Takeo Higashikata

Plaque Morphology at Coronary Sites With Focal Spasm in Variant Angina

In the present study, the intravascular ultrasound (IVUS) morphologic appearance of coronary atherosclerotic plaque associated with focal spasm was prospectively studied in 45 patients with or without focal coronary spasm provoked by ergonovine or acetylcholine. The percent plaque area and plaque arc were determined from the IVUS images at the sites of spasm. Calcified lesion was defined as the presence of high-intensity echo with acoustic shadowing. Twenty-three patients had focal coronary spasm defined as angiographic narrowing >75% and IVUS demonstrated atherosclerotic plaque in these 23 sites. In the 22 patients without focal spasm, IVUS demonstrated 18 atherosclerotic lesions in 17 patients and the remaining 5 patients did not have significant lesions. There was no difference in the percent plaque area and plaque arc between plaque lesions with (47+/-10%, 298+/-71 degrees ) and without (39+/-15%, 249+/-83 degrees ) coronary spasm. Interestingly, calcified lesion was less frequently present at the sites with than at those without spasm (p<0.05). These results indicate that the presence of plaque without calcification is likely to be related to the occurrence of focal vasospasm, although the severity and distribution of the disease did not differ between each patient group.

Relation between vascular morphologic changes during stent implantation and the magnitude of in-stent neointimal hyperplasia.

Intimal hyperplasia usually occurs after balloon overstretch injury or wire coil stimuli to coronary arteries. We examined whether the degree of vessel wall stretch during coronary stent placement could predict the amount of in-stent neointimal hyperplasia after a 6-month follow-up. Serial (preintervention, postballooning, poststent implantation, and a follow-up after 6 months) intravascular ultrasound (IVUS) was used to study 457 consecutive cross-sectional areas in 28 patients. IVUS imaging, using a motorized pullback system at 0.5 mm/s, allowed 1-mm axial increment measurements of the total vascular, stent, and lumen cross-sectional areas. The mean total vascular area changed from 10.89 +/- 2.50 mm2 before to 11.27 +/- 2.49 mm2 after ballooning, to 12.80 +/- 2.59 mm2 after stenting, and to 12.58 +/- 2.41 mm2 at follow-up (p < 0.0001). The mean lumen area changed from 3.36 +/- 1.95 mm2 before to 4.21 +/- 1.65 mm2 after ballooning, to 5.16 +/- 1.09 mm2 after stenting, and to 3.57 +/- 1.23 mm2 at follow-up (p < 0.0001). The mean stent area decreased from 5.25 +/- 1.17 mm2 after stenting to 5.09 +/- 0.90 mm2 at follow-up (p < 0.0001). Stepwise logistic regression analysis showed that delta total vascular area (after stent implantation - before intervention) was a strong predictor of the amount of intimal hyperplasia (r = 0.57, p < 0.0001). Vascular overstretch caused by the stenting procedure promotes intimal hyperplasia in proportion to the degree of sectional vascular stretch.

Expression and function of ephrin-B1 and its cognate receptor EphB2 in human atherosclerosis: from an aspect of chemotaxis

Although several cytokines and chemokines have been demonstrated to play pivotal roles in the pathophysiological conditions of atherosclerosis, few findings exist regarding the expression and function of cytokine-modulating molecules such as ephrin-Bs and their cognate receptors, EphBs, in human atherosclerosis. Therefore, in the present study, we screened novel genes modulating atherogenesis by cDNA array and quantitatively determined them by real-time RT (reverse transcription)-PCR in human carotid atherosclerotic plaques. Ephrin-B1 and EphB2, key regulators of embryogenesis, were significantly up-regulated in plaques compared with those in adjacent control tissues [ephrin-B1, 0.638+/-0.106 compared with 0.831+/-0.152, or 130% (P<0.05); EphB2, 1.296+/-0.281 compared with 2.233+/-0.506, or 172% (P<0.05)]. Immunohistological analysis demonstrated that both ephrin-B1 and EphB2 were expressed in macrophages and T-lymphocytes in plaques as well as in monocytes, T-lymphocytes and arterial endothelial cells isolated from healthy adults. Interestingly, the extracellular domains of ephrin-B1 and EphB2, the expression of which were both enhanced in stimulated THP-1 cells, significantly inhibited spontaneous (22.5 and 27.6% respectively; P<0.01) and MCP-1 (monocyte chemoattractant protein-1)-dependent (29.7 and 22.6% respectively; P<0.01) migration of monocytes. In conclusion, these results demonstrate that ephrin-B1 and EphB2 are overexpressed in atherosclerotic tissue and might locally regulate cell migration, possibly through modulating cytokine-related chemotaxic activity; however, the functional role of these molecules in atherogenesis should be investigated further.

