The Subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) trial. Results of a multicenter randomized trial investigating the effects of high dose unfractionated heparin on angiographic restenosis and clinical outcome.

OBJECTIVES: We sought to determine whether 12,500 IU of unfractionated heparin given subcutaneously twice daily for 4 months after percutaneous transluminal coronary angioplasty beneficially influences the subsequent rate of angiographic restenosis and the incidence of clinical events. BACKGROUND: Heparin has been shown to exhibit powerful antiproliferative effects against smooth muscle cells in several animal models. METHODS: A randomized trial with blinded data analysis was undertaken to assess the effect of unfractionated subcutaneous heparin on angiographic restenosis after coronary angioplasty. After successful angioplasty, patients were randomized to receive no heparin or 12,500 IU of heparin given subcutaneously twice daily for 4 months. Quantitative coronary angiography was performed before angioplasty, immediately after angioplasty and at follow-up ("early" [before 4 months] or electively [at 4 months]). RESULTS: The study group comprised 339 patients, 167 randomly assigned to receive heparin, 172 to receive no heparin. Repeat cardiac catheterization was performed in 90% of randomized patients. At early and elective restudy (mean 4.2 months), the mean +/- SD difference in minimal lumen diameter between the postangioplasty and follow-up measurement was -0.55 +/- 0.58 mm for the no heparin group and -0.43 +/- 0.59 mm for the heparin group (p = NS). Clinical events during the follow-up period did not differ significantly between groups: fatal myocardial infarction (1 patient in each group), coronary bypass grafting (5 patients in each group), repeat angioplasty (12 in the no heparin, 6 in the heparin group), angina at 4-month assessment (33% in the no heparin, 32% in the heparin group). CONCLUSIONS: Long-term treatment with high dose subcutaneous heparin (12,500 IU twice daily) for 4 months did not favorably influence angiographic or clinical outcome after coronary angioplasty.

Changes in vessel wall plasminogen activator activity and smooth muscle cell proliferation and activation after arterial injury.

OBJECTIVES: The aim was to examine changes in vessel wall fibrinolytic activity following angioplasty and to assess any relationship to changes in smooth muscle cell proliferation and activation. METHODS: Balloon angioplasty was performed to the iliac arteries of New Zealand White rabbits and vessel wall changes assessed at 2 h, 1 d, 7 d, 14 d, and 1 month postprocedure. Tissue-type (tPA) and urokinase-type (uPA) plasminogen activator activity was assessed using chromogenic substrate assays, while smooth muscle cell proliferation and activation was monitored using expression of proliferating cell nuclear antigen (PCNA) and of basic fibroblast growth factor (bFGF) respectively. RESULTS: Intimal thickening progressively increased up to 1 month. uPA activity increased at 2 h [1.94(SEM 0.19) v 1.59(0.05) U.mg-1 tissue for control vessels, P = 0.03], remained increased at 24 h, but by 7 d had decreased to below control levels and remained low. In contrast, tPA activity fell significantly at 2 h [0.9(0.3) v 1.96(0.13) micrograms.mg-1 tissue for control vessels, P = 0.03], remained low at 24 h, but by 7 d had reverted back to control levels [2.19(0.39) micrograms.mg-1]. PCNA positivity of the media increased at day 1, reached maximum on day 7 [16.9(5.1)% positively staining cells] before returning to baseline by 1 month. PCNA positivity of the intima first evident at day 7 [0.7(0.3)%], reached a maximum at day 14 [4.1(0.4)%]. bFGF expression increased early at 2 h [mean(SE) positively staining cells: 15.7(5.3)% v 11.2(4.8)% for control vessels] and continued to increase, reaching a maximum in the media at day 7 [59(8.6)%] and in the intima at day 14 [57.5(5.7)%]. CONCLUSIONS: Balloon injury produced an initial fall in tPA and rise in uPA activity. tPA increased back to control levels by 7 d, while uPA fell to below control levels at 7 d and 1 month. This would be compatible with a mechanism whereby acute injury suppressed tPA and upregulated uPA activity, with increased tPA activity acting as a marker for vessel repair.

