Background High urine flow rate (UFR) has been suggested as a target for effective prevention of contrast-induced acute kidney injury (CI-AKI). The RenalGuard therapy (saline infusion plus furosemide ...controlled by the RenalGuard system) facilitates the achievement of this target. Methods Four hundred consecutive patients with an estimated glomerular filtration rate ≤30 mL/min per 1.73 m2 and/or a high predicted risk (according to the Mehran score ≥11 and/or the Gurm score >7%) treated by the RenalGuard therapy were analyzed. The primary end points were (1) the relationship between CI-AKI and UFR during preprocedural, intraprocedural, and postprocedural phases of the RenalGuard therapy and (2) the rate of acute pulmonary edema and impairment in electrolytes balance. Results Urine flow rate was significantly lower in the patients with CI-AKI in the preprocedural phase (208 ± 117 vs 283 ± 160 mL/h, P < .001) and in the intraprocedural phase (389 ± 198 vs 483 ± 225 mL/h, P = .009). The best threshold for CI-AKI prevention was a mean intraprocedural phase UFR ≥450 mL/h (area under curve 0.62, P = .009, sensitivity 80%, specificity 46%). Performance of percutaneous coronary intervention (hazard ratio HR 4.13, 95% CI 1.81-9.10, P < .001), the intraprocedural phase UFR <450 mL/h (HR 2.27, 95% CI 1.05-2.01, P = .012), and total furosemide dose >0.32 mg/kg (HR 5.03, 95% CI 2.33-10.87, P < .001) were independent predictors of CI-AKI. Pulmonary edema occurred in 4 patients (1%). Potassium replacement was required in 16 patients (4%). No patients developed severe hypomagnesemia, hyponatremia, or hypernatremia. Conclusions RenalGuard therapy is safe and effective in reaching high UFR. Mean intraprocedural UFR ≥450 mL/h should be the target for optimal CI-AKI prevention.
Objectives This study sought to assess the usefulness of clopidogrel-pathway genotyping and on-treatment platelet reactivity (OTR) testing in predicting major adverse cardiac events (MACE) in stable ...coronary artery disease (CAD) patients receiving drug-eluting stents (DES) under dual antiplatelet (clopidogrel plus aspirin) therapy. Background The role of pharmacogenetics and OTR in predicting MACE—death, myocardial infarction, or stent thrombosis—in stable CAD patients scheduled for DES implantation is still debated. Methods Patients with stable CAD treated by DES implantation (n = 1,432) were genotyped with a TaqMan OpenArray (Applied Biosystems, Carlsbad, California) and assessed for OTR with the VerifyNow P2Y12 test (Accumetrics Inc., San Diego, California). Genes tested were ABCB1, CYP1A2, CYP2B6*9, CYP2C8*3, CYP2C9*2, CYP2C19, CYP3A4, CYP3A5*3, P2RY12 , and PON1CYP2C19 . High OTR was defined as P2Y12 reaction units ≥230. The endpoint at 12-month follow-up was MACE occurring during antiplatelet therapy. Results All groups that were stratified for loss-of-function variants of the cytochrome P450 gene CYP2C19 had significant hazard ratios (HR) for MACE (genotypic HR: 1.41, 95% confidence interval CI: 1.06 to 1.89, p = 0.01; allelic HR: 1.56, 95% CI: 2.26 to 1.2, p = 0.01). Variants of other clopidogrel-pathway genes were not significantly associated with MACE. When OTR was assessed, clinical significance was found only in high-risk diabetic (HR: 2.11, 95% CI: 1.29 to 3.45, p < 0.001) and chronic kidney disease (HR: 2.03, 95% CI: 1.03 to 4.02, p = 0.04) patients. Conclusions CYP2C19 metabolizer status is an independent predictor of MACE after DES implantation and can be used for prognostication in all stable CAD patients. High OTR, as assessed by the VerifyNow P2Y12 test, is an independent predictor of MACE only for high-risk subsets, that is, patients with diabetes or chronic kidney disease.
