Factor XI Inhibition to Uncouple Thrombosis From Hemostasis: JACC Review Topic of the Week.

Hemostasis and thrombosis are believed to be so intricately linked that any strategies that reduce thrombosis will have an inevitable impact on hemostasis. Consequently, bleeding is viewed as an unavoidable side effect of anticoagulant therapy. Emerging evidence suggests that factor XI is important for thrombosis but has a minor role in hemostasis.

CRD-733, a Novel PDE9 (Phosphodiesterase 9) Inhibitor, Reverses Pressure Overload-Induced Heart Failure.

Background: Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies.

Trajectories of Changes in Renal Function in Patients with Acute Heart Failure.

Background: Changes in renal function have been associated with differential outcomes in patients with acute heart failure (HF). However, individual trajectories of changes in renal function are unknown, and it is unclear whether they relate to different clinical characteristics and clinical outcomes. Our aim was to investigate the prognostic importance of individual trajectories of change in renal function in acute HF.

Prognostic Significance of Creatinine Increases During an Acute Heart Failure Admission in Patients With and Without Residual Congestion: A Post Hoc Analysis of the PROTECT Data.

Background: The importance of a serum creatinine increase, traditionally considered worsening renal function (WRF), during admission for acute heart failure has been recently debated, with data suggesting an interaction between congestion and creatinine changes.

Methods And Results: In post hoc analyses, we analyzed the association of WRF with length of hospital stay, 30-day death or cardiovascular/renal readmission and 90-day mortality in the PROTECT study (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Daily creatinine changes from baseline were categorized as WRF (an increase of 0.

Prevalence, predictors and clinical outcome of residual congestion in acute decompensated heart failure.

Background: Congestion is the main reason for hospital admission for acute decompensated heart failure (ADHF). A better understanding of the clinical course of congestion and factors associated with decongestion are therefore important. We studied the clinical course, predictors and prognostic value of congestion in a cohort of patients admitted for ADHF by including different indirect markers of congestion (residual clinical congestion, brain natriuretic peptides (BNP) trajectories, hemoconcentration or diuretic response).

Plasma Neutrophil Gelatinase-Associated Lipocalin and Predicting Clinically Relevant Worsening Renal Function in Acute Heart Failure.

The aim of this study was to evaluate the ability of Neutrophil Gelatinase-Associated Lipocalin (NGAL) to predict clinically relevant worsening renal function (WRF) in acute heart failure (AHF). Plasma NGAL and serum creatinine changes during the first 4 days of admission were investigated in 1447 patients hospitalized for AHF and enrolled in the Placebo-Controlled Randomized Study of the Selective A₁Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) study. WRF was defined as serum creatinine rise ≥ 0.

Identifying Subpopulations with Distinct Response to Treatment Using Plasma Biomarkers in Acute Heart Failure: Results from the PROTECT Trial : Differential Response in Acute Heart Failure.

Background: Over the last 50 years, clinical trials of novel interventions for acute heart failure (AHF) have, with few exceptions, been neutral or shown harm. We hypothesize that this might be related to a differential response to pharmacological therapy.

Methods: We studied the magnitude of treatment effect of rolofylline across clinical characteristics and plasma biomarkers in 2033 AHF patients and derived a biomarker-based responder sum score model.

A network analysis to compare biomarker profiles in patients with and without diabetes mellitus in acute heart failure.

Aims: It is unclear whether distinct pathophysiological processes are present among patients with acute heart failure (AHF), with and without diabetes. Network analysis of biomarkers may identify correlative associations that reflect different pathophysiological pathways.

Methods And Results: We analysed a panel of 48 circulating biomarkers measured within 24 h of admission for AHF in a subset of patients enrolled in the PROTECT trial.

Biomarker Profiles of Acute Heart Failure Patients With a Mid-Range Ejection Fraction.

