AIMS:Residual congestion (RC) is common at discharge after acute decompensated heart failure (ADHF) and is associated with early mortality and rehospitalization. The prognostic value of distinct RC phenotypes (i.e. intravascular and tissue congestion) remains unclear. This analysis investigated RC phenotypes and their outcomes. METHODS AND RESULTS:Patients with congestion at admission from two large ADHF trials, PROTECT (rolofylline; index) and RELAX-AHF-2 (serelaxin; replication), were classified based on clinical signs at day 7/discharge as intravascular (jugular venous pressure) or tissue (pulmonary rales/peripheral oedema) congestion, each alone, combined or neither. Cox regression assessed 180-day mortality after adjusting for risk factors. Overall, 1557 patients with predominantly combined (i.e. tissue and intravascular) congestion at admission were included, with a median age of 72 years. By day 7 or discharge, 580 (37%) patients had RC. In these patients, intravascular congestion (n = 260; 45%) was most common, followed by combined (n = 185; 32%) and tissue (n = 135; 23%) congestion. During hospitalization, patients with solely intravascular RC had greater diuretic responses, shorter hospital stays and received lower doses of intravenous loop diuretics than those with tissue or combined congestion (all p < 0.05). Residual intravascular and tissue congestion were independently associated with increased 180-day mortality (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.15-2.49, and HR 2.07, 95% CI 1.25-3.41, respectively) compared to decongested patients. In the RELAX-AHF-2 substudy (n = 476), similar findings were observed. CONCLUSIONS:Patients with intravascular RC had better diuretic responses and shorter hospital stays than those with tissue/combined RC, but worse outcomes than decongested patients. This study highlights the importance of RC assessment to identify at-risk patients. Future studies should evaluate phenotype-guided treatments.

AIMS:Serelaxin is recombinant human relaxin-2, a hormone responsible for haemodynamic adaptations and organ protection in pregnancy. In the RELAX-AHF trial, serelaxin demonstrated reductions in cardiac, renal and hepatic damage. In RELAX-AHF-2, organ damage-related biomarkers were assessed in a biomarker substudy. METHODS AND RESULTS:Patients enrolled within 16 h of presentation for heart failure hospitalization were randomized to 48-h infusions of either serelaxin (30 μg/kg/day) or placebo, and plasma samples were obtained at baseline, 2, 5, and 14 days in patients participating in the biomarker substudy. Of the 6545 patients analysed in RELAX-AHF-2, 1020 (15.6%) patients (mean age 72 ± 12 years; 61% male) were enrolled in the biomarker substudy. Compared to placebo, serelaxin decreased percentage change from baseline in troponin T through day 14 (serelaxin +0.2% vs. placebo +40.3%; p = 0.042), as well as creatinine (-0.8% vs. +5.8%; p = 0.002), cystatin C (+3.8% vs. +8.3%; p = 0.016), and uric acid (+0.8% vs. +7.2%; p = 0.0014) at day 2. The decrease of N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to day 2 was greater in serelaxin-treated patients (-39.8% vs. -27.6%; p = 0.002). Early changes in NT-proBNP and troponin, but not creatinine, cystatin C and uric acid, were associated with 180-day mortality. In this substudy population, serelaxin did not reduce 180-day cardiovascular death (hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.49-1.25; p = 0.30), but significantly reduced worsening heart failure through day 5 (HR 0.55; 95% CI 0.33-0.93; p = 0.027). CONCLUSION:In this substudy, serelaxin decreased plasma concentrations of cardiac, renal and hepatic injury markers. Changes of most of these markers were associated with cardiovascular mortality. In this pre-specified biomarker subgroup, serelaxin did not reduce 180-day cardiovascular mortality but significantly reduced worsening heart failure through day 5.

