Search

Background: The prognostic merit of insulin-like growth factor-binding protein 7 (IGFBP7) is unknown in heart failure and preserved ejection fraction (HFpEF)., Methods and Results: Baseline IGFBP7 (BL-IGFBP7; n = 302) and 6-month change (Δ; n = 293) were evaluated in the Irbesartan in Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial. Primary outcome was all-cause mortality or cardiovascular hospitalization with median follow-up of 3.6 years; secondary outcomes included HF events. Median BL-IGFBP7 concentration was 218 ng/mL. BL-IGFBP7 was significantly correlated with age (R 2  = 0.13; P < .0001), amino-terminal pro-B-type NP (R 2  = 0.22; P < .0001), and estimated glomerular filtration rate (eGFR; R 2  = 0.14; P < .0001), but not with signs/symptoms of HFpEF. BL-IGFBP7 was significantly associated with the primary outcome (hazard ratio [HR] = 1.007 per ng/mL; P < .001), all-cause mortality (HR = 1.008 per ng/mL; P < .001), and HF events (HR = 1.007 per ng/mL; P < .001). IGFBP7 remained significant for each outcome after adjustment for ln amino-terminal pro-B-type NP and eGFR but not all variables in the I-PRESERVE prediction model. After 6 months, IGFBP7 did not change significantly in either treatment group. ΔIGFBP7 was significantly associated with decrease in eGFR in patients randomized to irbesartan (R 2  = 0.09; P = .002). ΔIGFBP7 was not independently associated with outcome., Conclusions: Higher concentrations of IGFBP7 were associated with increased risk of cardiovascular events, but after multivariable adjustment this association was no longer present. Further studies of IGFBP7 are needed to elucidate its mechanism., Clinical Trial Registration: www.clinicaltrials.gov, NCT00095238., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Soluble ST2 (sST2), a biomarker related to inflammation, is associated with outcomes of patients with heart failure. In-depth analyses of the relationship among sST2, changes in sST2, and patient outcomes are reported., Methods and Results: sST2 was measured at baseline (n=1650), 4 months (n=1345), and 12 months (n=1094) in Valsartan Heart Failure Trial. Baseline sST2 averaged 28.7±16.2 ng/mL, significantly (P<0.001) higher in men than women but supranormal in only 9% and 15%, respectively. A continuous relationship between sST2 and the log hazard ratio for outcomes was modeled as 2 linear segments with a significant decrease in the rate of increase in hazard ratios >33.2 ng/mL. Each segment of the sST2 distribution was significantly (P<0.0001) associated with the risks of morbid event, mortality, and hospitalization for heart failure. Only sST2 values <33.2 ng/mL were significantly related to the outcomes when 23 readily available clinical variables including N-terminal probrain natriuretic peptide were included in the Cox regression model. sST2 did not improve discrimination of patient outcomes. Compared with placebo, valsartan significantly (P<0.001) reduced the rate of increase in sST2. Increases in sST2 for 12 months, but not decreases, were significantly associated with subsequent outcomes, independent of clinical variables, sST2, and valsartan treatment., Conclusions: In this study, baseline sST2 was nonlinearly associated with patient outcomes but did not provide substantial prognostic information when added to a clinical prediction model that included N-terminal probrain natriuretic peptide. An increase but not decrease in sST2 was independently associated with outcomes. Additional research is needed to determine whether monitoring ST2 levels can improve patient outcomes., (© 2014 American Heart Association, Inc.)

