Tissue transglutaminase 2 promotes apoptosis of rat neonatal cardiomyocytes under oxidative stress.

The role of tissue transglutaminase 2 (TG2) in cardiac myocyte apoptosis under oxidative stress induced by ischemic injury remains unclear. Here, we investigated the effects of TG2 on apoptosis of cardiomyocytes under oxidative stress. Ectopic expression of TG2 increased caspase-3 activity and calcium overload in cardiomyocytes. Expression levels of TG2 were significantly increased in H(2)O(2)-treated cardiomyocytes. Caspase-3 activity assay demonstrated its considerable correlation with TG2 expression, which supported that caspase-3 inhibitor inhibited the apoptosis induced by the ectopic overexpression of TG2. In addition, the other apoptotic signals, such as caspase-8, cytochrome c, and Bax, were increased dependent with TG2 expression in H(2)O(2)-treated cardiomyocytes. These results indicated that apoptotic signals had a positive correlation with TG2 expression. The decreased expression of phospholipase C (PLC)-δ1 and phospho-PKC in H(2)O(2)-treated cardiomyocytes were rescued by TG2 silencing. Together, our data strongly suggest that oxidative stress up-regulates TG2 expression in cardiomyocytes, leading to apoptosis.

Angiographic and intravascular ultrasound follow up of paclitaxel- and sirolimus-eluting stent after poststent high-pressure balloon dilation: from the poststent optimal stent expansion trial.

OBJECTIVES: The aims of this study were to identify the efficacy of optimal stent expansion (OSE) according to the Multicenter Ultrasound Stenting in Coronaries Study (MUSIC Study) criteria in drug-eluting stent (DES) and compare paclitaxel-eluting stent (PES) to sirolimus-eluting stent (SES). BACKGROUND: Although poststent high-pressure balloon dilatation is proposed after bare metal stent implantation according to OSE, defined by the criteria of the MUSIC Study, very little data are available in DES. METHODS: Two hundred fifty patients (M:F = 149:101; age, 61.5 ± 9.2 years) who underwent 9-month follow-up angiography in the Poststent Optimal Stent Expansion Trial (POET) were included in this study. We assessed angiographic in-stent restenosis (ISR) and neointima volume (NV) using IVUS at 9 months. RESULTS: At 9-month follow up, there were no significant differences in ISR and NV index (NV/stent length, mm(2) ) between patients with and without OSE. However, the rate of ISR and NV index were higher in PES [ISR: 18 (13.7%) and 4 (3.4%), P = 0.004; NV index: 1.02 ± 0.99 mm(2) and 0.21 ± 0.37, P < 0.001 in PES and SES]. CONCLUSIONS: OSE according to the MUSIC Study criteria was not related to ISR and NV in the DES era but PES had a significantly higher ISR rate and NV than SES after poststent high-pressure balloon dilatation.

Comparison of the effect of preinterventional arterial remodeling on intimal hyperplasia after implantation of a sirolimus- or paclitaxel-eluting stent.

BACKGROUND: We compared the effect of arterial remodeling on intimal hyperplasia (IH) after the implantation of a sirolimus-eluting stent (SES) and a paclitaxel-eluting stent (PES). METHODS: The study population consisted of patients with positive or intermediate remodeling and negative remodeling. RESULTS: Sixty-nine patients had positive or intermediate remodeling and 107 patients had negative remodeling. At follow-up, late loss was significantly larger (0.58 +/- 0.65 vs. 0.38 +/- 0.55 mm; p = 0.026) in the patients with positive or intermediate remodeling. The IH volume (22.6 +/- 26.2 vs. 12.4 +/- 17.4 mm(3); p = 0.002) and the percent IH (12.9 +/- 14.8 vs. 7.0 +/- 9.6%; p = 0.002) were significantly higher in the patients with positive or intermediate remodeling. Compared to negative remodeling, the IH volume was higher in the PES patients with positive or intermediate remodeling, but this difference was not noted in the SES patients. Multiple-regression analysis revealed that arterial remodeling was a significant independent variable for predicting IH volume in the PES patients (p = 0.018). A positive correlation was found between the remodeling index and the IH volume in the PES patients (r = 0.234, p = 0.028), but not in the SES patients. CONCLUSIONS: This prospective observational intravascular ultrasound study showed that drug-eluting stents may have a different effect on reducing IH accumulation in lesions with preinterventional positive remodeling characteristics which may be related to the different properties of the drug and delivery platform.