Heart failure (HF) is a systemic disease associated with a high risk of morbidity, mortality, increased risk of hospitalizations, and low quality of life. Therefore, effective, systemic treatment strategies are necessary to mitigate these risks. In this manuscript, we emphasize the concept of high-intensity care to optimize guideline-directed medical therapy (GDMT) in HF patients. The document highlights the importance of achieving optimal recommended doses of GDMT medications, including beta-blockers, renin-angiotensin-aldosterone inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter inhibitors to improve patient outcomes, achieve effective, sustainable decongestion, and improve patient quality of life. The document also discusses potential obstacles to GDMT optimization, such as clinical inertia, physiological limitations, comorbidities, non-adherence, and frailty. Lastly, it also attempts to provide possible future scenarios of high-intensive care that could improve patient outcomes.

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. Analyses were performed in 1180 patients enrolled in the Placebo-Controlled Randomized Study of the Selective Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) trial and validated in 1776 patients enrolled in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial. Poor diuretic response was associated with low systolic blood pressure, high blood urea nitrogen, and history of coronary revascularization in both data sets (all P<0.05). Hemoconcentration was mainly associated with better renal function (P<0.05). Patients who displayed both favorable diuretic response and hemoconcentration had a markedly lower risk of rehospitalization for HF in PROTECT (multivariable HR, 0.41; 95% CI, 0.24 to 0.70; P<0.001) compared with all other patients. This finding was confirmed in EVEREST (multivariable HR, 0.52; 95% CI, 0.33 to 0.82; P=0.004) for patients with favorable diuretic response and hemoconcentration compared with all other patients. Conclusions—Combining 2 indicators of decongestion, hemoconcentration and diuretic response improves risk prediction for early rehospitalization after an admission for acute HF and may provide clinicians with an easily accessible tool to identify low-risk patients. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00354458 and NCT00071331.

AimsOur aim was to identify circulating microRNAs (miRNAs) associated with acute heart failure (AHF).Methods and resultsPlasma miRNA profiling included 137 patients with AHF from 3 different cohorts, 20 with chronic heart failure (CHF), 8 with acute exacerbation of COPD, and 41 healthy controls. Levels of circulating miRNAs were measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Plasma levels of miRNAs in patients with AHF were decreased compared with CHF patients or healthy subjects, whereas no significant changes were observed between acute COPD patients and controls. Fifteen miRNAs found in the discovery phase to differ most significantly between healthy controls and patients with AHF were further investigated in an extended cohort of 100 AHF patients at admission and a separate cohort of 18 AHF patients at different time points. Out of these 15 miRNAs, 12 could be confirmed in an additional AHF validation cohort and 7 passed the Bonferroni correction threshold (miR-18a-5p, miR-26b-5p, miR-27a-3p, miR-30e-5p, miR-106a-5p, miR-199a-3p, and miR-652-3p, all P < 0.00005). A further drop in miRNA levels within 48 h after AHF admission was associated with an increased risk of 180-day mortality in a subset of the identified miRNAs.ConclusionsDeclining levels of circulating miRNAs were associated with increasing acuity of heart failure. Early in-hospital decreasing miRNA levels were predictive for mortality in a subset of miRNAs in patients with AHF. The discovered miRNA panel may serve as a launch-pad for molecular pathway studies to identify new pharmacological targets and miRNA-based therapies.

Acute worsening heart failure ( WHF ) is seen in a sizable portion of patients hospitalized for heart failure, and is increasingly being recognized as an entity that is associated with an adverse in‐hospital course. WHF is generally defined as worsening heart failure symptoms and signs requiring an intensification of therapy, and is reported to be seen in anywhere from 5% to 42% of heart failure admissions. It is difficult to ascertain the exact epidemiology of WHF due to varying definitions used in the literature. Studies indicate that WHF cannot be precisely predicted on the basis of baseline variables assessed at the time of admission. Recent data suggest that some experimental therapies may reduce the risk of development of WHF among hospitalized heart failure patients, and this is associated with a reduction in risk of subsequent post‐discharge cardiovascular mortality. In this respect, WHF holds promise as a endpoint for acute heart failure clinical trials to better elucidate the benefit of targeted novel therapies. Better understanding of the pathophysiology and a consensus on the definition of WHF will further improve our epidemiological and clinical understanding of this entity.

