Simplified Rapid Hydration Prevents Contrast-Associated Acute Kidney Injury Among CKD Patients Undergoing Coronary Angiography.

BACKGROUND: Patients with chronic kidney disease (CKD) undergoing coronary angiography (CAG) are at high risk of contrast-associated acute kidney injury (CA-AKI) and mortality. Therefore, there is a clinical need to explore safe, convenient, and effective strategies for preventing CA-AKI. OBJECTIVES: This study sought to assess whether simplified rapid hydration is noninferior to standard hydration for CA-AKI prevention in patients with CKD. METHODS: This multicenter, open-label, randomized controlled study was conducted across 21 teaching hospitals and included 1,002 patients with CKD. Patients were randomized to either simplified hydration (SH) (SH group, with normal saline from 1 hour before to 4 hours after CAG at a rate of 3 mL/kg/h) or standard hydration (control group, with normal saline 12 hours before and 12 hours after CAG at a rate of 1 mL/kg/h). The primary endpoint of CA-AKI was a ≥25% or 0.5-mg/dL rise in serum creatinine from baseline within 48 to 72 hours. RESULTS: CA-AKI occurred in 29 of 466 (6.2%) patients in the SH group and in 38 of 455 (8.4%) patients in the control group (relative risk: 0.8; 95% CI: 0.5-1.2; P = 0.216). In addition, the risk of acute heart failure and 1-year major adverse cardiovascular events did not differ significantly between the groups. However, the median hydration duration was significantly shorter in the SH group than in the control group (6 vs 25 hours; P < 0.001). CONCLUSIONS: In CKD patients undergoing CAG, SH is noninferior to standard hydration in preventing CA-AKI with a shorter hydration duration.

A reliable and high throughput HPLC-HRMS method for the rapid screening of ß-thalassemia and hemoglobinopathy in dried blood spots.

OBJECTIVES: Traditional methods for ß-thalassemia screening usually rely on the structural integrity of hemoglobin (Hb), which can be affected by the hemolysis of red blood cells and Hb degradation. Here, we aim to develop a reliable and high throughput method for rapid detection of ß-thalassemia using dried blood spots (DBS). METHODS: Hb components were extracted from a disc (3.2 mm diameter) punched from the DBS samples and digested by trypsin to produce a series of Hb-specific peptides. An analytical system combining high-resolution mass spectrometry and high-performance liquid chromatography was used for biomarker selection. The selected marker peptides were used to calculate delta/beta (δ/ß) and beta-mutated/beta (ßM/ß) globin ratios for disease evaluation. RESULTS: Totally, 699 patients and 629 normal individuals, aged 3 days to 89 years, were recruited for method construction. Method assessment showed both the inter-assay and intra-assay relative standard deviation values were less than 10.8%, and the limits of quantitation for the proteo-specific peptides were quite low (1.0-5.0 µg/L). No appreciable matrix effects or carryover rates were observed. The extraction recoveries ranged from 93.8 to 128.7%, and the method was shown to be stable even when the samples were stored for 24 days. Prospective applications of this method in 909 participants also indicated good performance with a sensitivity of 100% and a specificity of 99.6%. CONCLUSIONS: We have developed a fast, high throughput and reliable method for screening of ß-thalassemia and hemoglobinopathy in children and adults, which is expected to be used as a first-line screening assay.

Efficacy and Safety of Sacubitril/Valsartan Therapy for Acute Decompensated Heart Failure with Reduced Ejection Fraction during the Vulnerable Phase: A Multicenter, Assessor-Blinded, Prospective, Observational, Cohort Study.

BACKGROUND: The 3-month period after hospitalization for acute cardiac failure is a vulnerable phase with the highest risk of mortality and rehospitalization. Safety and efficacy of early initiation of sacubitril/valsartan during the index hospitalization for acute decompensated heart failure (ADHF) is unclear. Therefore, we tested whether sacubitril/valsartan could result in a lower rate of a composite outcome of first hospitalization for heart failure and death from cardiovascular causes compared to inhibition of the renin-angiotensin system alone. METHODS: We enrolled patients hospitalized for ADHF and reduced ejection fraction at 4 sites; patients were divided into a sacubitril/valsartan group or an angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) group. All patients were followed up for 3 months after discharge. The primary endpoint was outcomes as a composite of death from cardiovascular causes and rehospitalization for heart failure. RESULTS: In total, 251 patients who received sacubitril/valsartan and 251 patients who received ACEIs/ARBs had similar propensity scores and were included and compared. The primary endpoint was reached in 40 patients (15.9%) treated with sacubitril/valsartan and in 59 patients (23.5%) managed by ACEI/ARB (HR, 0.650; 95% CI: 0.435-0.971; p = 0.035). The NYHA class improved in 72.1% of patients in the sacubitril/valsartan group and in 59.8% of patients in the ACEI/ARB group (HR, 1.303; 95% CI: 1.097-1.548, p = 0.004). The key safety outcomes endpoints did not significantly differ. CONCLUSIONS: Among patients hospitalized with ADHF and reduced left ventricular ejection fraction, we observed that sacubitril/valsartan therapy led to reduction in death from cardiovascular causes and rehospitalizations for heart failure when compared to ACEI/ARB therapy alone during the vulnerable phase. Our results support that sacubitril/valsartan may be administered early in the vulnerable phase after ADHF and improves NYHA class.