A targeted antithrombotic conjugate with antiplatelet and fibrinolytic properties which reduces in vivo thrombus formation.

OBJECTIVE: Potent therapy that could be locally delivered to inhibit blood factor-vessel wall interaction and which would remain localised to the site of damage may avoid the side effects of systemic drugs in the treatment of disorders such as subacute thrombosis of saphenous vein grafts and intravascular stents. We therefore assessed the feasibility of developing a targeted antithrombotic conjugate by covalently cross-linking urokinase to a monoclonal antibody to platelet glycoprotein IIb/IIIa (M735) and a monoclonal antibody against damaged endothelium (P14G11). METHODS: Conjugation was carried out using N-succinimidyl-3-(2-pyridyldithio) propionate as the cross-linking reagent. The conjugate was assessed in vitro and in an in vivo model of thrombosis and local delivery. RESULTS: The conjugate formed, ATC(3), retained specificity for damaged endothelial cells and platelets and had urokinase activity of approximately 10,000 IU.mg-1 protein. Persistence of urokinase activity on binding to intact platelets and scratch damaged endothelial monolayer preparations was confirmed. Platelet aggregation studies (using ADP and collagen) revealed complete inhibition by ATC(3) at a dose of 5 micrograms.ml-1 while an unconjugated mixture of M735 (20 micrograms.ml-1), P14G11 (20 micrograms.ml-1), and urokinase (200 IU.ml-1) failed to inhibit completely platelet aggregation induced by ADP. In an in vivo model of thrombosis and vascular injury, local delivery of ATC(3) significantly reduced the weight of thrombus formed [median 13 mg (interquartile range 9-20)] compared to an unconjugated mixture of M735, P14G11 and urokinase [35 mg (28-45)] and urokinase alone [41 mg (33-55)]. CONCLUSIONS: It is possible to produce a targeted antithrombotic conjugate which retains activity of all its individual components.

Apolipoprotein E polymorphism does not predict risk of restenosis after coronary angioplasty.

A recent report has suggested that the E4 allele of apolipoprotein (apo) E increases the risk of restenosis after percutaneous transluminal coronary angioplasty (PTCA) and also that it interacts synergistically with the deletion (D) allele of the angiotensin-converting enzyme (ACE) to increase the risk sixteen-fold. To investigate this further, we genotyped 231 subjects with successful PTCA who underwent planned repeat angiography at 4 months to assess the degree of restenosis. Subjects carrying the apo E4 allele (n = 71) were well matched with non-carriers (n = 160) for clinical and pre- and post-PTCA angiographic features. We found no increase in either apo E4 allele frequency (18.4% versus 15.6%, P = 0.42) or apo E4 homozygosity (2/106 versus 5/125, P = 0.30) in those with restenosis compared with those without. The relative risk of restenosis for apo E4 carriers was 1.11 (95% CI = 0.87-1.42). In apo E4 carriers, restenosis frequency was similar in those also carrying the ACE D allele and those without (28/55 (50.9%) versus 9/16 (56.2%), P = 0.71) and there was no significant increase in restenosis risk in carriers of both the apo E4 and ACE D alleles compared to the rest (odds ratio 1.30, 95% CI 0.68-2.50, P = 0.39). We conclude that in our cohort, the apo E4 allele does not either independently or acting synergistically with the ACE D allele increase the risk of restenosis after PTCA, and that apo E genotyping will not be a useful predictor of risk before the procedure.

Eikenella corrodens-caused botryomycosis-type pneumonia in a barbary ape (Macaca sylvanus).

An 18-year-old female barbary ape in a safari park died from a mixed bacterial infection. Staphylococus aureus was isolated from a purulent necrotic mastitis and from a chronic purulent granulomatous sialoadenitis of the sublingual glands, Eikenella corrodens from a botryomycosis-type pneumonia. As judged by histopathology, mixed infection of S. aureus and E. corrodens was present in the sialoadenitis, and E. corrodens botryomycosis-type bacterial colonies were also present in the pancreatic parenchyma, though here no bacteriological isolation was attempted. A generalized amyloidosis, and especially pancreatic islet amyloidosis, probably indicated an altered immunological competence.

