Kenichi Tsujita

C/EBP Homologous Protein Deficiency Attenuates Myocardial Reperfusion Injury by Inhibiting Myocardial Apoptosis and Inflammation

Objective—To investigate whether and how the endoplasmic reticulum (ER) stress–induced, CCAAT/enhancer-binding protein-homologous protein (CHOP)-mediated pathway regulates myocardial ischemia/reperfusion injury. Methods and Results—Wild-type and chop-deficient mice underwent 50 minutes of left coronary artery occlusion followed by reperfusion. Expression of chop and spliced x-box binding protein-1 (sxbp1) mRNA was rapidly and significantly increased in reperfused myocardium of wild-type mice. chop-deficient mice exhibited markedly reduced injury size after reperfusion compared with wild-type mice, accompanied by a decreasing number of terminal deoxynucleotidyl transferase dUTP nick-end labeling–positive cardiomyocytes. Interestingly, myocardial inflammation, as assessed by expression of inflammatory cytokines and chemokines and numbers of infiltrated inflammatory cells, was also attenuated in chop-deficient mice. Moreover, expression of interleukin-6 mRNA in response to lipopolysaccharide was enhanced by simultaneous stimulation with thapsigargin, a potent ER stressor, in wild-type cardiomyocytes but not in chop-deficient cardiomyocytes. Finally, we found that superoxide was produced in reperfused myocardium and that intravenous administration of edaravone, a free radical scavenger, immediately before reperfusion significantly suppressed the superoxide overproduction and subsequent expression of sxbp1 and chop mRNA, followed by reduced injury size in wild-type mice. Conclusion—The ER stress–induced, CHOP-mediated pathway, which is activated in part by superoxide overproduction after reperfusion, exacerbates myocardial ischemia/reperfusion injury by inducing cardiomyocyte apoptosis and myocardial inflammation.

Classification and Potential Mechanisms of Intravascular Ultrasound Patterns of Stent Fracture

We sought to examine the intravascular ultrasound (IVUS) findings of stent fracture. Stent fracture has been implicated as a cause of drug-eluting stent failure. IVUS is more likely to identify mechanisms of stent failure -- including stent fracture -- than angiography. Twenty stent fractures diagnosed by IVUS in 17 patients were evaluated. Eighteen stent fractures (90%) occurred in sirolimus-eluting Cypher stents, and 2 stent fractures (10%) occurred in bare metal stents, but none occurred in paclitaxel-eluting Taxus stents. Half of the stent fractures presented < or =1 year after implantation, and (1/2) presented >1 year after implantation. IVUS analysis showed that 9 stent fractures were complete (45%) and 11 were partial (55%); 10 (50%) were adjacent to stent metal overlap; and 5 occurred in a coronary aneurysm accompanied by malapposition (all Cypher stents) despite the absence of an aneurysm at index stenting. Compared with 60 matched control segments in patients without stent fracture, but with similar clinical events, the stent fracture group had longer stent segments (45.2 +/- 23.0 vs 28.5 +/- 14.9 mm, p = 0.003). Comparing stent fractures associated with an aneurysm (n = 5) with those that did not occur in association with an aneurysm (n = 15) showed that complete stent fracture was more frequent (100% vs 27%, p = 0.008), and all presented >1 year after index stenting (vs 33%, p = 0.03). In conclusion, IVUS is helpful to identify stent fracture as a cause of stent failure and to understand possible mechanisms of stent fracture such as aneurysm formation.

Intravascular Ultrasound Classification of Plaque Distribution in Left Main Coronary Artery Bifurcations Where Is the Plaque Really Located

Background—Angiographic classifications of the location and severity of disease in the main vessel and side branch of coronary artery bifurcations have been proposed and applied to distal left main coronary artery (LMCA) bifurcation. Methods and Results—We reviewed 140 angiograms of distal LMCA and ostial left anterior descending (LAD) and left circumflex (LCX) artery lesions with preintervention intravascular ultrasound (IVUS) of both the LAD and LCX arteries as well as the LMCA. Of 140 patients, 92.9% had at least 1 cross section with ≥40% IVUS plaque burden versus 57.2% of patients with an angiographic diameter stenosis ≥50%. Contrary to angiographic classifications, IVUS showed that bifurcation disease was rarely focal and that both sides of the flow divider were always disease-free. Continuous plaque from the LMCA into the proximal LAD artery was seen in 90%, from the LMCA into the LCX artery in 66.4%, and from the LMCA into both the LAD and LCX arteries in 62%. Plaque localized to either the LAD or LCX ostium and not involving the distal LMCA was seen in only 9.3% of LAD arteries and 17.1% of LCX arteries. Plaque distribution was not influenced by the LAD/LCX angiographic angle, lesion severity, LMCA length, or remodeling. We proposed an IVUS classification for bifurcation lesions illustrating longitudinal and circumferential spatial plaque distribution. Conclusions—Angiographic classification of LMCA bifurcation lesions is rarely accurate. IVUS shows that the carina is always spared and that the disease is diffuse rather than focal. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180466.