Intravascular ultrasound evaluation of optimal drug-eluting stent expansion after poststent balloon dilation using a noncompliant balloon versus a semicompliant balloon (from the Poststent Optimal Stent Expansion Trial [POET]).

The impact of type of balloon such as noncompliant (NC; Quantum) or semicompliant (SC; Maverick(2)) used after stent dilation on optimal stent expansion (OSE) has not been established for drug-eluting stents (DESs). We conducted a prospective multicenter, randomized study to compare NC with SC balloons after stent balloon dilatation. A total of 301 patients (127 men, 83 women, 62 +/- 9 years of age) treated with a DES (sirolimus-eluting stent [SES], n = 152; paclitaxel-eluting stent, n = 149) were included. OSE followed the definition of the Multicenter Ultrasound Stenting in Coronaries (MUSIC) study. The primary end point was the incidence of OSE using intravascular ultrasound according to type of balloon. Baseline characteristics of each group showed no significant differences. OSE in the SC balloon group was achieved at higher rates than the NC balloon group (53 +/- 35%, vs 73 +/- 48%, p = 0.022 in all stents; 25 +/- 33%, vs 36, 48%, p = 0.051 in SESs). However, any differences in the achievement of OSE between the NC and SC balloon groups were not present in paclitaxel-eluting stents. In conclusion, despite postadjuvant balloon inflations with high pressures, underexpansion of the DES was seen commonly. Between the 2 types of balloon for adjuvant dilation after DES implantation, same-size SC balloons could be more useful for obtaining OSE than NC balloons, especially in SESs.

Effect of the 252A>G polymorphism of the lymphotoxin-alpha gene on inflammatory markers of response to cigarette smoking in Korean healthy men.

BACKGROUND: The systemic inflammatory response is heightened in smokers. We examined whether the established cardiovascular risk factor, smoking status, might interact with the lymphotoxin-alpha (LTA) gene 252A>G polymorphism in determining concentrations of TNF-alpha and eventually IL-6, adiponectin and CRP downstream in the inflammatory cascade. METHODS: We measured anthropometric parameters, serum lipid profile, glucose, TNF-alpha, IL-6, CRP, adiponectin and urinary excretion of 8-epi PGF2alpha as well as a genotyping for 252A>G polymorphism of LTA in 480 healthy Korean men. RESULTS: After adjustment for age, 208 smokers with an average consumption of 18+/-1 cigarettes/d had higher concentrations of TNF-alpha, IL-6, CRP and urinary excretion of 8-epi PGF2alpha than nonsmokers (n=272). Nonsmokers with G/G had higher TNF-alpha and 8-epi PGF2alpha concentrations than those with A/A or A/G. TNF-alpha concentrations were higher in smokers than nonsmokers of the same genotype. Smokers with G/G showed higher TNF-alpha concentration than those with A/A and had higher IL-6 and urinary 8-epi PGF2alpha concentrations than those with A/G or A/A. Furthermore, smokers carrying the G allele showed lower adiponectin concentrations than those with A/A. There are main effects of genotype and smoking, as well as the smoking-genotype interaction to TNF-alpha concentration. CONCLUSION: Our results suggest that the LTA 252A>G polymorphism may modulate the inflammatory effects and oxidative stress of smoking. The detrimental effect of smoking is most clearly seen in men with G/G, suggesting a genotype-specific interaction with smoking.

Histopathologic validation of optical coherence tomography findings of non-apposed side-branch struts in porcine arteries.

BACKGROUND: The presence of uncovered struts overlying side branch is considered to be a potential risk of stent thrombosis. The accuracy in detection of neointimal strut coverage at branch point by optical coherence tomography (OCT) has not been validated in comparison with histology. METHODS: A total of 5 stents (3 drug-eluting stents and 2 bare-metal stents) were implanted in the bifurcation segment of normal coronary arteries in 4 domestic swine (weight, 25-40 kg). The animals underwent follow-up OCT at 30 days after stent implantation and were then sacrificed for histologic evaluation. The neointimal coverage of the non-apposed struts over the side branch was assessed by light microscopy. Every millimeter of the stent was specified by the OCT frame rate, and comparisons between OCT and pathologic findings were performed through precise histological-OCT frame matching. RESULTS: OCT images at the side branch corresponded well with histological cross-sections. The tissues covering struts as assessed by OCT contained smooth muscle cells with proteoglycan-collagen matrix, but platelets are attached above the neointima in one of them on histologic examination, suggesting that most of the struts were well healed, with normal neointimal coverage. CONCLUSION: This study demonstrated the accuracy of OCT for the detection of neointimal coverage of non-apposed struts over the side branch.

