Von Willebrand Factor Improves Risk Prediction in Addition to N-Terminal Pro-B-type Natriuretic Peptide in Patients Referred to Coronary Angiography and Signs and Symptoms of Heart Failure and Preserved Ejection Fraction.

BACKGROUND Heart failure with preserved ejection fraction (HFpEF) represents a growing health burden associated with substantial mortality and morbidity. Consequently, risk prediction is of highest importance. Endothelial dysfunction has been recently shown to play an important role in the complex pathophysiology of HFpEF. We therefore aimed to assess von Willebrand factor (vWF), a marker of endothelial damage, as potential biomarker for risk assessment in patients with HFpEF. METHODS AND RESULTS Concentrations of vWF were assessed in 457 patients with HFpEF enrolled as part of the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. All-cause mortality was observed in 40% of patients during a median follow-up time of 9.7 years. vWF significantly predicted mortality with a hazard ratio (HR) per increase of 1 SD of 1.45 (95% confidence interval, 1.26-1.68; P<0.001) and remained a significant predictor after adjustment for age, sex, body mass index, N-terminal pro-B-type natriuretic peptide (NT-proBNP), renal function, and frequent HFpEF-related comorbidities (adjusted HR per 1 SD, 1.22; 95% confidence interval, 1.05-1.42; P=0.001). Most notably, vWF showed additional prognostic value beyond that achievable with NT-proBNP indicated by improvements in C-Statistic (vWF×NT-proBNP: 0.65 versus NT-proBNP: 0.63; P for comparison, 0.004) and category-free net reclassification index (37.6%; P<0.001). CONCLUSIONS vWF is an independent predictor of long-term outcome in patients with HFpEF, which is in line with endothelial dysfunction as potential mediator in the pathophysiology of HFpEF. In particular, combined assessment of vWF and NT-proBNP improved risk prediction in this vulnerable group of patients.

Impact of mitral regurgitation on clinical outcomes of patients with low-ejection fraction, low-gradient severe aortic stenosis undergoing transcatheter aortic valve implantation.

BACKGROUND Up to 1 in 6 patients undergoing transcatheter aortic valve implantation (TAVI) present with low-ejection fraction, low-gradient (LEF-LG) severe aortic stenosis and concomitant relevant mitral regurgitation (MR) is present in 30% to 55% of these patients. The effect of MR on clinical outcomes of LEF-LG patients undergoing TAVI is unknown. METHODS AND RESULTS Of 606 consecutive patients undergoing TAVI, 113 (18.7%) patients with LEF-LG severe aortic stenosis (mean gradient ≤40 mm Hg, aortic valve area <1.0 cm(2), left ventricular ejection fraction <50%) were analyzed. LEF-LG patients were dichotomized into ≤mild MR (n=52) and ≥moderate MR (n=61). Primary end point was all-cause mortality at 1 year. No differences in mortality were observed at 30 days (P=0.76). At 1 year, LEF-LG patients with ≥moderate MR had an adjusted 3-fold higher rate of all-cause mortality (11.5% versus 38.1%; adjusted hazard ratio, 3.27 [95% confidence interval, 1.31-8.15]; P=0.011), as compared with LEF-LG patients with ≤mild MR. Mortality was mainly driven by cardiac death (adjusted hazard ratio, 4.62; P=0.005). As compared with LEF-LG patients with ≥moderate MR assigned to medical therapy, LEF-LG patients with ≥moderate MR undergoing TAVI had significantly lower all-cause mortality (hazard ratio, 0.38; 95% confidence interval, 0.019-0.75) at 1 year. CONCLUSIONS Moderate or severe MR is a strong independent predictor of late mortality in LEF-LG patients undergoing TAVI. However, LEF-LG patients assigned to medical therapy have a dismal prognosis independent of MR severity suggesting that TAVI should not be withheld from symptomatic patients with LEF-LG severe aortic stenosis even in the presence of moderate or severe MR.

Seasonal variation of high-molecular-weight compounds in the water-soluble fraction of organic urban aerosols

Aerosol samples were collected in Zurich, Switzerland, at an urban background site and were analyzed with size exclusion chromatography (SEC) and laser/desorption ionization mass spectrometry (LDI-MS) for water-soluble organic compounds with high molecular weight. Daily samples were collected during two campaigns in winter and summer, for 1 month each. The concentration of high-molecular-weight compounds (humic-like substances (HULIS)) was between 0.4 and 4 μg/m3 in winter and summer. The most intense signals in the LDI-MS mass spectra were measured between m/z150 and 500, comparing well with the mode of the two main high mass peaks determined with SEC corresponding to masses between 200 and 600 Da. For the maximum molecular weight, however, different results were obtained by the two techniques: whereas a maximum molecular weight between 1300 and 3300 Da was found with SEC, hardly any peaks above m/z700 were measured with LDI-MS. During summer the maximum molecular weight of HULIS (determined with SEC) correlates positively with several parameters such as ozone and increased temperature indicative of enhanced atmospheric photo-oxidation. The HULIS concentration also correlates positively with the oxalic acid concentration in the particles. This suggests that HULIS are generated by secondary processes in summer. The lack of such correlations during winter suggests that other sources and processes might be important during colder seasons.

