530 research outputs found

    Biomarker-Guided Versus Guideline-Based Treatment of Patients With Heart Failure:Results From BIOSTAT-CHF

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    BACKGROUND: Heart failure guidelines recommend up-titration of angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) to doses used in randomized clinical trials, but these recommended doses are often not reached. Up-titration may, however, not be necessary in all patients. OBJECTIVES: This study sought to establish the role of blood biomarkers to determine which patients should or should not be up-titrated. METHODS: Clinical outcomes of 2,516 patients with worsening heart failure from the BIOSTAT-CHF (BIOlogy Study to Tailored Treatment in Chronic Heart Failure) were compared between 3 theoretical treatment scenarios: scenario A, in which all patients are up-titrated to >50% of recommended doses; scenario B, in which patients are up-titrated according to a biomarker-based treatment selection model; and scenario C, in which no patient is up-titrated to >50% of recommended doses. The study conducted multivariable Cox regression using 161 biomarkers and their interaction with treatment, weighted for treatment-indication bias to estimate the expected number of deaths or heart failure hospitalizations at 24 months for all 3 scenarios. RESULTS: Estimated death or hospitalization rates in 1,802 patients with available (bio)markers were 16%, 16%, and 26%, respectively, in the ACE inhibitor/ARB up-titration scenarios A, B, and C. Similar rates for beta-blocker and MRA up-titration scenarios A, B, and C were 23%, 19%, and 24%, and 12%, 11%, and 24%, respectively. If up-titration was successful in all patients, an estimated 9.8, 1.3, and 12.3 events per 100 treated patients could be prevented at 24 months by ACE inhibitor/ARB, beta-blocker, and MRA therapy, respectively.Similar numbers were 9.9, 4.7, and 13.1 if up-titration treatment decision was based on a biomarker-based treatment selection model. CONCLUSIONS: Up-titrating patients with heart failure based on biomarker values might have resulted in fewer deaths or hospitalizations compared with a hypothetical scenario in which all patients were successfully up-titrated

    Assessment of Proximal Tubular Function by Tubular Maximum Phosphate Reabsorption Capacity in Heart Failure

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    BACKGROUND AND OBJECTIVES: The estimated glomerular filtration rate (eGFR) is a crucial parameter in heart failure. Much less is known about the importance of tubular function. We addressed the effect of tubular maximum phosphate reabsorption capacity (TmP/GFR), a parameter of proximal tubular function, in patients with heart failure.DESIGN, SETTING, PARTICIPANTS, &amp; MEASUREMENTS: We established TmP/GFR (Bijvoet formula) in 2085 patients with heart failure and studied its association with deterioration of kidney function (&gt;25% eGFR decrease from baseline) and plasma neutrophil gelatinase-associated lipocalin (NGAL) doubling (baseline to 9 months) using logistic regression analysis and clinical outcomes using Cox proportional hazards regression. Additionally, we evaluated the effect of sodium-glucose transport protein 2 (SGLT2) inhibition by empagliflozin on tubular maximum phosphate reabsorption capacity in 78 patients with acute heart failure using analysis of covariance.RESULTS: Low TmP/GFR (&lt;0.80 mmol/L) was observed in 1392 (67%) and 21 (27%) patients. Patients with lower TmP/GFR had more advanced heart failure, lower eGFR, and higher levels of tubular damage markers. The main determinant of lower TmP/GFR was higher fractional excretion of urea (P&lt;0.001). Lower TmP/GFR was independently associated with higher risk of plasma NGAL doubling (odds ratio, 2.20; 95% confidence interval, 1.05 to 4.66; P=0.04) but not with deterioration of kidney function. Lower TmP/GFR was associated with higher risk of all-cause mortality (hazard ratio, 2.80; 95% confidence interval, 1.37 to 5.73; P=0.005), heart failure hospitalization (hazard ratio, 2.29; 95% confidence interval, 1.08 to 4.88; P=0.03), and their combination (hazard ratio, 1.89; 95% confidence interval, 1.07 to 3.36; P=0.03) after multivariable adjustment. Empagliflozin significantly increased TmP/GFR compared with placebo after 1 day (P=0.004) but not after adjustment for eGFR change.CONCLUSIONS: TmP/GFR, a measure of proximal tubular function, is frequently reduced in heart failure, especially in patients with more advanced heart failure. Lower TmP/GFR is furthermore associated with future risk of plasma NGAL doubling and worse clinical outcomes, independent of glomerular function.</p

