Effects of combination therapy with celecoxib and doxycycline on neointimal hyperplasia and inflammatory biomarkers in coronary artery disease patients treated with bare metal stents.

PURPOSE: Cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-9 play a key role in the pathogenesis of in-stent restenosis. We investigated the effect of a short-term therapy of celecoxib, a COX-2 inhibitor, with or without doxycycline, an MMP inhibitor, after coronary stenting on inflammatory biomarkers and neointimal hyperplasia. MATERIALS AND METHODS: A total of 75 patients (86 lesions) treated with bare metal stents were randomized into three groups: 1) combination therapy (200 mg celecoxib and 20 mg doxycycline, both twice daily), 2) celecoxib (200 mg twice daily) only, and 3) non-therapy control. Celecoxib and doxycycline were administered for 3 weeks after coronary stenting. The primary endpoint was neointimal volume obstruction by intravascular ultrasound (IVUS) at 6 months. The secondary endpoints included clinical outcomes, angiographic data, and changes in blood levels of inflammatory biomarkers. RESULTS: Follow-up IVUS revealed no significant difference in the neointimal volume obstruction among the three treatment groups. There was no difference in cardiac deaths, myocardial infarctions, target lesion revascularization or stent thrombosis among the groups. Blood levels of high-sensitivity C-reactive protein, soluble CD40 ligand, and MMP-9 varied widely 48 hours and 3 weeks after coronary stenting, however, they did not show any significant difference among the groups. CONCLUSION: Our study failed to demonstrate any beneficial effects of the short-term therapy with celecoxib and doxycycline or with celecoxib alone in the suppression of inflammatory biomarkers or in the inhibition of neointimal hyperplasia. Large scale randomized trials are necessary to define the role of anti- inflammatory therapy in the inhibition of neointimal hyperplasia.

Relation of homocysteinemia to contrast-induced nephropathy in patients undergoing percutaneous coronary intervention.

Hyperhomocysteinemia induces oxidative stress and endothelial dysfunction, which share the proposed pathophysiologic mechanisms of contrast-induced nephropathy (CIN). However, no study has investigated the relation between hyperhomocysteinemia and CIN. The aim of the present study was to evaluate the effects of hyperhomocysteinemia on CIN in patients undergoing percutaneous coronary intervention. This was an observational cohort study that included 572 patients who underwent percutaneous coronary intervention. CIN was defined as an absolute ≥0.5 mg/dl or a relative ≥25% increase in the serum creatinine level at 48 hours after the procedure. The incidence of CIN was significantly greater in patients in the third homocysteine tertile (from lowest to highest, 4.7%, 7.3%, and 24.2%, p <0.001). Furthermore, the homocysteine levels were significantly greater in patients with CIN than in those without CIN (16.9 ± 4.9 vs 13.5 ± 4.2 µmol/L, p <0.001). In multiple logistic regression models, hyperhomocysteinemia was an independent risk factor for CIN (per the SD change in the plasma homocysteine level [4.44 µmol/L], odds ratio 1.70, 95% confidence interval 1.07 to 2.71, p = 0.025) after adjusting for major risk factors such as age, diabetes, and baseline cardiac and renal function. In subgroup analyses according to diabetes, acute coronary syndrome, or baseline estimated glomerular filtration rate, significant, graded associations were found between the homocysteine level and the incidence of CIN. In conclusion, hyperhomocysteinemia is independently associated with a greater risk of CIN in patients undergoing percutaneous coronary intervention.

Interleukin-6 (IL-6) -572C-->G promoter polymorphism is associated with type 2 diabetes risk in Koreans.

OBJECTIVE: Increased levels of inflammatory markers, such as interleukin-6 (IL-6), are associated with type 2 diabetes (T2DM). We investigated the association of IL-6 gene polymorphisms with T2DM and circulating levels of IL-6 in Koreans. SUBJECTS: A total of 1477 subjects with normal glucose tolerance and 476 T2DM patients were included. MEASUREMENTS: We examined IL-6 -174G-->C, -572C-->G, -597G-->A and -1363G-->T promoter region polymorphisms. The main outcome measures were the odds ratio (OR) on T2DM risk and serum concentrations of IL-6 and high-sensitivity C-reactive protein (hs-CRP). RESULTS: Homozygosity for the rare G allele IL-6 -572C-->G was associated with a higher risk of T2DM [OR 1.69 (95%CI 1.11-2.58), P = 0.015]. Serum IL-6 concentrations were associated with the IL-6 -572C-->G genotype in control subjects (G/G: 2.33 +/- 0.41: C/G: 1.53 +/- 0.09: C/C: 1.72 +/- 0.08 ng/l, P = 0.023). Also in the control group, subjects homozygous for the rare G allele showed significantly higher concentrations of hs-CRP than C/C and C/G carriers (G/G: 13.6 +/- 2.9: C/G: 9.2 +/- 0.6: C/C: 7.8 +/- 0.4 mg/l, P = 0.003). The C-allele at the IL-6 -174 SNP was very rare (< 0.01) and -597G-->A and -1363G-->T were monomorphic in this population. CONCLUSIONS: Our data demonstrate that the IL-6 -572G/G genotype is associated with higher serum IL-6 and hs-CRP concentrations and with increased risk for T2DM.

Lymphotoxin-alpha gene 252A>G and metabolic syndrome features in Korean men with coronary artery disease.

BACKGROUND: Associations between variations in the lymphotoxin-alpha (LTA) gene and coronary artery disease (CAD) and type 2 diabetes have previously been reported. We investigated the influence of the LTA 252A>G and 804C>A polymorphisms on circulating parameters related to metabolic syndrome in Korean patients with CAD. METHODS: The study subjects comprised 446 Korean male patients with CAD (age 53.9 y, BMI 25.2 kg/m2). RESULTS: The LTA 252A>G and 804C>A polymorphisms were almost in complete linkage disequilibrium (R(2)=99.4%). The LTA 252A>G polymorphism was associated with LDL particle size (P=0.046), HOMA-IR (P=0.022) and circulating levels of triglyceride (P=0.006), HDL-cholesterol (P=0.008), apo A1 (P=0.031), insulin (P=0.046), and adiponectin (P=0.018), after adjustment for BMI. CAD patients with LTA 252G/G (n=96) had a lower concentration of HDL-cholesterol, a smaller LDL particle size, and a higher triglyceride level, compared to those with 252A/A (n=121) or 252A/G (n=229). In addition, CAD patients with LTA 252G/G had lower concentrations of adiponectin and higher levels of insulin, and HOMA-IR than those with 252A/A. CONCLUSION: Homozygosity for rare alleles of the LTA 252A>G polymorphisms was associated with features of metabolic syndrome such as hyperinsulinemia, dyslipidemia, small LDL particle and low adiponectin level in CAD patients, suggesting that CAD patients with LTA 252GG are at high risk and needed an intensive intervention against further progression.