Masaru Araki

A Rac switch regulates random versus directionally persistent cell migration

Directional migration moves cells rapidly between points, whereas random migration allows cells to explore their local environments. We describe a Rac1 mechanism for determining whether cell patterns of migration are intrinsically random or directionally persistent. Rac activity promoted the formation of peripheral lamellae that mediated random migration. Decreasing Rac activity suppressed peripheral lamellae and switched the cell migration patterns of fibroblasts and epithelial cells from random to directionally persistent. In three-dimensional rather than traditional two-dimensional cell culture, cells had a lower level of Rac activity that was associated with rapid, directional migration. In contrast to the directed migration of chemotaxis, this intrinsic directional persistence of migration was not mediated by phosphatidylinositol 3′-kinase lipid signaling. Total Rac1 activity can therefore provide a regulatory switch between patterns of cell migration by a mechanism distinct from chemotaxis.

Comparison of Dobutamine Stress Echocardiography and Stress Thallium-201 Single-Photon Emission Computed Tomography for Detecting Coronary Artery Disease

Dobutamine stress echocardiography and stress thallium-201 single-photon emission computed tomography (SPECT) were compared for detecting coronary artery disease in 120 consecutive patients who underwent concomitant quantitative coronary angiography. The left ventricle was divided into anterior, inferior, and lateral regions. Wall motion or perfusion abnormalities observed within each region were classified as ischemia or fixed abnormality. Both tests showed 81% agreement in all 120 patients. Complete agreement was observed in 77% of the 360 regions analyzed. The overall sensitivity of dobutamine stress echocardiography and thallium-201 SPECT for the detection of coronary artery disease was 85% and 89%, and the specificity was 93% and 85%, respectively. A good correlation was found between the wall motion score index and perfusion defect size at peak stress and at rest (r = 0.70). Dobutamine stress echocardiography and thallium-201 SPECT exhibit a comparable accuracy for diagnosing coronary artery disease, localizing coronary artery stenosis, and detecting regional myocardial abnormalities. The wall motion score index may be useful for evaluating the myocardial area at risk.

Tyrosine phosphorylation of the CrkII adaptor protein modulates cell migration

CrkII belongs to a family of adaptor proteins that become tyrosine phosphorylated after various stimuli. We examined the role of CrkII tyrosine phosphorylation in fibronectin-induced cell migration. Overexpression of CrkII inhibited dephosphorylation of focal adhesion components such as p130 Crk-associated substrate (p130cas) and paxillin by protein tyrosine phosphatase 1B (PTP1B). Tyrosine-phosphorylated CrkII was dephosphorylated by PTP1B both in vitro and in vivo, showing for the first time that PTP1B directly dephosphorylates CrkII. A CrkII mutant in which tyrosine residue 221 was substituted by phenylalanine (CrkII-Y221F) could not be tyrosine phosphorylated, and it showed significantly increased binding to p130cas and paxillin. Enhanced binding of CrkII to p130cas has been reported to promote cell migration. Nonphosphorylated CrkII-Y221F promoted HT1080 cell migration on fibronectin, whereas wild-type CrkII did not at moderate expression levels. Moreover, co-expression of CrkII and PTP1B promoted HT1080 cell migration on fibronectin and retained tyrosine phosphorylation and binding of p130cas to CrkII, whereas paxillin tyrosine phosphorylation was reduced. These findings support the concepts that CrkII binding activity is regulated by tyrosine kinases and phosphatases, and that tyrosine phosphorylation of CrkII can downmodulate cell migration mediated by the focal adhesion kinase/p130cas pathway.

The Detection of Residual Ischemia and Stenosis in Patients With Acute Myocardial Infarction with Dobutamine Stress Echocardiography

