Aoki, J.

Development of an Activity-Based Probe for Autotaxin (Article)

2010-11-02T00:00:00Z

Autotaxin (ATX), or ecto-nucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a secreted lysophospholipase D that hydrolyses lysophosphatidylcholine into the lipid mediator lysophosphatidic acid (LPA), a mitogen and chemoattractant for many cell types. ATX has been implicated in tumour progression and inflammation, and might serve as a biomarker. Here we describe the development of a fluorescent activity-based probe that covalently binds to the active site of ATX. The probe consists of a lysophospholipid-based backbone linked to a trapping moiety that becomes reactive after phosphate ester hydrolysis, and a Cy5 fluorescent dye to allow visualisation of active ATX. The probe reacts specifically with the three known isoforms of ATX, it competes with small-molecule inhibitors for binding to ATX and allows ATX activity in plasma to be determined. Our activity-based reporter will be useful for monitoring ATX activity in biological fluids and for inhibitor screening.Marking biomarkers: ATX is a secreted lysophospholipase D that produces the lipid mediator lysophosphatidic acid. We have developed a fluorescent activity-based probe that covalently binds to the active site of ATX, allowing visualisation of active ATX. This probe can be used for monitoring ATX activity in body fluids and for inhibitor screening.

Long Term Follow-up after Drug-eluting Stent Implantation and Early Experience with Endothelial Progenitor Cell Capture Stent (Doctoral Thesis)

2006-06-14T00:00:00Z

Intracoronary stent replacement is being used increasingly for the treatment of atherosclerotic coronary artery disease and has gained widespread acceptance. Although stent implantation itself has been shown to reduce restenosis compared to balloon angioplasty, in-stent restenosis still occurs in 10-40% of patients. In-stent restenosis has long been considered the main limitation hampering the long-term efficacy of coronary stenting. Restenosis after stent occurs secondary to the accumulation of smooth muscle cells and extracellular matrix which consists of proteoglycans, hyaluronan and collagen. To overcome this major limitation, drug-eluting stents were developed. Drug-eluting stents consist of a drug (immunosuppressive, antiproliferative, or anti-inflammatory drug), a polymer, and a stent platform. Several drugs with durable or erodable polymers were tested in clinical trials and showed that drug-eluting stents significantly inhibit neointimal growth compared with bare metal stents. Currently, drug-eluting stents have been widely distributed all over the world and become main-stream of percutaneous coronary intervention. However, (1) long-term efficacy and chronic vascular response after drug-eluting stents implantation in humans (Part 1 of this thesis) (2) effect of drugeluting stents for patients with high in-stent resteonsis risk factors, such as diffuse lesion, diabetes mellitus, left main coronary artery lesion, chronic total occlusion or bifurcation lesion (Part 2 of this thesis), have not been fully investigated. Furthermore, problem of stent thrombosis is still observed in drug-eluting stent era. Drug-eluting stents interferes with the natural healing response by preventing or significantly delaying the formation of a functional endothelial lining over stent. The early establishment of a functional endothelial layer after stent implantation may resolve this issue. Recently, the existence of circulating endothelial progenitor cells has been identified as a key factor for re-endothelialization. 8,9 New concept stent using immobilized antibodies targeted at endothelial progenitor cell surface antigens has been developed. (Part 3 of this thesis).

Five year clinical effect of coronary stenting and coronary artery bypass grafting in renal insufficient patients with multivessel coronary artery disease: insights from ARTS trial. (Article)

2005-08-01T00:00:00Z

AIMS: To compare coronary stent implantation and bypass surgery for multivessel coronary disease in patients with renal insufficiency. METHODS AND RESULTS: In the ARTS trial, 142 moderate renal insufficient patients (Ccr<60 mL/min) with multivessel coronary disease were randomly assigned to stent implantation (n=69) or CABG (n=73). At 5 years, there was no significant difference between the two groups in terms of mortality (14.5% in the stent group vs. 12.3% in the CABG group, P=0.81), or combined endpoint of death, cerebrovascular accident (CVA), or myocardial infarction (MI) (30.4% in the stent group vs. 23.3% in the CABG group, P=0.35). Among patients who survived without CVA or MI, 18.8% in the stent group underwent a second revascularization procedure when compared with 8.2% in the surgery group (P=0.08). The event-free survival at 5 years was 50.7% in the stent group and 68.5% in the surgery group (P=0.04). CONCLUSION: At 5 years, the differences in mortality and combined incidence of death, CVA, and MI between coronary stenting and surgery did not reach statistically significant level. However, the occurrence of MACCE in the stent group was higher than in the CABG group, mainly driven by the higher incidence of repeat revascularization in the stent group.