Long-term (≥2 years) follow-up optical coherence tomographic study after sirolimus- and paclitaxel-eluting stent implantation: comparison to 9-month follow-up results.

Many studies have demonstrated that late or very late thrombosis after drug-eluting stent (DES) implantation may be related with incomplete neointimal coverage. We investigated long-term (≥2 years) results of neointimal coverage following sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES) implantation using optical coherence tomography (OCT). A follow-up angiography with OCT examination was performed in 29 patients with 32 lesions for more than 2 years (group 1; 1,066 ± 381 days) and 101 patients with 104 lesions at 9 months (group 2; 273 ± 33 days) after the index procedure. The status of neointimal coverage and stent apposition was evaluated. The number of stents with completely covered struts was higher (25.0% in group 1 vs. 13.5% in group 2, P = 0.12). The percentage of uncovered struts (5.4 ± 7.5% in group 1 vs. 8.5 ± 11.6% in group 2, P = 0.19) and that of malapposed strut (0.5 ± 1.4% vs. 1.5 ± 4.2%, respectively, P = 0.19) were lower in group 1. While the percentage of uncovered and malapposed struts were quite similar in the PES groups between the two groups (P = 0.54 and 0.65, respectively), there were lower trends in the percentage of uncovered and malapposed struts in the SES group (P = 0.09 and 0.09, respectively). In conclusion, incomplete neointimal coverage was still observed in a majority of DESs and considerable struts were not covered with neointima even at more than 2 years after DES implantation. The pattern of neointimal coverage between 9-month and 2-year appeared to be somewhat different between PES and SES.

Neointimal coverage on drug-eluting stent struts crossing side-branch vessels using optical coherence tomography.

The status of neointimal coverage on the drug-eluting stent (DES) struts, which are placed across the side-branch vessels, remains unclear. The degree of neointimal coverage of stent struts crossing the side-branch vessel was evaluated according to the different types of DESs. Follow-up optical coherence tomography images at 9.3 months after the index procedure were identified in 51 patients who had undergone DES (sirolimus-eluting stents [SESs] in 22 patients, paclitaxel-eluting stents [PESs] in 15, and zotarolimus-eluting stents [ZESs] in 14) implantation with crossover of the side-branch vessels (size >2.0 mm). The enrolled patients were classified as a covered group if every unapposed strut showed neointimal coverage or an uncovered group if any struts lacked neointimal coverage. The neointimal hyperplasia thickness was also measured. The number of patients in the covered group was 15 (29%), with 36 patients in the uncovered group. Significant differences were found in the proportion of the covered group among the 3 DES types (6 [27%] of 22 with SESs, 1 [7%] of 15 with PESs, and 8 [57%] of 14 with ZESs; p = 0.011). The percentage of neointimal coverage in the overall stent struts was also significantly different among the 3 DES types (65% of 356 struts, 20% of 165 struts, and 83% of 143 struts for the SESs, PESs, and ZESs, respectively; p<0.001). The neointimal hyperplasia thickness in the PES group was significantly smaller than those of the ZES and SES groups (0.02 +/- 0.02 mm vs 0.08 +/- 0.06 mm and 0.04 +/- 0.03 mm, respectively; p = 0.002). In conclusion, different patterns of neointimal coverage of the stent struts crossing the side branch vessels were observed according to the type of DES.

Efficacy of fractional flow reserve measurements at side branch vessels treated with the crush stenting technique in true coronary bifurcation lesions.