The aim of this study was to validate the usefulness of dobutamine stress echocardiography to detect residual ischemia and significant stenosis at the infarct zone in patients with acute myocardial infarction. Dobutamine stress echocardiography and stress thallium-201 single-photon emission computed tomography were performed on 40 consecutive patients 1 month after the onset of acute myocardial infarction. Dobutamine was infused incrementally, and wall motion score index at the infarct zone was calculated before and at peak dobutamine infusion. The patients were divided into three groups according to the change in wall motion at the infarct zone (improved, unchanged, or worsened wall motion, respectively). Tomographic thallium images of the infarct zone were assessed visually. All patients underwent quantitative coronary angiography, and significant stenosis was defined as 50% or greater stenosis. In patients who showed a persistent defect and significant stenosis of the infarct-related artery, resting thallium-201 single-photon emission computed tomography was performed when possible. There was a significantly higher incidence of residual ischemia at the infarct zone in patients with worsened wall motion (85%) and unchanged wall motion (63%) than in those with improved wall motion (8%). The residual stenosis of the infarct-related artery was more severe in patients with worsened or unchanged wall motion than in those with improved wall motion (worsened 82.6% +/- 17.7%, unchanged 93.7% +/- 12.6%, and improved 37.1% +/- 24.4%). The use of worsened or unchanged wall motion at the infarct zone for detecting significant residual stenosis of the infarct-related artery resulted in a sensitivity of 93% and a specificity of 91%, respectively. Worsened wall motion at the infarct zone by dobutamine stress echocardiography strongly suggests residual ischemia. Conversely, less ischemia and less significant stenosis are associated with improved wall motion. Unchanged wall motion suggests severe residual stenosis and sometimes indicates ischemia. It may reflect a hibernating myocardium, but the prognostic significance of this finding should be determined by revascularization.

The comparative diagnostic value of dobutamine stress echocardiography and thallium stress tomography for detecting restenosis after coronary angioplasty.

The noninvasive detection of restenosis is clinically important for the subsequent management of patients in whom percutaneous transluminal coronary angioplasty (PTCA) has been performed. The aim of this study was to compare the diagnostic value of dobutamine stress echocardiography (DSE) and stress 201Tl single-photon emission computed tomography (SPECT) for detecting restenosis after PTCA. Fifty-three consecutive patients referred for the evaluation of possible restenosis or whom had been scheduled for follow-up study underwent DSE a mean of 5 months after angiographically successful PTCA. Dobutamine was infused incrementally under two-dimensional echocardiographic imaging. The left ventricle was divided into 16 segments and grouped into three coronary vascular territories. Rest, low-dose, and peak-dose images were digitized and displayed in a quad-screen format. Positive findings for restenosis were defined as new or worsened wall motion abnormality at a previously dilated vascular territory. All but one patient underwent SPECT. Positive findings for restenosis were defined as the presence of redistribution. All patients underwent quantitative coronary angiography after two tests. Restenosis was angiographically demonstrated in 23 (43%) of 53 patients and 25 (42) of 59 vessels. The sensitivity of DSE and SPECT for detecting restenosis was 78% and 74%, specificity was 93% and 93%, and accuracy was 87% and 85%, respectively. In a total of 59 vascular regions, DSE was 76% sensitive and 94% specific for detecting individual restenosis. It is concluded that DSE is comparable in diagnostic accuracy to SPECT for detecting restenosis in patients after PTCA.

Contribution of Poststent Irregular Protrusion to Subsequent In-Stent Neoatherosclerosis after the Second-Generation Drug-Eluting Stent Implantation: Optical Coherence Tomography Study

Previous optical coherence tomography (OCT) study reported that irregular protrusion (IP) post drug-eluting stent (DES) implantation was an independent predictor of clinical outcome; however, the relationship between IP and the presence of subsequent in-stent neoatherosclerosis remains unclear. This study aimed to assess the relationship between IP and in-stent neoatheroscrerosis formation using OCT. We evaluated 83 patients (101 lesions) who underwent second-generation DES implantation and 8-month follow-up (8M-FU) using OCT. Lesions were divided into two groups in presence of IP (IP: n = 43, non-IP: n = 58). At prepercutaneous coronary intervention (pre-PCI), lipid-rich plaque, lesions with positive remodeling, and in-stent thrombus formation were more frequent in IP than in non-IP. On multivariate analysis, the thrombus at pre-PCI and the lesions with positive remodeling were independent predictors of IP. At 8M-FU, heterogeneous neointima, microvessel, lipid-laden neointima, and thin-cap fibro-atheroma like neointima were more frequent in IP than in non-IP (respectively, P < 0.05). On multivariate analysis, IP was associated with heterogeneous neointima. Binary restenosis was more frequent and late lumen loss tended to be larger in IP than in non-IP (19% versus 5%, P = 0.04; 1.25 ± 1.24 mm versus 0.91 ± 0.63 mm, P = 0.09); however, the target lesion revascularization rate was similar in both groups at 8M-FU. In conclusion, our study suggested that poststent IP was associated with subsequent neoatherosclerosis formation at 8M-FU after the second-generation DES implantation.