Objectives: In this study, the authors used biomarker profiles to characterize differences between patients with acute heart failure with a midrange ejection fraction (HFmrEF) and compare them with patients with a reduced (heart failure with a reduced ejection fraction [HFrEF]) and preserved (heart failure with a preserved ejection fraction [HFpEF]) ejection fraction.

Background: Limited data are available on biomarker profiles in acute HFmrEF.

Methods: A panel of 37 biomarkers from different pathophysiological domains (e.

New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment.

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure.

Plasma biomarkers to predict or rule out early post-discharge events after hospitalization for acute heart failure.

Aim: Improved prediction of early post-discharge death or rehospitalization after admission for acute heart failure is a major unmet need. We evaluated the value of biomarkers to predict either low or high risk for early post-discharge events.

Methods And Results: A total of 1653 patients enrolled in the PROTECT trial who were discharged alive and with available blood samples were included.

Associations of Body Mass Index With Laboratory and Biomarkers in Patients With Acute Heart Failure.

Background: Plasma concentrations of natriuretic peptides decline with obesity in patients with heart failure. Whether this is true for other biomarkers is unknown. We investigated a wide range of biomarker profiles in acute heart failure across the body mass index (BMI) spectrum.

Serum Potassium Levels and Outcome in Acute Heart Failure (Data from the PROTECT and COACH Trials).

Serum potassium is routinely measured at admission for acute heart failure (AHF), but information on association with clinical variables and prognosis is limited. Potassium measurements at admission were available in 1,867 patients with AHF in the original cohort of 2,033 patients included in the Patients Hospitalized with acute heart failure and Volume Overload to Assess Treatment Effect on Congestion and Renal FuncTion trial. Patients were grouped according to low potassium (<3.

Clinical Correlates and Prognostic Value of Proenkephalin in Acute and Chronic Heart Failure.

Background: Proenkephalin (pro-ENK) has emerged as a novel biomarker associated with both renal function and cardiac function. However, its clinical and prognostic value have not been well evaluated in symptomatic patients with heart failure.

Methods And Results: The association between pro-ENK and markers of renal function was evaluated in 95 patients with chronic heart failure who underwent renal hemodynamic measurements, including renal blood flow (RBF) and glomerular filtration rate (GFR) with the use of I-Hippuran and I-iothalamate clearances, respectively.

Blood urea nitrogen-to-creatinine ratio in the general population and in patients with acute heart failure.

Objective: The blood urea nitrogen-to-creatinine (BUN/creatinine) ratio has been proposed as a useful parameter in acute heart failure (AHF), but data on the normal range and the added value of the ratio compared with its separate components in patients with AHF are lacking. The aim of this study is to define the normal range of BUN/creatinine ratio and to investigate its clinical significance in patients with AHF.

Methods: In 4484 subjects from the general population without cardiovascular comorbidities, we calculated age-specific and sex-specific normal values of the BUN/creatinine ratio, deriving a higher and lower than normal range of BUN/creatinine ratio (exceeding the 95% prediction intervals).

Risk-based evaluation of efficacy of rolofylline in patients hospitalized with acute heart failure - Post-hoc analysis of the PROTECT trial.

Background: The selective adenosine A1 receptor antagonist rolofylline showed a neutral overall result on clinical outcomes in the PROTECT trial. However, we hypothesized that response to rolofylline treatment could be influenced by underlying clinical risk.

Methods: We performed a post-hoc analysis of the PROTECT trial - a large, double-blind, randomized, placebo-controlled trial that enrolled 2033 patients.

Hypochloremia, Diuretic Resistance, and Outcome in Patients With Acute Heart Failure.

Background: Chloride plays a role in renal salt sensing, neurohormonal activation, and regulation of diuretic targets, and hypochloremia predicts mortality in acute heart failure (AHF). AHF therapies, such as diuretics, alter chloride homeostasis. We studied the association between (changes in) chloride levels and diuretic responsiveness, decongestion, and mortality in patients with AHF.

Acute heart failure in the young: Clinical characteristics and biomarker profiles.

