Jin-Shik Park

Prevention of radiocontrast medium-induced nephropathy using short-term high-dose simvastatin in patients with renal insufficiency undergoing coronary angiography (PROMISS) trial--a randomized controlled study

BACKGROUND Contrast media cause oxidative stress, which has been suggested as one possible mechanism responsible for contrast-induced nephropathy. Statins appear to have pleiotropic effects, including antioxidant properties. We investigated to determine whether simvastatin pretreatment reduces the risk of contrast-induced nephropathy in a high-risk population of patients with renal insufficiency undergoing coronary angiography. METHODS We conducted a prospective, randomized, double-blind, placebo-controlled, 2-center trial, involving 247 consecutive patients with chronic renal insufficiency (calculated creatinine clearance < or = 60 mL/min and/or serum creatinine > or = 1.1 mg/dL) undergoing coronary angiography. Patients were randomized to simvastatin (n = 124; 160 mg total, 40 mg orally every 12 hours starting the evening before and ending the morning after the procedure) or placebo (n = 123). All patients received pre - and postprocedure hydration. The iso-osmolar contrast agent iodixanol was used for coronary angiography in all patients. RESULTS There was no difference between simvastatin and placebo in mean peak increase in serum creatinine measured within 48 hours after coronary angiography, the primary study end point (0.002 +/- 0.164 vs 0.017 +/- 0.230 mg/mL respectively, P = .559). The incidence of contrast-induced nephropathy, a secondary end point defined as increase of either > or = 25% or > or = 0.5 mg/dL in serum creatinine, was 2.5% in simvastatin-treated patients (3/118) and 3.4% in placebo-treated patients (4/118), a nonsignificant difference (P = 1.00). There were also no differences between the 2 groups in length of hospital stay or 1- and 6-month clinical outcomes. CONCLUSIONS Simvastatin pretreatment for short-term at high dose do not prevent renal function deterioration after administration of contrast medium in patients with baseline renal insufficiency undergoing coronary angiography.

Determinants of Surgical Outcome in Patients With Isolated Tricuspid Regurgitation

Background— We sought to identify preoperative predictors of clinical outcomes after surgery in patients with severe tricuspid regurgitation. Methods and Results— We prospectively enrolled 61 consecutive patients (54 women, aged 57±9 years) with isolated severe tricuspid regurgitation undergoing corrective surgery. Twenty-one patients (34%) were in New York Heart Association functional class II, 35 (57%) in class III, and 5 (9%) in class IV. Fifty-seven patients (93%) had previous history of left-sided valve surgery. Preoperative echocardiography revealed pulmonary artery systolic pressure of 41.5±8.7 mm Hg, right ventricular (RV) end-diastolic area of 35.1±9.0 cm2, and RV fractional area change of 41.3±8.4%. The median follow-up duration after surgery was 32 months (range, 12 to 70). Six of the 61 patients died before discharge; thus, operative mortality was 10%. Three of the 55 patients who survived surgery died during follow-up, and 6 patients required readmission because of cardiovascular problems. Thus, 46 patients (75%) remained event free at the end of follow-up. In the 54 patients who underwent 6-month clinical and echocardiographic follow-up, RV end-diastolic area decreased by 29%, with a corresponding 26% reduction in RV fractional area change. Thirty-three patients (61%) showed improved functional capacity after surgery. On multivariable Cox regression analysis, preoperative hemoglobin level (P<0.001) and RV end-systolic area (P<0.001) emerged as independent determinants of clinical outcomes. On receiver operating characteristic curve analysis, we found that RV end-systolic area <20 cm2 predicted event-free survival with a sensitivity of 73% and a specificity of 67%, and a hemoglobin level >11.3 g/dL predicted event-free survival with a sensitivity of 73% and a specificity of 83%. Conclusions— Timely correction of severe tricuspid regurgitation carries an acceptable risk and improves functional capacity. Surgery should be considered before the development of advanced RV systolic dysfunction and before the development of anemia.

