Life after abciximab; what's next for intracoronary thrombus?

A case is described in which the short-acting glycoprotein IIb/IIIa receptor antagonist tirofiban was used in combination with heparin, aspirin and prasugrel to successfully treat extensive intracoronary thrombus in a delayed presentation STEMI, illustrating the utility of this approach.

New DNA enzyme targeting Egr-1 mRNA inhibits vascular smooth muscle proliferation and regrowth after injury.

Early growth response factor-1 (Egr-1) binds to the promoters of many genes whose products influence cell movement and replication in the artery wall. Here we targeted Egr-1 using a new class of DNA-based enzyme that specifically cleaved Egr-1 mRNA, blocked induction of Egr-1 protein, and inhibited cell proliferation and wound repair in culture. The DNA enzyme also inhibited Egr-1 induction and neointima formation after balloon injury to the rat carotid artery wall. These findings demonstrate the utility of DNA enzymes as biological tools to delineate the specific functions of a given gene, and implicate catalytic nucleic acid molecules composed entirely of DNA as potential therapeutic agents.

DNAzymes and cardiovascular disease.

Gene silencing techniques are gaining increasing popularity in the literature, both as a tool for unravelling gene function and to potentially deliver therapeutic benefit, especially in the context of cardiovascular disease. Gene-specific catalytic DNA molecules, or DNAzymes, have shown promise in ameliorating the effects of myocardial ischaemia reperfusion injury and in-stent restenosis in various animal models, demonstrating that these agents may be useful in a clinical setting. A review of the recent advances in the use of DNAzymes in treating cardiovascular disease is therefore essential given the increasing clinical burden of cardiovascular disease worldwide. We have thus sought to firstly provide background into the construct and mechanism of action of DNAzymes, with a discussion of recent improvements in design. Secondly, we have examined the effects of DNAzyme-mediated gene inhibition in in vitro studies of both endothelial and smooth muscle migration and proliferation, as well as in vivo models of acute myocardial infraction and neointima formation. Lastly we compare DNAzymes with other gene silencing tools and discuss issues involved in successfully delivering these drugs in a clinical setting.

Polymorphonuclear leukocyte phagocytic function increases in plasminogen knockout mice.

BACKGROUND: Mice lacking plasminogen (PG-/-) require alternative pathways of fibrinolysis for survival. This may depend on polymorphonuclear leukocytes (PMN) that can clear soluble and insoluble fibrin(ogen) through PG-independent processes. Our objective was to demonstrate that PMNs from PG-/- mice exhibit increased Mac-1 dependent phagocytic activity, which may explain their increased fibrin(ogen)lytic activity compared with wild type (PG+/+) mice. METHODS: Phagocytic activity of PMNs from PG-/- and PG+/+ mice was compared following exposure to Staphylococcus aureus (S. aureus) particles and the expression of Mac-1 was assessed in parallel by flow cytometric analysis. Resistance to phorbol-12-myristate-13-acetate (PMA)-induced cell death was compared between PMNs from the different genotypes. RESULTS: Stimulation of PG-/- PMNs by opsonized S. aureus diluted in PG-/- plasma significantly increased phagocytosis (15-fold) compared with stimulation of PG+/+ PMNs in PG+/+ plasma. Incubation of PG-/- PMNs with PG+/+ plasma (control) or PG-/- plasma supplemented with human PG inhibited this increased phagocytic activity. Mac-1 cell surface density increased 6.2+/-1.0-fold in PG-/- PMNs versus 2.9+/-0.6-fold in PG+/+ PMNs (P < 0.01) indicating that Mac-1 may be associated with increased phagocytic activity. Supporting this, treatment of PG-/- PMNs with an anti-Mac-1 antibody in PG-/- plasma inhibited phagocytic activity. In addition, physiologic PG blocked Mac-1 accessibility at the surface of PMNs. Addition of PMA resulted in 33% death of PMNs from PG-/- mice versus 68% in PG+/+ controls (P < 0.001). CONCLUSIONS: PMNs from PG-/- mice exhibit a Mac-1 dependent increase in phagocytic activity that is suppressed with human PG, an anti-Mac-1 antibody or the plasma from PG+/+ mice. The propensity for PMNs from PG-/- mice to be activated in response to PMA together with their relative resistance to PMA-toxicity may contribute to increased PMN half-life and enhanced fibrin(ogen) clearance in the setting of PG deficiency.