Event-related brain potentials to unfamiliar faces in explicit and implicit memory tasks.

The purpose of this study was to investigate electrophysiological correlates related to the recognition of repeated faces in the intact human by means of event-related brain potentials (ERPs). A group of young healthy adults performed a continuous face recognition task, in which 240 unfamiliar faces were flashed upon a computer screen with 80 of the faces being repetitions. The subjects had to classify faces as previously seen and previously unseen faces. The concomitantly recorded ERPs from 19 scalp sites revealed a more positive going waveform for the correctly classified repeated faces beginning at about 280 ms (old/new effect). The same subjects performed a similar task with visually presented concrete nouns as stimuli. The old/new effect in this task showed a similar distribution, amplitude and onset latency. It is thus concluded that the old/new effect is not specific to the materials to be memorized. In contrast, the old/new effect in an implicit face repetition experiment (with the detection of famous persons being the task) showed a different distribution. It is argued that the differential distribution might reflect the different requirements of the two tasks (explicit vs. implicit task). Recent interpretations of the old/new effects are discussed.

Brain potentials reveal the timing of face identity and expression judgments.

Event-related brain potentials (ERPs) were recorded from multiple scalp locations from young human subjects while they performed two different face processing tasks. The first task entailed the presentation of pairs of faces in which the second face was either a different view of the first face or a different view of a different face. The subjects had to decide whether or not the two faces depicted the same person. In the second task, pairs of faces (frontal views) were presented with the task of judging whether the expression of the second face matched that of the face. Incongruous faces in the view (identity) matching task gave rise to a negativity peaking at about 350 ms with a frontocentral maximum. This effect was similar to the N400 obtained in linguistic tasks. ERP effects in the expression matching task were much later and had a different distribution. This pattern of results corresponds well with neuropsychological and neuroimaging data suggesting specialized neuronal populations subserving identity and expression analysis but adds a temporal dimension to previous investigations.

Transesophageal echocardiography in patients with mechanical circulatory assistance.

Transesophageal echocardiography was used to assess myocardial function and to detect complications after mechanical circulatory support for 8 patients with cardiogenic shock. In 3 of 8 patients, serial transesophageal echocardiography documented improvement of systolic ventricular function, and it was possible to wean these 3 patients from the ventricular assist device. In all patients, transesophageal echocardiography added clinically important information including the extent of left and right ventricular dysfunction (6 patients), presence of atrial or ventricular thrombus (5 patients), presence of pericardial effusion or clot (2 patients), and verification of the position of the intravascular device (1 patient). Thus, transesophageal echocardiography may provide clinically useful information regarding both the underlying cardiac disease and potential complications from the mechanical circulatory assistance.

Therapeutic levels of nitroglycerin do not affect the uptake and release of heparin by endothelial cells in vitro.

Intravenous heparin and nitroglycerin are frequently given in combination to patients with acute coronary syndromes such as unstable angina and post myocardial infarction angina. Heparin is prescribed since it has been shown that intracoronary thrombus formation is important in the pathophysiology of these acute conditions. However, it has been demonstrated that intravenous nitroglycerin can interfere with the anticoagulant effect of heparin. The exact mechanism of the interaction is unknown but it has been suggested that there is a direct effect on plasma heparin characterised by a reduction in circulating plasma heparin levels. Heparin binds to the surface of endothelial cells in a process that is time dependent, reversible and exhibits saturation kinetics. A possible mechanism of the observed effects on the plasma heparin levels produced by nitroglycerin may be the altered handling of heparin by endothelial cells. We have investigated this further by assessing the effects of therapeutic doses of nitroglycerin on heparin uptake and release by endothelial cells, using 35S labelled heparin and human umbilical vein endothelial cell cultures.

The mucopolysaccharidoses: characterization by cranial MR imaging.