Development of tricuspid regurgitation late after left-sided valve surgery: A single-center experience with long-term echocardiographic examinations

OBJECTIVES This study sought to investigate the incidence and identify the predictors of significant tricuspid regurgitation (TR) development long after left-sided valve surgery. METHODS Of 615 patients who underwent surgery for left-sided valve disease between 1992 and 1995, 335 patients without significant TR who completed at least 5 years of clinical and echocardiographic follow-up were enrolled. Late significant TR development was assessed by echocardiography with a mean follow-up duration of 11.6 +/- 2.1 years. RESULTS Significant late TR was found in 90 patients (26.9%). Patients with late TR showed an advanced age (47.6 +/- 13.4 vs 44.3 +/- 13.2 years, P = .04), a higher prevalence of preoperative atrial fibrillation (83.3 vs 46.5%, P < .001), a greater left atrial dimension (56.9 +/- 13.2 vs 52.4 +/- 11.5 mm, P = .006), and a higher prevalence of prior valve surgery (40.0 vs 25.3%, P = .01). In addition, late TR occurred more frequently in patients who had undergone mitral valve surgery than in those who did not (93.3 vs 72.2%, P < .001). However, multivariate analysis showed that the presence of preoperative atrial fibrillation (odds ratio 5.37; 95% CI 2.71-10.65; P < .001) was the only independent factor of late TR development. Patients who developed late TR had a lower event-free survival rate than those who did not (P = .03). CONCLUSIONS The development of significant TR long after left-sided valve surgery is not uncommon with an estimated incidence of 27% and is closely associated with a poor prognosis. The presence of preoperative atrial fibrillation was identified as the only independent predictor of the development of late TR.

N-acetylcysteine versus AScorbic acid for preventing contrast-induced nephropathy in patients with renal insufficiency undergoing coronary angiography: NASPI study - a prospective randomized controlled trial.

BACKGROUND Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired renal failure and affects mortality and morbidity. There has been no study comparing the efficacy of N-acetylcysteine (NAC) and ascorbic acid that have potential for CIN prevention in patients with renal insufficiency. METHODS We conducted a prospective randomized controlled trial. A total of 212 patients who had pre-existing renal impairment with basal creatinine clearance < or =60 mL/min and/or serum creatinine (SCr) level of > or =1.1 mg/dL, were randomized to have either high-dose NAC (1,200 mg orally twice a day before and on the day of coronary catheterization, n = 106) or ascorbic acid (3 g and 2 g orally before, and 2 g twice after coronary catheterization with a 12-hour interval, n = 106). The primary end point was the maximum increase of SCr level, and the secondary end point was the incidence of CIN. RESULTS The maximum increase of SCr level was significantly lower in NAC group than in ascorbic acid group as follows: -0.03 +/- 0.18 mg/dL versus 0.04 +/- 0.20 mg/mL, respectively (P = .026). Patients with diabetes or who had received a high dose of contrast media experienced significantly less rise of SCr level with NAC than ascorbic acid; in diabetic subgroup, -0.05 +/- 0.22 mg/dL versus 0.09 +/- 0.29 mg/mL, respectively (P = .020); in patients with high dose of dye, -0.03 +/- 0.17 mg/dL versus 0.04 +/- 0.21 mg/mL, respectively (P = .032). The incidence of CIN, the secondary end point, tended to be in favor of NAC rather than ascorbic acid, 1.2% versus 4.4%, respectively (P = .370). Notably, among the diabetes patients, the NAC significantly lowered CIN rate than ascorbic acid, 0% (0/38) versus 12.5% (4/32), respectively (P = .039). CONCLUSION High-dose NAC seems more beneficial than ascorbic acid in preventing contrast-induced renal function deterioration in patients, especially diabetic patients, with renal insufficiency undergoing coronary angiography.

Effect of celecoxib on restenosis after coronary angioplasty with a Taxus stent (COREA-TAXUS trial): an open-label randomised controlled study