DNAzymes targeting the transcription factor Egr-1 reduce myocardial infarct size following ischemia-reperfusion in rats.

BACKGROUND AND AIM: The transcription factor and immediate-early gene Egr-1 is widely viewed as a key upstream activator in a variety of settings within cardiovascular pathobiology. The role that Egr-1 plays in myocardial ischemia-reperfusion (IR) injury is unknown. We hypothesized that Egr-1 upregulation is of pathophysiologic importance in myocardial IR injury. METHODS AND RESOURCES: First, abrogation of Egr-1 mRNA upregulation using Egr-1 targeting DNAzymes in a rat cardiomyocyte in vitro model was demonstrated. Egr-1 mRNA and protein upregulation following myocardial IR in rats were then selectively suppressed by locally delivered DNAzyme. Furthermore, myocardial neutrophil infiltration, intercellular adhesion molecule 1 mRNA and protein expression, and myocardial infarct size were all attenuated in DNAzyme-treated animals. CONCLUSIONS: These data support the hypothesis that Egr-1 is a key contributor to myocardial IR injury, and that Egr-1 targeting strategies have therapeutic potential in this context.

Catalytic oligodeoxynucleotides define a key regulatory role for early growth response factor-1 in the porcine model of coronary in-stent restenosis.

Early growth response factor-1 (Egr-1) controls the expression of a growing number of genes involved in the pathogenesis of atherosclerosis and postangioplasty restenosis. Egr-1 is activated by diverse proatherogenic stimuli. As such, this transcription factor represents a key molecular target in efforts to control vascular lesion formation in humans. In this study, we have generated DNAzymes targeting specific sequences in human EGR-1 mRNA. These molecules cleave in vitro transcribed EGR-1 mRNA efficiently at preselected sites, inhibit EGR-1 protein expression in human aortic smooth muscle cells, block serum-inducible cell proliferation, and abrogate cellular regrowth after mechanical injury in vitro. These DNAzymes also selectively inhibit EGR-1 expression and proliferation of porcine arterial smooth muscle cells and reduce intimal thickening after stenting pig coronary arteries in vivo. These findings demonstrate that endoluminally delivered DNAzymes targeting EGR-1 may serve as inhibitors of in-stent restenosis.

Vessel wall apoptosis and atherosclerotic plaque instability.

Atherosclerotic cardiovascular disease remains the leading cause of death in the industrialized world. Most cardiovascular deaths result from acute coronary syndromes, including unstable angina pectoris and acute myocardial infarction. Coronary syndromes often arise from acute coronary thrombosis, itself commonly a result of disruption or rupture of the fibrous cap of a lipid-laden atherosclerotic plaque. Despite this huge clinical burden of atherosclerotic plaque instability, our understanding of the molecular mechanisms mediating atherosclerotic plaque disruption and rupture, at a cellular level, remains limited. Placed in a clinical context, this review discusses our current understanding of the molecular basis for atherosclerotic plaque instability, with particular emphasis on the process of apoptosis-or programmed cell death-seen increasingly as playing a key role in a number of cell types within the vessel wall.

Animal models of atherosclerosis progression: current concepts.

The last decade has seen a number of important advances in the use of animal models of atherosclerosis progression. Small animal models, particularly mouse knockouts and rabbit models, are finding increasing use. This review discusses those models of particular research utility, highlights their advantages and limitations, and specifically addresses methodologies and current developments, in what is a rapidly changing field.