Impact of CYP2C19 polymorphism on residual platelet reactivity in patients with coronary heart disease during antiplatelet therapy

BACKGROUND AND PURPOSE CYP2C19*2 loss-of-function allele in Caucasians may be associated with wide interindividual variability in platelet response to clopidogrel, and the incidence of gene mutation varies with racial differences, especially between Asians and Caucasians. The aim was to examine the impact of CYP2C19 genotype on the residual platelet reactivity in Japanese patients with coronary heart disease (CHD) during antiplatelet therapy. METHODS AND RESULTS We measured the CYP2C19 genotype and platelet aggregation in 201 patients with stable CHD. Moreover, we examined the relation of CYP2C19 polymorphism to cardiovascular events in 98 patients treated with stent implantation. The distribution of CYP2C19 genotype was 37%, 33%, 11%, 11%, 7%, and 1% in CYP2C19*1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. Residual platelet reactivity was lower in patients during dual antiplatelet therapy (DAT) than in those with aspirin (3975 ± 1569 aggregation units minute (AU min) vs 5850 ± 938 AU min, p<0.05). In the DAT group, the platelet reactivity decreased significantly in the wild-type homozygotes (CYP2C19*1/*1), subsequently in the *2, or *3 heterozygotes (*1/*2, *1/*3), and was not well inhibited in the *2, and/or *3 homozygotes (*2/*2, *2/*3, *3/*3; 3194 ± 1570 AU min, 4148 ± 1400 AU min, and 5088 ± 1080 AU min, respectively). However, when the duration of DAT was used to divide subjects into 2 groups, <7 days, and >7 days, patients carrying the variant allele showed significantly decreased platelet reactivities at >7 days compared with those at <7 days. Moreover, the incidence of cardiovascular events was higher in patients carrying at least one variant allele than in wild-type homozygotes. CONCLUSIONS CYP2C19 polymorphism may be associated with high residual platelet reactivity and the occurrence of cardiovascular events.

Intravascular Ultrasound Classification of Plaque Distribution in Left Main Coronary Artery Bifurcations

Background—Angiographic classifications of the location and severity of disease in the main vessel and side branch of coronary artery bifurcations have been proposed and applied to distal left main coronary artery (LMCA) bifurcation. Methods and Results—We reviewed 140 angiograms of distal LMCA and ostial left anterior descending (LAD) and left circumflex (LCX) artery lesions with preintervention intravascular ultrasound (IVUS) of both the LAD and LCX arteries as well as the LMCA. Of 140 patients, 92.9% had at least 1 cross section with ≥40% IVUS plaque burden versus 57.2% of patients with an angiographic diameter stenosis ≥50%. Contrary to angiographic classifications, IVUS showed that bifurcation disease was rarely focal and that both sides of the flow divider were always disease-free. Continuous plaque from the LMCA into the proximal LAD artery was seen in 90%, from the LMCA into the LCX artery in 66.4%, and from the LMCA into both the LAD and LCX arteries in 62%. Plaque localized to either the LAD or LCX ostium and not involving the distal LMCA was seen in only 9.3% of LAD arteries and 17.1% of LCX arteries. Plaque distribution was not influenced by the LAD/LCX angiographic angle, lesion severity, LMCA length, or remodeling. We proposed an IVUS classification for bifurcation lesions illustrating longitudinal and circumferential spatial plaque distribution. Conclusions—Angiographic classification of LMCA bifurcation lesions is rarely accurate. IVUS shows that the carina is always spared and that the disease is diffuse rather than focal. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180466.

Intravascular ultrasound assessment of the incidence and predictors of edge dissections after drug-eluting stent implantation.