    Biomarker changes as surrogate endpoints in early-phase trials in heart failure with reduced ejection fraction

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    Aims: No biomarker has achieved widespread acceptance as a surrogate endpoint for early‐phase heart failure (HF) trials. We assessed whether changes over time in a panel of plasma biomarkers were associated with subsequent morbidity/mortality in HF with reduced ejection fraction (HFrEF). Methods and results: In 1040 patients with HFrEF from the BIOSTAT‐CHF cohort, we investigated the associations between changes in the plasma concentrations of 30 biomarkers, before (baseline) and after (9 months) attempted optimization of guideline‐recommended therapy, on top of the BIOSTAT risk score and the subsequent risk of HF hospitalization/all‐cause mortality using Cox regression models. C‐statistics were calculated to assess discriminatory power of biomarker changes/month‐nine assessment. Changes in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and WAP four‐disulphide core domain protein HE4 (WAP‐4C) were the only independent predictors of the outcome after adjusting for their baseline plasma concentration, 28 other biomarkers (both baseline and changes), and BIOSTAT risk score at baseline. When adjusting for month‐nine rather than baseline biomarkers concentrations, only changes in NT‐proBNP were independently associated with the outcome. The C‐statistic of the model including the BIOSTAT risk score and NT‐proBNP increased by 4% when changes were considered on top of baseline concentrations and by 1% when changes in NT‐proBNP were considered on top of its month‐nine concentrations and the BIOSTAT risk score. Conclusions: Among 30 relevant biomarkers, a change over time was significantly and independently associated with HF hospitalization/all‐cause death only for NT‐proBNP. Changes over time were modestly more prognostic than baseline or end‐values alone. Changes in biomarkers should be further explored as potential surrogate endpoints in early phase HF trials

    Association with outcomes and response to treatment of trimethylamine N-oxide in heart failure (from BIOSTAT-CHF)

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    Aims: Association of elevated circulating levels of trimethylamine N-oxide (TMAO) with adverse outcomes in patients with heart failure (HF) has been described. However, response of TMAO levels to treatment and medications has not been investigated. Therefore, we investigated whether TMAO levels are responsive to guideline-recommended treatment and medications, and further reflect changes in outcomes. Methods and Results: TMAO levels were investigated in the systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF), which addressed response to guideline-recommended pharmacological treatment. TMAO levels in 2,234 patients with new-onset or progressively worsening HF showed strong associations with adverse events (mortality and /or rehospitalisation) at 1,2 and 3 years (HR 1.37–1.51, p≀0.019). Analysis of 972 patients with plasma available at both enrolment and follow-up visit showed reductions of B-type natriuretic peptide levels with guideline-based treatment (p&lt;0.001), but not for TMAO levels. Moreover, patients with higher TMAO levels than median before and after treatment showed increased association with adverse outcomes (HR 2.21, 95% CI: 1.43-3.43, p&lt;0.001) compared to patients with lower than median levels either before or after treatment (HR 1.13, 95% CI: 0.63-2.04, p=0.684 and HR 1.14, 95% CI: 0.64-2.03, p=0.662, respectively). Conclusion: TMAO levels were associated with adverse outcomes (mortality and/or rehospitalisation) in BIOSTAT-CHF, and did not respond to guideline-based pharmaceutical treatment in contrast to BNP levels which did as expected. Lower TMAO levels regardless of treatment were associated with favorable outcome