The cardiovascular system is essentially a complex system of pumps and pipes, and as such it belongs to the branch of fluid dynamics in engineering science, the equivalent of which in cardiovascular physiology is haemodynamics, dealing with measureable variables including pressure and flow. Less well known to cardiologists is the study of cardiovascular energetics which obeys the fundamental Law of Conservation of Energy. According to this Law of physics, to prevent the cessation of the circulation owing to dissipation of energy in the vasculature, the cardiac pump needs to generate and impart a continuous supply of hydraulic energy.1 The primary function of the cardiac pump is therefore to convert chemical energy into hydraulic energy to maintain a physiologically viable circulation.1 How good the cardiac pump is can be represented by how well it can impart hydraulic energy to maintain a circulation that can meet the most demanding physiological stresses.2 The variable that represents this entity is cardiac power output (CPO) at peak stress, which can be calculated by the product of cardiac flow and pressure measured, for example, at maximal exercise. The mean value of CPO is approximated by multiplying cardiac output (CO in L/min), with mean arterial pressure (MAP in mmHg), and a factor to convert into watts (cardiac power output, CPO = CO × MAP × 2.22 × 0−3 W).3 Peak cardiac power output (CPOmax) would therefore best represent the extent of the heart's failure to deliver adequate hydraulic energy sufficient to maintain a circulation that copes with any physiological stresses. It is therefore commonly found in multivariate analyses to be a powerful independent predictor of heart failure (HF) prognosis.4 In this issue of the European Journal of Heart Failure, Grodin and colleagues from Cleveland and Belgium5 extended this scheme of conceptual thinking to study heart function, not from the common and near-ubiquitous perspective of left ventricular ejection fraction (LVEF), but by considering the heart's role as a hydraulic pump at rest, quantified as the cardiac power index (CPI), obtained by indexing resting CPO by body surface area (BSA), during invasive haemodynamic assessment. This retrospective cohort study included 495 sequential ambulatory patients with advanced heart failure on evidence-based treatment followed up for a median of 3.3 years. Their demographics included mean age 54 ± 11 years, 76% male, 48% with ischaemic cardiomyopathy, mean LVEF 20%, 91% in New York Heart Association (NYHA) class III, and 39% having an implantable cardioverter defibrillator (ICD) in situ. Resting CPI less than 0.44 W/m2 was associated with increased adverse outcomes (death, transplant or VAD placement) with a hazard ratio of 2.4. An independent association remained after multivariate analyses for age, gender, pulmonary capillary wedge pressure (PCWP), Fick CI, creatinine, LVEF, B-type natriuretic peptide (BNP), and peak oxygen consumption (VO2max). The authors acknowledge a limitation that this was a single-centre, retrospective study, performed mostly in patients with advanced HF. Furthermore, resting CPI is limited by the fact that it is difficult to determine how much of the peak CPO the patient ‘uses’ at rest. Conceivably minor changes in pulse rate or adrenergic activity (related to stress for example) can lead to increases in CPI thus creating the false assessment of a ‘better’ patient prognosis. Although the definition of advanced HF was rather vague, in advanced HF it is likely that the CPO reserve is relatively low and hence resting CPI may correlate well with peak CPO and therefore provide a good representation of near-maximal cardiac pumping capacity. This assumption should not be made in patients with less severe HF, where peak CPO rather than resting CPI should be assessed. Curiously, one of the earliest indicators of HF prognosis was published in a non-cardiological journal in 1948. In it the authors reported that it is ‘justifiable to consider the prognosis as very grave’ in patients with severe HF if normoblasts are found in their blood and their disappearance was ‘concomitant with an improvement in the heart failure’.6 Since then, there has been a marked proliferation of reported HF prognostic indicators (PrI), which pose a problem for clinicians because of the impossibility of adopting the entire range into routine practice. Over the years, multiple determinants of HF prognosis have been found covering many aspects of the HF syndrome, derived with various statistical tools, especially multivariate analysis, and utilized for worthy clinical and research objectives.7 Now that CPIrest has joined a lengthening list of PrIs for