Outcomes In Systolic Heart Failure Research Articles

1111 INTACT FIBROBLAST GROWTH FACTOR 23 TESTED BY A FULLY AUTOMATED ASSAY: CLINICAL CORRELATES AND PROGNOSTIC VALUE IN CHRONIC SYSTOLIC HEART FAILURE

Abstract Background and aims Fibroblast growth factor-23 (FGF23) has been associated with left ventricular (LV) hypertrophy, fibrosis, and heart failure (HF). We aimed to investigate the clinical correlates and prognostic value of intact FGF23 (iFGF23) in HF patients. Methods Patients with systolic HF (left ventricular ejection fraction – LVEF <50%) were prospectively enrolled. iFGF23 was tested with a fully automated immuno-chemiluminescent assay. Patients were divided into iFGF23 tertiles and followed-up for all-cause death, cardiac death, and the composite of all-cause death and HF hospitalizations. Results We enrolled 150 patients (82% males; median age 65 years). First, second, and third iFGF23 tertiles were <35.2 pg/mL, 35.2-50.9 pg/mL, and >50.9 pg/mL. Patients in the upper iFGF23 tertile had lower LVEF (p=0.014), higher N-terminal pro-B-type natriuretic peptide (NT-proBNP, p=0.001), and lower peak VO2 (p<0.001). Plasma phosphate, estimated glomerular filtration rate (eGFR), and LV mass index were independently associated with higher iFGF23 levels (all p<0.05). Patients in the upper tertile were at higher risk of all-cause death (p=0.001), cardiac death (p=0.001), and of the composite of all-cause death and HF hospitalizations (p=0.003). iFGF-23 was an independent predictor of all the endpoints after adjustment for age, LVEF, eGFR, and NT-proBNP. Conclusions Circulating iFGF23 is associated with renal dysfunction, disease severity and outcome in systolic HF. Figure. Prognostic impact of FGF23 levels in patients with systolic heart failure (HF). In a cohort of HF patients with systolic dysfunction, higher iFGF23 levels (marker of increased cardiac fibrosis and hypertrophy) were associated with a more severe disease, as expressed by lower left ventricular systolic function, higher circulating levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), lower oxygen consumption at cardiopulmonary exercise test and worse renal function. Moreover, iFGF23 elevation identified patients at higher risk for all-cause and cardiac mortality, and HF hospitalization.

Abstract 11485: Left Ventricular Dimensions and Cardiovascular Outcomes in Systolic Heart Failure: The WARCEF Trial

Introduction: There is limited information on the association between left ventricular (LV) dimensions and cardiovascular (CV) outcomes in patients with heart failure with reduced LV ejection fraction (HFrEF) receiving recommended HF treatment. We investigated the association between LV dimensions and CV outcomes in HFrEF patients receiving recommended HF treatment. Methods: We investigated the association between LV echocardiographic dimensions and CV outcomes using conventional Cox models in 1138 HFrEF patients in sinus rhythm randomized to warfarin or aspirin treatment in the WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial. Results: LV enlargement, whether by diameter (LV end-diastolic diameter index: LVEDDI, and LV end-systolic diameter index: LVESDI) or volume (LV end-diastolic volume index: LVEDVI, and LV end-systolic volume index: LVESVI), was independently associated with all-cause death [LVEDDI: hazard ratio (HR) per cm/m 2 1.53, LVESDI: HR per cm/m 2 1.65, LVEDVI: HR per 10 ml/m 2 1.07 and LVESVI: HR per 10 ml/m 2 1.10; all p-values < 0.001], CV death (HR 1.68, 1.79, 1.09 and 1.12, respectively; all p-values < 0.001) and HF hospitalization (HR 1.59, 1.79, 1.06 and 1.08, respectively; all p-values < 0.001). No association was observed with myocardial infarction or stroke. The associations were independent of LV ejection fraction values, and incremental to them. LV volumes conferred additional predictive value over LV diameters. Conclusions: LV enlargement is an independent predictor of CV events in patients with HFrEF and recommended HF treatment. LV dimensions should be considered in the risk assessment.