Short- and long-term clinical outcome after drug-eluting stent implantation for the percutaneous treatment of left main coronary artery disease: insights from the Rapamycin-Eluting and Taxus Stent Evaluated At Rotterdam Cardiology Hospital registries (RESEARCH and T-SEARCH). (Article)

2005-03-22T00:00:00Z

BACKGROUND: The impact of drug-eluting stent (DES) implantation on the incidence of major adverse cardiovascular events in patients undergoing percutaneous intervention for left main (LM) coronary disease is largely unknown. METHODS AND RESULTS: From April 2001 to December 2003, 181 patients underwent percutaneous coronary intervention for LM stenosis at our institution. The first cohort consisted of 86 patients (19 protected LM) treated with bare metal stents (pre-DES group); the second cohort comprised 95 patients (15 protected LM) treated exclusively with DES. The 2 cohorts were well balanced for all baseline characteristics. At a median follow-up of 503 days (range, 331 to 873 days), the cumulative incidence of major adverse cardiovascular events was lower in the DES cohort than in patients in the pre-DES group (24% versus 45%, respectively; hazard ratio [HR], 0.52 [95% CI, 0.31 to 0.88]; P=0.01). Total mortality did not differ between cohorts; however, there were significantly lower rates of both myocardial infarction (4% versus 12%, respectively; HR, 0.22 [95% CI, 0.07 to 0.65]; P=0.006) and target vessel revascularization (6% versus 23%, respectively; HR, 0.26 [95% CI, 0.10 to 0.65]; P=0.004) in the DES group. On multivariate analysis, use of DES, Parsonnet classification, troponin elevation at entry, distal LM location, and reference vessel diameter were independent predictors of major adverse cardiovascular events. CONCLUSIONS: When percutaneous coronary intervention is undertaken at LM lesions, routine DES implantation, which reduces the cumulative incidence of myocardial infarction and the need for target vessel revascularization compared with bare metal stents, should currently be the preferred strategy.

[Emergent strategies in interventional cardiology] (Article)

2005-01-01T00:00:00Z

Despite the advances in the treatment of patients with coronary artery disease, sudden cardiac death is still unacceptably prevalent. Patients with ischemic heart disease usually require a combination of therapies (drugs and coronary intervention) and may continue to experience symptoms. Recently, numerous percutaneous interventional treatments and diagnostic tools have been developed to diagnose the vulnerable plaque and to treat the large number of patients with myocardial ischemia. Ongoing research on the use of drug eluting stents, catheter based bypass graft (percutaneous approaches that use the adjacent venous circulation to bypass an obstructed artery and stent-based approach for ventricle to coronary artery bypass), therapeutic angiogenesis and myogenesis, and the catheter based devices to detect the plaque vulnerability and composition (lipid-rich atheromatous core, thin fibrous cap, and expansive vessel remodeling) may result in additional diagnostic and therapeutic options for patients with coronary artery disease.

One year clinical follow up of paclitaxel eluting stents for acute myocardial infarction compared with sirolimus eluting stents (Article)

2005-01-01T00:00:00Z

OBJECTIVE: To compare clinical outcome of paclitaxel eluting stents (PES) versus sirolimus eluting stents (SES) for the treatment of acute ST elevation myocardial infarction. DESIGN AND PATIENTS: The first 136 consecutive patients treated exclusively with PES in the setting of primary percutaneous coronary intervention for acute myocardial infarction in this single centre registry were prospectively clinically assessed at 30 days and one year. They were compared with 186 consecutive patients treated exclusively with SES in the preceding period. SETTING: Academic tertiary referral centre. RESULTS: At 30 days, the rate of all cause mortality and reinfarction was similar between groups (6.5% v 6.6% for SES and PES, respectively, p = 1.0). A significant difference in target vessel revascularisation (TVR) was seen in favour of SES (1.1% v 5.1% for PES, p = 0.04). This was driven by stent thrombosis (n = 4), especially in the bifurcation stenting (n = 2). At one year, no significant differences were seen between groups, with no late thrombosis and 1.5% in-stent restenosis (needing TVR) in PES versus no reinterventions in SES (p = 0.2). One year survival free of major adverse cardiac events (MACE) was 90.2% for SES and 85% for PES (p = 0.16). CONCLUSIONS: No significant differences were seen in MACE-free survival at one year between SES and PES for the treatment of acute myocardial infarction with very low rates of reintervention for restenosis. Bifurcation stenting in acute myocardial infarction should, if possible, be avoided because of the increased risk of stent thrombosis.

Comparison of three-year outcomes after coronary stenting versus coronary artery bypass grafting in patients with multivessel coronary disease; including involvement of the left anterior descending coronary artery proximally (a subanalysis of the arterial revascularization therapies study trial). (Article)

2004-09-01T00:00:00Z

The long-term effect of stents in patients with multivessel disease involving the proximal left anterior descending artery was investigated. At 3 years, there was no difference in the combined incidence of death, stroke, and myocardial infarction in either group, but the need for repeat revascularization was more frequent in the group with stenting than in the group with coronary artery bypass grafting.

Classification and current treatment options of in-stent restenosis. Present status and future perspectives. (Article)

2004-01-01T00:00:00Z