HF, where does it rank amongst other competing PrIs? With so many PrIs already reported in the literature, frequent emergence of newly reported PrIs and questions raised over previously advocated PrIs, practising clinicians are overwhelmed and in danger of becoming inattentive to newer PrIs. The time has come to reappraise and draw a shortlist of PrIs that are worthy of being adopted into routine clinical practice. A major handicap with testing and selecting the best PrI is that, unlike symptoms and functional capacities, it is impossible to measure the prognosis of an individual patient and measure how it is altered by certain therapeutic interventions in that individual.8 Prognosis of HF can only be determined in a cohort of patients over a period of time and the PrIs derived thereby would then require validation in different HF populations to verify their general applicability.9 However, HF populations are changing significantly over time, for example, with evolving demographics such as rising proportions of older patients with preserved LVEF and degenerative valve disease, and with progressively improving pharmacological, device, and interventional therapies. Each multiparametric combination set of PrIs will therefore require periodical redevelopment ad infinitum, followed by validation iteratively in different HF populations. Are there alternative and better ways of selecting PrIs for clinicians? Table 1 lists proposed methods for the classification of HF PrIs. In statistics, it is axiomatic that ‘Bigger is Better’, implying that the larger the sample size, the greater the power, confidence, and generalizability of the PrIs. An ideal approach would be to conduct a mega-study involving millions of consecutive HF patients and entering all known candidate PrIs into conclusive multivariate analyses. However, this approach may not be practical, as it will be necessary to repeat such a mega-study every few years, especially if there are significant drifts in HF management options. An alternative approach would be to test PrIs in smaller studies using a priori hypothesis. They could, for example, be considered according to pathophysiological mechanisms. The HF syndrome is caused by a combination of the cardiac pump's failure to maintain a physiological circulation1 and downstream derangements consequential upon tissue hypoperfusion, congestion, and neurohormonal and inflammatory activation, giving rise to measureable markers. Thus, PrIs can be divided into those pertaining to the primary causes of HF (structural and functional defects) and those pertaining to downstream effects. One might therefore speculate that PrIs related to the primary cardiac dysfunction4 will be more prognostic than PrIs derived from downstream consequences, especially in patients with advanced HF irrespective of aetiology. In this context, measuring CPIrest, and even more so peak CPO, would accurately assess the cardiac pumping capacity and, hence, be strongly associated with outcomes, as shown by Grodin et al.5 Another important consideration when assessing PrIs is to ‘stress’ them longitudinally to verify whether any improvement in their values, however biologically achieved (and not caused by differences in measurement techniques), are accompanied by concordant improvements in HF status and prognosis. For example, applying such a stress test to BNP, it would appear that any alteration in the rates of BNP synthesis, metabolism, or excretion would alter plasma BNP levels unaccompanied by actual alterations in cardiac status and prognosis. This may partly explain why trials of BNP-guided HF therapy have so far produced rather mixed results.10 Peak CPO or resting CPI were not assessed previously in such a study examining their changes with therapies. However, conceivably, resting CPI could be altered by therapies such as inotropes that have not been shown to improve outcomes,11 adding to the caution needed in applying it to clinical practice. What constitutes an optimal and useful PrI? It is one that not only predicts prognosis well, but is also generally applicable to heterogeneous HF patients worldwide and would respond to interventions that change prognosis in a way that correlates with the intervention's effect while not responding to interventions that do not change or worsen prognosis. The selection process for such HF PrIs should now be undertaken in earnest. In addition, as in drug development, where new agents in an existing class are required to demonstrate superiority before approval, the onus should now be on investigators claiming a newly discovered HF PrI to provide evidence of its superiority over existing PrIs. Conflict of interest: none declared.

