivatives of PGE1 are active, counterbalancing a lower biological activity with a longer half-life.

The economy class syndrome--a survey of 19 cases.

BACKGROUND Thromboembolic events during or immediately after long-distance flights (economy class syndrome--ECS) are gaining more importance due to the rapidly increasing number of flights. Systematic data on haemostatic parameters in these patients are not available yet. PATIENTS AND METHODS We were therefore analyzing the anamnestic, laboratory and clinical findings in 19 patients (17 males, 2 females, aged 33-75 years) with the final clinical diagnosis ECS. RESULTS Symptoms commenced either immediately or up to 93 hours after disembarkation (mean 42.3 hours). In the great majority (84.2%) myocardial infarction was the initial diagnosis. No defect in the coagulation and/or prostaglandin system was discovered in either of the patients. Prevalence of smoking (26.3%) was even lower than in the normal population. No predisposing factors were found. Apparent anamnestic similarities were flu and fever (47.4%) while 4 of the patients (26.3%) had severe diarrhoea and dehydration before the flight. Almost all the patients (78.9%) were drinking alcohol during the flight and not actively moving their legs (84.2%). ECS occurred also in business and first class passengers. CONCLUSION Surprisingly the onset of ECS is definitely not associated with haemostatic defects and not necessarily associated with the clinical risk factors reported.Background: Thromboembolic events during or immediately after long-distance flights (economy class syndrome – ECS) are gaining more importance due to the rapidly increasing number of flights. Systematic data on haemostatic parameters in these patients are not available yet. Patients and methods: We were therefore analyzing the anamnestic, laboratory and clinical findings in 19 patients (17 males, 2 females, aged 33–75 years) with the final clinical diagnosis ECS. Results: Symptoms commenced either immediately or up to 93 hours after disembarkation (mean 42.3 hours). In the great majority (84.2%) myocardial infarction was the initial diagnosis. No defect in the coagulation and/or prostaglandin system was discovered in either of the patients. Prevalence of smoking (26.3%) was even lower than in the normal population. No predisposing factors were found. Apparent anamnestic similarities were flu and fever (47.4%) while 4 of the patients (26.3%) had severe diarrhoea and dehydration before the flight. Almost al...

Low density lipoprotein labelling characterizes experimentally induced atherosclerotic lesions in rabbits in vivo as to presence of foam cells and endothelial coverage

The entry of autologous iodine-125 low density lipoprotein (125I-LDL) into the aortic wall in rabbits was measured. After abdominal endothelium abrasion with a Fogarthy catheter the animals were fed a 1% cholesterol-supplemented diet for 4 weeks. The animals were killed 1–48 h after administration of 25 μCi 125I-LDL. Local entry of radiolabelled LDL was estimated and correlated to endothelial surface lining and foam cell content, both controlled morphologically. Endothelialized segments showed the lowest entry of 125I-LDL, the maximum uptake was reached at around 8 h. In deendothelialized segments the entry was higher and the peak later (12 h), while in re-endothelialized segments a continuous increase in 125I-LDL entry up to 48 h was measured. Number and extent of foam cells correlated with the entry of LDL. The data indicate the usefulness of LDL radiolabelling for qualitative in vivo information on surface lining and foam cell content.

Isradipine improves platelet function in hypertensives

SummaryThe effect of treatment for eight weeks with isradipine 1.25 mg twice daily for 4 weeks and thereafter 2.5 mg twice daily for 4 weeks on ex vivo platelet function was investigated in 10 male hypertensive patients, aged 51 (6.1) y.Systolic and diastolic blood pressure, platelet aggregation in response to ADP, serum thromboxane B2 and β-thromboglobulin levels were significantly decreased at rest before exercise ergometry, during exercise and at rest after exercise. The platelet count, platelet sensitivity and the plasma levels of 6-oxo-prostaglandin F1α were not affected by isradipine.It is concluded that a compound that lowers blood pressure and inhibits platelet activation may be of clinical benefit in the routine treatment of hypertension.

Beneficial effect of long-term PGE1-treatment in left ventricular heart failure.

Five male patients aged 34-47 years with congestive heart failure showed an improvement of left ventricular ejection fraction (LVEF) at rather low PGE1-doses (10-30 ng/kg/min) without affecting blood pressure or heart rate. LVEF was estimated by means of radionuclide ventriculography (RNV) prior to and during i.v.-infusion of PGE1 at increasing dose rates (10-100 ng/kg/min). Therefore, we administered to these responders PGE1 at a rate of 20 ng/kg/min i.v. continuously on a long-term basis by means of a portable infusion pump. Until up to 4 months the remarkable benefit in LVEF induced by PGE1 was still present to a comparable extent in all the patients. No rebound desensitization phenomenon occurred either on platelet activity or on LVEF. PGE1, via a more practical route of application or by a stable analogue, may be a promising therapy at this stage of cardiomyopathy (CMP).

The diminished extracellular matrix production induced by isradipine, a calcium channel blocker, is completely abolished by cyclooxygenase inhibition

Collagen and glycosaminoglycan synthesis are well known to be enhanced during early atherogenesis. In this experimental study the synthesis of collagen was determined using 14C proline incorporation, the glycosaminoglycan production by means of 35S-sulphate incorporation and subsequent quantification by means of autoradiography. Isradipine, a new calcium channel blocker of the dihydropyridine family at a dose of 0.3 mg/kg significantly (p less than 0.01) decreased the incorporation of both the radioactive precursors. This effect was abolished by a concomitant aspirin treatment, while aspirin alone did not exert any significant effect on the precursor incorporation. These data suggest that isradipine, which is known to stimulate PGI2 synthesis, may exert this antiatherosclerotic inhibitory action on extracellular matrix production via the endogenous liberation of PGI2.

Diminished platelet residence time on active human atherosclerotic lesions in-vivo — Evidence for an optimal dose of aspirin?

Although aspirin is an old drug, its optimal dose for the treatment of human atherosclerosis has not been finally proven. Various in-vitro and ex-vivo platelet function tests revealed a dose range from 1 to 3000 mg as being optimal. It was thus the goal to examine its in-vivo efficacy in human suffering from peripheral vascular disease in 7 different doses ranging from 1 mg to 1000 mg a day. All these patients have been treated for 3 months. Platelet half-life and platelet uptake ratio show an in part significant improvement being most pronounced at the daily doses of 20 and 1000 mg respectively. No change occurs in the placebo treated controls. These findings indicate, that 20 or 1000 mg aspirin taken daily per os, are superior to the other doses examined concerning the in-vivo platelet function (as measured by platelet half-life) and rendering the arterial surface less thrombogenic (as reflected by platelet uptake ratio-measurements).