    Coronary angiography in worsening heart failure:determinants, findings, and prognostic implications

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    Introduction: Coronary angiography is regularly performed in patients with worsening signs and/or symptoms of heart failure (HF). However, little is known on the determinants, findings, and associated clinical outcomes of coronary angiography performed in patients with worsening HF.Methods: The BIOSTAT-CHF (A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) program enrolled 2516 patients with worsening symptoms and/or signs of HF, either hospitalized or in the out-patient setting. All patients were included in the present analysis.Results: Of the 2516 patients included, 315 (12.5%) underwent coronary angiography within the 30 days after the onset of worsening symptoms and/or signs of HF. Subjects who underwent angiography were younger, more often conducted on inpatients, had more often an overt acute coronary syndrome, had higher troponin I levels, were younger, and had better renal function (all p≀0.01). Only 35% (n=54) of patients with an ACS (n=155) underwent coronary angiography. Patients who underwent coronary angiography had a lower risk of the primary outcome of death and/or HF hospitalization (adjusted HR=0.71, 95%CI=0.57-0.89; p=0.003) and death (adjusted HR=0.59, 95%CI=0.43-0.80, p=0.001). Among the patients who underwent coronary angiography, those with a coronary stenosis (39%) had a worse prognosis than those without stenosis (adjusted HR for the primary outcome=1.71, 95%CI=1.10-2.64, p =0.016).Conclusions: Coronary angiography was performed in &lt;13% of patients with symptoms and/or signs of worsening heart failure. Coronary angiography appears to be underutilized among patients who present with an ACS and HF. Strategies to optimize the use of coronary angiography among eligible patients may represent an opportunity to improve outcomes

    Identifying Pathophysiological Mechanisms in Heart Failure With Reduced Versus Preserved Ejection Fraction

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    Background: Information on the pathophysiological differences between heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF) is needed Objectives: The purpose of this study was to establish biological pathways specifically related to HFrEF and HFpEF. Methods: The authors performed a network analysis to identify unique biomarker correlations in HFrEF and HFpEF using 92 biomarkers from different pathophysiological domains in a cohort of 1,544 heart failure (HF) patients. Data were independently validated in 804 patients with HF. Networks were enriched with existing knowledge on protein–protein interactions and translated into biological pathways uniquely related to HFrEF, HF with a midrange ejection fraction, and HFpEF. Results: In the index cohort (mean age 74 years; 34% female), 718 (47%) patients had HFrEF (left ventricular ejection fraction [LVEF] <40%) and 431 (27%) patients had HFpEF (LVEF ≄50%). A total of 8 (12%) correlations were unique for HFrEF and 6 (9%) were unique to HFpEF. Central proteins in HFrEF were N-terminal B-type natriuretic peptide, growth differentiation factor-15, interleukin-1 receptor type 1, and activating transcription factor 2, while central proteins in HFpEF were integrin subunit beta-2 and catenin beta-1. Biological pathways in HFrEF were related to DNA binding transcription factor activity, cellular protein metabolism, and regulation of nitric oxide biosynthesis. Unique pathways in patients with HFpEF were related to cytokine response, extracellular matrix organization, and inflammation. Biological pathways of patients with HF with a midrange ejection fraction were in between HFrEF and HFpEF. Conclusions: Network analysis showed that biomarker profiles specific for HFrEF are related to cellular proliferation and metabolism, whereas biomarker profiles specific for HFpEF are related to inflammation and extracellular matrix reorganization. (The BIOlogy Study to TAilored Treatment in Chronic Heart Failure [BIOSTAT-CHF]; EudraCT 2010-020808-29