Effects of a High Dose of the Contrast Medium Iodixanol on Renal Function in Patients Following Percutaneous Coronary Intervention.

Iodixanol is associated with lower rates of contrast-induced acute kidney injury (CI-AKI). However, the effects of high volumes of iodixanol on renal function after percutaneous coronary intervention (PCI) have not been fully elucidated. This study evaluates the effects of high-dose (>300 mL) iodixanol on renal function within 72 hours of PCI. We retrospectively reviewed 676 consecutive patients who received high-dose (>300 mL) iodixanol during PCI between October 2015 and December 2017 in 4 centers. Logistic regression analysis was used to identify significant independent predictors for CI-AKI. The incidence of CI-AKI was 3.5% (23/651). In patients administered 300 to 500 mL and >500 mL iodixanol, the incidence of CI-AKI was 3.9% and 1.7%, respectively. In patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, the incidence of CI-AKI was 2.6%. In high-risk and very high-risk patients, stratified by the Mehran risk score, the incidence of CI-AKI was 3.3% and 4.3%, respectively. In patients received high-dose iodixanol (>300 mL), logistic regression analysis demonstrated that female sex, chronic kidney disease, and eGFR were independent risk factors for CI-AKI, but contrast volume was not. The administration of high (300-500 mL) and very high (>500 mL) dose of iodixanol is associated with low rates of CI-AKI.

Quality of life and outcomes in heart failure patients with ejection fractions in different ranges.

AIMS: Guidelines divide patients with heart failure (HF) into 3 distinct groups based on left ventricular ejection fraction (LVEF) We used the Minnesota Living with Heart Failure Questionnaire (MLHFQ) to quantify the health-related quality of life in patients with HF. METHODS: Patients were stratified into three cohorts: preserved LVEF (>50%), mid-range LVEF (40-49%) and reduced LVEF (<40%). The MLHFQ scores were evaluated using one-way ANOVA, and differences were observed among the groups. The association of New York Heart Association (NYHA) class with the physical scores was analyzed by Spearman's correlation analysis. The predictive utility of the total MLHFQ scores was assessed with Kaplan-Meier curves for death and HF-related hospitalization. The Cox proportional hazards model was used to identify the risk factors for prognosis. Internal reliability was assessed with Cronbach's α. RESULTS: There were significant differences in the total MLHFQ scores and the MLHFQ subscale scores among the three groups (p<0.05). MLHFQ domains demonstrated high internal consistency among the three groups (Cronbach's α = 0.92, 0.96 and 0.93). The MLHFQ physical subscale scores were significantly associated with NYHA class in HFrEF (r = 0.59, p<0.001) and HFmrEF patients (r = 0.537, p<0.001). The survival analysis indicated that there was a significant difference among the three groups regarding high MLHFQ scores (p = 0.038). In the groups with low MLHFQ scores, the HFmrEF group exhibited significantly increased rates of death and HF-related hospitalization compared with the HFpEF group (p = 0.035). CONCLUSIONS: The features and clinical outcomes varied among heart failure patients with different EF values. The MLHFQ appears to be a valid and reliable measurement of health status and offers excellent prognostic ability.