Effect of disease eccentricity on compensatory remodeling of coronary arteries: evidence from intravascular ultrasound before interventions.

BACKGROUND Compensatory remodeling occurs to maintain lumen area in human coronary vessels. However, few data exist regarding the relationship between vessel remodeling and plaque distribution. Therefore, we studied coronary sites with or without remodeling by intravascular ultrasound and correlated with disease distribution. METHODS AND RESULTS A total of 90 coronary sites with significant stenosis (>50%) from 80 patients were examined before interventions. For identifying the vessel remodeling, external elastic membrane (EEM) area was measured at the stenotic sites and the adjacent proximal and distal sites. The reference EEM area was calculated by averaging proximal and distal EEM areas, and percent enlargement of the EEM area was calculated by the formula: [(stenosis EEM area-reference EEM area)/reference EEM area]x100. Plaque area was determined by reducing the lumen from EEM areas. The maximal (max) and minimal (min) distances from the center of the lumen to the EEM were also measured, and the disease eccentricity index was calculated by the formula: [(max-min)/max]. The lesion was defined as eccentric if the index was >0.5 and as concentric if <or=0.5. There were 39 eccentric and 51 concentric lesions. The enlargement remodeling was observed at 32 lesions with the enlargement of EEM area of 28.0+/-16.0% (5.5 to 71.3%). Enlargement was more frequently observed in the eccentric than in concentric lesions (P<0.05). However, within 32 stenoses, which showed enlargement, there was no difference in enlargement between eccentric (n=19, 25.6+/-21.0%) and concentric lesions (n=13, 21.5+/-12.0%). Also, there was no statistical correlation between the increase in plaque area and % enlargement of EEM area irrespective of plaque morphology. CONCLUSIONS These data demonstrate that in advanced coronary disease compensatory enlargement occurs more frequently at the eccentric than concentric coronary lesions. However, the EEM area was limited to expand regardless of the disease morphology.

Expression and Function of Ephrin-B1 and Its Cognate Receptor EphB2 in Human Abdominal Aortic Aneurysm

We examined the expression of ephrin-B1 and its cognate receptor EphB2, key regulators of angiogenesis and embryogenesis, in human abdominal aortic aneurysm (AAA) and analyzed their functional roles in cell migration. From 10 patients (9 males and 1 female; age, 68.5 ± 2.4) who underwent vascular surgery for AAA, we obtained AAA and adjacent control tissues. Using real-time RT-PCR, we analyzed expression of ephrin-B1 and EphB2. We also histologically localized these molecules in AAA tissues. Finally, effects of ephrin-B1 and EphB2 on inflammatory cell chemotaxis were examined by cell migration assay. Expression levels of ephrin-B1 (0.410 ± 0.046 versus 1.198 ± 0.252, P = 0.027) and EphB2 (0.764 ± 0.212 versus 1.272 ± 0.137, P = 0.594) were higher in AAA than normal control. Both ephrin-B1 and EphB2 were expressed in macrophages, T lymphocytes, and endothelial cells within AAA. In chemotaxis assay, ephrin-B1 and EphB2 inhibited mononuclear-cell chemotaxis induced by stromal derived factor-1 down to 54.7 ± 12.7% (P = 0.01) and 50.7 ± 13.1% (P = 0.01), respectively. These data suggest that ephrin-B1 and EphB2 might be functional in human adult inflammatory cells and involved in the pathogenesis of AAA, although specific roles of these molecules should further be sought.