Left ventricular dimensions and cardiovascular outcomes in systolic heart failure: the WARCEF trial.

AimsThere is limited information on the association between left ventricular (LV) dimensions and cardiovascular (CV) outcomes in patients with heart failure (HF) with reduced LV ejection fraction (HFrEF) receiving recommended HF treatment. We investigated the association between LV dimensions and CV outcomes in HFrEF patients receiving recommended HF treatment.Methods and resultsWe investigated the association between LV echocardiographic dimensions and CV outcomes using conventional Cox models in 1138 HFrEF patients in sinus rhythm randomized to warfarin or aspirin treatment in the Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial. LV enlargement, whether by diameter [LV end‐diastolic diameter index (LVEDDI) and LV end‐systolic diameter index (LVESDI)] or volume [LV end‐diastolic volume index (LVEDVI) and LV end‐systolic volume index (LVESVI)], was independently associated with all‐cause death [LVEDDI: hazard ratio (HR) per cm/m2 1.53, LVESDI: HR per cm/m2 1.65, LVEDVI: HR per 10 mL/m2 1.07, and LVESVI: HR per 10 mL/m2 1.10; all P values < 0.001], CV death (HR 1.68, 1.79, 1.09, and 1.12, respectively; all P values < 0.001), and HF hospitalization (HR 1.59, 1.79, 1.06, and 1.08, respectively; all P values < 0.001). No association was observed with myocardial infarction or stroke. The associations were independent of LV ejection fraction values, and incremental to them. LV volumes conferred additional predictive value over LV diameters.ConclusionsLeft ventricular enlargement is an independent predictor of CV events in patients with HFrEF and recommended HF treatment. LV dimensions should be considered in the risk assessment.

424 Left ventricular function after correction of a proportionate mitral regurgitation: impact of the clipping approach

Abstract Aims : Secondary mitral regurgitation (MR) is associated with poor outcome in systolic heart failure (HF-)patients. Percutaneous edge-to-edge mitral valve repair (PMVR) recently failed to prove any beneficial effect over optimal medical treatment (OMT). Nevertheless, little is known about the effect of PMVR on LV performance and mechanics in HF-patients with severe secondary MR. Method and results Thirty-seven patients with severe secondary MR treated by PMVR were included and compared (according to indices of LV myocardial function) to nineteen patients with treated by OMT. Both groups were clinically comparable. At 6-month follow-up, only LV constructive work improve significantly in both groups (977 vs 1101 mmHg.%, p =0,003, 967 vs 1110 mmHg.%, p = 0,002 for PMVR and OMT groups, respectively) whereas left ventricular (LV) end-systolic volume index, LV ejection fraction and global longitudinal strain were not different. Compared to MITRA-FR and COAPT studies, our population had a proportionate MR (blue point in Figure 1, panel A). Figure 1-panel B demonstrate that only five patients of PMVR group had disproportionate MR (red points). Interestingly, these patients hadn’t any major event during 6 months FU. Conclusion Echocardiographic characteristics at 6-month follow-up are not different when compare PMVR and OMT for HF- patients with a severe proportionate secondary MR. Main echocardiographic characteristics PMVR OMT Inclusion 6-month p Inclusion 6-month p NYHA 2.6 ± 0.6* 1.8 ± 0.7* &amp;lt;0.0001 2.3 ± 0.5* 2.2 ± 0.4* 0.43 LVESVi(ml.m-2) 76 ± 36 75 ± 35 0.6 94 ± 32 90 ± 31 0.35 LVEF (%) 33 ± 6 33 ± 13 0.78 30 ± 8 31 ± 8 0.53 GLS (%) -9.8 ± 4 -9.9 ± 3.9 0.84 -10.0 ± 4 -10.3 ± 3.3 0.62 MR grade 3.4 ± 0.5 1.3 ± 1.0* &amp;lt;0.0001 3.5 ± 0.5 2.8 ± 1.1* 0.007 Global work index (mmHg.%) 831 ± 370 933 ± 406 0.07 875 ± 314 939 ± 304 0.14 Constructive work (mmHg.%) 977 ± 366 1101 ± 404 0.003 967 ± 290 1110 ± 349 0.002 *symbols denote p &amp;lt; 0.05 between both groups Abstract 424 Figure.