With one possible exception, the last decade of clinical trials in hospitalized heart failure (HHF) patients has failed to demonstrate improvement in long-term clinical outcomes. This trend necessitates a need to evaluate optimal drug development strategies and standards of trial conduct. It has become increasingly important to recognize the heterogeneity among HHF patients and the differential characterization of novel drug candidates. Targeting these agents to specific subpopulations may afford optimal net response related to the particular mode of action of the drug. Analyses of previous trials demonstrate profound differences in the baseline characteristics of patients enrolled across global regions and participating sites. Such differences may influence risks for events and interpretation of results. Therefore, the actual execution of trials and the epidemiology of HHF populations at the investigative sites must be taken into consideration. Collaboration among participating sites including the provision of registry data tailored to the planned development program will optimize trial conduct. Observational data prior to study initiation may enable sites to feedback and engage in protocol development to allow for feasible and valid clinical trial conduct. This site-centered, epidemiology-based network environment may facilitate studies in specific patient populations and promote optimal data collection and clear interpretation of drug safety and efficacy. This review summarizes the roundtable discussion held by a multidisciplinary team of representatives from academia, National Institutes of Health, industry, regulatory agencies, payers, and contract and academic research organizations to answer the question: Who should be targeted for novel therapies in HHF?

Biomarkers play an important role in heart failure. They provide us information about the mechanisms involved in specific types of heart failure and can identify patients at higher risk. Although the majority of biomarker studies in heart failure focus on their prognostic value, the clinical applicability of prognostication in heart failure needs to be established. However, biomarkers can be used for many other purposes. For example, they can help us with the diagnosis of heart failure, and they can be used to select our therapy, leading to personalized tailored therapy. Finally, when biomarkers are causally involved in the disease process, they can even become targets for therapy. The present paper reviews the established and potential value of the novel heart failure biomarkers, mid-regional atrial natriuretic peptide, soluble ST2, growth differentiation factor 15, galectin-3, renal tubular damage markers, and microRNAs. Their potential clinical value will be discussed and compared with the reference markers, the natriuretic peptides.

There are over 1 million hospitalizations for heart failure (HF) annually in the United States alone, and a similar number has been reported in Europe. Recent clinical trials investigating novel therapies in patients with hospitalized HF (HHF) have been negative, and the post-discharge event rate remains unacceptably high. The lack of success with HHF trials stem from problems with understanding the study drug, matching the drug to the appropriate HF subgroup, and study execution. Related to the concept of study execution is the importance of including appropriate study sites in HHF trials. Often overlooked issues include consideration of the geographic region and the number of patients enrolled at each study center. Marked differences in baseline patient co-morbidities, serum biomarkers, treatment utilization and outcomes have been demonstrated across geographic regions. Furthermore, patients from sites with low recruitment may have worse outcomes compared to sites with higher enrollment patterns. Consequently, sites with poor trial enrollment may influence key patient end points and likely do not justify the costs of site training and maintenance. Accordingly, there is an unmet need to develop strategies to identify the right study sites that have acceptable patient quantity and quality. Potential approaches include, but are not limited to, establishing a pre-trial registry, developing site performance metrics, identifying a local regionally involved leader and bolstering recruitment incentives. This manuscript summarizes the roundtable discussion hosted by the Food and Drug Administration between members of academia, the National Institutes of Health, industry partners, contract research organizations and academic research organizations on the importance of selecting optimal sites for successful trials in HHF.

