Takaaki Isshiki

Comparisons of Baseline Demographics, Clinical Presentation, and Long-Term Outcome Among Patients With Early, Late, and Very Late Stent Thrombosis of Sirolimus-Eluting Stents Observations From the Registry of Stent Thrombosis for Review and Reevaluation (RESTART)

Background— Stent thrombosis (ST) after sirolimus-eluting stent implantation has not yet been adequately characterized, mainly because of its low incidence. Methods and Results— The Registry of Stent Thrombosis for Review and Reevaluation (RESTART) is a Japanese nationwide registry of sirolimus-eluting stent–associated ST comprising 611 patients with definite ST (early [within 30 days; EST], 322 patients; late [between 31 and 365 days; LST], 105 patients; and very late [>1 year; VLST], 184 patients). Baseline demographics, clinical presentation, and long-term outcome of sirolimus-eluting stent–associated ST were compared among patients with EST, LST, and VLST. Baseline demographics were significantly different according to the timing of ST. Characteristic demographic factors for LST/VLST versus EST identified by multivariable model were hemodialysis, end-stage renal disease not on hemodialysis, absence of circumflex target, target of chronic total occlusion, prior percutaneous coronary intervention, and age <65 years. For LST versus VLST, they were hemodialysis, heart failure, insulin-dependent diabetes mellitus, and low body mass index. Patients with LST had a significantly higher rate of Thrombolysis in Myocardial Infarction grade 2/3 flow (36%) at the time of ST than those with EST (13%) (P<0.0001) and VLST (17%; P<0.0001). Mortality rate at 1 year after ST was significantly lower in patients with VLST (10.5%) compared with those with EST (22.4%; P=0.003) or LST (23.5%; P=0.009). Conclusion— ST timing–dependent differences in baseline demographic features, Thrombolysis in Myocardial Infarction flow grade, and mortality rate suggest possible differences in the predominant pathophysiological mechanisms of ST according to timing after sirolimus-eluting stent implantation.

Anatomic Variations of the Radial Artery in Patients Undergoing Transradial Coronary Intervention

Anatomic variations of the radial artery and their effect on the use of the radial artery as a route for transradial coronary intervention (TRI) were studied. Ultrasonography of the radial artery was performed prospectively in 115 patients selected to undergo elective TRI. Anatomic variations were observed in 11 of 115 patients (9.6%). Variations included six tortuous configurations (5.2%), two stenoses (1.7%), two hypoplasias (1.7%), and one radioulnar loop (0.9%). The hypoplastic radial arteries and the radioulnar loop were inaccessible for catheterization, and coronary intervention was planned via the femoral artery. The transradial approach was attempted in the remaining 112 patients (97.4%) with only one instance of access failure, in a patient who had a stenotic vessel. These findings indicate that anatomic variations of the radial artery is not rare, and that preoperative ultrasound examination may help to exclude patients with inaccessible arteries and those at high risk for access failure. Cathet. Cardiovasc. Intervent. 49:357–362, 2000.

Upfront thrombus aspiration in primary coronary intervention for patients with ST-segment elevation acute myocardial infarction: report of the VAMPIRE (VAcuuM asPIration thrombus REmoval) trial.

OBJECTIVES This study evaluated safety and efficacy of upfront thrombus aspiration during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Distal embolization during primary PCI results in reduced myocardial perfusion and poor clinical outcomes. METHODS The VAMPIRE (VAcuuM asPIration thrombus REmoval) study was a prospective, randomized, controlled multicenter trial conducted in 23 institutions. Patients (N = 355) presenting within 24 h of STEMI symptoms onset were randomized to primary PCI with (n = 180) or without (n = 175) upfront thrombus aspiration using Nipros TransVascular Aspiration Catheter (Osaka, Japan). RESULTS The TransVascular Aspiration Catheter reached the lesion in 100% of cases. It successfully crossed the target obstruction in 86% without any delay in procedure time or time to reperfusion; whereas macroscopic thrombi were removed in 75% of the cases. Procedure success was similar between groups (98.9% vs. 98.3%). There was a trend toward lower incidence of slow or no reflow (primary end point-defined as a Thrombolysis In Myocardial Infarction flow grade <3) in patients treated with aspiration versus conventional primary PCI (12.4% vs. 19.4%, p = 0.07). Rate of myocardial blush grade 3 was higher in the aspiration group (46.0% vs. 20.5%, p < 0.001). Aspiration was most effective in patients presenting after 6 h of symptoms onset (slow flow rate: 8.1% vs. 37.6%, p = 0.01). CONCLUSIONS This study suggested the safety of primary PCI with upfront thrombectomy using a novel device in patients with STEMI. The study showed a trend toward improved myocardial perfusion and lower clinical events in patients treated with aspiration. Patients presenting late after STEMI appear to benefit the most from thrombectomy.