OBJECTIVES We used intravascular ultrasound (IVUS) to assess incidence, predictors, morphology, and angiographic findings of edge dissections after drug-eluting stent (DES) implantation. BACKGROUND DES implantation strategies differ compared with bare-metal stenting; coronary dissections after DES implantation have not been well studied. METHODS We studied 887 patients with 1,045 non-in-stent restenosis lesions in 977 native arteries undergoing DES implantation with IVUS imaging. RESULTS Eighty-two dissections were detected; 51.2% (42 of 82) involved the proximal and 48.8% (40 of 82) the distal stent edge. Residual plaque area (8.0 +/- 4.3 mm(2) vs. 5.2 +/- 3.0 mm(2), p < 0.0001); plaque burden (52.2 +/- 11.7% vs. 36.2 +/- 15.3%, p < 0.0001); plaque eccentricity (8.4 +/- 5.5 vs. 4.0 +/- 3.4, p < 0.0001); and stent edge symmetry (1.2 +/- 0.1 vs. 1.1 +/- 0.1, p = 0.02) were larger; plaque burden > or =50% was more frequent (62.0% vs. 17.2%, p < 0.0001); calcium deposits (52.1% vs. 35.2%, p = 0.03) more common; and lumen-to-stent-edge-area ratio (0.9 +/- 0.2 vs. 1.0 +/- 0.2, p < 0.0001) was smaller in the edge dissection group compared with the nondissection group. Intramural hematomas occurred in 34.1% (28 of 82) of dissections. When compared with nonhematoma dissections, residual plaque and media area (6.4 +/- 2.5 mm(2) vs. 8.9 +/- 4.6 mm(2), p = 0.04) was smaller, and stent edges less asymmetric (1.1 +/- 0.1 vs. 1.2 +/- 0.1, p = 0.009) in the dissection with hematoma group. Independent predictors of any stent edge dissection were residual plaque eccentricity (odds ratio [OR]: 1.4, p = 0.02), lumen-to-stent-edge-area ratio (OR: 0.0, p = 0.007), and stent edge symmetry (OR: 1.2, p = 0.02 for each 0.01 increase). CONCLUSIONS IVUS identified edge dissections after 9.2% of DES implantations. Residual plaque eccentricity, lumen-to-stent-edge-area ratio, and stent edge symmetry predicted coronary stent edge dissections. Dissections in less diseased reference segments more often evolved into an intramural hematoma.

Impact of Anemia on Clinical Outcomes of Patients With ST-Segment Elevation Myocardial Infarction in Relation to Gender and Adjunctive Antithrombotic Therapy (from the HORIZONS-AMI Trial)

The aim of this study was to assess the impact of baseline anemia on the outcomes of patients with ST elevation myocardial infarctions who underwent primary percutaneous coronary intervention in relation to contemporary adjunctive antithrombotic therapy and gender. In the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, patients were randomized to bivalirudin alone or to unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor before primary percutaneous coronary intervention. Outcomes were assessed at 30 days and 1 year according to anemia and gender. Baseline anemia was present in 331 of 3,153 patients (10.5%). Patients with versus without baseline anemia had a more than twofold increase in major bleeding at 30 days (13.5% vs 6.7%, p <0.0001) and at 1 year (14.8% vs 7.2%, p <0.0001), an association that on multivariate analysis was independent of gender. Mortality was significantly higher in men with versus without baseline anemia (4.6% vs 1.8% at 30 days, p = 0.003; 8.9% vs 3.0% at 1 year, p <0.0001) but not in women (5.3% vs 3.6% at 30 days, p = 0.42; 7.5% vs 5.9% at 1 year, p = 0.54). On multivariate analysis, anemia independently predicted 1-year all-cause mortality in men but not in women. Bivalirudin compared with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor resulted in twofold lower rates of all-cause and cardiac mortality and major bleeding in patients without but not in those with baseline anemia. In conclusion, baseline anemia was associated with increased major bleeding and death in patients with ST elevation myocardial infarctions who underwent primary PCI but was a stronger predictor of early and late mortality in men than in women. Paradoxically, in this post hoc analysis, the reductions in major bleeding and mortality in ST elevation myocardial infarction afforded by bivalirudin occurred primarily in patients without baseline anemia.

Targeted Deletion of Class A Macrophage Scavenger Receptor Increases the Risk of Cardiac Rupture After Experimental Myocardial Infarction