Left ventricular function after correction of a proportionate mitral regurgitation: Impact of the clipping approach

Secondary mitral regurgitation (MR) is associated with poor outcome in systolic heart failure (HF-) patients. Percutaneous edge-to-edge mitral valve repair (PMVR) recently failed to prove any beneficial effect over optimal medical treatment (OMT). Nevertheless, little is known about the effect of PMVR on LV performance and mechanics in HF-patients with severe secondary MR. Thirty-seven patients with severe secondary MR treated by PMVR were included and compared (according to indices of LV myocardial function) to nineteen patients with treated by OMT. Both groups were clinically comparable. At 6-month follow-up, only LV constructive work improve significantly in both groups (977 vs. 1101 mmHg%, P = 0,003, 967 vs. 1110 mmHg%, P = 0,002 for PMVR and OMT groups, respectively) whereas left ventricular (LV) end-systolic volume index, LV ejection fraction and global longitudinal strain were not different. Compared to MITRA-FR and COAPT studies, our population had a proportionate MR (blue point in Fig. 1 , panel A). Fig. 1 , panel B demonstrate that only five patients of PMVR group had disproportionate MR. Interestingly, these patients hadn’t any major event during 6 months FU ( Table 1 ). Echocardiographic characteristics at 6-month follow-up are not different when compare PMVR and OMT for HF- patients with a severe proportionate secondary MR.

Left ventricular function after correction of mitral regurgitation: Impact of the clipping approach.

Functional mitral regurgitation (FMR) is associated with poor outcome in systolic heart failure (HF) patients. Percutaneous edge-to-edge mitral valve repair (PMVR) in Mitra-Fr study failed to prove any beneficial effect over optimal medical treatment (OMT) but win in COAPT study. Nevertheless, little is known about the effect of PMVR on LV performance and mechanics in HF patients with severe secondary MR. Thirty-seven patients with severe FMR undergoing PMVR were included and compared (according to indices of LV myocardial function and the relationship between LV-size and the degree of regurgitation) to nineteen patients with FMR treated by OMT. Both groups were clinically comparable. At 6-month follow-up, cardiac index such as LV global constructive work (GCW) improved significantly in both groups (1.86 vs 2.13L/min/m2 , P=.02, 1.73 vs 2.28L/min/m2 P=.002 and 977 vs 1101mmHg.%, P=.003, 967 vs 1110mmHg.%, P=.002 for PMVR and OMT groups, respectively) whereas left ventricular (LV) end-systolic volume index, LV ejection fraction, and global longitudinal strain were not different. Receiver operating characteristics in PMVR with LVEF≤35% subgroup analysis demonstrated that global work index (GWI) had the best ability to identify patients with worse evolution (AUC=0.882; P=.009), confirmed by univariable logistic regression, particularly for patients with GWI<482mmHg.%. Echocardiographic characteristics at 6-month follow-up are not different when compare PMVR and OMT for HF patients with severe FMR. A low global work index might be a tool for discouraging the implantation of clips for this indication.

Mechanisms of Improved Mortality Following Ablation: Does Ablation Restore Beta-Blocker Benefit in Atrial Fibrillation/Heart Failure?