PURPOSE: To characterize MR findings in mucopolysaccharidoses (MPS), to aid in diagnosis and categorization, and to define the role of MR in preoperative evaluation. MATERIALS AND METHODS: Six children with Hurler syndrome (MPS IH), five with Hunter syndrome (MPS II), and three with Sanfilippo A syndrome (MPS IIIA) were studied by routine T1-weighted and T2-weighted images at 1.5 T. MR findings were graded retrospectively. RESULTS: All had hallmark cribriform changes (sieve-like or multicystic) involving peri- and supraventricular, parietal, white matter (12), corpus callosum (8), and basal ganglia (4), which did not enhance. The cerebellum and brain stem were not involved with these cribriform changes. The most severe degree of cribriform changes occurred in children with Hunter and Hurler syndromes, correlating with non-central nervous system somatic involvement, but inversely related to degree of atrophy, ventricular enlargement, and white matter changes. Mental retardation was most severe in children with Hurler syndrome and correlated with chronicity of the disease. Severity of mental retardation did not correlate with severity of cribriform changes. CONCLUSIONS: Based on our observations, we postulate that in the natural course of MPS, cribriform changes occurred first, followed by white-matter changes and, last, atrophy. More severe degrees of cribriform changes plus involvement of the corpus callosum may suggest a poorer prognosis. Optimal therapeutic intervention may be at the time of cribriform changes before atrophy has occurred. MR can define and grade these changes.

Absence of a prothrombotic state in restenotic patients?

AIMS: To determine whether, in patients undergoing percutaneous transluminal coronary angioplasty (PTCA), there are prothrombotic markers indicating those with a predisposition to restenosis. METHODS: Venous blood samples were obtained from patients undergoing PTCA for chronic stable angina. Patients with restenotic lesions, conduit stenoses or occlusive lesions were not included in the study. Samples were assayed for coagulation factors (fibrinopeptide A, antithrombin III, protein C), fibrinolytic factors [tissue-type plasminogen activator (t-PA), alpha 2 antiplasmin, plasminogen activator inhibitor (PAI-1)] and markers of platelet activation (platelet factor 4, beta thromboglobulin). RESULTS: Of 46 patients who underwent successful PTCA, restenosis, defined as loss in absolute gain of more than 50%, occurred in 16 (35%). The minimal luminal diameter (mean +/- SD) at follow-up in those who had suffered restenosis was 1.07 +/- 0.7 mm compared with 1.73 +/- 0.5 mm in the non-restenotic patients. However, no significant differences in the levels of markers of platelet activation, coagulation factors, or fibrinolytic factors were observed between the two groups. The only significant difference between the groups was a higher platelet count in the restenotic patients [median (interquartile range): 263 (247-278) versus 224 (175-263), P < 0.05]. CONCLUSION: Our results suggest that patients who suffer restenosis following PTCA appear to have no clearly detectable pre-existing imbalance in their prothrombotic/antithrombotic status. Although the platelet count was higher in restenotic patients, the levels of markers of platelet activation were no different in the two groups. Thus, it is at present unlikely that simple blood assays before PTCA assessing an individual's 'thrombotic state' can help to predict which of the 30-40% of patients undergoing PTCA will suffer restenosis.

Angiographic restenosis after angioplasty: comparison of definitions and correlation with clinical outcome.