AIMS:We aimed to determine the relation between baseline systolic blood pressure (SBP), change in SBP, and worsening renal function (WRF) in acute heart failure (AHF) patients enrolled in the Pre-RELAX-AHF trial.METHODS AND RESULTS:The Pre-RELAX-AHF study enrolled 234 patients within 16 h of admission (median 7 h) for AHF and randomized them to relaxin given intravenous (i.v.) for 48 h or placebo. Blood pressure was measured at baseline, at 3, 6, 9, 12, 24, 36, and 48 h and at 3, 4, and 5 days after enrolment. Worsening renal function was defined as a serum creatinine increase of ≥0.3 mg/dL by Day 5. Worsening renal function was found in 68 of the 225 evaluable patients (30%). Patients with WRF were older (73.5 ± 9.4 vs. 69.1 ± 10.6 years; P= 0.003), had a higher baseline SBP (147.3 ± 19.9 vs. 140.8 ± 16.7 mmHg; P= 0.01), and had a greater early drop in SBP (37.9 ± 16.0 vs. 31.4 ± 12.2 mmHg; P= 0.004). In a multivariable model, higher age, higher baseline creatinine, and a greater early drop in SBP, but not baseline SBP, remained independent predictors of WRF. Furthermore, WRF was associated with a higher Day 60 (P= 0.01), and Day 180 (P= 0.003) mortality.CONCLUSIONS:Worsening renal function in hospitalized AHF patients is related to a poor clinical outcome and is predicted by a greater early drop in SBP. Trial registration clinicaltrials.gov identifier NCT00520806.

Intravenous diuretics are the cornerstone of management for patients hospitalized for heart failure. Physiologic data suggest that intermittent high-dose furosemide promotes neurohormonal activation, which a slow continuous infusion might remediate. However, the limited clinical data comparing dosing schemes are confounded. This study was a randomized, open-label, single-center trial of twice-daily bolus injection versus continuous infusion furosemide in patients hospitalized with heart failure and volume overload. The primary outcome was change in creatinine from admission to hospital day 3 or discharge. Twenty-one patients were randomized to bolus injection and 20 patients to continuous infusion. Baseline characteristics were balanced between study arms except for gender, with a mean age of 60 +/- 15 years, a mean ejection fraction of 35 +/- 19%, and a mean creatinine level of 1.9 +/- 1.2 mg/dl. The mean doses of furosemide were similar between arms over the first 48 hours (162 +/- 48 and 162 +/- 52 mg/24 hours). None of the outcomes differed significantly between bolus and continuous dosing from admission to hospital day 3 or discharge (mean change in creatinine -0.02 vs 0.13 mg/dl, p = 0.18; urine output 5,113 vs 4,894 ml, p = 0.78; length of stay 8.8 vs 9.9 days, p = 0.69). All patients survived to discharge. In conclusion, there were no substantial differences between bolus injection and continuous infusion of equal doses of furosemide for the treatment of patients hospitalized with heart failure. Given the high prevalence of heart failure hospitalization and the disparate results of small studies regarding optimal dosing of loop diuretics to treat these patients, larger multicenter blinded studies are needed. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:1794-1797)

Treatment with inotropic agents is one of the most controversial topics in heart failure. Initial enthusiasm, based on strong pathophysiological rationale and apparent empirical efficacy, has been progressively limited by results of controlled trials and registries showing poorer outcomes of the patients on inotropic therapy. The use of these agents remains, however, potentially indicated in a significant proportion of patients with low cardiac output, peripheral hypoperfusion and end-organ dysfunction caused by heart failure. Limitations of inotropic therapy seem to be mainly related to their mechanisms of action entailing arrhythmogenesis, peripheral vasodilation, myocardial ischemia and damage, and possibly due to their use in patients without a clear indication, rather than to the general principle of inotropic therapy itself. This review will discuss the characteristics of the patients with a potential indication for inotropic therapy, the main data from registries and controlled trials, the mechanism of the untoward effects of these agents on outcomes and, lastly, perspectives with new agents with novel mechanisms of action.