Observational trials have shown that atrial fibrillation ablation favorably impacts long-term outcomes in systolic heart failure. These outcomes have been confirmed by randomized prospective trials highlighting the favorable impact of ablation on left ventricular function and remodeling, risk of heart failure hospitalization, and mortality. Ablation along with established heart failure medications is new and supported conceptually by the value of restoring sinus rhythm, avoiding long-term antiarrhythmic drugs, and minimizing drug-drug interactions. Observational data suggest a potential long-term benefit of beta-blockers with ablation that becomes augmented as follow-up is extended from 1to 5years.

The impact of catheter ablation for atrial fibrillation in heart failure.

Atrial fibrillation (AF) commonly co‐exists with systolic heart failure (SHF) and its presence is associated with a worse prognosis. Despite this, a rhythm control approach using antiarrhythmic drugs (AADs) to reduce AF burden has demonstrated no prognostic benefit. Catheter ablation (AFA) is more effective than AADs at reducing AF burden. We performed a meta‐analysis to evaluate the impact of AFA on outcomes in SHF. Electronic databases were systematically searched. We included only randomized controlled trials that examined the impact of AFA on clinical outcomes in patients with SHF (LVEF <50%). We included studies with any ablation strategy that incorporated pulmonary vein isolation and any control group. Seven studies (n = 858) were included with a mean follow‐up of 6‐38 months. In comparison to controls, AFA was associated with significant reductions in all‐cause mortality (relative risk [RR] 0.52, P = 0.0009) and unplanned or heart failure hospitalization (RR 0.58, P < 0.00001). Compared to controls, AFA was also associated with significant improvements in LVEF (mean difference 6.30%, P < 0.00001), Minnesota Living with Heart Failure Questionnaire score (mean difference 9.58, P = 0.0003), 6‐minute walk distance (mean difference 31.78 m, P = 0.003) and VO 2 max (mean difference 3.17, P = 0.003). However, major procedure‐related complications occurred in 2.4%‐15% of ablation patients. In patients with AF and SHF, catheter ablation has significant benefits. Further work is needed to establish the role of ablation in the routine treatment of SHF patients with AF.

Left atrial volume and cardiovascular outcomes in systolic heart failure: effect of antithrombotic treatment.

AimsLeft atrium (LA) dilation is associated with adverse cardiovascular (CV) outcomes. Blood stasis, thrombus formation and atrial fibrillation may occur, especially in heart failure (HF) patients. It is not known whether preventive antithrombotic treatment may decrease the incidence of CV events in HF patients with LA enlargement.We investigated the relationship between LA enlargement and CV outcomes in HF patients and the effect of different antithrombotic treatments.Methods and resultsTwo‐dimensional echocardiography with LA volume index (LAVi) measurement was performed in 1148 patients with systolic HF from the Warfarin versus Aspirin in Reduced Ejection Fraction (WARCEF) trial. Patients were randomized to warfarin or aspirin and followed for 3.4 ± 1.7 years. While the primary aim of the trial was a composite of ischaemic stroke, death, and intracerebral haemorrhage, the present report focuses on the individual CV events, whose incidence was compared across different LAVi and treatment subgroups.After adjustment for demographics and clinical covariates, moderate or severe LA enlargement was significantly associated with total death (hazard ratio 1.6 and 2.7, respectively), CV death (HR 1.7 and 3.3), and HF hospitalization (HR 2.3 and 2.6) but not myocardial infarction (HR 1.0 and 1.4) or ischaemic stroke (1.1 and 1.5). The increased risk was observed in both patients treated with warfarin or aspirin. In warfarin‐treated patients, a time in therapeutic range >60% was associated with lower event rates, and an interaction between LAVi and time in therapeutic range was observed for death (P = 0.034).ConclusionsIn patients with systolic HF, moderate or severe LA enlargement is associated with death and HF hospitalization despite treatment with antithrombotic medications. The possibility that achieving a more consistent therapeutic level of anticoagulation may decrease the risk of death requires further investigation.

Amiodarone-Induced Thyrotoxicosis in Systolic Heart Failure – A Retrospective Cohort Study

Amiodarone is the most commonly used antiarrhythmic in heart failure (HF). We aimed to describe amiodarone-induced thyrotoxicosis (AIT) and its clinical outcomes in systolic HF.

