Post-percutaneous Intervention Research Articles

Abstract 17034: The Novel Extracellular Matrix Protein Podocan Shows a Distinct Expression Pattern in Human Primary versus Restenotic Atherosclerotic Coronary Lesions and its Lack of Extra-Cellular Expression in Restenotic Tissue is Associated with Increased Wnt-Pathway Activation

Background: Vascular smooth muscle cell (VSMC) migration and proliferation are associated with restenosis post percutaneous intervention. Podocan is a novel member of the small leucin rich repeat protein family. We recently have described podocan as an inhbitor of VSMC migration and proliferation via the Wnt-pathway. Now we are reporting the expression of podocan and Wnt-pathway related molecules in human primary stable coronary atherosclerosis compared to restenosis. Methods and Results: The expression of podocan and non-phospho-beta catenin (NPBC) an indicator of Wnt-pathway activation was evaluated by immunohistochemistry in coronary atherectomy samples (n=32) (data presented as mean % cells positive for NPBC, ± SEM). The antibody against the human form of podocan was generated in our lab whereas antibodies for NPBC, Wnt 1 and LRP-6 were obtained commercially. In atherectomy samples from patients with primary stable atherosclerosis (n=20) podocan expression was abundant in extra-cellular as well as intra-cellular location. Podocan deposits were seen especially in plaque areas surrounding neovessels. Out of 20 coronary primary lesions 16 showed podocan expression. In contrast, restenotic lesions showed a paucity of podocan with only 5 out of 12 lesions staining positive for podocan. Of note, extra-cellular podocan deposition was completely absent in all restenosis samples and podocan present was restricted to an intra-cellular/cytoplasmic staining pattern. The expression of NPBC was strongly increased in restenotic compared to primary lesions (35 ± 6 % vs. 4 ± 2 %, P<0.05). Importantly, nuclear staining of NPBC indicative of nuclear translocation of beta catenin was observed only in restenotic lesions. Immuno-fluorescence double labeling showed a strong co-localization of Wnt-1 and LRP-6 on VSMC in areas of hyperplasia in restenotic lesions. Conclusions: We are reporting for the first time the expression of podocan in human coronary atheroma. The paucity of podocan and the absence of extra-cellular podocan in restenotic tissue were associated with a strong increase in NPBC expression in VSMC indicating increased Wnt-pathway activation. This points to podocan and the Wnt-pathway as possible key regulators of VSMC in human atherosclerosis.

Clopidogrel response variability and the advent of personalised antiplatelet therapy

Platelet-mediated thrombosis is a dreaded clinical event and is the primary cause of acute coronary syndromes and post-percutaneous intervention (PCI) ischaemic events. There has been a long standing interest in the ex vivo quantification of platelet reactivity to assess the risk of thrombosis. Early studies demonstrated platelet activation and heightened platelet reactivity in acute coronary syndromes and after PCI. However, a demonstration that heightened reactivity actually precipitated the ischaemic event was lacking. Our knowledge of platelet receptor physiology and the advent of novel inhibitors have significantly advanced the field. The P2Y12 receptor has been shown to play a pivotal role in the amplification of platelet activation by multiple agonists and its inhibition has resulted in improved clinical outcomes. The most widely used drug to block P2Y12 receptor, clopidogrel is associated with resistance in selected patients and these patients have been shown to be at increased risk for post-PCI ischaemic event occurrence in multiple studies. Importantly, a threshold of high platelet reactivity has been demonstrated, and beyond this threshold ischaemic events occur precipitously. Based on the current evidence, it is rational to quantify the intensity of the ADP-P2Y12 interaction in the patient at the greatest risk for thrombosis-the PCI patient. However, there is only evidence from small clinical trials demonstrating the clinical efficacy of changing an antiplatelet regimen based on an ex vivo platelet function measurement. Moreover, there are numerous patients with vulnerable coronary anatomy that have not yet experienced plaque rupture; the prognostic role of a measurement of platelet reactivity in the latter group has never been studied. Large-scale trials are ongoing that will investigate the role of personalised antiplatelet therapy in the PCI patient.

Prehospital high-dose tirofiban in patients undergoing primary percutaneous intervention. The AGIR-2 study

Compared with administration in the catheterization laboratory, early treatment with glycoprotein IIb/IIIa inhibitors provides benefits to patients with ST-segment elevation myocardial infarction who undergo primary percutaneous intervention. Whether this benefit is maintained on top of a 600 mg loading dose of clopidogrel is unknown. In a multicentre, controlled, randomized study, 320 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention received a high-dose bolus of tirofiban given either in the ambulance (prehospital group) or in the catheterization laboratory. The primary endpoint was a TIMI flow grade 2-3 of the infarct-related vessel at initial angiography. Secondary endpoints included ST-segment resolution 1h after percutaneous coronary intervention and peak serum troponin I concentration. Tirofiban was administered 48 (95% confidence interval 21.4-75.0) min earlier in the prehospital group. At initial angiography, the combined incidence of TIMI 2-3 flow was 39.7% in the catheterization-laboratory group and 44.2% in the prehospital group (p=0.45). No difference was found on postpercutaneous intervention angiography or peak troponin concentration. Complete ST-segment resolution 60 min after the start of intervention was 55.4% in the catheterization-laboratory group and 52.6% in the prehospital group (p=0.32). Prehospital initiation of high-dose bolus tirofiban did not improve significantly initial TIMI 2 or 3 flow of the infarct-related artery or complete ST-segment resolution after coronary intervention compared with initiation of tirofiban in the catheterization laboratory (NCT00538317).