Background: Young patients (<50years) exhibit specific characteristics in chronic heart failure (HF), but their phenotype in acute heart failure (AHF) is not well described.

Methods And Results: 2033 patients of the PROTECT trial were divided into two groups: young patients (≤50years) and older patients (>50years). Biomarkers from different pathophysiological domains were available in 1266 patients.

Combining Diuretic Response and Hemoconcentration to Predict Rehospitalization After Admission for Acute Heart Failure.

Background: Both diuretic response and hemoconcentration are indicators of decongestion and have individually been found to predict rehospitalization after admission for acute heart failure (HF). This study examines the value of combining diuretic response and hemoconcentration to better predict patients at low risk for rehospitalization after admission for acute HF.

Methods And Results: Diuretic response (defined as weight change per 40 mg of furosemide on day 4 after admission) and hemoconcentration (change in hemoglobin at discharge or day 7) were tested both individually and combined to predict the risk of HF and cardiovascular rehospitalization 60 days after hospitalization for acute HF.

Abnormal liver function tests in acute heart failure: relationship with clinical characteristics and outcome in the PROTECT study.

Aims: Episodes of acute heart failure (AHF) unfavourably affect multiple organs, which may have an adverse impact on the outcomes. We investigated the prevalence and clinical consequences of abnormal liver function tests (LFTs) in AHF patients enrolled in the PROTECT study.

Methods And Results: The LFTs comprised serial assessment of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin at baseline and during follow-up (daily until discharge, on days 7 and 14).

Patient journey after admission for acute heart failure: length of stay, 30-day readmission and 90-day mortality.

Aims: The course of patients following admission for acute heart failure (AHF) is of major importance to patients and healthcare providers. We examined predictors and associations of length of stay (LOS), 30-day post-discharge readmission and 90-day post-discharge mortality in 1990 patients enrolled in the PROTECT study.

Methods And Results: PROTECT was a randomized study that examined the effect of the adenosine blocker rolofylline in patients within 24 h of admission for AHF with mild to moderate renal impairment.

Procalcitonin-based indication of bacterial infection identifies high risk acute heart failure patients.

Background: Bacterial infections in patients hospitalized with acute heart failure are related to worse prognosis, but they can be difficult to diagnose. In this study we evaluated the prevalence, clinical correlates and association with outcomes of significantly elevated procalcitonin levels in patients hospitalized for acute heart failure without clear signs of bacterial infection.

Methods: 1781 patients from the PROTECT trial were included.

Optimizing clinical use of biomarkers in high-risk acute heart failure patients.

Aim: The clinical value of single biomarkers at single time-points to predict outcomes in patients with acute heart failure (AHF) is limited. We performed a multimarker, multi-time-point analysis of biomarkers for the prediction of post-discharge clinical outcomes in high-risk AHF patients.

Methods And Results: A set of 48 circulating biomarkers were measured in the PROTECT trial which enrolled 2033 patients with AHF.

MicroRNAs relate to early worsening of renal function in patients with acute heart failure.

Background: Deregulation of microRNAs (miRNAs) may be involved in the pathogenesis of heart failure (HF) and renal disease. Our aim is to describe miRNA levels related to early worsening renal function in acute HF patients.

Method And Results: We studied the association between 12 circulating miRNAs and Worsening Renal Function (WRF; defined as an increase in the serum creatinine level of 0.

Plasma kidney injury molecule-1 in heart failure: renal mechanisms and clinical outcome.

Aims: Urinary kidney injury molecule-1 (KIM-1) is a marker of tubular damage and associated with worse outcome in heart failure (HF). Plasma KIM-1 has not been described in HF.

Methods And Results: In a renal mechanistic cohort of 120 chronic HF patients, we established the association between plasma KIM-1, renal invasive haemodynamic parameters {renal blood flow ([(131) I]hippuran clearance) and measured glomerular filtration rate (GFR; [(125) I]iothalamate)} and urinary tubular damage markers.