BACKGROUND In-vitro and animal experiments have shown that the cyclo-oxygenase 2 inhibitor celecoxib can reduce formation of neointima within stents. We aimed to test whether celecoxib has similar effects in a clinical setting. METHODS In a randomised two-centre trial, we enrolled 274 patients who had angina pectoris or a positive stress test and who had native coronary artery lesions for which implantation of paclitaxel-eluting stents was feasible. All patients were given aspirin (100 mg daily) and clopidogrel (75 mg daily). 136 patients were randomly assigned to receive celecoxib (400 mg before the intervention, and 200 mg twice daily for 6 months after the procedure). The primary endpoint was late luminal loss on quantitative coronary angiography at 6 months after the intervention. Secondary endpoints were cardiac death, non-fatal myocardial infarction, and revascularisation of the target lesion. Analysis was done on a modified intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00292721. FINDINGS At 6 months, mean in-stent late luminal loss was lower in the celecoxib group (0.49 mm, SD 0.47) than in the control group (0.75 mm, 0.60) (absolute difference 0.26 mm; 95% CI 0.12-0.40). Frequency of secondary outcomes at 6 months was also lower in the celecoxib group, mainly because of a reduced need for revascularisation of the target lesion. INTERPRETATION These data suggest that the adjunctive use of celecoxib for 6 months after stent implantation in patients with coronary artery disease is safe and can reduce the need for revascularisation of the target lesion.

Renal dysfunction and high levels of hsCRP are additively associated with hard endpoints after percutaneous coronary intervention with drug eluting stents

BACKGROUND Chronic kidney disease (CKD) and high C-reactive protein (CRP) are known risk factors of cardiovascular disease. In the drug eluting stent (DES) era, the relationship among CKD, CRP, and long-term outcomes after percutaneous coronary intervention (PCI) has not yet been demonstrated. We investigated the combined effects of renal dysfunction and CRP on outcomes in patients who underwent PCI using DES. METHODS A total of 1859 patients (mean age 64 ± 10 years) who underwent PCI with DES between February 2003 and June 2006, were divided into 4 groups (quartile) according to estimated glomerular filtration rate (eGFR) and hsCRP at admission. RESULTS The composite of cumulative death and non-fatal myocardial infarction (mortality+MI) during median follow-up of 27 months, was significantly higher in the lowest eGFR quartile than in the other three groups (hazard ratio (HR) for mortality+MI: 3.32, 95% CI: 2.21-5.00, P<0.001). Mortality+MI was also significantly higher in the highest hsCRP quartile (HR: 3.29, 95% CI: 2.02-5.37, P<0.001). A combined analysis of mortality+MI on the basis of hsCRP and renal function showed the exaggerated hazard in the combined worst quartile of hsCRP and GFR (HR of the combined worst quartile, 10.876, 95% CI: 3.74-31.63, P<0.001). Furthermore, both the lowest eGFR quartile and the highest hsCRP quartile were significantly associated with increased risk of stent thrombosis. In a multivariate analysis, low GFR and high hsCRP were independent predictors of mortality+MI after PCI with DES along with left ventricular dysfunction, diabetes, and left main disease. CONCLUSIONS In an unselected cohort of patients receiving PCI with DES, poor renal function and high hsCRP were additively associated with a higher risk of hard endpoints and were independent predictors of mortality+MI even after correction for other factors. Our data suggest the importance of systemic factors on mortality even in the DES era.

The incidence and predictors of postprocedural incomplete stent apposition after angiographically successful drug-eluting stent implantation†

Objectives: The aim of this study was to evaluate the incidence and predictors of postprocedural incomplete stent apposition (ISA) after angiographically successful drug‐eluting stent (DES) implantation. Background: The deployed stents are usually evaluated by angiography alone; however, there are possibilities of postprocedural ISA despite the angiographically successful implantation. Methods: A total of 339 lesions in which poststent intravascular ultrasound (IVUS) was performed after successful DES implantation was included. Paclitaxel‐eluting stents were implanted in 237 lesions and sirolimus‐eluting stents (SES) in 102 lesions. Clinical, angiographic and procedural characteristics and IVUS findings for all cases were analyzed. Results: The overall incidence of ISA was 13.9% (47/339). By multivariate analysis, male gender (OR: 2.36, 95% CI: 1.09–5.11), deployment of SES (OR: 2.90, 95% CI: 1.49–5.67), the presence of intracoronary thrombus (OR: 7.47, 95% CI: 1.67–33.47), and non‐ST elevation myocardial infarction (OR: 2.73, 95% CI: 1.09–6.83) were independent predictors for postprocedural ISA after angiographically successful DES implantation. Conclusions: The incidence of postprocedural ISA after angiographically successful implantation of DES was not infrequent. A DES deployment strategy incorporating IVUS guidance might be helpful to reduce the incidence of postprocedural ISA.