BACKGROUND: The aim of this study was to assess which of the currently used definitions of restenosis most closely indicates degree of recurrence and clinical status by 1) correlating percentage luminal renarrowing with restenosis defined according to each of four definitions, and 2) evaluating which definition was best predicted by clinical recurrence. METHODS: Quantitative angiography in 125 patients was undertaken either at time of early clinical presentation or at 6-month follow-up after percutaneous transluminal coronary angioplasty (PTCA). Absolute luminal diameters measured before and after PTCA and at follow-up were plotted as the percentage return from post-PTCA toward pre-PTCA value. All patients were also defined as restenosed or not restenosed according to each of the four definitions. RESULTS: The angiographic restenosis rate varied from 31% to 47%. Other than for "loss of 50% absolute gain," all definitions defined restenosis in some patients, despite the degree of return from post-PTCA to pre-PTCA value being less than 50%. Early recurrent symptoms predicted angiographic restenosis best, irrespective of angiographic definition, whereas history of recurrent angina or positive exercise testing alone at follow-up were poor predictors (range, 0.46 to 0.54). The predictive value increased (0.75 to 0.87) when exercise testing was positive in patients complaining of angina. The definition "loss of 2 standard deviations" gave the lowest values for positive or negative predictive values irrespective of clinical parameter. CONCLUSIONS: "Loss of 50% absolute gain" may be the best compromise definition. Patients admitted early with angina should undergo recatheterization, whereas exercise tests should be reserved for patients who complain of angina at routine follow-up.

Neoplastic angina: a case report.

A 54-year-old Caucasian woman, with a 1-year history of exertional angina was investigated by means of coronary angiography. On injection of contrast into both coronary arteries an unusual area of capillary blushing was seen around the point of a left main stem stenosis. At surgery a mass was seen arising from the area of the aortic root extending around the left main stem. Histology confirmed this to be an aortic paraganglioma. Three-vessel coronary artery bypass grafting was performed and at 6-month follow-up the patient remained symptom free.

Prothrombin fragment F1 + 2 concentrations for monitoring anticoagulation therapy with heparin.

We have compared the activated partial thromboplastin time with measurement of prothrombin fragment F1 + 2 concentrations (ELISA assay) during a 24-h period in a group of patients (n = 10) who had undergone elective coronary angioplasty and were anticoagulated post-procedure with heparin 1000 U/h. Four hours after the procedure all the patients were adequately anticoagulated according to activated partial thromboplastin time (median ratio 4.7:1) and the prothrombin fragment F1 + 2 concentration was significantly lower than pre-angioplasty values (0.5 vs 1.4 nmol/l, p = 0.04). At 24 h the median activated partial thromboplastin time ratio was still higher than the pre-procedure value (1.35 vs 0.9, p < 0.01), but the prothrombin fragment F1 + 2 concentration had risen to 2.1 nmol/l, with more variability in individual results within the patient group for the prothrombin fragment F1 + 2 concentration than for activated partial thromboplastin time (interquartile ranges (Q1, Q3) prothrombin fragment F1 + 2, 1.2-2.5; activated partial thromboplastin time, 1.2-1.5). The activated partial thromboplastin time is the standard method of monitoring the anticoagulant effect of heparin but may not fully reflect the functional coagulation status and accurately identify individual patients with less than adequate anticoagulation. Prothrombin fragment F1 + 2 concentrations may provide a more reliable indicator in individual patients of functional coagulation status in certain important situations where anticoagulation is critical such as following complicated coronary angioplasty.

Plaque herniation through an intracoronary stent.

We present a case where a Wiktor intracoronary stent was inserted for 'poor angiographic result' following balloon angioplasty. Despite appropriate positioning and repeated dilation of the stent a suboptimal result was achieved because of plaque herniation through the stent. The case emphasizes that the choice of stent used is important and will become more so as the number of choices available increases.

Monitoring anticoagulation following intracoronary procedures: which method?

We have assessed bedside kits for monitoring the activated partial thromboplastin time and the activated clotting time by comparing them with laboratory activated partial thromboplastin time values. To determine the accuracy of anticoagulation we have concurrently measured the plasma heparin concentrations, and plasma prothrombin fragment F1 + 2 concentrations. Serial samples were taken from patients undergoing elective percutaneous transluminal coronary angioplasty (n = 14). Readings were taken pre-procedure, 30 min after administration of a heparin bolus (10,000 U) and 1, 2 and 3 h after commencement of a constant heparin infusion (15 U/kg/h) postprocedure. Activated partial thromboplastin time results obtained with the bedside kit compared reliably with laboratory values (r = 0.8), were rapidly available and were reflected by appropriate changes in prothrombin fragment F1 + 2 and heparin concentrations. However, the relationship between activated partial thromboplastin time values and activated clotting time was less precise (r = 0.59). Therefore, for routine and frequent monitoring of anticoagulation with heparin, a bedside activated partial thromboplastin time kit provides adequate control of therapy but in instances were particularly tight control of anticoagulation is required, use of prothrombin fragment F1 + 2 concentrations may be more appropriate.