CORONARY ARTERIAL REMODELING AND PERISTENT PLAQUE CHANGE AFTER DRUG-ELUTING STENT IMPLANTATION – COMPARISON BETWEEN ZOTAROLIMUS-ELUTING STENTS AND PACLITAXEL-ELUTING STENTS -

BACKGROUND Out-stent plaque characteristics and eosinophilic inflammatory response, which correlates with positive remodeling after first-generation drug-eluting stent implantation, may be associated with late restenosis and very late stent thrombosis. The differences of out-stent plaque characteristics were compared between paclitaxel-eluting stents (PES) and zotarolimus-eluting stents (ZES), using integrated backscatter-intravascular ultrasound (IB-IVUS). METHODS AND RESULTS Of 78 patients enrolled, 25 receiving PES and 25 receiving ZES had adequate IVUS assessment. Volumetric IVUS analysis was performed after stenting and at 8-month follow-up. Out-stent plaque change in the stented segment was compared on IB-IVUS. The relationship between systemic inflammatory response and out-stent plaque change was evaluated. In PES, vessel volume significantly increased (365-389 mm(3), P<0.0001), whereas it did not change in ZES (315-314 mm(3), P=0.81). In culprit lesions at baseline in PES, fibrous plaque tended to increase (3.1-3.6mm(2), P=0.051) and lipid plaque significantly increased (4.3-5.1mm(2), P=0.02), whereas in ZES the fibrous plaque significantly increased (2.9-4.0mm(2), P<0.0001) but lipid plaque significantly decreased (5.1-3.6mm(2), P<0.0001). Systemic eosinophil increase was significantly correlated with positive remodeling and out-stent lipid plaque increase. CONCLUSIONS Chronic out-stent plaque change in ZES consisted of less positive remodeling and more favorable effects on out-stent plaque characteristics than PES. Systemic eosinophil change might be a marker of out-stent lipid plaque change.

LONG-TERM PROGNOSIS OF PATIENTS WITH IRREGULAR PROTRUSION AFTER SECOND-GENERATION DRUG-ELUTING STENT IMPLANTATION: OPTICAL COHERENCE TOMOGRAPHY STUDY

Previous optical coherence tomography (OCT) study reported that irregular protrusion (IP) post drug-eluting stent (DES) implantation associated with adverse clinical outcome. However, the relationship between IP, neointimal characteristics at follow-up, and future prognosis is still unknown. We

TCT-565 Fate of irregular protrusion after second-generation drug-eluting stent implantation: Serial optical coherence tomography study.

Previous optical coherence tomography (OCT) study reported that irregular protrusion (IP), defined as protrusion of material with an irregular surface into lumen between stent struts, and small minimal stent area (MSA) at post drug-eluting stent (DES) implantation were independent predictors of 1-

Successful coronary intervention for spontaneous coronary dissection in a patient with fibromuscular dysplasia

Spontaneous coronary artery dissection (SCAD) is a reported rare cause of acute coronary syndrome (ACS) and sudden death among middle-aged women. Some institutes have recently reported fibromuscular dysplasia (FMD) concomitant with SCAD. Therefore, a survey of the presence of comorbid FMD in SCAD patients is important to obtain a definitive diagnosis and for the prediction of possible SCAD recurrence. The optimal treatment of ACS due to SCAD remains undetermined, and technical failures are frequently encountered in primary percutaneous coronary intervention (PCI) owing to the unusual non-atherosclerotic cause of the disease. We report a case of SCAD successfully treated with cutting balloon PCI under intravascular ultrasound guidance without stent implantation, in which FMD was detected in the right external iliac artery through screening by noncoronary angiography, not duplex ultrasound. <Learning objective: SCAD is a rare cause of ACS. Intravascular ultrasound is helpful to avoid the technical failures associated with primary percutaneous coronary intervention in the treatment of ACS due to SCAD. FMD has been recently reported to be concomitant with SCAD. Therefore, this report aimed to survey the presence of comorbid FMD in SCAD patients given its important role in obtaining a definitive diagnosis and predicting the possible recurrence of SCAD.>.