Abstract Objectives This study sought to investigate acute kidney injury (AKI) following carotid artery stenting (CAS). Background Few data exist on AKI following CAS. Methods This study evaluated ...126 chronic kidney disease (CKD) patients who underwent CAS. The risk for contrast-induced AKI was defined by the Mehran score. Hemodynamic depression (i.e., periprocedural systolic blood pressure <90 mm Hg or heart rate <60 beats/min), AKI (i.e., an increase of ≥0.3 mg/dl in the serum creatinine concentration at 48 h), and 30-day major adverse events (including death, stroke, and acute myocardial infarction) were assessed. Results AKI occurred in 26 patients (21%). Although baseline kidney function and contrast volume were similar in the AKI group and the non-AKI group, the risk score was higher (10 ± 3 vs. 8 ± 3; p = 0.032), and hemodynamic depression (mostly due to hypotension) (65.5% vs. 35%; p = 0.005) was more common in the AKI group. The threshold of hemodynamic depression duration for AKI development was 2.5 min (sensitivity 54%, specificity 82%). Independent predictors of AKI were hemodynamic depression (odds ratio OR: 4.01; 95% confidence interval CI: 1.07 to 15.03; p = 0.009), risk score (OR: 1.29; 95% CI: 1.03 to 1.60; p = 0.024), and male sex (OR: 6.07; 95% CI: 1.18 to 31.08; p = 0.021). Independent predictors of 30-day major adverse events that occurred more often in the AKI group (19.5% vs. 7%; p = 0.058) were AKI (HR: 4.83; 95% CI: 1.10 to 21.24; p = 0.037) and hemodynamic depression (HR: 5.58; 95% CI: 1.10 to 28.31; p = 0.038). Conclusions AKI in CKD patients undergoing CAS is mostly due to hemodynamic depression and is associated with a higher 30-day major adverse events rate.
Bivalirudin demonstrated similar efficacy but resulted in a lower rate of bleeding compared to unfractionated heparin (UFH) plus platelet glycoprotein IIb/IIIa inhibitors in patients undergoing ...percutaneous coronary intervention. It has not been clearly evaluated whether this can also be applied to patients with diabetes mellitus. A total of 335 consecutive patients with diabetes mellitus referred for elective percutaneous coronary intervention were randomized in the Novel Approaches for Preventing or Limiting EventS (NAPLES) trial to receive bivalirudin monotherapy or UFH plus routine tirofiban. The primary composite end point (30-day composite incidence of death, urgent repeat revascularization, myocardial infarction, and all bleeding) was lower in the bivalirudin group than in the UFH plus tirofiban group (18.0% vs 31.5%, odds ratio 0.47, 95% confidence interval 0.28 to 0.79, p = 0.004). No death, urgent revascularization, or Q-wave myocardial infarction occurred. The rate of non–Q-wave myocardial infarction was similar in the 2 groups (10.2% in the bivalirudin group vs 12.5% in the UFH plus tirofiban group, p = 0.606). In contrast, fewer patients in the bivalirudin group experienced bleeding (8.4% vs 20.8%, odds ratio 0.34, 95% confidence interval 0.18 to 0.67, p = 0.002). This difference was mainly ascribed to the lower rate of minor bleeding (7.8% in the bivalirudin group vs 18.5% in the UFH plus tirofiban group, odds ratio 0.37, 95% confidence interval 0.19 to 0.74, p = 0.005), although the rate of major bleeding in the 2 groups was comparable (0.6% vs 2.4%, respectively; p = 0.371). In conclusion, in patients with diabetes mellitus undergoing elective percutaneous coronary intervention, the strategy of bivalirudin monotherapy compared to UFH plus routine tirofiban is safe and feasible and associated with a significant reduction of in-hospital bleeding.
