Inhibition of cytochrome P450 monooxygenase-catalyzed oxylipin formation by flavonoids: Evaluation of structure-activity relationship towards CYP4F2-selective inhibitors.

Epoxy- and hydroxy-fatty acids are physiologically active lipid mediators which are formed from arachidonic acid and other fatty acids by cytochrome P450 monooxygenase (CYP) catalytic activity. In this study, we investigated the structure-activity relationship of the inhibition of fatty acid-oxidizing CYP by flavonoids. A sum of 65 naturally occurring as well as new flavonoids were synthesized and tested in a multi-enzyme assay. Substituents at C2' and C7-position of the flavone structure caused epoxygenase blockade, while electronegative substituents at C4'-position led to ω-hydroxylase-selective inhibition. We identified 4'-trifluoromethylflavone as a potent and selective compound, inhibiting 20-HETE formation with an IC50 of 2.8 µM (1.3 µM-6.1 µM) in human liver microsomes. This inhibition is achieved by selective inhibition of CYP4F2 [IC50: 0.76 µM (0.42 µM-1.4 µM)], while the other human ω-hydroxylating CYP, CYP4A11, is not affected. The compound is also active in microsomes from rat and mouse liver [IC50: 1.4 µM (0.77 µM-2.7 µM) and 0.71 µM (0.24 µM-2.2 µM), respectively]. Moreover, it exhibits moderate permeability properties in PAMPA and CaCo-2 transwell systems (papp: 4.6 ±â€¯0.6 × 10-6 cm/s and 4.1 ±â€¯0.4 × 10-6 cm/s, respectively) and is stable to metabolic conversion in vitro. With this inhibitor, we provide a novel tool to selectively investigate the CYP4F2-catalyzed 20-HETE formation and its role in physiology.

Inflammatory Conditions in Acute Coronary Syndrome Patients Treated with Percutaneous Coronary Intervention of Saphenous Vein Graft.

The study aimed to evaluate the inflammatory blood parameters in acute coronary syndrome (ACS) patients with a history of coronary artery bypass graft (CABG) and treated with percutaneous coronary intervention (PCI) of saphenous vein graft (SVG). A total of 347 patients who underwent urgent SVG PCI with the diagnosis of ACS were included in the study. After the application of exclusion criteria, 79 patients were allocated into two groups, namely, successful PCI ( n = 59) and unsuccessful PCI ( n = 20), and included in the statistical analysis. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) levels were significantly higher in patients with unsuccessful SVG PCI. In the logistic regression analysis, PLR, C-reactive protein, and diabetes mellitus emerged as independent factors associated with unsuccessful SVG PCI. The area under the curve for PLR was 0.70 (95% confidence interval: 0.55-0.85, p = 0.006). The cut-off value of PLR (128.99) was associated with 70.0% sensitivity and 69.5% specificity. Elevated inflammatory status is associated with unsuccessful PCI of SVG in ACS patients. Increased PLR levels on admission is an independent predictor of this situation. This cheap and simple marker can help us to predict unsuccessful SVG PCI in ACS patients.

Relationship between mild renal dysfunction and coronary artery disease in young patients with stable angina pectoris.

Aim: We investigated the relationship between mild renal dysfunction (MRD) and the presence of coronary artery disease (CAD) in people under 60 years of age. Materials & methods: A total of 634 (317 patients with vessel stenosis ≥50% and 317 with normal angiography) individuals diagnosed with stable angina pectoris and estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2 were included in the present study. Results: The mean eGFR was lower (95.3 ± 23.7 vs 109.7 ± 22.3, respectively, p = 0.002) and the number of patients with MRD was higher in patients with CAD (137, 43.2%) than in the control group (52, 16.4%, p < 0.001). The multivariate analysis showed that lower eGFR is an independent risk factor for presence of CAD in people under 60 years of age with stable angina pectoris. Conclusion: According to our retrospective study, the risk of developing CAD appears to be slightly increased in individuals under 60 years of age with MRD.

The association of serum procalcitonin level with the no-reflow phenomenon after a primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction.

OBJECTIVE: The no-reflow phenomenon is associated with adverse outcomes in patients with acute ST-elevation myocardial infarction (STEMI) treated by a primary percutaneous coronary intervention (PPCI). Procalcitonin (PCT) is a marker of systemic inflammatory states and an elevated serum PCT concentration is related to an increased risk of cardiovascular events. We aimed to assess whether serum PCT level at admission is an independent predictor of no-reflow in patients with STEMI treated with PPCI. PATIENTS AND METHODS: Between November 2012 and December 2014, 501 consecutive patients with STEMI who underwent PPCI within the first 12 h following the onset of symptoms were enrolled. Serum PCT levels were measured on admission. Patients (age: 59±13 years, 73.5% men) were divided into the two groups: no-reflow and reflow. The no-reflow phenomenon was defined as final Thrombolysis In Myocardial Infarction flow grade less than 3 after PPCI. RESULTS: No-reflow was diagnosed in 91 (18.2%) patients. PCT levels were significantly higher in patients who developed no-reflow than in those who did not [0.102 (0.063-0.247) vs. 0.042 (0.020-0.076) µg/l, P<0.001]. In receiver operating characteristics curve analysis, the cut-off value of PCT was 0.066 µg/l for the prediction of no-reflow (area under the curve: 0.776, 95% confidence interval: 0.720-0.831, P<0.001, sensitivity: 73%, specificity: 70%). On multivariate analysis, serum PCT (>0.066 µg/l) value was an independent predictor of no-reflow (odds ratio: 3.377, 95% confidence interval: 1.572-7.255, P=0.002), together with early patency of culprit artery (P=0.046), Killip class more than or equal to 2 at presentation (P=0.028), and total stent length (P=0.004). CONCLUSION: Increased admission PCT level is associated independently with no-reflow after PPCI in STEMI patients.

Elevated serum fibrinogen levels and risk of contrast-induced acute kidney injury in patients undergoing a percutaneous coronary intervention for the treatment of acute coronary syndrome.

OBJECTIVES: Contrast-induced acute kidney injury (CI-AKI) is a common complication of diagnostic and therapeutic catheterizations, especially in the setting of acute coronary syndrome (ACS). Fibrinogen is a well-known cardiovascular risk factor. We evaluated whether serum fibrinogen level is associated independently with CI-AKI in patients with ACS who underwent a percutaneous coronary intervention (PCI). METHODS: Patients (n=710, aged 61 ± 13, 69% men) were classified into two groups: CI-AKI and non-CI-AKI. CI-AKI was defined as an increase of at least 0.5 mg/dl or at least 25% in the serum creatinine level within 72 h following PCI. RESULTS: CI-AKI occurred in 75 (10.6%) patients. We found significantly higher serum fibrinogen levels in patients who developed CI-AKI than in those who did not (498 ± 152 vs. 386 ± 96 mg/dl, P<0.001). Multivariate logistic regression analysis showed that serum fibrinogen level (odds ratio 1.006, 95% confidence interval 1.003-1.009, P<0.001), age, glomerular filtration rate, female sex, and white blood cell count were correlated with the development of CI-AKI. CONCLUSION: Serum fibrinogen level is associated independently with a higher risk of CI-AKI in patients with ACS undergoing PCI.