Three-Year Outcomes After Sirolimus-Eluting Stent Implantation for Unprotected Left Main Coronary Artery Disease Insights From the j-Cypher Registry

Background— Long-term outcomes after stenting of an unprotected left main coronary artery (ULMCA) with drug-eluting stents have not been addressed adequately despite the growing popularity of this procedure. Methods and Results— j-Cypher is a multicenter prospective registry of consecutive patients undergoing sirolimus-eluting stent implantation in Japan. Among 12 824 patients enrolled in the j-Cypher registry, the unadjusted mortality rate at 3 years was significantly higher in patients with ULMCA stenting (n=582) than in patients without ULMCA stenting (n=12 242; 14.6% versus 9.2%, respectively; P<0.0001); however, there was no significant difference between the 2 groups in the adjusted risk of death (hazard ratio 1.23, 95% confidence interval 0.95 to 1.60, P=0.12). Among 476 patients whose ULMCA lesions were treated exclusively with a sirolimus-eluting stent, patients with ostial/shaft lesions (n=96) compared with those with bifurcation lesions (n=380) had a significantly lower rate of target-lesion revascularization for the ULMCA lesions (3.6% versus 17.1%, P=0.005), with similar cardiac death rates at 3 years (9.8% versus 7.6%, P=0.41). Among patients with bifurcation lesions, patients with stenting of both the main and side branches (n=119) had significantly higher rates of cardiac death (12.2% versus 5.5%; P=0.02) and target-lesion revascularization (30.9% versus 11.1%; P<0.0001) than those with main-branch stenting alone (n=261). Conclusions— The higher unadjusted mortality rate of patients undergoing ULMCA stenting with a sirolimus-eluting stent did not appear to be related to ULMCA treatment itself but rather to the patients’ high-risk profile. Although long-term outcomes in patients with ostial/shaft ULMCA lesions were favorable, outcomes in patients with bifurcation lesions treated with stenting of both the main and side branches appeared unacceptable.

Effects of competitive blood flow on arterial graft patency and diameter: Medium-term postoperative follow-up

To identify predictors of arterial graft patency, we followed up 30 internal thoracic arterial grafts and 23 right gastroepiploic arterial grafts in situ with patency documented during postoperative angiography. After 24 months of follow-up on average, repeat angiography detected that one internal thoracic artery and two gastroepiploic arteries were anatomically occluded and that the other three gastroepiploic arteries were nonfunctioning. The logistic regression model identified a relationship between graft patency and competitive flow, which was detected as stenosis in the recipient coronary arteries (coefficients, p < 0.05; model, Hosmer-Lemeshow chi2 statistic 3.59, p = 0.89). The linear regression model demonstrated that changes in graft luminal diameter correlated with competitive flow (p < 0.01), smoking history (p < 0.05), and type of arterial grafts (p < 0.001) (R2 = 0.40, adjusted R2 = 0.36). The findings suggest a temporal relationship between competitive flow and prognosis of arterial graft.