Das Ministerium Brandenburg und die Fraction Unruh, und Eiserner Bestand an Regierungs-Rechten, ohne welche ein Staat überhaupt nicht lebensfähig ist

Boberach: Weil Völker nicht selten an ihren politischen Ideen zugrundegehen, war auch Preußen durch die Politik der Linken bedroht und das Ministerium hat die dem Staat gebührenden Regierungsfunktionen mit Recht in Anspruch genommen

Hepatocellular Carcinoma Screening With Computed Tomography Using the Arterial Enhancement Fraction With Radiologic-Pathologic Correlation.

OBJECTIVE The aim of this study was to investigate the performance of the arterial enhancement fraction (AEF) in multiphasic computed tomography (CT) acquisitions to detect hepatocellular carcinoma (HCC) in liver transplant recipients in correlation with the pathologic analysis of the corresponding liver explants. MATERIALS AND METHODS Fifty-five transplant recipients were analyzed: 35 patients with 108 histologically proven HCC lesions and 20 patients with end-stage liver disease without HCC. Six radiologists looked at the triphasic CT acquisitions with the AEF maps in a first readout. For the second readout without the AEF maps, 3 radiologists analyzed triphasic CT acquisitions (group 1), whereas the other 3 readers had 4 contrast acquisitions available (group 2). A jackknife free-response reader receiver operating characteristic analysis was used to compare the readout performance of the readers. Receiver operating characteristic analysis was used to determine the optimal cutoff value of the AEF. RESULTS The figure of merit (θ = 0.6935) for the conventional triphasic readout was significantly inferior compared with the triphasic readout with additional use of the AEF (θ = 0.7478, P < 0.0001) in group 1. There was no significant difference between the fourphasic conventional readout (θ = 0.7569) and the triphasic readout (θ = 0.7615, P = 0.7541) with the AEF in group 2. Without the AEF, HCC lesions were detected with a sensitivity of 30.7% (95% confidence interval [CI], 25.5%-36.4%) and a specificity of 97.1% (96.0%-98.0%) by group 1 looking at 3 CT acquisition phases and with a sensitivity of 42.1% (36.2%-48.1%) and a specificity of 97.5% (96.4%-98.3%) in group 2 looking at 4 CT acquisition phases. Using the AEF maps, both groups looking at the same 3 acquisition phases, the sensitivity was 47.7% (95% CI, 41.9%-53.5%) with a specificity of 97.4% (96.4%-98.3%) in group 1 and 49.8% (95% CI, 43.9%-55.8%)/97.6% (96.6%-98.4%) in group 2. The optimal cutoff for the AEF was 50%. CONCLUSION The AEF is a helpful tool to screen for HCC with CT. The use of the AEF maps may significantly improve HCC detection, which allows omitting the fourth CT acquisition phase and thus making a 25% reduction of radiation dose possible.

Inhalation anesthesia of rats: influence of the fraction of inspired oxygen on limb ischemia/reperfusion injury

Inhalation anesthesia with isoflurane is a well-established and safe method used in small laboratory animals. In most cases oxygen is used as a carrier gas for isoflurane, but room air or mixtures of oxygen with air or nitrous oxide are also being used. Anesthesia is therefore administered using different fractions of inspired oxygen (FiO2), and this may have consequences for the outcome of experiments. The aim of the present study was to investigate the influence of FiO2 on rat hind limb ischemia/reperfusion injury and to refine the used inhalation anesthesia. Male Wistar rats were subjected to 3.5 h of ischemia and 2 h of reperfusion, and divided into three groups according to FiO2 in the O2/air/isoflurane anesthesia gas mixture: 40%, 60%, and 100% O2. Normal, healthy rats were used as controls. Muscle edema and creatine kinase MM, a marker for myocyte necrosis, were significantly increased with 40% FiO2 as compared with 100% FiO2 (P<0.05). Partial pressure of oxygen, oxygen saturation, and oxyhemoglobin were significantly higher in the 100% O2 group as compared with 40% O2. No significant differences were detected for other parameters, such as the oxidative stress markers malondialdehyde and superoxide dismutase. We conclude that a refined inhalation anesthesia setting using 40% FiO2, reflecting more or less the clinical situation, leads to a more severe and more physiologically relevant reperfusion injury than higher FiO2. Oxidative stress did not correlate with FiO2 and seemed to have no influence on reperfusion injury.