BACKGROUND: Measurement of fractional flow reserve (FFR) has been frequently used to optimize the results of coronary stenting in patients with significant narrowing of coronary arteries. HYPOTHESIS: There has been a consensus that an FFR value > 0.90 after stenting is a useful surrogate for favorable long-term clinical outcome. We evaluated the efficacy of FFR measurement at side branch vessels of true coronary bifurcation lesions that were treated with the crush stenting technique. METHODS: This study included 12 patients with significant narrowing in both a main coronary vessel and side branch vessel who underwent the crush stenting procedure. RESULTS: After crush stenting, FFR measurement was performed at the side branch vessel prior to and after kissing balloon angioplasty (KBA). FFR values increased significantly, from 0.94 +/- 0.04 pre-KBA to 0.97 +/- 0.03 post-KBA (P = 0.011). FFR values after crush stenting but prior to KBA already measured > 0.90 in 9 of the 12 patients (75%). FFR values for the remaining 3 patients were 0.88, 0.88, and 0.90, respectively. CONCLUSIONS: FFR measurement at side branch vessels of coronary bifurcation lesions treated with crush stenting may not contribute to adequate decision-making for improvement of long-term clinical outcomes. KBA should be strongly considered for patients with bifurcation lesions treated with crush stenting.

Serial changes of minimal stent malapposition not detected by intravascular ultrasound: follow-up optical coherence tomography study.

Morphologic changes of small-sized post-stent malapposition have not been sufficiently evaluated. We investigated serial changes of minimal post-stent malapposition with a follow-up optical coherence tomography (OCT) study. Post-stent OCT and intravascular ultrasound (IVUS) and follow-up OCT were performed in 26 patients with minimal post-stent malapposition. Serial changes of number and percent of malapposition struts, and mean extra-stent malapposition area were measured in OCT analysis. Zotarolimus-eluting stent (ZES), sirolimus-eluting stent (SES), and paclitaxel-eluting stent (PES) were deployed in 17, 7 and 2 patients, respectively. Mean durations of the follow-up OCT study were 5.7 ± 3.0 months. The minimal post-stent malapposition cannot be detected by the IVUS, but be visualized with an OCT examination. According to different drug-eluting stents, malapposed stent struts were defined as the struts with detachment from the vessel wall ≥160 µm for SES, ≥130 µm for PES, and ≥110 µm for ZES. The percent of malapposition struts significantly decreased from 12.2 ± 11.0% post-stent to 1.0 ± 2.2% follow-up (P < 0.001). There was a significant decrease in the mean extra-stent malapposition area from 0.35 ± 0.16 mm(2) post-stent to 0.04 ± 0.11 mm(2) follow-up (P < 0.001). Complete disappearance of stent malapposition was also observed in 22 (85%) patients. In conclusion, minimal stent malapposition which is not detectable by IVUS may disappear or decrease in follow-up OCT evaluation.

Efficacy of high-dose atorvastatin loading before primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: the STATIN STEMI trial.

OBJECTIVES: This study sought to determine the efficacy of high-dose atorvastatin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). BACKGROUND: Previous randomized trials have demonstrated that statin pre-treatment reduced major adverse cardiac events (MACEs) in patients with stable angina pectoris and acute coronary syndrome. However, no randomized studies have been carried out with STEMI patients in a primary PCI setting. METHODS: A total 171 patients with STEMI were randomized to 80-mg atorvastatin (n = 86) or 10-mg atorvastatin (n = 85) arms for pre-treatment before PCI. All patients were prescribed clopidogrel (600 mg) before PCI. After PCI, both groups were treated with atorvastatin (10 mg). The primary end point was 30-day incidence of MACE including death, nonfatal MI, and target vessel revascularization. Secondary end points included corrected thrombolysis in myocardial infarction frame count, myocardial blush grade, and ST-segment resolution at 90 min after PCI. RESULTS: MACE occurred in 5 (5.8%) and 9 (10.6%) patients in the 80-mg and 10-mg atorvastatin pre-treatment arms, respectively (p = 0.26). Corrected thrombolysis in myocardial infarction frame count was lower in the 80-mg atorvastatin arm (26.9 +/- 12.3 vs. 34.1 +/- 19.0, p = 0.01). Myocardial blush grade and ST-segment resolution were also higher in the 80-mg atorvastatin arm (2.2 +/- 0.8 vs. 1.9 +/- 0.8, p = 0.02 and 61.8 +/- 26.2 vs. 50.6 +/- 25.8%, p = 0.01). CONCLUSIONS: High-dose atorvastatin pre-treatment before PCI did not show a significant reduction of MACEs compared with low-dose atorvastatin but did show improved immediate coronary flow after primary PCI. High-dose atorvastatin may produce an optimal result for STEMI patients undergoing PCI by improving microvascular myocardial perfusion. (Efficacy of High-Dose AtorvaSTATIN Loading Before Primary Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction [STATIN STEMI]; NCT00808717).