Aims: This study was conducted to determine whether galectin-3, a β-galactoside-binding lectin, plays a role in the pathogenesis of heart failure (HF)., Methods and Results: Galectin-3 was measured at baseline (n = 1650), after 4 months (n = 1346), and after 12 months (n = 1097) in the Valsartan Heart Failure Trial (Val-HeFT). Galectin-3 levels at baseline ranged from 4.8 to 53 ng/mL. Higher levels were associated with features of worse HF. In a fully adjusted Cox regression model comprising 23 other prognostic variables, baseline galectin-3 was not associated with the risks of all-cause mortality, the composite of the first morbid event, or hospitalization for HF. However, when changes in galectin-3 over time were examined, the increases in galectin-3 between baseline and 4 months were independently and significantly associated with the risks of subsequent all-cause mortality, first morbid event, and hospitalizations for HF, even after adjusting for all baseline and concurrent changes in all variables including estimated glomerular filtration rate (eGFR) and NT-proBNP. The strongest correlate of galectin-3 levels was eGFR, which accounted for 20% of the variability in galectin-3 levels at baseline. There was a significant interaction (P = 0.03) between baseline galectin-3 and the effect of valsartan on hospitalizations for HF. Valsartan caused a significant 44% reduction in hospitalizations for HF in patients with galectin-3 levels below the median level of 16.2 ng/mL, but not in patients with levels above the median., Conclusions: Galectin-3 levels are elevated in a substantial proportion of patients with HF, particularly those with more severe HF and renal dysfunction. Galectin-3 increased over time in this cohort, and the increase was independently associated with worse outcomes. Valsartan use was associated with a reduction in hospitalizations for HF in patients with low galectin-3, but not in those with higher levels of galectin-3.

Background: There are few sex-specific outcome data in heart failure with preserved ejection fraction., Methods and Results: We assessed sex differences in baseline characteristics and outcomes among 4128 patients with heart failure with preserved ejection fraction in the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial. Women (n=2491) with heart failure with preserved ejection fraction were ≈1 year older (72±7 years versus 71±7 years) and more likely to be obese (46% versus 35%) and have chronic kidney disease (34% versus 26%) and hypertension (91% versus 85%) than men but less likely to have an ischemic cause (19% versus 34%), atrial fibrillation (27% versus 33%), or chronic obstructive pulmonary disease (8% versus 13%) (all P<0.001). During a mean of 49.5 months, there were 881 deaths (447 in women, 434 in men; risk ratio, 0.64; 95% CI, 0.56-0.74) and 5776 hospitalizations (3239 in women, 2537 in men; risk ratio, 0.80; 95% CI, 0.76-0.84). Women had lower risk of all-cause events (deaths and hospitalizations), even after adjusting for baseline characteristics (adjusted hazards ratio, 0.81; 95% CI, 0.73-0.89). However, the sex-related difference in risk of all-cause events was modified in the presence or absence of atrial fibrillation, renal dysfunction, stable angina pectoris, or advanced New York Heart Association class symptoms., Conclusions: In patients with typical heart failure with preserved ejection fraction, there were prominent sex differences in baseline characteristics and outcomes. Women had better overall prognosis, although the presence of 4 common baseline characteristics seemed to moderate this finding.

Background: The Minnesota Living with Heart Failure Questionnaire (MLHFQ) was used in a large, multinational, randomized, placebo-controlled trial to measure adverse effects of heart failure with preserved ejection fraction (HF-PEF) on patients' lives and the effects of irbesartan., Methods and Results: Patients with symptomatic HF-PEF were randomly assigned to irbesartan (up to 300 mg daily) or placebo. The MLHFQ was administered at baseline (n=3605), month 6 (n=3137), month 14 (n=2904), and the end of study (median, 56 months, n=2205). Baseline MLHFQ scores of 43±21 indicated that HF-PEF had a substantial adverse effects. Estimated retest reliability was 0.80. Baseline MLHFQ scores were associated with other measures of the severity of heart failure including symptoms, signs of congestion, cardiac structure, and time to hospitalizations or deaths attributed to heart failure. Slight improvement in shortness of breath or fatigue was associated with significant improvement in MLHFQ scores (-5.9 and -5.0, P<0.0001). Compared with placebo, further improvement in MLHFQ scores was not observed with irbesartan after 6 months (mean adjusted difference, 0.4; 95% confidence interval, -0.8 to 1.7), 14 months (0.5; 95% confidence interval, -0.9 to 1.8), or the end of study (2.0; 95% confidence interval, -4.1 to 0.01)., Conclusions: The MLHFQ scores are a reliable, valid, and sensitive measure of the adverse impact of HF-PEF on patients' lives. Irbesartan did not substantially improve MLHFQ scores during a long period of follow-up. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Background: Plasma concentrations of natriuretic peptides (NPs) are associated with morbidity and mortality in patients with systolic heart failure (HF). However, the role of NP as a prognostic marker in patients with HF and preserved ejection fraction (HFpEF) has not been studied in a large cohort of well-characterized patients. Moreover, it is unclear whether treatments have a differential effect on morbidity and mortality across the spectrum of NP levels., Methods and Results: N-terminal pro-brain natriuretic peptide (NT-proBNP) was measured at baseline in 3480 patients in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Trial). In a multivariable Cox regression model, NT-proBNP above the median of 339 pg/mL was independently associated with an increased risk of the primary end point of all-cause mortality and prespecified cardiovascular hospitalizations (adjusted hazard ratio [HR], 1.79; 95% CI, 1.56 to 2.10; P<0.001); all-cause mortality (adjusted HR, 2.04; 95% CI, 1.68 to 2.47; P<0.001); and a composite of HF events, including death due to worsening HF or sudden death or hospitalization due to worsening HF (adjusted HR, 1.77; 95% CI, 1.43 to 2.20; P<0.001). There were significant interactions between the effect of irbesartan and median split of baseline NT-proBNP for the primary outcome (P=0.005), all-cause mortality (P=0.05), and the HF composite outcome (P<0.001). Use of irbesartan was associated with improved outcomes in patients with NT-proBNP below, but not above, the median. After adjusting for 20 baseline covariates, irbesartan still had a beneficial effect on the primary outcome (HR, 0.74; 95% CI, 0.60 to 90; P=0.003), all-cause mortality (HR, 0.75; 95% CI, 0.56 to 0.99; P=0.046), and HF composite outcome (HR, 0.57; 95% CI, 0.41 to 0.80; P=0.001) in patients with NT-proBNP below the median., Conclusions: The unexpected benefit of irbesartan in lower-risk patients with HFpEF in this post hoc analysis may indicate effects on early, but not later, high-risk stages of the disease. These findings question the strategy of using elevated plasma concentrations of NP as a patient selection criterion in HFpEF trials. More studies are needed to support or contest this practice. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Background: Growth-differentiation factor-15 (GDF-15) is emerging as a prognostic biomarker in patients with coronary artery disease. Little is known about GDF-15 as a biomarker in patients with heart failure., Methods and Results: The circulating concentration of GDF-15 was measured at baseline (n=1734) and at 12 months (n=1517) in patients randomized in the Valsartan Heart Failure Trial (Val-HeFT). GDF-15 levels at baseline ranged from 259 to 25 637 ng/L and were abnormally high (>1200 ng/L) in 85% of patients. Higher levels were associated with features of worse heart failure and biomarkers of neurohormonal activation, inflammation, myocyte injury, and renal dysfunction. Baseline GDF-15 levels (per 100 ng/L) were associated with the risks of mortality (hazard ratio, 1.017; 95% confidence interval, 1.014 to 1.019; P<0.001) and first morbid event (hazard ratio, 1.020; 95% confidence interval, 1.017 to 1.023; P<0.001). In a comprehensive multiple-variable Cox regression model that included clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T, GDF-15 remained independently associated with mortality (hazard ratio, 1.007; 95% confidence interval, 1.001 to 1.014; P=0.02) but not first morbid event. At 12 months, the GDF-15 levels had increased by a similar amount in the placebo and valsartan groups (P=0.94). Increases in GDF-15 over 12 months were independently associated with the risks of future mortality and first morbid event also after adjustment for clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T and their changes., Conclusions: GDF-15 reflects information from several pathological pathways and provides independent prognostic information in heart failure. GDF-15 levels increase over time, suggesting that GDF-15 reflects a pathophysiological axis that is not completely addressed by the therapies prescribed in Val-HeFT.