Does the target dose of neurohormonal blockade matter for outcome in Systolic heart failure in octogenarians?

BackgroundIn elderly patients with chronic heart failure (CHF), a gap exists between widespread use of lower doses of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-receptor blockers (ARBs) and β-blockers (BBs) and guideline recommendations. Therefore, the aim of the present study was to investigate whether patients receiving ≥50% target dose outperform those receiving <50% target dose, despite maximum up-titration, and whether the target dose outperforms all other doses. Methods and ResultsPatients (n=185) aged ≥80 years with CHF and left ventricular ejection fraction ≤40% referred (between January 2000 and January 2008) to two CHF outpatient clinics at two university hospitals, were included and retrospectively studied. Of the study population, 53% received the target dose of ACEIs/ARBs, whereas 26% received <50% of the target dose. Half received <50% of the target dose of BBs and 21% received the target dose. After ≥5 years of follow-up, all-cause mortality was 76.8%. Patients who received the target dose of ACEIs/ARBs had higher survival rates from all-cause mortality than those receiving <50% of target dose (HR=0.6, 95%CI 0.4-0.9, P=0.033), but those receiving ≥50% of target dose did not statistically differ from those who achieved target dose. This dose-survival relationship was not the case for BBs. ConclusionsTarget dose of ACEIs/ARBs is associated with reduced all-cause five-year mortality in very old patients with systolic heart failure, despite that this was achievable in only about half of the patients. However, the clinical outcome of BB therapy is independent of BB dose when the target heart rate is achieved.

USE OF β-BLOCKERS IN MEDICARE BENEFICIARIES WITH SYSTOLIC HEART FAILURE AND HYPOTENSION, ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE OR PERIPHERAL VASCULAR DISEASE

Metoprolol succinate, bisoprolol and carvedilol (evidence-based β-blockers) improve outcomes in systolic heart failure (HF). However, conditions such as hypotension, asthma, chronic obstructive pulmonary disease (COPD) and peripheral vascular disease (PVD) may limit their use. We identified

Influence of renal impairment on myocardial function in outpatients with systolic heart failure: An echocardiographic and cardiac biomarker study

BackgroundRenal dysfunction (RD) is associated with poor outcome in systolic heart failure (HF). Left ventricular ejection fraction (LVEF) is not depressed to a greater extent in patients with RD compared to patients with normal renal function, but it is relatively unknown whether other measures of myocardial function are impaired by RD. The objective of the present study is to evaluate whether RD in systolic HF is associated with excessive impairment of myocardial function, evaluated by strain analysis and cardiac biomarkers. MethodsPatients with LVEF <0.45% were enrolled from an outpatient HF clinic. The patients underwent advanced echocardiography. Glomerular filtration rate was estimated by the CKD-EPI equation (eGFR) and patients grouped by eGFR: eGFRgroup-I, ≥90ml/min/1.73m2; eGFRgroup-II, 60–89ml/min/1.73m2; and eGFRgroup-III, ≤59ml/min/1.73m2. Multivariate regression models were developed to evaluate the associations between eGFR groups, echocardiographic measures and cardiac biomarkers. ResultsA total of 149 patients participated in the study. Median age was 69years, 26% were female; LVEF was 33%. Patients with a low eGFR were older (P<0.001), but there were no differences in frequency of atrial fibrillation, hypertension, diabetes and ischemic heart disease between eGFR groups (P>0.05 for all). RD was associated with impaired global longitudinal strain (P=0.018), increased E/e′ (P=0.032), larger left atria (P=0.038) and increased levels of proANP (P<0.001), NT-proBNP (P<0.001) and troponin I (P=0.019) after adjustment for traditional confounders. ConclusionsEchocardiographic measures and biomarkers reflecting different aspects of myocardial function are impaired in systolic HF patients with RD and the increased mortality risk in these patients may partly be explained by a depressed cardiac function.