Background— Class A macrophage scavenger receptor (SR-A) is a macrophage-restricted multifunctional molecule that optimizes the inflammatory response by modulation of the activity of inflammatory cytokines. This study was conducted with SR-A–deficient (SR-A−/−) mice to evaluate the relationship between SR-A and cardiac remodeling after myocardial infarction. Methods and Results— Experimental myocardial infarction (MI) was produced by ligation of the left coronary artery in SR-A−/− and wild-type (WT) male mice. The number of mice that died within 4 weeks after MI was significantly greater in SR-A−/− mice than in WT mice (P=0.03). Importantly, death caused by cardiac rupture within 1 week after MI was 31% (17 of 54 mice) in SR-A−/− mice and 12% (6 of 51 mice) in WT mice (P=0.01). In situ zymography demonstrated augmented gelatinolytic activity in the infarcted myocardium in SR-A−/− mice compared with WT mice. Real-time reverse transcription–polymerase chain reaction at day 3 after MI showed that the expression of matrix metalloproteinase-9 mRNA increased significantly in the infarcted myocardium in SR-A−/− mice compared with WT mice. Furthermore, SR-A−/− mice showed augmented expression of tumor necrosis factor-α and reduction of interleukin-10 in the infarcted myocardium at day 3 after MI. In vitro experiments also demonstrated increased tumor necrosis factor-α and decreased interleukin-10 expression in activated SR-A−/− macrophages. Conclusions— The present findings suggest that SR-A deficiency might cause impairment of infarct remodeling that results in cardiac rupture via insufficient production of interleukin-10 and enhanced expression of tumor necrosis factor-α and of matrix metalloproteinase-9. SR-A might contribute to the prevention of cardiac rupture after MI.

Coronary Vasomotor Response to Intracoronary Acetylcholine Injection, Clinical Features, and Long-term Prognosis in 873 Consecutive Patients With Coronary Spasm: Analysis of a Single-Center Study Over 20 Years

Background The aim of this study was to elucidate the correlation between angiographic coronary vasomotor responses to intracoronary acetylcholine (ACh) injection, clinical features, and long‐term prognosis in patients with vasospastic angina (VSA). Methods and Results This is a retrospective, observational, single‐center study of 1877 consecutive patients who underwent ACh‐provocation test between January 1991 and December 2010. ACh‐provoked coronary spasm was observed in 873 of 1637 patients included in the present analysis. ACh‐positive patients were more likely to be older male smokers with dyslipidemia, to have a family history of ischemic heart disease, and to have a comorbidity of coronary epicardial stenosis than were ACh‐negative patients. ACh‐positive patients were divided into 2 groups: those with focal (total or subtotal obstruction, n=511) and those with diffuse (severe diffuse vasoconstriction, n=362) spasm patterns. Multivariable logistic regression analysis identified female sex and low comorbidity of coronary epicardial stenosis to correlate with the ACh‐provoked diffuse spasm pattern in patients with VSA. Kaplan–Meier survival curve indicated better 5‐year survival rates free from major adverse cardiovascular events in patients with diffuse spasm pattern compared with those with focal spasm pattern (P=0.019). Multivariable Cox hazard regression analysis identified diffuse spasm pattern as a negative predictor of major adverse cardiovascular events in patients with VSA. Conclusions ACh‐induced diffuse coronary spasm was frequently observed in female VSA patients free of severe coronary epicardial stenosis and was associated with better prognosis than focal spasm. These results suggest the need to identify the ACh‐provoked coronary spasm subtypes in patients with VSA.

Intravascular Ultrasound Comparison of the Retrograde Versus Antegrade Approach to Percutaneous Intervention for Chronic Total Coronary Occlusions

OBJECTIVES We sought to evaluate the results of the antegrade versus retrograde chronic total occlusion (CTO) technique with intravascular ultrasound (IVUS) imaging. BACKGROUND The most common failure mode of CTO interventions remains the inability to successfully cross the occlusion with a guidewire. Recently, the retrograde approach through collateral channels has been introduced to cross complex CTOs. METHODS Between October 2002 and April 2008, IVUS was performed in 48 de novo CTO lesions after guidewire crossing +/- pre-dilation with a 1.5- to 2.0-mm balloon. Twenty-three lesions were treated via the antegrade approach (Ante), and 25 lesions were treated via the retrograde approach (Retro). RESULTS Right coronary artery (RCA) CTOs were treated more frequently via the Retro technique. Although the CTO length was much longer in the Retro group (45 +/- 26 mm vs. 18 +/- 9 mm, p < 0.0001), at the end of the procedure Thrombolysis In Myocardial Infarction flow grade 3 was obtained in all patients. There were no significant differences between the 2 groups in minimum stent area and stent expansion. However, the incidence of the composite end point-subintimal wiring, angiographic extravasation, coronary hematoma, or IVUS-detected coronary perforation-was higher in the Retro group (68% vs. 30%, p = 0.01); and the guidewire was more often subintimal in the Retro group (40% vs. 9%, p = 0.02). CONCLUSIONS The retrograde approach is a promising option for complex CTO segments, especially long RCA CTOs. Intravascular ultrasound can be a useful tool for the detection of procedure-related vessel damage and subintimal wire tracking.