Background: Chronic kidney disease (CKD) is an established risk factor for poor outcomes in heart failure (HF). Whether proteinuria provides additional prognostic information is not known. Renin-angiotensin blockade medications improve outcomes in HF but are underutilized in HF patients with renal dysfunction because of safety concerns and a lack of evidence of their effectiveness., Methods and Results: In the Valsartan in Heart Failure Trial (Val-HeFT), 5010 patients with class II, III, or IV heart failure were randomly assigned to receive valsartan or placebo. The 2 primary outcomes were death and first morbid event, defined as death, sudden death with resuscitation, hospitalization for HF, or administration of intravenous inotropic or vasodilator drugs for 4 hours or more without hospitalization. The study cohort was divided into subgroups according to the presence of CKD (estimated glomerular filtration rate <60 mL x min(-1) x 1.73 m(-2)) and proteinuria (positive dipstick). Multivariable Cox proportional hazards regression models were used to examine the relationships between study outcomes and proteinuria, including its interaction with CKD. The interaction between valsartan and CKD was also tested. The effect of valsartan on estimated glomerular filtration rate was estimated by generalized linear models, including tests of interactions between treatment and CKD. At baseline, CKD was found in 58% and dipstick-positive proteinuria in 8% of patients. Dipstick-positive proteinuria was independently associated with mortality (hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.01 to 1.62, P=0.05) and first morbid event (HR 1.28, 95% CI 1.06 to 1.55, P=0.01). The increased risk of death associated with dipstick-positive proteinuria was similar for those with and without CKD (HR 1.26, 95% CI 0.96 to 1.66 versus HR 1.37, 95% CI 0.83 to 2.26; P=0.94), as was the hazard for first morbid event (HR 1.26, 95% CI 1.01 to 1.57 versus HR 1.42, 95% CI 0.98 to 2.07; P=0.71). Valsartan reduced estimated glomerular filtration rate compared with placebo to a similar extent (P=0.52) in the subgroups with CKD (mean reduction -3.6 mL x min(-1) x 1.73 m(-2)) and without CKD (mean reduction -4.0 mL x min(-1) x 1.73 m(-2)) and by -3.8 mL x min(-1) x 1.73 m(-2) in both groups combined. The beneficial effect of valsartan on first morbid events was similar in those with and without CKD (HR 0.86, 95% CI 0.74 to 0.99 versus HR 0.91, 95% CI 0.73 to 1.12; P=0.23) and was significant in the subgroup with CKD. The effect of valsartan on mortality did not differ in patients with and without CKD (HR 1.01, 95% CI 0.85 to 1.20 versus HR 0.91, 95% CI 0.69 to 1.25; P=0.08)., Conclusions: CKD was common and dipstick-positive proteinuria was infrequent in this sample of patients with HF. After controlling for other risk factors, including CKD, the relatively small subgroup with dipstick-positive proteinuria did have worse outcomes. Valsartan reduced the estimated glomerular filtration rate by the same amount in patients with and without CKD and reduced the risk of the first morbid event in patients with CKD, which suggests its beneficial effects in patients with HF and CKD.

Background: Low systolic blood pressure (SBP) is a risk factor for adverse outcomes in patients with heart failure (HF). Valsartan improved morbidity rates in the Valsartan Heart Failure Trial (Val-HeFT) despite a reduction in SBP. The aim of the present study was to investigate the relationship between the SBP-lowering effects of valsartan and its cardiovascular protective effects in this population., Methods and Results: Baseline measurements and changes in SBP at 4 months were related to mortality and morbidity rates. The effects of valsartan on these end points were compared in quartiles of baseline SBP with multivariable Cox proportional hazards regression models that included a test for interaction between the effects of valsartan treatment and baseline SBP and examined the effects of changes in SBP on the valsartan effect. The mean+/-SD baseline SBP in all patients (n=5010) was 124+/-18 mm Hg. Patients in the lowest quartile of SBP (SBP