Prognostic implications of left ventricular dyssynchrony for major adverse cardiovascular events in asymptomatic women and men: the Multi-Ethnic Study of Atherosclerosis.

BackgroundLeft ventricular (LV) dyssynchrony is related to adverse outcomes in systolic heart failure, but its prognostic importance in asymptomatic population is not known. Our objective was to assess the prognostic implications of LV mechanical dyssynchrony in a large multiethnic population before the occurrence of global LV dysfunction.Methods and ResultsA total of 1392 participants in the Multi‐Ethnic Study of Atherosclerosis (MESA; mean age: 64.7 years; 46% were women) with cardiac magnetic resonance imaging at baseline were followed for a median duration of 8.3 years. Harmonic phase imaging analysis was used to derive systolic circumferential strain. Greater standard deviation of time to peak systolic strain (SD‐TPS) indicates greater dyssynchrony. With SD‐TPS as a continuous variable, Cox proportional hazards analysis was used to assess hazards ratio after adjusting for demographics, cardiovascular risk factors, LV mass‐to‐volume ratio, and ejection fraction. Using the 75th percentile of SD‐TPS as a cutoff, Kaplan–Meier analysis was performed between 2 categorical groups for each gender. Higher values of dyssynchrony in women predicted major adverse cardiovascular events, defined as myocardial infarction, heart failure, stroke, and death (hazard ratio: 1.01 per 1‐ms increment in SD‐TPS, P=0.015), hard coronary events (hazard ratio: 1.05 per 1‐ms increment in SD‐TPS, P=0.026), and cerebrovascular events (hazard ratio: 1.03 per 1‐ms increment in SD‐TPS, P=0.013). In contrast, dyssynchrony in men was not predictive of events. Kaplan–Meier analyses in women revealed increased event occurrence in the higher dyssynchrony group, but this was not the case in men.ConclusionsIn an asymptomatic cohort, greater LV dyssynchrony determined by cardiac magnetic resonance imaging predicts adverse cardiovascular outcome in women but not in men.Clinical Trial RegistrationURL: http://clinicaltrials.gov. Unique identifier: NCT00005487.

CLINICAL OUTCOMES OF PATIENTS WITH SYSTOLIC HEART FAILURE AND ANEMIA OF CHRONIC DISEASE: MORTALITY AND READMISSION

Anemia of chronic disease (AOCD) is the most common anemia in systolic heart failure (SHF). While generalized anemia in SHF has been linked to a poor prognosis and greater risk of hospitalization, the effect of AOCD on outcomes in SHF is unknown. The aim of this study was to determine the effect of

Effects of enalapril in systolic heart failure patients with and without chronic kidney disease: Insights from the SOLVD Treatment trial

BackgroundAngiotensin-converting enzyme inhibitors improve outcomes in systolic heart failure (SHF). However, doubts linger about their effect in SHF patients with chronic kidney disease (CKD). MethodsIn the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial, 2569 ambulatory chronic HF patients with left ventricular ejection fraction ≤35% and serum creatinine level ≤2.5mg/dl were randomized to receive either placebo (n=1284) or enalapril (n=1285). Of the 2502 patients with baseline serum creatinine data, 1036 had CKD (estimated glomerular filtration rate <60ml/min/1.73m2). ResultsOverall, during 35months of median follow-up, all-cause mortality occurred in 40% (502/1252) and 35% (440/1250) of placebo and enalapril patients, respectively (hazard ratio {HR}, 0.84; 95% confidence interval {CI}, 0.74–0.95; p=0.007). All-cause mortality occurred in 45% and 42% of patients with CKD (HR, 0.88; 95% CI, 0.73–1.06; p=0.164), and 36% and 31% of non-CKD patients (HR, 0.82; 95% CI, 0.69–0.98; p=0.028) in the placebo and enalapril groups, respectively (p for interaction=0.615). Enalapril reduced cardiovascular hospitalization in those with CKD (HR, 0.77; 95% CI, 0.66–0.90; p<0.001) and without CKD (HR, 0.80; 95% CI, 0.70–0.91; p<0.001). Among patients in the enalapril group, serum creatinine elevation was significantly higher in those without CKD (0.09 versus 0.04mg/dl in CKD; p=0.003) during first year of follow-up, but there was no differences in changes in systolic blood pressure (mean drop, 7mm Hg, both) and serum potassium (mean increase, 0.2mEq/L, both). ConclusionsEnalapril reduces mortality and hospitalization in SHF patients without significant heterogeneity between those with and without CKD.