Introduction: Dyspnea is the most common presenting symptom for patients (pts) hospitalized for acute heart failure (AHF) and a key endpoint in AHF clinical trials. However, its measurement properties have not been well documented. Objective: To assess the correlation between dyspnea improvement and changes in other patient-reported and physician-assessed signs/symptoms of HF and to characterize the stability over short-term hospital duration. Methods: Blinded data were analyzed from the PROTECT Study (n=1,196), a double-blind clinical trial of AHF pts with eGFR 20-80 mL/min, BNP >500 or nt-pro-BNP >2000 pg/mL, dyspnea at rest or on minimal exertion, randomized within 24 hrs of presentation. Changes in self-reported dyspnea and general well-being (GWB) compared to study start were assessed using 7-point Likert scales from Markedly Better to Markedly Worse. Physicians rated orthopnea, dyspnea on exertion, rales, edema, and JVP from normal to more severe and weighed pts daily through discharge or Day 7. Pts with and w/o moderately or markedly better dyspnea on both Days 2 and 3 were compared regarding proportion of pts with moderately/markedly better GWB and mean changes in HF signs/symptoms from baseline to Days 2 and 3. Kappa statistics characterized stability (reliability) between consecutive days during the first 6 days of hospitalization. Results: 91% of pts with and 18% of pts w/o improved dyspnea had improved GWB on Day 2 (97%, 48% on Day 3). Greater improvement in HF signs was observed in pts with improved dyspnea (below). Consecutive daily assessments showed increasing stability with increasing time in hospital, with excellent reliability later in hospital stay (kappa 0.75 [CI 0.71-0.79] for Days 5-6. Conclusions: Dyspnea improvement is correlated with improvement in GWB and HF signs/symptoms; increasing stability with time in the hospital mirrors the expected clinical course of dyspnea resolution, supporting use of the 7-point dyspnea assessment in clinical trials of AHF.

Background: The natural evolution of signs and symptoms during acute heart failure (AFF) is poorly characterized.Methods and Results: We followed a prospective international cohort of 182 patients hospitalized with AHF. Patient-reported dyspnea and general well-being (GWB) were measured daily using 7-tier Likert (-3 to +3) and visual analog scales (VAS, 0-100). Physician assessments were also recorded daily. Mean age was 69 years and 68% had ejection fraction <40%. Likert Measures of dyspnea initially improved rapidly (day 1, 0.22; day 2, 1.31: P < .001) with no significant improvement therafter (day 7, 1.51: day 2 versus 7 P = .16). In contrast, VAS measure of dyspnea improved throughout hospitalization (day 1, 50.1; day 2, 64.7: day 7, 83.2: day 1 versus 2 P < .001, day 2 versus 7 P < .001). Symptoms of dyspnea and GWB tracked closely (correlation r = .813 P < .001). Physical signs resolved more completely than did symptoms (eg, from day 1 to discharge/day 7, absence of edema increased from 33% to 72% of patients, whereas significant improvements in dyspnea increased from 27% to 52% of patients: P < .001).Conclusions: Changes in patient-reported symptoms and physician-assessed signs followed different patterns during an AHF episode and are influenced by the measurement scales used. Multiple clinical measures should be considered in discharge decisions and evaluation of AHF therapies. (J Cardiac Fail 2008:14:777-784)

BACKGROUND:Renal function is a powerful prognostic variable in patients with heart failure (HF). Hospitalisations for acute HF (AHF) may be associated with further worsening of renal function (WRF). METHODS AND RESULTS:We analysed the clinical significance of WRF in 318 consecutive patients admitted at our institute for AHF. WRF was defined as the occurrence, at any time during the hospitalisation, of both a > or =25% and a > or =0.3 mg/dL increase in serum creatinine (s-Cr) from admission (WRF-Abs-%). RESULTS:Patients were followed for 480+/-363 days. Fifty-three patients (17%) died and 132 (41%) were rehospitalised for HF. WRF-Abs-% occurred in 107 (34%) patients. At multivariable survival analysis, WRF-Abs-% was an independent predictor of death or HF rehospitalisation (adjusted HR, 1.47; 95%CI, 1.13-1.81; p=0.024). The independent predictors of WRF-Abs-%, evaluated using multivariable logistic regression, were history of chronic kidney disease (p=0.002), LV ejection fraction (p=0.012), furosemide daily dose (p=0.03) and NYHA class (p=0.05) on admission. CONCLUSION:WRF is a frequent finding in patients hospitalised for AHF and is associated with a poor prognosis. Severity of HF and daily furosemide dose are the most important predictors of the occurrence of WRF.