    Tumor biomarkers:association with heart failure outcomes

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    Background: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics. Objectives: To explore the association between tumor biomarkers and HF outcomes. Methods: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumor biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1, and AFP. Results: During a median follow-up of 21 months, 555 (27%) patients reached the primary endpoint of all-cause mortality. CA125, CYFRA 21-1, CEA, and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P&lt;0.001, P for trend &lt;0.001), and were respectively associated with a hazard ratio of 1.17 (95% CI 1.12 – 1.23; P&lt;0.0001), 1.45 (95% CI 1.30 – 1.61; P&lt;0.0001), 1.19 (95% CI 1.09 – 1.30; P =0.006), and 1.10 (95% CI 1.05 – 1.16; P&lt;0.001)for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, hemoglobin, and beta-blocker). All tumor biomarkers (except AFP) had significant associations with secondary endpoints (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality, and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a non-inferior AUC compared to NT-proBNP (0.68) for all-cause mortality (P =0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC =0.71) improved the predictive value of the model for all-cause mortality (P =0.0002 compared to NT-proBNP). Conclusions: Several established tumor biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumor biomarkers are also dysregulated in HF

    The Clinical Significance of Interleukin-6 in Heart Failure:Results from the BIOSTAT-CHF Study

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    Aims: Inflammation is a central process in the pathophysiology of heart failure (HF), but trials targeting tumour necrosis factor (TNF)‐α were largely unsuccessful. Interleukin (IL)‐6 is an important inflammatory mediator and might constitute a potential pharmacologic target in HF. However, little is known regarding the association between IL‐6 and clinical characteristics, outcomes and other inflammatory biomarkers in HF. We thus aimed to identify and characterize these associations. Methods and results: Interleukin‐6 was measured in 2329 patients [89.4% with a left ventricular ejection fraction (LVEF) ≀ 40%] of the BIOSTAT‐CHF cohort. The primary outcome was all‐cause mortality and HF hospitalization during 2 years, with all‐cause, cardiovascular (CV), and non‐CV death as secondary outcomes. Approximately half (56%) of all included patients had plasma IL‐6 values greater than the previously determined 95th percentile of normal values at baseline. Elevated N‐terminal pro‐brain natriuretic peptide, procalcitonin and hepcidin, younger age, TNF‐α/IL‐1‐related biomarkers, or having iron deficiency, atrial fibrillation and LVEF &gt; 40% independently predicted elevated IL‐6 levels. IL‐6 independently predicted the primary outcome [HR (95% confidence interval) per doubling: 1.16 (1.11–1.21), P &lt; 0.001], all‐cause mortality [1.22 (1.16–1.29), P &lt; 0.001] and CV as well as non‐CV mortality [1.16 (1.09–1.24), P &lt; 0.001; 1.31 (1.18–1.45), P &lt; 0.001], but did not improve discrimination in previously published risk models. Conclusions: In a large, heterogeneous cohort of HF patients, elevated IL‐6 levels were found in more than 50% of patients and were associated with iron deficiency, reduced LVEF, atrial fibrillation and poorer clinical outcomes. These findings warrant further investigation of IL‐6 as a potential therapeutic target in specific HF subpopulations

    Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication.

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    RationaleWe recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest.ObjectivesWe now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients.MethodsWe conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test.Measurements and main resultsUrinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)(2)/1,000 was 92% (95% confidence interval [CI], 85-98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06-0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4-22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63-0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80-0.90 for clinical variables plus [TIMP-2]·[IGFBP7]).ConclusionsUrinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962)

    Radiative Decay Modes of the D0D^{0} Meson

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    Using data recorded by the CLEO-II detector at CESR we have searched for four radiative decay modes of the D0D^0 meson: D0â†’Ï•ÎłD^0\to\phi\gamma, D0â†’Ï‰ÎłD^0\to\omega\gamma, D0→Kˉ∗γD^0\to\bar{K}^{*}\gamma, and D0→ρ0ÎłD^0\to\rho^0\gamma. We obtain 90% CL upper limits on the branching ratios of these modes of 1.9×10−41.9\times 10^{-4}, 2.4×10−42.4\times 10^{-4}, 7.6×10−47.6\times 10^{-4} and 2.4×10−42.4\times 10^{-4} respectively.Comment: 15 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN
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