Endothelium-Dependent Relaxation of Collateral Microvessels After Intramuscular Gene Transfer of Vascular Endothelial Growth Factor in a Rat Model of Hindlimb Ischemia

BACKGROUND Recent investigations have demonstrated the ability of vascular endothelial growth factor (VEGF) to augment the development of collateral arteries in vivo. In vitro studies have suggested that the use of VEGF also improves the endothelium-dependent relaxation of collaterals at the microvascular level. The purpose of this study was to determine in vivo the extent to which vasomotor responses of collateral microvessels are altered after VEGF treatment. METHODS AND RESULTS Ischemia was induced in the hindlimb of 35 rats by excision of the femoral artery. Immediately thereafter, 400 microg of a plasmid encoding VEGF or ss-galactosidase (control) was transfected into limb muscles. Four weeks later, synchrotron radiation microangiography, with a spatial resolution of 30 microm, was performed to document the reactivity of collateral microvessels. Administration of the endothelium-dependent vasodilator acetylcholine failed to induce dilation of collateral microvessels in control animals. By contrast, profound dilation of collaterals was observed after acetylcholine in VEGF-treated animals. This response was evident in vessels with a linear appearance but not in those with an undulating appearance. The resulting blood flow in the ischemic limb after administration of acetylcholine in the control animals was only 64.6+/-17.0% of that of the contralateral normal limb, whereas blood flow was augmented to 106.1+/-8.4% in VEGF-treated animals (P<0.05). CONCLUSIONS These results demonstrate in vivo that the use of VEGF restores impaired vasomotor responses in some types of collateral microvessels, which may help to provide a basis for understanding the microcirculation after therapeutic angiogenesis with VEGF.

Platelet aggregation in acute coronary syndromes: use of a new aggregometer with laser light scattering to assess platelet aggregability

OBJECTIVE Platelet aggregation has been implicated in the pathogenesis of acute coronary syndromes. Small aggregates consisting of < or = 100 platelets cannot be quantified with a conventional aggregometer employing optical density. Using a recently developed aggregometer based on laser light scattering, we studied platelet aggregability in patients with acute coronary syndromes. METHODS Peripheral blood samples were obtained from 39 patients with acute myocardial infarction or unstable angina who had received no prior antiplatelet or anticoagulant therapy, to be assayed immediately using a PA-100 platelet aggregometer. Blood samples from 14 healthy volunteers were used as controls. RESULTS Spontaneous formation of platelet aggregates was observed only in patients with acute coronary syndromes. The size of these aggregates was small, consisting of < or = 100 platelets (primary aggregation). Agonist-induced aggregation consisted of two phases. In the first few minutes, the number of small aggregates increased markedly (primary aggregation), followed by an increase in larger aggregates (secondary aggregation). The EC50 of epinephrine for primary aggregation was nearly 50 times lower in acute coronary patients than in controls (P < 0.001), while the EC50 for secondary aggregation was only 2 times lower (P < 0.001). CONCLUSIONS Aggregometry using light scattering suggests that platelet hyperaggregability and hypersensitivity in acute coronary syndromes may occur in primary but not secondary aggregation.

Comprehensive analysis of the renin-angiotensin gene polymorphisms with relation to hypertension in the Japanese

Background Components of the renin–angiotensin (R–A) system have been repeatedly investigated as candidate genes for essential hypertension. In particular, suggestive or significant association has been detected in some studies for the angiotensinogen M235T, angiotensin I-converting enzyme I/D, angiotensin II type 1 receptor A1166C, and aldosterone synthase C-344T polymorphisms, although the results remain inconclusive. Objective and Methods To evaluate the importance of these candidate genes for hypertension, we undertook an extensive association study in the Japanese. This case–control study was conducted in a total of 1476 individuals using the four R–A gene polymorphisms. In the assessment of genotyping data, 843 hypertensive subjects were divided into three case subgroups according to severity of hypertension, while 633 normotensive subjects divided into two control subgroups by the age of enrollment. Each subgroup was further divided by sex. Subsequently, the presence of synergy (or gene–gene interaction) was evaluated among four R–A gene polymorphisms. Results No significant association was observed between the individual R–A gene polymorphisms and hypertension status in our case–control study. The results were almost unchanged when severity of hypertension, sex-specificity, and synergy were taken into account. Conclusions Despite a relatively large number of subjects, we did not find significant evidence for disease association in the Japanese population. Given confounding factors in the case–control strategy, the lack of association does not exclude the relevance of the R–A genes to hypertension. Further investigation needs to be performed in large-scale populations, where the use of not only hypertension status, but also ‘intermediate’ phenotypes would be useful.