The Role of Oxygen Therapy in Normoxemic Acute Coronary Syndrome: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: Supplemental oxygen has been commonly used in the cases of acute coronary syndrome (ACS); however, recent evidence suggests that high-concentration oxygen supplementation and hyperbaric oxygen in ACS patients are associated with adverse cardiovascular effects. OBJECTIVE: The purpose of this article is to systematically review the role of supplemental oxygen therapy in normoxemic patients with ACS. METHODS: A search for randomized controlled trials before November 2017 in biomedical databases was performed, and a total of 6 eligible studies with 7508 participants were identified. Four studies reported all-cause mortality after randomization, whereas 3 studies measured myocardial infarct size using cardiac enzyme levels and magnetic resonance imaging. The effect size of our primary end point was the odds ratio for all-cause mortality. The mean difference was calculated as a secondary outcome for myocardial infarct size. RESULTS: Compared with ambient air or titrated oxygen, high-concentration oxygen therapy did not significantly decrease all-cause mortality (odds ratio, 1.01; 95% confidence interval [CI], 0.81-1.25; P = .95) within 1 year nor infarct size detected by peak cardiac troponin (mean difference, -0.53 ng/mL; 95% CI, -1.20 to 0.14; P = .12) and magnetic resonance imaging (mean difference, 1.45 g; 95% CI, -1.82 to 4.73; P = .39). These outcomes were listed through a fixed-effects model because of low statistical heterogeneity across the studies. CONCLUSIONS: Oxygen therapy did not significantly reduce clinical all-cause mortality and myocardial infarct size in ACS patients with normoxemia. Further large-scale randomized clinical trials are warranted to evaluate the cardiovascular effects in this field.

Time-specific blockade of PDGFR with Imatinib (Glivec®) causes cataract and disruption of lens fiber cells in neonatal mice.

This study aimed at investigating the response of lens epithelial cells in postnatal mice to Imatinib (Glivec®, a potent inhibitor of platelet-derived growth factor receptor (PDGFR)) treatment. Mouse eyes were sampled 10 days after administration of Imatinib (0.5 mg·g(-1)·day(-1)) for 3 days, at either 7, 14, or 21 days postpartum. Structural changes of lens were revealed by routine H.E. staining. Levels of proliferation and apoptosis were revealed by BrdU incorporation and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, respectively, and immunofluorescent staining with anti-PDGFRα antibody was carried out on the sections of eyeball. PDGFRα and p-PDGFRαprotein levels were evaluated by Western blot. Our results indicated that administration of Imatinib led to blockade of PDGFR signaling. Formation of cataracts was found only in those mice where treatment started from 7 days postpartum (P7), but was not observed in those samples from P14 nor P21. Fiber cells were disorganized in cataract lens core as observed histologically, and migration of epithelial cells was also inhibited. No apoptosis was detected with the TUNEL method. Our results indicated blockade of PDGFR at the neonatal stage (P7) would lead to cataracts and lens fiber cells disorganization, suggesting that PDGFR signaling plays a time-specific and crucial role in the postnatal development of lens in the mouse, and also may provide a new approach to produce a congenital cataract animal model.

Postnatal development of interstitial cells of Cajal in mouse colon in response to Kit signal blockade with Imatinib (Glivec).

This study investigated the response of interstitial cells of Cajal (ICC) in postnatal mouse colon to treatment with Imatinib (Glivec), a potent inhibitor of Kit receptor). ICC were revealed by immunofluorescent staining on frozen cross-sections and whole-mount preparations by anti-Kit and DOG1 antibodies. Kit and p-Kit protein were also evaluated by Western blot. After administration of Imatinib for 4 days beginning at 8 days post-partum (P8), the mean density of Kit+ ICC, which were localized around the myenteric nerve plexus (ICC-MY), within smooth muscle layers (ICC-IM) and in the connective tissue beneath the serosa (ICC-SS), was dramatically decreased to about 50% when compared with controls, but those Kit+ cells located at the submucosal border of circular smooth muscle layer (ICC-SM) seemed to be unchanged in both cell number and morphology. A small number of DOG1+/Kit(-) cells appeared during Imatinib administration. However, these Kit+ ICC were not changed in mice even after 12 days of Imatinib treatment from P24. When Imatinib was discontinued, the number of ICC recovered to normal within 4 days. Our results indicate that the postnatal development of ICC in the mouse colon is Kit dependent, but ICC-SM are unlikely, and the Kit dependence of ICC development is also age-dependent.

[Association among circulating endothelial progenitor cells, insulin resistance and severity of coronary lesions in patients with coronary artery disease].