307 Contemporary treatment of isolated vsd in children: amplatzer vs surgical closure

Isolated hemodynamically significant Ventricular septal defects (VSD) were once solely surgical lesions. Since the introduction of percutaneous devices, the management of isolated VSD has evolved. In our center, Amplatzer devices have been implanted since 1998 and for selected isolated perimembranous and muscular VSD since 2002. We therefore reviewed our institutional practice selectively using percutaneous and surgical approaches. We retrospectively reviewed clinical, electrocardiographic and echocardiographic data of all isolated percutaneous and surgical VSD closures since 2002. Pre-operative (preop), immediate post-operative (postop) in addition to 1 month, 6 month and annual postop results were studied. The following table summarizes demographic data: 37 patients who underwent percutaneous closures and 34 who treated surgically, mean follow-up 42 months. Percutanous group were older ( p < 0.01 ) and bigger ( p<0.001 ). The VSD gradient preop was lower in the surgical group ( p < 0.004 ), thus patients were in greater clinical heart failure. There was no mortality in either group. At follow-up there were no differences in the incidence of residual VSD ( p = 0.34 ). 2 patients with perimembranous VSD and pre-existing aortic valve deformity increased its level to moderate post-Amplatzer implantation versus none in the surgical group ( p = 0.45 ). A permanent pacemaker was implanted for complete heart block following post device closure of a perimembranous VSD in one patient and none in the surgical group. The surgical results are excellent in this sicker patient population, as reported in the literature. Patient selection remains a challenge to avoid post-percutaneous intervention complications such as heart block and aortic insufficiency in the perimembranous VSD patients. Percutaneous closure of isolated VSD, which avoids some morbidity of open heart surgery should however remain part of the therapeutic armamentarium. Results table Amplatzer group median (min-max) Surgical group median (min-max) P value Age (year) 12,83 (0,67-21,33) 1,41 (0,16-5,66) p<0,001 Weight (Kg) 24,6 (5,35-77,9) 5,00 (4,1-18,5) p<0,001 VSD size (mm) 5,7 (2,1-19) 11,00 (9,00-12,00) p<0,02 VSD Gradient (mmHg) 87 (54-138) 33 (25-66) p<0,004 LVEF (%) 59 (52,21-68,87) 60 (56,42-72,52) NS CPB duration (min.) N.A. 78,5 (70-150) - Aortic cross-clamp (min.) N.A. 55,5 (36-125) - Device size (mm) 8 (6-14) N.A. -

High-dose tirofiban with enoxaparin and inflammatory markers in high-risk percutaneous intervention

The study assessed the benefit of high bolus dose tirofiban (HD-tirofiban) with enoxaparin compared with HD-tirofiban with unfractionated heparin (UFH). The study examined markers of platelet activation, thrombin generation and inflammation. The study is a prospective single centre open-label trial of patients with high-risk acute coronary syndrome treated with percutaneous intervention (PCI) who were randomized to anticoagulation with UFH or enoxaparin with HD-tirofiban (25 microg kg(-1) bolus). This study measured a panel of platelet activation markers, inflammatory biomarkers and thrombus generation between the two groups. Sixty patients undergoing high-risk PCI were enroled in the study. Platelet inhibition as assessed by whole blood aggregometry following HD-tirofiban infusion was similar in both the UFH and enoxaparin groups. CD40 ligand expression on platelets was significantly reduced following PCI with HD-tirofiban and either UFH or enoxaparin. Following PCI, there were significant reductions measured in other markers of platelet activation including PAC-1, P selectin, factor V/Va, platelet-monocyte aggregates and monocyte expression of Mac-1 as determined by analysis of venous blood samples using flow cytometry. Prothrombin fragment 1+2, D-dimer, von Willebrand factor and high sensitive C-reactive protein levels were significantly less post PCI in the enoxaparin group compared with those patients receiving UFH. The combination of HD tirofiban with enoxaparin resulted in an attenuated inflammatory response when compared with that of the combination of HD tirofiban with UFH.

The use of thrombin in the radiology department

Thrombin is a naturally occurring coagulation protein that converts soluble fibrinogen into insoluble fibrin and plays a vital role in the coagulation cascade and in turn haemostasis. Thrombin also promotes platelet activation. In the last few years, there has been a rapid increase in the use of thrombin by radiologists in a variety of clinical circumstances. It is best known for its use in the treatment of pseudoaneurysms following angiography. However, there are now a variety of cases in the literature describing the treatment of traumatic, inflammatory and infected aneurysms with thrombin in a variety of locations within the human body. There have even been recent reports describing the use of thrombin in conventional aneurysms as well as ruptured aneurysms. Its use has also been described in the treatment of endoleaks (type II) following aneurysm repair. In nearly all of these cases, treatment with thrombin requires imaging guidance. Recently, thrombin has also been used as a topical treatment post-percutaneous intervention to reduce or stop bleeding. Most radiologists have only a limited knowledge of the pharmacodynamics of thrombin, its wide range of utilisation and its limitations. Apart from a few case reports and case series, there is little in the radiological literature encompassing the wide range of applications that thrombin may have in the radiology department. In this review article, we comprehensively describe the role and pathophysiology of thrombin, describing with examples many of its potential uses. Techniques of usage as well as pitfalls and limitations are also described.