Fibroblast Growth Factor 23 Is an Independent and Specific Predictor of Mortality in Patients With Heart Failure and Reduced Ejection Fraction

BACKGROUND Strategies to improve risk prediction are of major importance in patients with heart failure (HF). Fibroblast growth factor 23 (FGF-23) is an endocrine regulator of phosphate and vitamin D homeostasis associated with an increased cardiovascular risk. We aimed to assess the prognostic effect of FGF-23 on mortality in HF patients with a particular focus on differences between patients with HF with preserved ejection fraction and patients with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS FGF-23 levels were measured in 980 patients with HF enrolled in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study including 511 patients with HFrEF and 469 patients with HF with preserved ejection fraction and a median follow-up time of 8.6 years. FGF-23 was additionally measured in a second cohort comprising 320 patients with advanced HFrEF. FGF-23 was independently associated with mortality with an adjusted hazard ratio per 1-SD increase of 1.30 (95% confidence interval, 1.14-1.48; P<0.001) in patients with HFrEF, whereas no such association was found in patients with HF with preserved ejection fraction (for interaction, P=0.043). External validation confirmed the significant association with mortality with an adjusted hazard ratio per 1 SD of 1.23 (95% confidence interval, 1.02-1.60; P=0.027). FGF-23 demonstrated an increased discriminatory power for mortality in addition to N-terminal pro-B-type natriuretic peptide (C-statistic: 0.59 versus 0.63) and an improvement in net reclassification index (39.6%; P<0.001). CONCLUSIONS FGF-23 is independently associated with an increased risk of mortality in patients with HFrEF but not in those with HF with preserved ejection fraction, suggesting a different pathophysiologic role for both entities.

Continued Fraction Solutions to Hermite's, Legendre's and Laguerre's Differential Equation

The continued fraction method for solving differential equations is illustrated using three famous differential equations used in quantum chemistry.

Secondary left ventricular ejection fraction response to beta blocker therapy in heart failure patients

Chronic β-blocker treatment improves survival and left ventricular ejection fraction (LVEF) in patients with systolic heart failure (HF). Data on whether the improvement in LVEF after β-blocker therapy is sustained for a long term or whether there is a loss in LVEF after an initial gain is not known. Our study sought to determine the prevalence and prognostic role of secondary decline in LVEF in chronic systolic HF patients on β-blocker therapy and characterize these patients. Retrospective chart review of HF hospitalizations fulfilling Framingham Criteria was performed at the MEDVAMC between April 2000 and June 2006. Follow up vital status and recurrent hospitalizations were ascertained until May 2010. Three groups of patients were identified based on LVEF response to beta blockers; group A with secondary decline in LVEF following an initial increase, group B with progressive increase in LVEF and group C with progressive decline in LVEF. Covariate adjusted Cox proportional hazard models were used to examine differences in heart failure re-hospitalizations and all cause mortality between the groups. Twenty five percent (n=27) of patients had a secondary decline in LVEF following an initial gain. The baseline, peak and final LVEF in this group were 27.6±12%, 40.1±14% and 27.4±13% respectively. The mean nadir LVEF after decline was 27.4±13% and this decline occurred at a mean interval of 2.8±1.9 years from the day of beta blocker initiation. These patients were older, more likely to be whites, had advanced heart failure (NYHA class III/IV) more due to a non ischemic etiology compared to groups B & C. They were also more likely to be treated with metoprolol (p=0.03) compared to the other two groups. No significant differences were observed in combined risk of all cause mortality and HF re-hospitalization [hazard ratio 0.80, 95% CI 0.47 to 1.38, p=0.42]. No significant difference was observed in survival estimates between the groups. In conclusion, a late decline in LVEF does occur in a significant proportion of heart failure patients treated with beta blockers, more so in patients treated with metoprolol.^

Racial differences in heart failure with preserved ejection fraction in the ambulatory heart failure population

Racial differences in heart failure with preserved ejection fraction (HFpEF) have rarely been studied in an ambulatory, financially "equal access" cohort, although the majority of such patients are treated as outpatients. ^ Retrospective data was collected from 2,526 patients (2,240 Whites, 286 African American) with HFpEF treated at 153 VA clinics, as part of the VA External Peer Review Program (EPRP) between October 2000 and September 2002. Kaplan Meier curves (stratified by race) were created for time to first heart failure (HF) hospitalization, all cause hospitalization and death and Cox proportional multivariate regression models were constructed to evaluate the effect of race on these outcomes. ^ African American patients were younger (67.7 ± 11.3 vs. 71.2 ± 9.8 years; p < 0.001), had lower prevalence of atrial fibrillation (24.5 % vs. 37%; p <0.001), chronic obstructive pulmonary disease (23.4 % vs. 36.9%, p <0.001), but had higher blood pressure (systolic blood pressure > 120 mm Hg 77.6% vs. 67.8%; p < 0.01), glomerular filtration rate (67.9 ± 31.0 vs. 61.6 ± 22.6 mL/min/1.73 m2; p < 0.001), anemia (56.6% vs. 41.7%; p <0.001) as compared to whites. African Americans were found to have higher risk adjusted rate of HF hospitalization (HR 1.52, 95% CI 1.1 - 2.11; p = 0.01), with no difference in risk-adjusted all cause hospitalization (p = 0.80) and death (p= 0.21). ^ In a financially "equal access" setting of the VA, among ambulatory patients with HFpEF, African Americans have similar rates of mortality and all cause hospitalization but have an increased risk of HF hospitalizations compared to whites.^