Inorganic phosphate and FGF‐23 predict outcome in stable systolic heart failure

Recent studies show associations between inorganic phosphate and risk of heart failure in the general population as well as between fibroblast growth factor 23 (FGF-23) and outcome in coronary heart disease. This study was carried out to assess whether circulating levels of inorganic phosphate and FGF-23, a new central hormone in mineral bone metabolism, predict outcome in systolic heart failure. Ninety-nine consecutive outpatients with systolic heart failure were enrolled. Mean (SD) age was 61 years (11), mean left ventricular ejection fraction (LVEF) was 33% (10), 82 patients were men, median estimated creatinine clearance was 83 mL/min (Q(1) -Q(3) 58-106), median NTproBNP level was 803 pg/mL (Q(1) -Q(3) 404-2757), median inorganic phosphate was 1·12 mM (Q(1) -Q(3) 1·02-1·22), median FGF-23 was 39·02 pg/mL (Q(1) -Q(3) 32·45-55·86) and median follow-up was 35 months. Associations between inorganic phosphate, FGF-23 and endpoints were assessed using Cox regression analyses. Inorganic phosphate and FGF-23 levels were significantly higher (P < 0·001 and P = 0·009) in patients reaching the combined endpoint of cardiac hospitalization or death. FGF-23 (ln) predicted all-cause mortality (hazard ratio (HR) 5·042, P = 0·032) in a model adjusted for age, gender, estimated creatinine clearance, LVEF, New York Heart Association (NYHA) stage and NTproBNP level. Inorganic phosphate predicted heart failure hospitalization (HR 26·944, P = 0·021), cardiac hospitalization (HR 16·016, P = 0·017) and the combined endpoint (HR 13·294, P = 0·015) in models adjusted for the same co-variables. The results of this study demonstrate the independent prognostic value of inorganic phosphate and FGF-23 in heart failure even in the context of established risk markers.

Bucindolol, Systolic Blood Pressure, and Outcomes in Systolic Heart Failure: A Prespecified Post Hoc Analysis of BEST

BackgroundIn the Beta-Blocker Evaluation of Survival Trial (BEST), systolic blood pressure (SBP) ≤ 120 mm Hg was an independent predictor of poor prognosis in ambulatory patients with chronic systolic heart failure (HF). Because SBP is an important predictor of response to β-blocker therapy, the BEST protocol prespecified a post hoc analysis to determine whether the effect of bucindolol varied by baseline SBP. MethodsIn the BEST, 2706 patients with chronic systolic (left ventricular ejection fraction < 35%) HF and New York Heart Association class III (92%) or IV (8%) symptoms and receiving standard background therapy were randomized to receive either bucindolol (n = 1354) or placebo (n = 1354). Of these, 1751 had SBP ≤ 120 mm Hg, and 955 had SBP > 120 mm Hg at baseline. ResultsAmong patients with SBP > 120 mm Hg, all-cause mortality occurred in 28% and 22% of patients receiving placebo and bucindolol, respectively (hazard ratio when bucindolol was compared with placebo, 0.77; 95% confidence interval [CI], 0.59-0.99; P = 0.039). In contrast, among those with SBP ≤ 120 mm Hg, 36% and 35% of patients in the placebo and bucindolol groups died, respectively (hazard ratio, 0.95; 95% CI, 0.81-1.12; P = 0.541). Hazard ratios (95% CIs; P values) for HF hospitalization associated with bucindolol use were 0.70 (0.56-0.89; P = 0.003) and 0.82 (0.71-0.95; P = 0.008) for patients with SBP > 120 and ≤ 120 mm Hg, respectively. ConclusionBucindolol, a nonselective β-blocker with weak α2-blocking properties, significantly reduced HF hospitalization in systolic HF patients regardless of baseline SBP. However, bucindolol reduced mortality only in those with SBP > 120 mm Hg.