The effect of low dose nitroglycerin on plasma heparin concentrations and activated partial thromboplastin times.

We have investigated the effects of low dose nitroglycerin on the activated partial thromboplastin time (APTT), plasma heparin concentration, antithrombin III activity (AT-III) and platelet factor 4 (PF4) levels in a group of 42 patients receiving intravenous heparin and low dose nitroglycerin (GTN) following percutaneous transluminal coronary angioplasty (PTCA). Venous samples were taken before PTCA and at 2, 4 and 24 h after the start of the infusions. Despite the heparin infusion being constant, the median APTT ratio (interquartile range) was significantly lower at the 4 h sample time compared to the 2 h sample time (4.4 [3.8-4.5] vs 2.6 [1.8-4.0], P < 0.05). At this time there was also a significantly lower median plasma heparin concentration compared to the 2 h sample (0.35 [0.2-0.7] vs 0.17 [0.1-0.3] P < 0.05). There were no significant differences in AT-III activity or PF4 levels at 4 h compared to the 2 h sampling time. In another group of patients (n = 20) who received intravenous heparin alone following PTCA also at 1000 U/h there were no significant differences in median APTT ratios (4.4 [4.3-4.5] vs 4.2 [2.9-4.5]), or in median plasma heparin concentrations (0.26 [0.14-0.96] vs 0.22 [0.18-0.87]) at 4 h compared to 2 h. Our observations confirm that nitroglycerin can interfere with the anticoagulant effect of heparin even at low doses. Although the exact mechanism involved remains unknown, this study suggests it is likely to be a result of a reduction in plasma heparin levels, perhaps through acceleration of normal heparin elimination.

Semiclassical trace formulas for pitchfork bifurcation sequences.

In nonintegrable Hamiltonian systems with mixed phase space and discrete symmetries, sequences of pitchfork bifurcations of periodic orbits pave the way from integrability to chaos. In extending the semiclassical trace formula for the spectral density, we develop a uniform approximation for the combined contribution of pitchfork bifurcation pairs. For a two-dimensional double-well potential and the familiar Hénon-Heiles potential, we obtain very good agreement with exact quantum-mechanical calculations. We also consider the integrable limit of the scenario which corresponds to the bifurcation of a torus from an isolated periodic orbit. For the separable version of the Hénon-Heiles system we give an analytical uniform trace formula, which also yields the correct harmonic-oscillator SU(2) limit at low energies, and obtain excellent agreement with the slightly coarse-grained quantum-mechanical density of states.

Periodic orbit theory for the Hénon-Heiles system in the continuum region.

We investigate the resonance spectrum of the Hénon-Heiles potential up to twice the barrier energy. The quantum spectrum is obtained by the method of complex coordinate rotation. We use periodic orbit theory to approximate the oscillating part of the resonance spectrum semiclassically and Strutinsky smoothing to obtain its smooth part. Although the system in this energy range is almost chaotic, it still contains stable periodic orbits. Using Gutzwiller's trace formula, complemented by a uniform approximation for a co-dimension-two bifurcation scenario, we are able to reproduce the coarse-grained quantum-mechanical density of states very accurately, including only a few stable and unstable orbits.

Periodic-orbit bifurcations and superdeformed shell structure.

We have derived a semiclassical trace formula for the level density of the three-dimensional spheroidal cavity. To overcome the divergences occurring at bifurcations and in the spherical limit, the trace integrals over the action-angle variables were performed using an improved stationary phase method. The resulting semiclassical level density oscillations and shell-correction energies are in good agreement with quantum-mechanical results. We find that the bifurcations of some dominant short periodic orbits lead to an enhancement of the shell structure for "superdeformed" shapes related to those known from atomic nuclei.