Intracoronary stenting without intravascular ultrasound guidance followed by antiplatelet therapy with aspirin alone in selected patients.

One hundred selected patients with 103 lesions were treated with the deployment of 117 Palmaz-Schatz stents without the use of intravascular ultrasound, followed by antiplatelet therapy with aspirin alone. Angiographic and clinical follow-up revealed 2 stent thromboses; 3 stents required redilation, and 3 patients required intervention for disease progression elsewhere, suggesting that this approach can be applied effectively in selected patients.

Use of the multifunction probing catheter as an adjunctive device for occluded vein graft intervention.

We describe the use of the multifunction probing catheter (Schneider, Bulach, Switzerland) as an adjunct to conventional techniques in the treatment of a recent vein graft occlusion by thrombus, in order to highlight a possible further use for this device.

Second generation bifurcation stent: the rapid development of device technology.

A 57-year-old male with unstable angina and an eccentric 88% diameter stenosis of the left anterior descending artery prior to, and involving the first diagonal branch was treated with the 2nd generation Jomed Sidebranch stent (Jomed, Randingengen, Germany). This case outlines the improvements in this novel stent design and demonstrates the rapid advance of device design.

A novel approach for crossing a virtually occluded vessel using ultra-low-profile balloon backup.

We discuss a case in which a novel ultra-low-profile angioplasty balloon was used to provide wire backup by advancing the uninflated balloon nose into the entry point of a virtually occluded lesion. This enabled crossing of the lesion, and demonstrates how an improved balloon design can directly lead to improved clinical outcomes.

Intracoronary blood sampling using the multifunction probing catheter does not cause platelet activation.

We sought to test the hypothesis that intracoronary blood sampling in patients with angiographically demonstrated coronary artery disease could be performed using the multifunction probing catheter (Schneider, Bulach, Switzerland), without causing ex vivo platelet activation.

Eating attitudes in an adolescent schoolgirl population.

One thousand five hundred and fourteen Auckland school girls in the age range 13 to 17 were given an eating attitudes test. Fourteen percent of this large population produced a score on that test of greater than 30 which has been claimed to be indicative of potential eating disorder. We view this incidence with alarm and make commentary on the social process of coupling the thin feminine body ideal with success.

Acute coronary syndrome and stable coronary artery disease: are they so different? Long-term outcomes in a contemporary PCI cohort.

BACKGROUND: Patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) are known to have poorer short-term prognosis compared to stable coronary artery (CAD) patients undergoing elective PCI. Few studies have made direct comparison of long-term mortality between ACS and stable CAD patients undergoing PCI. The aim of our study was to compare the long-term mortality following PCI between patients with ACS and those with stable CAD. METHODS: We examined consecutive patients undergoing PCI with stenting at a tertiary referral hospital. Clinical, angiographic and biochemical data were collected and analysed. The primary outcome was all-cause mortality retrieved from the Statewide Death Registry database. RESULTS: Included were 1923 consecutive PCI patients (970 stable CAD and 953 ACS). The mean follow-up time was 4.1 years ± 1.8 years. In-hospital mortality was 1.4% overall, seen exclusively in patients with ACS (n=28, 2.9%). Post-discharge mortality was 6.7% among patients with stable CAD and 10.5% for ACS (P<0.01). Multivariate predictors of post-discharge deaths for both groups included age (HR 1.08 per year, P<0.001) and impaired renal function (HR 2.49, P<0.001). Following adjustment for these factors, an ACS indication for PCI was not associated with greater post-discharge mortality (adjusted HR 1.18: 0.85-1.64, P=0.32). CONCLUSIONS: Patients undergoing PCI following an ACS have higher long-term mortality to those with stable CAD, which is potentially explained by a greater prevalence of comorbidities. This suggests that for the ACS population, contemporary interventional and medical management strategies may effectively and specifically counter the adverse prognostic impact of coronary instability and myocardial damage.