Abstract Objectives This study sought to assess the safety and the efficacy of bivalirudin compared with unfractionated heparin (UFH) alone in the subset of patients at increased risk of bleeding ...undergoing transfemoral elective percutaneous coronary intervention (PCI). Background Bivalirudin, a synthetic direct thrombin inhibitor, determines a significant decrease of in-hospital bleeding following PCI. Methods This is a single-center, investigator-initiated, randomized, double-blind, controlled trial. Consecutive biomarker-negative patients at increased bleeding risk undergoing PCI through the femoral approach were randomized to UFH (UFH group; n = 419) or bivalirudin (bivalirudin group; n = 418). The primary endpoint was the rate of in-hospital major bleeding. Results The primary endpoint occurred in 11 patients (2.6%) in the UFH group versus 14 patients (3.3%) in the bivalirudin group (odds ratio: 0.78; 95% confidence interval: 0.35 to 1.72; p = 0.54). Distribution of access-site and non–access-site bleeding was 18% and 82% in the UFH group versus 50% and 50% in the bivalirudin group (p = 0.10). Conclusions The results of this randomized study, carried out at a single institution, suggest that there is no difference in major bleeding rate between bivalirudin and UFH in increased-risk patients undergoing transfemoral PCI. (Novel Approaches in Preventing and Limiting Events III Trial: Bivalirudin in High-Risk Bleeding Patients NAPLES III; NCT01465503 )
Objectives Atorvastatin administered at least 7 days before the percutaneous coronary intervention (PCI) reduces the rate of periprocedural myocardial infarction (MI). It is unknown whether a single, ...high (80 mg) loading dose of atorvastatin may reduce the rate of periprocedural MI. Background Periprocedural MI is a prognostically important complication of PCI. Methods The day before the elective PCI, 668 statin-naive patients were randomly assigned to atorvastatin 80 mg (atorvastatin group; n = 338) or no statin treatment (control group; n = 330). Creatine kinase-myocardial isoenzyme (CK-MB) (upper limit of normal ULN 3.5 ng/ml) and cardiac troponin I (ULN 0.10 ng/ml) were assessed before and 6 and 12 h after the intervention. Periprocedural MI was defined as a CK-MB elevation >3× ULN alone or associated with chest pain or ST-segment or T-wave abnormalities. Results The incidence of a periprocedural MI was 9.5% in the atorvastatin group and 15.8% in the control group (odds ratio: 0.56; 95% confidence interval: 0.35 to 0.89; p = 0.014). Median CK-MB peak after PCI was 2.10 ng/ml (interquartile range 1.00 to 12.50 ng/ml) in the atorvastatin group and 3.20 ng/ml (interquartile range 1.37 to 16.07 ng/ml) in the control group (p = 0.014). The incidence of cardiac troponin I elevation >3× ULN was 26.6% in the atorvastatin group and 39.1% in the control group (odds ratio: 0.56; 95% confidence interval: 0.40 to 0.78; p < 0.001). Conclusions A single, high (80 mg) loading (within 24 h) dose of atorvastatin reduces the incidence of periprocedural MI in elective PCI.
The RET tyrosine kinase is a functional receptor for neurotrophic ligands of the glial cell line-derived neurotrophic factor (GDNF) family. Loss of function of RET is associated with congenital ...megacolon or Hirschsprung's disease, whereas germ-line point mutations causing RET activation are responsible for multiple endocrine neoplasia type 2 (MEN2A, MEN2B, and familial medullary thyroid carcinoma) syndromes. Here we show that the expression of a constitutively active RET-MEN2A oncogene promotes survival of rat pheochromocytoma PC12 cells upon growth factor withdrawal. Moreover, we show that the RET-MEN2A-mediated survival depends on signals transduced by the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) cascades. Thus, in PC12 cells, RET-MEN2A associates with the PI3K regulatory subunit p85 and promotes activation of Akt (also referred to as protein kinase B) in a PI3K-dependent fashion; in addition, RET-MEN2A promotes MAPK activation. PI3K recruitment and Akt activation as well as MAPK activation depend on RET-MEN2A tyrosine residue 1062. As a result, tyrosine 1062 of RET-MEN2A is essential for RET-MEN2A-mediated survival of PC12 cells cultured in growth factor-depleted media.
The Akt/protein kinase B serine/threonine kinase is a downstream effector of phosphoinositide 3-kinase (PI3K). Akt is an important component of mitogenic and antiapoptotic signaling pathways and is ...implicated in neoplastic transformation. Thyroid cells in culture retain a differentiated phenotype consisting of epithelial cell morphology and the expression of several tissue-specific genes. The survival and proliferation of these cells depend on thyrotropin and a mixture of five additional hormones that includes insulin. The regulation of proliferation and the expression of the thyroid differentiation program are intimately connected processes. As a result, oncogenes that induce hormone-independent proliferation invariably impair the expression of the thyroid-specific differentiation markers. Given that thyrotropin and insulin stimulate Akt activation in thyroid cells, we set out to determine the effects of Akt on thyroid cell proliferation, survival, and differentiation. To this end, we expressed constitutively active myristylated Akt (myrAkt) in PC Cl 3 thyroid cells. The myrAkt-expressing cells continued to proliferate, even in the absence of hormones, and they were resistant to programmed cell death induced by starvation. These effects were paralleled by the induction of the G1 cyclins D3 and E and by the inhibition of induction of the proapoptotic Fas, Fas ligand, and BAD genes in starved cells. However, in marked contrast with several other oncogenes, myrAkt did not interfere with the expression of thyroid differentiation functions. These results unveil the existence of an Akt-triggered thyroid cell pathway that modulates proliferation and survival without affecting the expression of the thyroid cell differentiated phenotype.