Nf-κB decoy potentiates the effects of radiation on vascular smooth muscle cells by enhancing apoptosis

NF-κB promotes cell survival against external stress such as radiation. We examined whether NF-κB decoy transfection enhances the antiproliferative effects of radiation on vascular smooth muscle cells (VSMCs) in vitro. The irradiation induced activation or nuclear translocation of NF-κB p65 in VSMCs was confirmed by immunofluorescence. NF-kB decoy transfection resulted in inhibition of the radiation-induced NF-kB activation in VSMCs and the subsequent reduction of transcription and translocation of ICAM, iNOS, and TNF-α, downstream molecules under the control of NF-κB. By using MTT assay, NF-κB decoy augmented the antiproliferative effects of radiation, where the effect of low dose radiation (2 and 8-Gy) of the cells transfected with NF-κB decoy was equivalent to the high dose (16-Gy) irradiated non-transfected cells at 48 h after irradiation: 1.06±0.16, 1.11±0.22, 1.20±0.25, respectively. The decrease in proliferation and survival of the radiation treated cells by flow cytometry analysis showed that NF-κB inhibition did not show any additive effects on the cell cycle of the irradiated VSMCs, while apoptosis was significantly increased after NF-κB decoy transfection in the irradiated VSMCs (apoptosis fraction: 13.33±2.08% vs. 26.29±7.43%, for radiation only vs. radiation+NF-κB decoy transfection, P < 0.05). In addition, at 48 h, NF-κB decoy transfection dose dependently (10 µM vs. 20 µM) inhibited proliferation of 16Gy-irradiated VSMCs, and showed greater antiproliferative efficacy than 100 µM sulfasalazine, a specific NF-κB inhibitor. These results indicate that NF-κB inhibition reduces proliferation and survival of irradiated VSMCs, likely by increased apoptosis rather than additive cell cycle arrest and suggest the possibility of adjunctive gene therapy using NF-κB decoy to improve efficacy and to decrease the adverse effects of intracoronary radiation therapy.

Vitamin K epoxide reductase complex subunit 1 gene polymorphism is associated with atherothrombotic complication after drug-eluting stent implantation: 2-Center prospective cohort study

BACKGROUND Single nucleotide polymorphisms of vitamin K epoxide reductase complex subunit 1 (VKORC1) was reported to have association with arterial vascular disease. We investigated whether single nucleotide polymorphism of VKORC1 +2255 is associated with clinical outcomes among patients who underwent drug-eluting stent (DES) implantation. METHODS We prospectively collected genomic DNA in patients who underwent DES deployment from September 2003 to December 2006 and compared clinical outcomes according to their VKORC1 genotype at the locus + 2255 (rs 2359612). The primary end point was composite of atherothrombotic events (cardiac death, myocardial infarction, and nonhemorrhagic stroke). RESULTS Mean follow-up duration was 631 +/- 251 days. Genotyping was completed in 764 cases (TT genotype [n = 640, 83.8%] vs non-TT [CC or CT] genotype [n = 124, 16.2%]). Non-TT group showed more composite events than TT group (7.3% vs 3.0%, P = .032). In the Cox regression analysis, non-TT genotype of VKORC gene was a significant predictor of atherothrombotic events (hazard ratio 2.56, 95% confidence interval 1.14-5.78). In the event-free survival analysis, non-TT group also showed significantly poorer cardiovascular events-free survival rate than TT group (P = .02). CONCLUSIONS VKORC1 genotype is associated with cardiovascular events in patients with DES implantation, suggesting the role of coagulation system.

Association between OPG, RANK and RANKL gene polymorphisms and susceptibility to acute coronary syndrome in Korean population

B ligand (RANKL), its receptor RANK and osteo-protegerin (OPG) are members of tumour necrosis fac-tor (TNF) superfamily and they form a key cytokine triadinvolved in bone metabolism, specifically osteoclastogen-esis (Khosla 2001; Boyce and Xing 2008). Recent stud-ies have demonstrated that OPG/RANK/RANKL system isinvolved in plaque instability and rupture by inducing plaquecalcification (Panizo