Exercise Oscillatory Ventilation in Systolic Heart Failure

Background— Exercise oscillatory ventilation (EOV) is a noninvasive parameter that potently predicts outcomes in systolic heart failure (HF). However, mechanistic insights into EOV have been limited by the absence of studies relating EOV to invasive hemodynamic measurements and blood gases performed during exercise. Methods and Results— Fifty-six patients with systolic HF (mean±SEM age, 59±2 years; left ventricular ejection fraction, 30±1%) and 19 age-matched control subjects were studied with incremental cardiopulmonary exercise testing. Fick cardiac outputs, filling pressures, and arterial blood gases were measured at 1-minute intervals during exercise. We detected EOV in 45% of HF (HF+EOV) patients and in none of the control subjects. The HF+EOV group did not differ from the HF patients without EOV (HF−EOV) in age, sex, body mass index, left ventricular ejection fraction, or origin of HF. Univariate predictors of the presence of EOV in HF, among measurements performed during exercise, included higher right atrial pressure and pulmonary capillary wedge pressure and lower cardiac index (CI) but not Pa co 2 or Pa o 2 . Multivariate logistic regression identified that low exercise CI is the strongest predictor of EOV (odds ratio, 1.39 for each 1.0-L · min −1 · m −2 decrement in CI; 95% confidence interval, 1.14–1.70; P =0.001). Among HF patients with EOV, exercise CI was inversely related to EOV cycle length ( R =−0.71) and amplitude ( R =−0.60; both P &lt;0.001). In 11 HF+EOV subjects treated with 12 weeks of sildenafil, EOV cycle length and amplitude decreased proportionately to increases in CI. Conclusion— Exercise oscillatory ventilation is closely related to reduced CI and elevated filling pressures during exercise and may be an important surrogate for exercise-induced hemodynamic impairment in HF patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00309790.

Association of cerebral blood flow with the development of cardiac death or urgent heart transplantation in patients with systolic heart failure

Although cerebral blood flow (CBF) is known to be low in patients with advanced systolic heart failure (HF), little is known of the prognostic significance of this observation. We investigated whether CBF might be associated with the development of adverse outcomes in systolic HF, and whether it might provide prognostic information in addition to that provided by exercise tests. We performed a prospective observational study involving 224 systolic HF patients (left ventricular ejection fraction ≤35%). The study endpoint was the occurrence of cardiac death or urgent heart transplantation. Global CBF was measured using radionuclide angiography. Clinical, biochemical, echocardiographic, and exercise data were also obtained. During follow-up (median 36 months), 52 patients experienced death or urgent transplantation. Multivariable analysis showed that global CBF, the minute ventilation/carbon dioxide production (VE/VCO(2)) slope, New York Heart Association functional class ≥III, symptom duration ≥12 months, serum sodium, and serum creatinine were associated with the development of the endpoint. Patients with a CBF <35.4 mL/min/100 g were at increased risk of death or urgent transplantation (hazard ratio = 2.47; 95% confidence interval, 1.35-4.52). The addition of global CBF to a prognostic model including the VE/VCO(2) slope increased the C-index for the prediction of adverse outcomes with borderline significance. Cerebral blood flow was associated with the development of long-term outcomes in systolic HF, and therefore may be useful in identifying patients suitable for heart transplantation. This finding is especially relevant for patients in whom exercise tests may not be performed sufficiently.