Angiotensin-converting enzyme inhibition improves defective angiogenesis in the ischemic limb of spontaneously hypertensive rats.

OBJECTIVES Natural angiogenesis has been shown to be impaired in spontaneously hypertensive rats (SHR). The purpose of this study was to determine whether pathological angiogenesis in the setting of tissue ischemia is also impaired in SHR, and to what extent it is modified by angiotensin-converting enzyme (ACE) inhibition. METHODS Ischemia was induced in the hindlimb of SHR by excision of the femoral artery, after which the animals were randomly assigned to receive low-dose perindopril (sub-antihypertensive, 0.2 mg/kg/day), high-dose perindopril (antihypertensive, 2.0 mg/kg/day), or vehicle for 3 weeks. Wistar-Kyoto rats (WKY) with femoral artery excision served as a control group. RESULTS Tissue ACE activity in SHR was significantly increased compared to WKY (49.4+/-6.2 vs. 34.0+/-14.2 IU/mg, P<0.01). Administration of perindopril significantly reduced ACE activity in SHR (low dose: 12.4+/-2.3; high dose: 11.0+/-2.1 IU/mg, P<0.005). Angiogenesis of the ischemic limb muscles was significantly impaired at 4 weeks in SHR versus WKY as indicated by the lower capillary density in the former (364.5+/-43.0 vs. 463.8+/-63.0/mm(2), P<0.05) as well as the reduced hindlimb perfusion assessed by laser Doppler imaging (0.86+/-0.08 vs. 1.03+/-0.09, P<0.05). Administration of perindopril significantly augmented both the capillary density (low dose: 494.3+/-69.8; high dose: 543.9+/-76.9/mm(2), P<0.005) and the limb perfusion (low dose: 1.06+/-0.15; high dose: 1.05+/-0.12, P<0.05) of the ischemic limb in SHR. CONCLUSIONS These findings indicate that pathological angiogenesis in the setting of tissue ischemia is impaired in SHR compared with WKY, and that this impairment can be reversed by ACE inhibition. The angiogenic properties of an ACE inhibitor may benefit patients with essential hypertension presenting with lower limb vascular insufficiency.

Cilostazol Reduces Angiographic Restenosis After Endovascular Therapy for Femoropopliteal Lesions in the Sufficient Treatment of Peripheral Intervention by Cilostazol Study

Background— It remains unclear whether cilostazol, which has been shown to improve the clinical outcomes of endovascular therapy for femoropopliteal lesions, also reduces angiographic restenosis. Methods and Results— The Sufficient Treatment of Peripheral Intervention by Cilostazol (STOP-IC) study investigated whether cilostazol reduces the 12-month angiographic restenosis rate after percutaneous transluminal angioplasty with provisional nitinol stenting for femoropopliteal lesions. Two hundred patients with femoropopliteal lesions treated from March 2009 to April 2011 at 13 cardiovascular centers were randomly assigned 1:1 to receive oral aspirin with or without cilostazol. The primary end point was 12-month angiographic restenosis rate. Secondary end points were the restenosis rate on duplex ultrasound, the rate of major adverse cardiac events, and target lesion event-free survival. Researchers evaluated all follow-up data and assessed the end points in a blinded fashion. The mean lesion length and reference vessel diameter at the treated segment were 128±86 mm and 5.4±1.4 mm, respectively. The frequency of stent used was similar between groups (88% versus 90% in the cilostazol and noncilostazol group, respectively, P=0.82). During the 12-month follow-up period, 11 patients died and 152 patients (80%) had evaluable angiographic data at 12 months. The angiographic restenosis rate at 12 months was 20% (15/75) in the cilostazol group versus 49% (38/77) in the noncilostazol group (P=0.0001) by intention-to-treat analysis. The cilostazol group also had a significantly higher event-free survival at 12 months (83% versus 71%, P=0.02), although cardiovascular event rates were similar in both groups. Conclusions— Cilostazol reduced angiographic restenosis after percutaneous transluminal angioplasty with provisional nitinol stenting for femoropopliteal lesions. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00912756; and URL: https://www.umin.ac.jp. Unique identifier: UMIN000002091.