OBJECTIVE: To investigate the correlation between the number and activity of circulating endothelial progenitor cells (EPCs), insulin resistance and severity of coronary lesions in patients with coronary artery disease (CAD). METHODS: Patients with coronary angiography evidenced CAD were divided in insulin resistance group (IR, n = 25) and insulin sensitive group (IS, n = 44) according to insulin level, 25 health volunteers served as control. Circulating EPCs were marked as KDR/CD133+ cells via fluorescence-activated cell sorter analysis. EPCs were also isolated from peripheral blood and cultured in vitro for 7 days, identified by DiI-acLDL uptake and lectin staining methods. EPCs migration activities were determined by modified Boyden chamber assay, EPCs proliferation activities were determined by MTT assay. RESULT: Circulating EPCs number was significantly lower in IR group compared with IS group [(0.34 +/- 0.08) per thousand vs. (0.47 +/- 0.09) per thousand, P < 0.01] and control group (P < 0.05). Both insulin resistance index (r = -0.291, P = 0.01)and Gensini score (r = -0.3984, P = 0.006)were negatively correlated with number of circulating EPCs. Proliferation and migration capacities of EPCs were also significantly lower in IR group compared to those in IS group (all P < 0.05) and control group (all P < 0.05). CONCLUSIONS: Insulin resistance/hyperinsulinemia could aggravate severity of coronary artery lesions via reducing the number and activities of circulating EPCs in patients with CAD.

Autologous endothelial progenitor cells transplantation promoting endothelial recovery in mice.

Transplantation of endothelial progenitor cells (EPCs) restores endothelial function. The present study was designed to determine the effect of autologous EPCs transplantation on the regeneration of endothelium in mice. Mice splenectomy was performed 14 days before carotid artery injury, and mononuclear cells were isolated and cultured in endothelial growth media for 7 days. EPCs were confirmed by immunostaining (CD31, endothelial nitric oxide synthase (eNOS) and double positive for 1,1'dioctadecyl-3,3,3',3-tetramethylindocarbocyanine (DiI)-low-density lipoprotein and ulex europaeus agglutinin (UEA)). Cell counts and fluorescence-activated cell sorting for stem cell marker were performed. 1 x 10(6) 4-,6-Diamidino-2-phenylindole- labeled EPCs or saline were injected through tail vein after wire injury. Two weeks after transplantation, cell tracking and immunohistochemical staining showed homing and incorporation of labeled EPCs in injury artery. Administration of EPCs enhanced reendothelialization (P < 0.05) after 1 week and inhibition of neointima formation at 3 weeks compared with that of saline (P < 0.05, n = 6). These data demonstrate that delivery of autologous EPCs is associated with accelerated reendothelialization and reduced neointimal formation. Thus, delivery of autologous EPCs represents an important vasculoprotective approach to attenuate the response to acute vascular injury.

[The role of cyclooxygenase on angiogenesis and endothelial progenitor cell mobilization in rat ischemic myocardium].

OBJECTIVE: To investigate the effect of COX1 and COX2 on angiogenesis and endothelial progenitor cell mobilization in rats with experimental myocardial infarction (MI). METHODS: The rats were randomly divided into 3 groups: MI group, MI plus rofecoxib group and MI plus valeryl salicylate group. At the 7th day after operation, circulating EPCs, plasma VEGF and HIF-1alpha mRNA of ischemic myocardium were measured. At the 28th day post operation, capillary densities were also measured in ischemic myocardium. RESULT: Compared with the MI group and the MI plus valeryl salicylate group, circulating EPCs, plasma VEGF, HIF-1alpha mRNA and capillary densities of ischemic myocardium were all decreased in MI plus rofecoxib group. CONCLUSION: The present study revealed that COX2 play an important role with angiogenesis and endothelial progenitor cell mobilization in rat with experimental MI by modulating expression of VEGF and HIF-1alpha.

[Sirolimus inhibits the differentiation, proliferation and migration of endothelial progenitor cells in vitro].

OBJECTIVE: To investigate the effect of sirolimus on differentiation, proliferation, adhesion and migration of endothelial progenitor cells (EPC) in vitro. METHODS: (1) Mononuclear cells (MNC) were isolated from rat bone marrow by Ficoll density gradient centrifugation and cultured on fibronectin-coated culture dishes with or without sirolimus (0.01 - 100 ng/ml) for 12 days. (2) After 8 days cultured, attached cells were treated with sirolimus (0.1 - 200 ng/ml) or vehicle for various time points (12 h, 24 h, 48 h and 96 h). EPC were identified as adherent cells double positive stained for FITC-UEA-I and DiI-acLDL under laser confocal immunofluence microscope. EPC proliferation, migration were assayed with MTT assay and modified Boyden chamber assay respectively. RESULTS: EPC number differentiated from MNC at 12 days was significantly lower in sirolimus treated cells in a dose-dependent manner than that of vehicle-treated cells. Sirolimus also significantly inhibited the proliferative, migratory and adhesive capacity of EPC in a time and dose dependent manner. CONCLUSION: Present results suggested that sirolimus could inhibit EPC differentiation from MNC and reduce the proliferation, migration and adhesion capacities of EPC.